Advanced Solid TumorsPhase 1COMBONCT02994953
A Phase Ib Study to Evaluate the Safety, Tolerability, and Pharmacokinetics (PK) of Avelumab in Combination With M9241(NHS-IL12) (JAVELIN IL-12)
A Phase 1 study testing Avelumab, M9241 and Avelumab (Once weekly) in people with Advanced Solid Tumors, run by EMD Serono Research & Development Institute, Inc. at 33 sites in 7 countries.
Trial summary
The study consisted of 2 parts: Dose Escalation phase (Part A) and Expansion phase (Part B). The dose escalation phase evaluated the safety, tolerability, and PK of avelumab in combination with M9241 in subjects with locally advanced, unresectable, or metastatic solid tumors. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Solid Tumors
- What is being tested?
- Avelumab, M9241 and Avelumab (Once weekly)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 52 participants
- Where
- 33 sitesin 7 countries
- Study dates
- 31 Jan 2017to 8 Oct 2020
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Part A:
- subjects must had signed written informed consent.
- male or female subjects age greater than equals to (>=)18 years.
- subjects must had histologically or cytologically proven metastatic or locally advanced solid tumors for which no standard therapy exists, standard therapy had failed, subject was intolerant of established therapy known to provided clinical benefit for their condition, or standard therapy was not acceptable to subject.
- subjects who had been treated previously with a checkpoint inhibitor may enroll (except as outlined below for expansion cohorts).
- at least 1 unidimensional radiographically measurable lesion based on response evaluation criteria in solid tumors (recist) version 1. 1 (v1. 1), except for subjects with metastatic castration-resistant prostate cancer (crpc) or metastatic breast cancer who may been enrolled with objective evidence of disease without a measureable lesion. - eastern cooperative oncology group (ecog) performance status of 0 to 1 at screening
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- estimated life expectancy of more than 12 weeks
- adequate hematological function as defined below:
- white blood cells (wbc) count >= 3. 0 × 10^9 per liter (/l)
- absolute neutrophil count >= 1. 5 × 10^9/l
- lymphocyte count >= 0. 5 × 10^9/l
- platelet count >= 100 × 10^9/l
- hemoglobin >= 9 gram per deciliter (g/dl) (may had been transfused)
- adequate hepatic function as defined below:
- a total bilirubin level less than equals to (<=) 1. 5 × upper limit of normal (uln) range
- aspartate aminotransferase (ast) levels <= 2. 5 × uln (≤ 3 × uln for expansion cohorts)
- alanine aminotransferase (alt) levels <= 2. 5 × uln (≤ 3 × uln for expansion cohorts)
- subjects with documented gilbert disease were allowed if total bilirubin > 1. 5 but less than 3 × uln
- adequate renal function as defined by an estimated creatinine clearance >= 50 milliliter per minute (ml/min) according to cockcroft-gault formula
- negative blood pregnancy test at screening for women of childbearing potential. For purposes of this trial, women of childbearing potential were defined as all female subjects after puberty unless they were postmenopausal for at least 1 year, surgically sterile or sexually inactive.
- highly effective contraception (ie, methods with a failure rate of less than 1% per year) must been used before started of treatment, for duration of trial treatment, and for at least 50 days after stopping studied treatment for both men and women if risk of conception exists. The effects of avelumab and m9241 on developing human fetus were unknown; thus, women of childbearing potential and men agreed to use highly effective contraception.
- Part B:
- Availability of a fresh tumor biopsy was mandatory for eligibility in the RCC cohort. The biopsy or surgical specimen should be collected within 28 days prior to the first IMP administration. If a subject had 2 separate biopsy attempts in which usable tissue was not obtained, enrollment would have been possible after discussion with the Medical Monitor. For other expansion cohorts, availability of either tumor archival material (< 6 months old) or fresh biopsies (obtained within 28 days) was acceptable with one of these being mandatory. For formalin-fixed paraffin-embedded samples, either block or sections (> 15) provided. Tumor biopsies and tumor archival material should have been suitable for biomarker assessment - Locally advanced or metastatic UC that had progressed during or after at least one previous platinum-based chemotherapy and not previously treated with anti-PD-1/PD-L1 agents: Histologically or cytologically confirmed locally advanced or metastatic transitional cell carcinoma of urothelium(including renal pelvis, ureters, urinary bladder, and urethra). Participants must had progressed during or after treatment with at least 1 platinum-containing regimen for inoperable locally advanced or metastatic UC or disease recurrence. Participants who had received prior adjuvant/neoadjuvant chemotherapy and progressed within 12 months of treatment with a platinum-containing regimen were considered as second line. Participants with mixed histologies were required to have a dominant transitional cell pattern.
- Non-small cell lung cancer (NSCLC), first-line metastatic: Stage IV (per seventh International Association for the Study of Lung Cancer classification) histologically confirmed NSCLC. Participants must not had received treatment for their metastatic disease. Participants could have received adjuvant chemotherapy or loco-regional treatment that included chemotherapy for locally advanced disease, as long as disease recurrence occurred at least 6 months after the completion of the last administration of chemotherapy. Only epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type were allowed (ie, EGFR mutation and ALK translocation / re arrangement excluded). Non squamous cell histologies and never / former light smoker (< 15 pack years) squamous cell carcinoma Participants (per local standard of care) required testing if status was unknown. Participants must had low tumor PD-L1 expression defined as < 50% tumor proportion score determined using PD-L1 IHC 22C3 pharmDx test or an equivalent Food and Drug Administration (FDA)- approved PD-L1 test. Availability of either tumor archival material or fresh biopsies within 28 days was acceptable with one of these being mandatory. For FFPE samples, either block or sections (> 15) may be provided. Tumor biopsies and tumor archival material had been suitable for biomarker assessment. This cohort would not be opened for enrollment in Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Spain, and United Kingdom.
- Colorectal cancer (CRC): Histologically or cytologically confirmed recurrent or refractory metastatic CRC (according to American Joint Committee on Cancer / International Union Against Cancer Tumor Node Metastasis [TNM] Staging System seventh edition) after failure of prior therapy containing oxaliplatin / fluoropyrimidine and / or irinotecan / fluoropyrimidine and, if eligible, cetuximab (Erbitux®) and bevacizumab (Avastin®). Only Participants with microsatellite instability (MSI)-low or microsatellite stable (MSS) metastatic CRC are eligible. Participants without existing MSI test results had MSI status performed locally by a Clinical Laboratory Improvement Amendments (CLIA)-certified IHC or polymerase chain reaction (PCR)-based test (PCR based MSI test is preferred). Participants had to be willing to undergo an on-treatment biopsy procedure. Availability of either tumor archival material or fresh biopsies within 28 days was acceptable with one of these being mandatory. For FFPE samples, either a block or sections (> 15) could be provided. Tumor biopsies and tumor archival material had to be suitable for biomarker assessment. For Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Spain, and United Kingdom, participants in the second-line setting had exhausted or were considered ineligible or intolerant (in the opinion of the Investigator) of available second-line chemotherapy options.
- Renal cell carcinoma (RCC), primary immune checkpoint inhibitor failure: Histologically or cytologically documented metastatic RCC with a component of clear cell subtype. Participants must have had progressive disease (PD) within 6 months or best overall response of stable disease (SD) for ≥ 6 months following start of therapy with any antibody / drug targeting T cell co-regulatory proteins (immune checkpoints) such as anti-PD-1, anti-PD-L1, or anticytotoxic T lymphocyte antigen-4 (CTLA-4) for advanced or metastatic disease (either as monotherapy or combination therapy, in any line). Fresh tumor biopsy was required for enrollment. If a subject had 2 separate biopsy attempts in which usable tissue was not obtained, enrollment could be possible after discussion with the Medical Monitor. Participants had to be willing to undergo an on-treatment biopsy procedure. In France, in addition to having received checkpoint inhibitor therapy, participants should have already received recommended local-standard therapy per discretion of the Investigator.
Who cannot join
- Concurrent treatment with a non-permitted drug/intervention (listed below)
- Anticancer treatment (eg, cytoreductive therapy, radiotherapy, immune therapy, cytokine therapy, monoclonal antibody, targeted small molecule therapy) or any investigational drug within 4 weeks or 5 half-lives, whichever was shorter, prior to start of trial treatment, or not recovered from adverse event (AE) related to such therapies, with the following exceptions: Palliative radiotherapy delivered in a normal organ-sparing technique is permitted; Erythropoietin, darbepoetin-α and granulocyte colony-stimulating factor permitted; Hormonal therapies acting on the hypothalamic-pituitary-gonadal axis permitted (i.e. luteinizing hormone-releasing hormone agonist/antagonists). No other hormonal anticancer therapy was permitted.
- Major surgery (as deemed by Investigator) for any reason, except diagnostic biopsy, within 4 weeks prior to start of trial treatment, or not fully recovered from surgery within 4 weeks prior to start of trial treatment.
- Participants receiving immunosuppressive agents (such as steroids) for any reason were tapered off these drugs before start of trial treatment, with following exceptions: Participants with adrenal insufficiency, continued corticosteroids at physiologic replacement dose, equivalent to ≤ 10 mg prednisone daily; Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intra-ocular, or inhalation) was permitted; Previous or ongoing administration of systemic steroids for the management of an acute allergic phenomenon was acceptable as long as it was anticipated that the administration of steroids would be completed in 14 days, or that the dose after 14 days would be equivalent to <= 10 mg prednisone daily.
- Any prior treatment with any form of interlukin-12 (IL-12)
- For the NSCLC, CRC, and UC expansion cohorts, prior therapy with any antibody / drug targeting T-cell co-regulatory proteins (immune checkpoints) such as anti-PD-1, anti-PD-L1, or anticytotoxic T lymphocyte antigen-4 (CTLA-4) antibody was prohibited.
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- Intolerance to checkpoint inhibitor therapy, as defined by the occurrence of an AE requiring drug discontinuation. - Active or history of primary or metastatic central nervous system tumors
- Prior organ transplantation, including allogeneic stem-cell transplantation
- Previous malignant disease (other than the indication for this trial) within the last 5 years (except adequately treated non-melanoma skin cancers, carcinoma in situ of skin, bladder, cervix, colon/rectum, breast, or prostate) unless a complete remission without further recurrence was achieved at least 2 years prior to trial entry and subject was deemed to have been cured with no additional therapy required or anticipated to be required.
- Significant acute or chronic infections requiring systemic therapy including, among others:
- History of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome • Hepatitis B or C infection (HBV surface antigen positive and HBV core antibody positive with reflex to positive HBV deoxy ribonucleic acid (DNA) or HBV core antibody positive alone with reflex to positive HBV DNA or positive hepatitis C virus [HCV] antibody with reflex to positive HCV ribonucleic acid [RNA]). Participants with history of infection must had polymerase chain reaction documentation that infection was cleared.
- Active or history of autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Participants with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment wer eligible if they wer stable on other medical treatment and do not fulfill exclusion criterion including Uncontrolled intercurrent illness - Known severe hypersensitivity reactions to monoclonal antibodies (Grade>= 3 National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) v4.03, or uncontrolled asthma (ie, 3 or more features of partially controlled asthma)
- History of allergic reaction to methotrexate (trace methotrexate may be present in M9241 as a part of manufacturing process) or history of severe hypersensitivity reaction to any other ingredient of study drug(s) and / or their excipients. Since M9241 contains sucrose as an excipient, participants suffering from hereditary fructose intolerance also excluded - Persisting toxicity related to prior therapy of Grade > 1 NCI-CTCAE v4.03 with the following exceptions:
- Neuropathy Grade <= 2 was acceptable.
- All grades of alopecia acceptable.
- Endocrine dysfunction on replacement therapy was acceptable.
- Pregnancy or lactation
- Known alcohol or drug abuse as deemed by the Investigator
- Uncontrolled intercurrent illness including, but not limited to:
- Hypertension uncontrolled by standard therapies (not stabilized to 150/90 millimeter of mercury (mm Hg) or lower)
- Uncontrolled active infection
- Uncontrolled diabetes (eg, glycosylated hemoglobin [HgbA1c] >= 8%)
- Clinically significant (or active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class >= II), or serious cardiac arrhythmia requiring medication
- All other significant diseases (eg, inflammatory bowel disease, current severe acute or chronic colitis) or chronic medical conditions (including laboratory abnormalities) that in opinion of Investigator might impair subject's tolerance of trial treatment or interpretation of trial results.
- Any psychiatric condition that would prohibit understanding or endering of informed consent or that would limit compliance with trial requirements.
- Legal incapacity or limited legal capacity.
- Administration of a live vaccine within 30 days prior to trial entry.
- Any subject with possible area of ongoing necrosis (non-disease related), such as active ulcer, non-healing wound, or intercurrent bone fracture that may be at risk of delayed healing due to protocol therapy.
- Oxygen saturation < 90% at rest, known pulmonary fibrosis, or active interstitial lung disease.
- History of congenital or active immunodeficiency, with exception of acquired treatment-related hypogammaglobulinemia requiring periodic IV immunoglobulin infusion.
Trial locations and contacts
33 sites in 7 countries.
33 sites in 7 countries
United States17 sites
Cedar Sinai Medical Center
Ashland, Oregon, 97520
National Cancer Institute
Bethesda, Maryland, 20892
University of Vermont Medical Center
Burlington, Vermont, 05405
Medical University of South Carolina
Charleston, South Carolina, 29425
UC Health, LLC.
Cincinnati, Ohio, 45229
Mary Crowley Cancer Research Centers
Dallas, Texas, 75251
Holy Cross Hospital Inc.
Fort Lauderdale, Florida, 33308
Metairie Oncologists, LLC
Metairie, Louisiana, 70006
Virginia Piper Cancer Institute
Minneapolis, Minnesota, 55407
Yale University Institutional Review Board
New Haven, Connecticut, 06520
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
Hematology - Oncology Associates of the Treasure Coast
Port Saint Lucie, Florida, 34952
California Cancer Associates for Research & Excellence, Inc.
San Diego, California, 92111
Sharp Memorial Hospital
San Diego, California, 92123
St Joseph Heritage Healthcare
Santa Rosa, California, 95403
Washington University
St Louis, Missouri, 63110
Northwest Medical Specialties, PLLC
Tacoma, Washington, 98405
France6 sites
CHU Bordeaux - Hôpital Saint André
Bordeaux
Centre Georges François Leclerc
Dijon
Centre Oscar Lambret
Lille
Hôpital de la Timone# - CPCEM CIC - Bat F 1er étage
Marseille
Centre Hospitalier Lyon Sud
Pierre-Bénite
Centre Paul Strauss
Strasbourg
Italy3 sites
Fondazione IRCCS Istituto Nazionale dei Tumori
Milan
IOV - Istituto Oncologico Veneto IRCCS
Padova
A.O.U. Senese Policlinico Santa Maria alle Scotte
Siena
Netherlands3 sites
Amsterdam UMC, Locatie VUMC
Amsterdam
Antoni van Leeuwenhoek Ziekenhuis
Amsterdam
Maastricht University Medical Center
Maastricht
Belgium2 sites
Centre Hospitalier de l'Ardenne - Pharmacie
Libramont
GZA Ziekenhuizen - Campus Sint-Augustinus
Wilrijk
About this study
Official title: A Phase Ib Open-Label, Dose-Finding Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Avelumab in Combination With M9241(NHS-IL12) in Subjects With Locally Advanced, Unresectable, or Metastatic Solid Tumors
The study consisted of 2 parts: Dose Escalation phase (Part A) and Expansion phase (Part B). The dose escalation phase evaluated the safety, tolerability, and PK of avelumab in combination with M9241 in subjects with locally advanced, unresectable, or metastatic solid tumors. Expansion phase assessed the safety and clinical activity of the combination regimen in selected tumor types. In Expansion phase subjects who had completed the combination treatment of avelumab at a given dose level of M9241, a safety review was performed by the Safety monitoring committee in order to make a decision on the next dose level. Successive cohorts of 3 to 6 subjects were treated with escalating doses of M9241 with avelumab intravenous (IV).
- Conditions
- Advanced Solid Tumors
- Being tested
- Avelumab, M9241, Avelumab (Once weekly), M9241 (MTD), Avelumab (Expansion cohort)
- Keywords
- Avelumab, M9241, NHS-IL12, Advanced Solid Tumors
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AvelumabDrug
Also called MSB0010718C
Participants received avelumab intravenous (IV) infusion once a week on Day 1 and Day 15 of each cycle.
M9241Drug
Participants received Subcutaneous (SC) injection of M9241 in escalating doses on Day 1 of each cycle.
Avelumab (Once weekly)Drug
Participants received avelumab once weekly in combination with M9241 every 4 weeks at M9241 maximum tolerated dose (MTD) for first 12 weeks followed by avelumab once every 2 weeks plus M9241 once every 4 weeks at M9241 MTD until a criterion for treatment discontinuation has been met.
M9241 (MTD)Drug
Participants received M9241 at M9241 MTD once every 4 weeks until a criterion for treatment discontinuation has been met.
Avelumab (Expansion cohort)Drug
Participants in the expansion cohorts received Induction Therapy (Avelumab once weekly + M9241 once every 4 weeks) through Cycle 3 (for 12 weeks) then starting at Cycle 4, Continuation Therapy (Avelumab once every 2 weeks + M9241 once every 4 weeks).
| Study group | Role | What they receive |
|---|---|---|
| Part A Cohort 1: M9241 4 mcg/kg + Avelumab 10 mg/kg | Experimental | Participants received M9241 at a dose of 4 micrograms per kilogram (mcg/kg) a subcutaneous (SC) injection at time (up to -20 minutes) relative to the start of Avelumab infusion (time 0), once every 4 weeks, on Day 1 in combination with Avelumab 10 milligrams per kilogram (mg/kg) intravenous (IV) infusion every 2 weeks on Day 1 and 15 during each cycle (Each cycle=28 days) until any criterion for treatment discontinuation were met. Receives: Drug: Avelumab; Drug: M9241; Drug: M9241 (MTD) |
| Part A Cohort 2: M9241 8 mcg/kg + Avelumab 10 mg/kg | Experimental | Participants received M9241 at a dose of 8 mcg/kg SC injection at time (up to -20 minutes) relative to the start of avelumab infusion (time 0), once every 4 weeks, on Day 1 in combination with Avelumab 10 mg/kg IV infusion every 2 weeks on Day 1 and 15 of each cycle (Each cycle=28 days) until any criterion for treatment discontinuation were met. Receives: Drug: Avelumab; Drug: M9241 |
| Part A Cohort 3: M9241 12 mcg/kg + Avelumab 10 mg/kg | Experimental | Participants received M9241 at a dose of 12 mcg/kg SC injection at time (up to -20 minutes) relative to the start of avelumab infusion (time 0), once every 4 weeks, on Day 1 in combination with Avelumab 10 mg/kg IV infusion every 2 weeks on Day 1 and 15 of each cycle (Each cycle=28 days) until any criterion for treatment discontinuation were met. Receives: Drug: Avelumab; Drug: M9241 |
| Part A Cohort 4: M9241 16.8 mcg/kg +Avelumab 10 mg/kg | Experimental | Participants received M9241 at a dose of 16.8 mcg/kg SC injection at time (up to -20 minutes) relative to the start of avelumab infusion (time 0), once every 4 weeks, on Day 1 in combination with Avelumab 10 mg/kg IV infusion every 2 weeks on Day 1 and 15 of each cycle (Each cycle=28 days) until any criterion for treatment discontinuation were met. Receives: Drug: Avelumab; Drug: M9241 |
| Part A Cohort 5: M9241 16.8 mcg/kg + Avelumab 800 mg | Experimental | Participants received M9241 at a dose of 16.8 mcg/kg SC injection at time (up to -20 minutes) relative to the start of avelumab infusion (time 0), once every 4 weeks, on Day 1 in combination with Avelumab 800 milligrams (mg) IV infusion once weekly for the first 12 weeks, then 800 mg once every 2 weeks of each cycle (Each cycle=28 days) until any criterion for treatment discontinuation were met. Receives: Drug: Avelumab (Once weekly) |
| Part B Cohort 1: UC Cohort Stage 1 combination therapy | Experimental | Participants in the expansion cohorts received M9241 at dose of 16.8 mcg/kg SC injection at time (up to -20 minutes) relative to the start of avelumab infusion (time 0), once every 4 weeks on Day 1 in combination with Avelumab 800 mg IV infusion once weekly for the first 12 weeks, then 800 mg once every 2 weeks of each cycle (Each cycle=28 days) determined as the RP2D in the escalation part of the study. Receives: Drug: Avelumab (Once weekly); Drug: Avelumab (Expansion cohort) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) v4.03
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to the study intervention. Number of participants with TEAEs and treatment related TEAEs were reported.
Measured: From first dose of study treatment up to 1311 days
Part B: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) v4.03
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to the study intervention. Number of participants with TEAEs and treatment related TEAEs were reported.
Measured: Part B: From first dose of study treatment up to 443 days
Part A: Number of Participants With Treatment-Related Adverse Events (TRAEs) by Severity Based on Grade 3,4 and 5 According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
AE was any untoward medical occurrence in a participants who received study drug without regard to possibility of causal relationship. An AE was considered treatment emergent if occurred for the first time after the start of study treatment or occurred prior to the start of treatment. Severity of TEAEs were graded using NCI-CTCAE v4.03 toxicity grades, as follows: Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death. Number of participants with Grade 3,4 and 5 by severity were only reported.
Measured: From first dose of study treatment up to 1311 days
Part B: Number of Participants With Treatment-Related Adverse Events (TRAEs) by Severity According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
AE was any untoward medical occurrence in a participants who received study drug without regard to possibility of causal relationship. An AE was considered treatment emergent if occurred for the first time after the start of study treatment or occurred prior to the start of treatment. Severity of TEAEs were graded using NCI-CTCAE v4.03 toxicity grades, as follows: Grade 1= Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death. Number of participants with TEAEs and TRAEs by severity were reported.
Measured: First dose of study drug up to 443 days
Part A: Number of Participants Experiencing Dose Limiting Toxicities (DLTs)
A DLT is any Grade (>=) 3 non-hematologic AE or any Grade (>=) 4 hematologic AE according to the NCI-CTCAE v4.03, occurring during the DLT observation period that is related to either or both study drugs as determined by the Investigator or Sponsor at any dose and judged not to be related to the underlying disease or any previous or concomitant medication. The following are exceptions to the DLTs: Grade >=3 thrombocytopenia with medically concerning bleeding; Any Grade 3 autoimmune thyroid-related toxicity that doesn't clinically resolve to <= Grade 2 within 7 days of initiating therapy will be a DLT. Any Grade 4 neutropenia of < 5 days duration; Grade 3 infusion-related reaction resolving within 6 hours of infusion; Grade 3 diarrhea or skin toxicity that resolves to Grade <= 1 within 7 days after medical management; Transient Grade 3 fatigue, local reactions, flu-like symptoms; Tumor flare phenomenon of known or suspected tumor did not consider a DLT.
Measured: Time from first treatment to final assessment up to 3 weeks
Part B: Number of Participants With Confirmed Best Overall Response (BOR) Assessed by Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Confirmed BOR was defined as the best response of any of the confirmed complete response (CR), confirmed partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference).CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)= Neither sufficient increase to qualify for progression of disease (PD) nor sufficient shrinkage to qualify for PR. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Not evaluable (NE): No post-baseline assessment. BOR assessments were assessed by investigators.
Measured: First dose of study drug up to 443 days
Secondary outcomes (27)
Part A: Area Under Serum Concentration Time Curve From Time Zero to the Time of the Last Observation (AUC0-t) of Avelumab
Area under the serum concentration versus time curve from time zero to the last sampling time t at which concentration is at or above the lower limit of quantification (LLLQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.
Measured: Predose (PrD),1,4,8 hours postdose (PD) on Day 1,22 of Cycle 1 & 2; PrD,1 hour PD on Day 8,15 of Cycle 1 & Day 8,15,22 of Cycle 2; PrD, 1 hour PD on Day 1 Cycle 3 & Day 1,15 of Cycle 4; PrD on Day 1 of Cycle 7,10,13,16,19,22,25, & 28 (Each cycle: 28 days)
Part A: Area Under Serum Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab
The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.
Measured: PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)
Part A: Terminal Elimination Rate Constant (Lambdaz) of Avelumab
Lambda(z) was determined from the terminal slope of the log-transformed serum concentration curve using linear regression method.
Measured: PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)
Part A: Maximum Observed Serum Concentration (Cmax) of Avelumab
Cmax is the maximum observed serum concentration obtained directly from the concentration versus time curve.
Measured: PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)
Part A: Minimum Observed Serum Concentration (Cmin) of Avelumab
Cmin is minimum observed serum concentration obtained directly from the concentration versus time curve.
Measured: PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)
Part A: Time to Reach Maximum Observed Concentration (Tmax) of Avelumab
Tmax is time to reach maximum observed serum concentration obtained directly from the concentration versus time curve.
Measured: PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)
Part A: Apparent Terminal Half-life (t1/2) of Avelumab
Apparent terminal half-life was defined as the time required for the serum concentration of drug to decrease 50 percent in the final stage of its elimination.
Measured: PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)
Part A: Area Under the Serum Concentration-Time Curve Within One Dosing Interval (AUC0-tau) of Avelumab
AUCtau was defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
Measured: PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)
Part A: Area Under Serum Concentration Time Curve From Time Zero to the Time of the Last Observation (AUC0-t) of M9241
Area under the serum concentration versus time curve from time zero to the last sampling time t at which the concentration is at or above the lower limit of quantification (LLLQ). (AUC0-t) was calculated according to the mixed log-linear trapezoidal rule.
Measured: PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Area Under Serum Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M9241
The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.
Measured: PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Terminal Elimination Rate Constant (Lambdaz) of M9241
Lambda(z) was determined from the terminal slope of the log-transformed serum concentration curve using linear regression method.
Measured: PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Maximum Observed Serum Concentration (Cmax) of M9241
Cmax is the maximum observed serum concentration obtained directly from the concentration versus time curve.
Measured: PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Minimum Observed Serum Concentration (Cmin) of M9241
Cmin is minimum observed serum concentration obtained directly from the concentration versus time curve.
Measured: PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Time to Reach Maximum Observed Concentration (Tmax) of M9241
Tmax is time to reach maximum observed serum concentration obtained directly from the concentration versus time curve.
Measured: PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Apparent Terminal Half-life (t1/2) of M9241
Apparent terminal half-life was defined as the time required for the serum concentration of drug to decrease 50 percent in the final stage of its elimination.
Measured: PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Area Under the Serum Concentration-Time Curve Within One Dosing Interval (AUC0-tau) of M9241
AUCtau was defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).
Measured: PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Number of Participants With At Least One Positive Anti-drug Antibodies (ADA) for Avelumab and M9241
ADA category of each participant was classified as pre-existing immunoreactivity (positive ADA response at baseline (prior to treatment), treatment-boosted (positive response at baseline with at least one post baseline titer at >=8-fold baseline titer), or treatment-emergent (TE [any positive post baseline assay response when baseline results were negative or missing or not reported]). TE ADA responses were further classified as persistent (treatment-emergent positive ADA response detected in at least 2 consecutive post baseline samples separated by at least a 16-week post baseline period [based on nominal sampling time], with no ADA-negative samples in-between or positive response at last ADA sampling time point) and transient (not persistent/indeterminate, regardless of any missing samples).
Measured: First dose of study drug up to 1311 days
Part A: Number of Participants With Confirmed Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1
BOR is defined as best response of any of confirmed complete response, confirmed partial response, stable disease and progressive disease recorded from date of randomization until disease progression or recurrence. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)= Neither sufficient increase to qualify for progression of disease (PD) nor sufficient shrinkage to qualify for PR. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Non-CR/non-PD (for participants with non-measurable disease at baseline) = at least one Non-CR/non-PD assessment (or better) >= 6 weeks after first study treatment administration and before progression and Not Evaluable: all other cases. BOR assessments were assessed by investigators.
Measured: First dose of study drug up to 1311 days
Pat A: Number of Participants With Immune-related Best Overall Response (BOR) Using Immune-related Response Criteria Derived From Response Evaluation Criteria in Solid Tumors Version 1.1
BOR: best response of any of immune related complete response (irCR), immune related partial response (irPR), immune related stable disease (irSD) and immune related progressive disease (irPD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference). irCR: Complete disappearance of all tumor lesions (both index and non-index lesions with no new measurable/unmeasurable lesions). irPR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions). irSD: SLD of target and new measurable lesions neither irCR, irPR, or irPD. irPD: SLD of target and new measurable lesions increases greater than or equal to [>=] 20%, confirmed by a repeat, consecutive observations at least 4 weeks from the date first documented. Number of participants with immune-related best overall response in each category (irCR, irPR, irSD, irPD) was reported.
Measured: First dose of study drug up to 1311 days
Part B: Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria Assessed by Investigator
PFS was defined as the time from first treatment day until date of the first documentation of progressive disease (PD) or death due to any cause, whichever occurs first. PD was defined as at least a 20 percent (%) increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier estimates.
Measured: Time from first dose administration until progressive disease or death, assessed up to 443 days
Part B: Overall Survival (OS) Time
The OS time was defined as the time from treatment day 1 to the date of death due to any cause. The participants who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the participant was known to be alive before the data cutoff date. OS was measured using Kaplan-Meier estimates.
Measured: Time from first dose of study treatment up to 443 days
Part B: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria Assessed by Investigator
DOR according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and as assessed by an Investigator was defined as the time from first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the date of first documentation of objective progression of disease (PD) or death due to any cause whichever occurs first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. If a participant has not an event (PD or death), DOR was censored at the date of last adequate tumor assessment.
Measured: Time from first dose of study treatment up to 443 days
Part B: Maximum Observed Serum Concentration (Cmax) of M9241
Cmax is the maximum observed serum concentration obtained directly from the concentration versus time curve.
Measured: Pre-dose, 1 hour post-dose on Day 1 and Day 29 of Cycle 1 and 2 (Each cycle: 28 days)
Part B: Serum Trough Concentration Levels (Ctrough) of M9241
Ctrough was defined as the trough or minimum serum concentration.
Measured: Pre-dose, 1 hour post-dose on Day 1 of cycle 2; Day 1, 27 of cycle 3; Day 1 of cycle 5 (Each cycle: 28 days)
Part B: Concentration at the End of Infusion (Ceoi) of Avelumab
Ceoi is the observed serum drug concentration at the end of Intravenous (IV) infusion.
Measured: Pre-dose, 1 hour post-dose on Day 1 and 15 of Cycle 1 and 2 (Each cycle: 28 days)
Part B: Serum Trough Concentration Levels (Ctrough) of Avelumab
Ctrough was defined as the trough or minimum serum concentration.
Measured: Pre-dose, 1 hour post-dose on Day 15, 29 and 43
Part B: Number of Participants With At Least One Positive Anti-drug Antibodies (ADA) of Avelumab and M9241
ADA category of each participant was classified as pre-existing immunoreactivity (positive ADA response at baseline (prior to treatment), treatment-boosted (positive response at baseline with at least one post baseline titer at >=8-fold baseline titer), or treatment-emergent (TE [any positive post baseline assay response when baseline results were negative or missing or not reported]). TE ADA responses were further classified as persistent (treatment-emergent positive ADA response detected in at least 2 consecutive post baseline samples separated by at least a 16-week post baseline period [based on nominal sampling time], with no ADA-negative samples in-between or positive response at last ADA sampling time point) and transient (not persistent/indeterminate, regardless of any missing samples).
Measured: Time from first dose of study treatment up to 443 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Dec 2016 (estimated)
- Study start31 Jan 2017
- Primary completion8 Oct 2020
- Study completion8 Oct 2020
Why it stopped: The study was terminated due to pre-specified futility criteria met.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Advanced Solid TumorsStudies of the same condition, open and under way.
- More trials run by EMD Serono Research & Development Institute, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 52 participants (actual)
Sponsor and investigators
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Merck KGaA, Darmstadt, Germany
- Responsible party
- Sponsor
- Investigators
- Medical Responsible, Study director, EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02994953
- Sponsor's protocol ID
- MS201781_0031
- Other IDs
- 2017-002212-13, 2017
- Acronym
- COMBO
- Status last verified
- May 2024
- First submitted
- 14 Dec 2016
- Last updated
- 20 Sep 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21
Publications
Strauss J, Deville JL, Sznol M, Ravaud A, Maruzzo M, Pachynski RK, Gourdin TS, Maio M, Dirix L, Schlom J, Donahue RN, Tsai YT, Wang X, Vugmeyster Y, Beier F, Seebeck J, Schroeder A, Chennoufi S, Gulley JL. First-in-human phase Ib trial of M9241 (NHS-IL12) plus avelumab in patients with advanced solid tumors, including dose expansion in patients with advanced urothelial carcinoma. J Immunother Cancer. 2023 May;11(5):e005813. doi: 10.1136/jitc-2022-005813.
PubMed 37236636
Study at a glance
From the registry record, last updated by the sponsor on 20 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase Ib Open-Label, Dose-Finding Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Avelumab in Combination With M9241(NHS-IL12) in Subjects With Locally Advanced, Unresectable, or Metastatic Solid Tumors
- ClinicalTrials.gov ID
- NCT02994953
- Acronym / sponsor ID
- COMBO / MS201781_0031
- Conditions
- Advanced Solid Tumors
- Keywords
- Avelumab, M9241, NHS-IL12, Advanced Solid Tumors
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The study was terminated due to pre-specified futility criteria met.
- Enrolment
- 52 participants (actual)
- Lead sponsor
- EMD Serono Research & Development Institute, Inc.Industry (pharma, biotech, devices)
- Collaborators
- Merck KGaA, Darmstadt, Germany
- Study start
- 31 Jan 2017 (actual)
- Primary completion
- 8 Oct 2020 (actual)
- Study completion
- 8 Oct 2020 (actual)
- First posted
- 16 Dec 2016 (estimated)
- Results
- Posted 20 Sep 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The study consisted of 2 parts: Dose Escalation phase (Part A) and Expansion phase (Part B). The dose escalation phase evaluated the safety, tolerability, and PK of avelumab in combination with M9241 in subjects with locally advanced, unresectable, or metastatic solid tumors. Expansion phase assessed the safety and clinical activity of the combination regimen in selected tumor types. In Expansion phase subjects who had completed the combination treatment of avelumab at a given dose level of M9241, a safety review was performed by the Safety monitoring committee in order to make a decision on the next dose level. Successive cohorts of 3 to 6 subjects were treated with escalating doses of M9241 with avelumab intravenous (IV).
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Part A Cohort 1: M9241 4 mcg/kg + Avelumab 10 mg/kg | Experimental | Drug: Avelumab, Drug: M9241, Drug: M9241 (MTD)Participants received M9241 at a dose of 4 micrograms per kilogram (mcg/kg) a subcutaneous (SC) injection at time (up to -20 minutes) relative to the start of Avelumab infusion (time 0), once every 4 weeks, on Day 1 in combination with Avelumab 10 milligrams per kilogram (mg/kg) intravenous (IV) infusion every 2 weeks on Day 1 and 15 during each cycle (Each cycle=28 days) until any criterion for treatment discontinuation were met. |
| Part A Cohort 2: M9241 8 mcg/kg + Avelumab 10 mg/kg | Experimental | Drug: Avelumab, Drug: M9241Participants received M9241 at a dose of 8 mcg/kg SC injection at time (up to -20 minutes) relative to the start of avelumab infusion (time 0), once every 4 weeks, on Day 1 in combination with Avelumab 10 mg/kg IV infusion every 2 weeks on Day 1 and 15 of each cycle (Each cycle=28 days) until any criterion for treatment discontinuation were met. |
| Part A Cohort 3: M9241 12 mcg/kg + Avelumab 10 mg/kg | Experimental | Drug: Avelumab, Drug: M9241Participants received M9241 at a dose of 12 mcg/kg SC injection at time (up to -20 minutes) relative to the start of avelumab infusion (time 0), once every 4 weeks, on Day 1 in combination with Avelumab 10 mg/kg IV infusion every 2 weeks on Day 1 and 15 of each cycle (Each cycle=28 days) until any criterion for treatment discontinuation were met. |
| Part A Cohort 4: M9241 16.8 mcg/kg +Avelumab 10 mg/kg | Experimental | Drug: Avelumab, Drug: M9241Participants received M9241 at a dose of 16.8 mcg/kg SC injection at time (up to -20 minutes) relative to the start of avelumab infusion (time 0), once every 4 weeks, on Day 1 in combination with Avelumab 10 mg/kg IV infusion every 2 weeks on Day 1 and 15 of each cycle (Each cycle=28 days) until any criterion for treatment discontinuation were met. |
| Part A Cohort 5: M9241 16.8 mcg/kg + Avelumab 800 mg | Experimental | Drug: Avelumab (Once weekly)Participants received M9241 at a dose of 16.8 mcg/kg SC injection at time (up to -20 minutes) relative to the start of avelumab infusion (time 0), once every 4 weeks, on Day 1 in combination with Avelumab 800 milligrams (mg) IV infusion once weekly for the first 12 weeks, then 800 mg once every 2 weeks of each cycle (Each cycle=28 days) until any criterion for treatment discontinuation were met. |
| Part B Cohort 1: UC Cohort Stage 1 combination therapy | Experimental | Drug: Avelumab (Once weekly), Drug: Avelumab (Expansion cohort)Participants in the expansion cohorts received M9241 at dose of 16.8 mcg/kg SC injection at time (up to -20 minutes) relative to the start of avelumab infusion (time 0), once every 4 weeks on Day 1 in combination with Avelumab 800 mg IV infusion once weekly for the first 12 weeks, then 800 mg once every 2 weeks of each cycle (Each cycle=28 days) determined as the RP2D in the escalation part of the study. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (26 listed)
- subjects must had signed written informed consent.
- male or female subjects age greater than equals to (>=)18 years.
- subjects must had histologically or cytologically proven metastatic or locally advanced solid tumors for which no standard therapy exists, standard therapy had failed, subject was intolerant of established therapy known to provided clinical benefit for their condition, or standard therapy was not acceptable to subject.
- subjects who had been treated previously with a checkpoint inhibitor may enroll (except as outlined below for expansion cohorts).
- at least 1 unidimensional radiographically measurable lesion based on response evaluation criteria in solid tumors (recist) version 1. 1 (v1. 1), except for subjects with metastatic castration-resistant prostate cancer (crpc) or metastatic breast cancer who may been enrolled with objective evidence of disease without a measureable lesion. - eastern cooperative oncology group (ecog) performance status of 0 to 1 at screening
Key exclusion criteria (30 listed)
- Concurrent treatment with a non-permitted drug/intervention (listed below)
- Any prior treatment with any form of interlukin-12 (IL-12)
- For the NSCLC, CRC, and UC expansion cohorts, prior therapy with any antibody / drug targeting T-cell co-regulatory proteins (immune checkpoints) such as anti-PD-1, anti-PD-L1, or anticytotoxic T lymphocyte antigen-4 (CTLA-4) antibody was prohibited.
- Intolerance to checkpoint inhibitor therapy, as defined by the occurrence of an AE requiring drug discontinuation. - Active or history of primary or metastatic central nervous system tumors
- Prior organ transplantation, including allogeneic stem-cell transplantation
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AvelumabAlso: MSB0010718CParticipants received avelumab intravenous (IV) infusion once a week on Day 1 and Day 15 of each cycle. | Drug | Part A Cohort 1: M9241 4 mcg/kg + Avelumab 10 mg/kg, Part A Cohort 2: M9241 8 mcg/kg + Avelumab 10 mg/kg, Part A Cohort 3: M9241 12 mcg/kg + Avelumab 10 mg/kg, Part A Cohort 4: M9241 16.8 mcg/kg +Avelumab 10 mg/kg |
| M9241Participants received Subcutaneous (SC) injection of M9241 in escalating doses on Day 1 of each cycle. | Drug | Part A Cohort 1: M9241 4 mcg/kg + Avelumab 10 mg/kg, Part A Cohort 2: M9241 8 mcg/kg + Avelumab 10 mg/kg, Part A Cohort 3: M9241 12 mcg/kg + Avelumab 10 mg/kg, Part A Cohort 4: M9241 16.8 mcg/kg +Avelumab 10 mg/kg |
| Avelumab (Once weekly)Participants received avelumab once weekly in combination with M9241 every 4 weeks at M9241 maximum tolerated dose (MTD) for first 12 weeks followed by avelumab once every 2 weeks plus M9241 once every 4 weeks at M9241 MTD until a criterion for treatment discontinuation has been met. | Drug | Part A Cohort 5: M9241 16.8 mcg/kg + Avelumab 800 mg, Part B Cohort 1: UC Cohort Stage 1 combination therapy |
| M9241 (MTD)Participants received M9241 at M9241 MTD once every 4 weeks until a criterion for treatment discontinuation has been met. | Drug | Part A Cohort 1: M9241 4 mcg/kg + Avelumab 10 mg/kg |
| Avelumab (Expansion cohort)Participants in the expansion cohorts received Induction Therapy (Avelumab once weekly + M9241 once every 4 weeks) through Cycle 3 (for 12 weeks) then starting at Cycle 4, Continuation Therapy (Avelumab once every 2 weeks + M9241 once every 4 weeks). | Drug | Part B Cohort 1: UC Cohort Stage 1 combination therapy |
Primary outcome
Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) v4.03
Time frame: From first dose of study treatment up to 1311 days
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to the study intervention. Number of participants with TEAEs and treatment related TEAEs were reported.
Part B: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) v4.03
Time frame: Part B: From first dose of study treatment up to 443 days
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event needed not necessarily have a causal relationship with the treatment or usage. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to the study intervention. Number of participants with TEAEs and treatment related TEAEs were reported.
Part A: Number of Participants With Treatment-Related Adverse Events (TRAEs) by Severity Based on Grade 3,4 and 5 According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
Time frame: From first dose of study treatment up to 1311 days
AE was any untoward medical occurrence in a participants who received study drug without regard to possibility of causal relationship. An AE was considered treatment emergent if occurred for the first time after the start of study treatment or occurred prior to the start of treatment. Severity of TEAEs were graded using NCI-CTCAE v4.03 toxicity grades, as follows: Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death. Number of participants with Grade 3,4 and 5 by severity were only reported.
Part B: Number of Participants With Treatment-Related Adverse Events (TRAEs) by Severity According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
Time frame: First dose of study drug up to 443 days
AE was any untoward medical occurrence in a participants who received study drug without regard to possibility of causal relationship. An AE was considered treatment emergent if occurred for the first time after the start of study treatment or occurred prior to the start of treatment. Severity of TEAEs were graded using NCI-CTCAE v4.03 toxicity grades, as follows: Grade 1= Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death. Number of participants with TEAEs and TRAEs by severity were reported.
Part A: Number of Participants Experiencing Dose Limiting Toxicities (DLTs)
Time frame: Time from first treatment to final assessment up to 3 weeks
A DLT is any Grade (>=) 3 non-hematologic AE or any Grade (>=) 4 hematologic AE according to the NCI-CTCAE v4.03, occurring during the DLT observation period that is related to either or both study drugs as determined by the Investigator or Sponsor at any dose and judged not to be related to the underlying disease or any previous or concomitant medication. The following are exceptions to the DLTs: Grade >=3 thrombocytopenia with medically concerning bleeding; Any Grade 3 autoimmune thyroid-related toxicity that doesn't clinically resolve to <= Grade 2 within 7 days of initiating therapy will be a DLT. Any Grade 4 neutropenia of < 5 days duration; Grade 3 infusion-related reaction resolving within 6 hours of infusion; Grade 3 diarrhea or skin toxicity that resolves to Grade <= 1 within 7 days after medical management; Transient Grade 3 fatigue, local reactions, flu-like symptoms; Tumor flare phenomenon of known or suspected tumor did not consider a DLT.
Part B: Number of Participants With Confirmed Best Overall Response (BOR) Assessed by Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Time frame: First dose of study drug up to 443 days
Confirmed BOR was defined as the best response of any of the confirmed complete response (CR), confirmed partial response (PR), stable disease (SD) and progressive disease (PD) recorded from the date of randomization until disease progression or recurrence (taking the smallest measurement recorded since the start of treatment as reference).CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)= Neither sufficient increase to qualify for progression of disease (PD) nor sufficient shrinkage to qualify for PR. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Not evaluable (NE): No post-baseline assessment. BOR assessments were assessed by investigators.
27 secondary outcomes
Part A: Area Under Serum Concentration Time Curve From Time Zero to the Time of the Last Observation (AUC0-t) of Avelumab
Time frame: Predose (PrD),1,4,8 hours postdose (PD) on Day 1,22 of Cycle 1 & 2; PrD,1 hour PD on Day 8,15 of Cycle 1 & Day 8,15,22 of Cycle 2; PrD, 1 hour PD on Day 1 Cycle 3 & Day 1,15 of Cycle 4; PrD on Day 1 of Cycle 7,10,13,16,19,22,25, & 28 (Each cycle: 28 days)
Part A: Area Under Serum Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Avelumab
Time frame: PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)
Part A: Terminal Elimination Rate Constant (Lambdaz) of Avelumab
Time frame: PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)
Part A: Maximum Observed Serum Concentration (Cmax) of Avelumab
Time frame: PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)
Part A: Minimum Observed Serum Concentration (Cmin) of Avelumab
Time frame: PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)
Part A: Time to Reach Maximum Observed Concentration (Tmax) of Avelumab
Time frame: PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)
Part A: Apparent Terminal Half-life (t1/2) of Avelumab
Time frame: PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)
Part A: Area Under the Serum Concentration-Time Curve Within One Dosing Interval (AUC0-tau) of Avelumab
Time frame: PrD, 1, 4, 8 hours PD on Day 1, 22 of cycle 1 & 2; PrD, 1 hour PD on Day 8, 15 of cycle 1 & Day 8, 15, 22 of cycle 2; PrD, 1 hour PD on Day 1 cycle 3 & Day 1, 15 of cycle 4; PrD on Day 1 of cycle 7, 10,13,16,19,22,25, & 28 (Each cycle: 28 days)
Part A: Area Under Serum Concentration Time Curve From Time Zero to the Time of the Last Observation (AUC0-t) of M9241
Time frame: PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Area Under Serum Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M9241
Time frame: PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Terminal Elimination Rate Constant (Lambdaz) of M9241
Time frame: PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Maximum Observed Serum Concentration (Cmax) of M9241
Time frame: PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Minimum Observed Serum Concentration (Cmin) of M9241
Time frame: PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Time to Reach Maximum Observed Concentration (Tmax) of M9241
Time frame: PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Apparent Terminal Half-life (t1/2) of M9241
Time frame: PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Area Under the Serum Concentration-Time Curve Within One Dosing Interval (AUC0-tau) of M9241
Time frame: PrD, 1, 4, 8 hours PD on Day 1 of cycle 1 and Day 1 of cycle 2; PrD on Day 15 of cycle 1 and cycle 2; PrD, 1 hour PD on Day 1 of cycle 3 and cycle 4; PrD on Day 1 Cycle 7, 10, 13, 16, 19, 22, 25, and 28 (Each cycle: 28 days)
Part A: Number of Participants With At Least One Positive Anti-drug Antibodies (ADA) for Avelumab and M9241
Time frame: First dose of study drug up to 1311 days
Part A: Number of Participants With Confirmed Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1
Time frame: First dose of study drug up to 1311 days
Pat A: Number of Participants With Immune-related Best Overall Response (BOR) Using Immune-related Response Criteria Derived From Response Evaluation Criteria in Solid Tumors Version 1.1
Time frame: First dose of study drug up to 1311 days
Part B: Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria Assessed by Investigator
Time frame: Time from first dose administration until progressive disease or death, assessed up to 443 days
Part B: Overall Survival (OS) Time
Time frame: Time from first dose of study treatment up to 443 days
Part B: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Criteria Assessed by Investigator
Time frame: Time from first dose of study treatment up to 443 days
Part B: Maximum Observed Serum Concentration (Cmax) of M9241
Time frame: Pre-dose, 1 hour post-dose on Day 1 and Day 29 of Cycle 1 and 2 (Each cycle: 28 days)
Part B: Serum Trough Concentration Levels (Ctrough) of M9241
Time frame: Pre-dose, 1 hour post-dose on Day 1 of cycle 2; Day 1, 27 of cycle 3; Day 1 of cycle 5 (Each cycle: 28 days)
Part B: Concentration at the End of Infusion (Ceoi) of Avelumab
Time frame: Pre-dose, 1 hour post-dose on Day 1 and 15 of Cycle 1 and 2 (Each cycle: 28 days)
Part B: Serum Trough Concentration Levels (Ctrough) of Avelumab
Time frame: Pre-dose, 1 hour post-dose on Day 15, 29 and 43
Part B: Number of Participants With At Least One Positive Anti-drug Antibodies (ADA) of Avelumab and M9241
Time frame: Time from first dose of study treatment up to 443 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Sep 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 37236636Strauss J, Deville JL, Sznol M, Ravaud A, Maruzzo M, Pachynski RK, Gourdin TS, Maio M, Dirix L, Schlom J, Donahue RN, Tsai YT, Wang X, Vugmeyster Y, Beier F, Seebeck J, Schroeder A, Chennoufi S, Gulley JL. First-in-human phase Ib trial of M9241 (NHS-IL12) plus avelumab in patients with advanced solid tumors, including dose expansion in patients with advanced urothelial carcinoma. J Immunother Cancer. 2023 May;11(5):e005813. doi: 10.1136/jitc-2022-005813.
- Trial Awareness and Transparency websiteLink provided by the sponsor.
- US Medical Information website, Medical ResourcesLink provided by the sponsor.
- Individual participant dataSharing planned: No. We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Responsible study director
EMD Serono Inc., a business of Merck KGaA, Darmstadt, Germany
33 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Avelumab, M9241 and Avelumab (Once weekly) in people with Advanced Solid Tumors, run by EMD Serono Research & Development Institute, Inc. at 33 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 26 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 20 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 33 sites in United States, France, Italy, Netherlands, Belgium and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 Sep 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) v4.03 (time frame: From first dose of study treatment up to 1311 days). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02994953, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Sep 2024.