Solid TumorsPhase 1NCT03225105
M3541 in Combination With Radiotherapy in Solid Tumors
A Phase 1 study testing M3541 and Palliative Radiotherapy (RT) in people with Solid Tumors, run by EMD Serono Research & Development Institute, Inc. at 5 sites in United States.
Trial summary
This dose-escalation study evaluated the safety, tolerability, pharmacokinetic (PK), pharmacodynamic, and explore antitumor activity of M3541 in combination with fractionated palliative radiotherapy (RT) in participants with solid tumors with malignant lesions in the thorax, abdominal cavity, head and neck region, or… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Solid Tumors
- What is being tested?
- M3541 and Palliative Radiotherapy (RT)
- Type of treatment
- Pill or oral medicine, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 15 participants
- Where
- 5 sitesUnited States
- Study dates
- 6 Sep 2017to 27 Apr 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
- Participants must have solid tumors with malignant lesions in the thorax, abdominal cavity, head and neck region, or extremities (any histology) likely to benefit from palliative radiotherapy; participants requiring palliative RT for lesions in the spine or lesions adjacent to the spinal cord are excluded from this study
- Eastern Cooperative Oncology Group performance status (ECOG PS) =< 2
- Life expectancy >= 3 months
- Adequate hematologic, hepatic, and renal function
- Agree to use highly effective contraception (that is, methods with a failure rate of less than 1 percent per year) if the participant is male or a female of childbearing potential (female partners of childbearing potential of male participants must also agree to use highly effective contraception)
- Other protocol defined inclusion criteria could apply
Who cannot join
- Use of other anticancer therapy within 15 days before the first dose of M3541 administration and should not be within the "at risk follow-up period" for that specific anticancer therapy. The use of any investigational agent is not allowed within 28 days before the first dose of M3541
- Residual toxicity due to previous anticancer therapy with no return to baseline or =< Grade 1 (except alopecia) according to Common Terminology Criteria for Adverse Events (CTCAE) v4.03
- Extensive prior RT on more than 30 percent of bone marrow reserves (by Investigator judgment), or prior bone marrow/stem cell transplantation within 5 years before study start
- Prior RT to the same region that would be irradiated in this study
- Participants at increased risk for radiation toxicities, such as known collagen vascular disease (example, scleroderma, Sjogren's disease, etc) or other inherited radiation hypersensitivity syndromes (example, Gorlin syndrome, Fanconi anemia, ataxia-telangiectasia, etc.)
- Surgical intervention within 28 days prior to the first dose of M3541 administration
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- Known central nervous system metastases causing clinical symptoms or metastases that require therapeutic intervention. Participants with a history of treated central nervous system (CNS) metastases (by surgery or radiation therapy) are not eligible unless they have fully recovered from treatment, demonstrated no progression for at least 2 months, and do not require continued steroid therapy. Participants with CNS metastases incidentally detected during Screening that do not cause clinical symptoms and for which standard of care suggests no therapeutic intervention is indicated, should be discussed with the Sponsor Medical Responsible
- Active difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions (including pancreas deficiency requiring Creon therapy) that may hamper compliance and/or absorption of M3541
- Participants currently receiving or unable to stop using medications or herbal supplements known to be potent inhibitors of cytochrome P450 (CYP) 3A and / or P-glycoprotein (P-gp) (CYP and / P-gp must stop at least 1 week before treatment with M3541) or potent inducers of CYP3A or P-gp (must stop at least 3 weeks before treatment with M3541) or drugs mainly metabolized by CYP3A with a narrow therapeutic index (must stop at least 1 day prior).
- Other protocol defined exclusion criteria could apply
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
United States5 sites
Hackensack University Medical Center
Hackensack, New Jersey, 07601
IU Simon Cancer Center
Indianapolis, Indiana, 46202
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, 37212
Fox Chase Cancer Center
Philadelphia, Pennsylvania, 19111
Washington University
St Louis, Missouri, 63110
About this study
Official title: A Phase I, Open-label, Uncontrolled, Multicenter, Dose-escalation Study of M3541 in Combination With Palliative Radiotherapy in Subjects With Solid Tumors
This dose-escalation study evaluated the safety, tolerability, pharmacokinetic (PK), pharmacodynamic, and explore antitumor activity of M3541 in combination with fractionated palliative radiotherapy (RT) in participants with solid tumors with malignant lesions in the thorax, abdominal cavity, head and neck region, or extremities likely to benefit from palliative RT.
- Conditions
- Solid Tumors
- Being tested
- M3541, Palliative Radiotherapy (RT)
- Keywords
- Solid Tumors, M3541, Palliative radiotherapy, Adenosine triphosphate-competitive inhibitor
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
M3541Drug
Participants received M3541 orally once per fraction day (FD) for two consecutive calendar weeks (that is, Monday through Friday, with Saturday and Sunday as M3541 holidays).
Palliative Radiotherapy (RT)Radiation
Participants received RT dose of 30 Gray (Gy) given in 10 fractions (3 Gy given per fraction day) administered over two consecutive calendar weeks (that is, Monday through Friday, with Saturday and Sunday as RT holidays).
| Study group | Role | What they receive |
|---|---|---|
| M3541 50 mg + RT | Experimental | Participants received 50 milligrams (mg) M3541 orally once per fraction day (FD) in combination with palliative radiotherapy (RT) administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10, for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). Receives: Drug: M3541; Radiation: Palliative Radiotherapy (RT) |
| M3541 100 mg + RT | Experimental | Participants received 100 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). Receives: Drug: M3541; Radiation: Palliative Radiotherapy (RT) |
| M3541 200 mg + RT | Experimental | Participants received 200 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). Receives: Drug: M3541; Radiation: Palliative Radiotherapy (RT) |
| M3541 300 mg + RT | Experimental | Participants received 300 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). Receives: Drug: M3541; Radiation: Palliative Radiotherapy (RT) |
What is being measured
The primary outcome is the main question the study is designed to answer.
M3541 50 mg + 100 mg + 200 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs)
DLT is classified per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and defined as any of the following events occurring after first dose of study intervention and judged not to be related to underlying disease or any previous or concomitant medication. Grade (Gr) >=3 non-hematologic toxicity with exception of Nausea, vomiting and diarrhea lasting =<3 days in once per FD; Worsening of preexisting tumor pain associated with tumor lesions for which participant was irradiated in context of this study; Evidence of treatment-related hepatocellular injury for >3 days in the once per FD; Any occurrence of Hy's law; Gr 4 neutropenia lasting for >5 days, Gr 4 thrombocytopenia or Gr 4 anemia that was unexplained by underlying disease; Any toxicity related to study treatment that caused participant to interrupt treatment for not to be able to be treated within 24 hours of the scheduled treatment time.
Measured: Baseline up to 5 weeks (including 2 weeks of treatment and 3 weeks of follow-up period)
M3541 300 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs)
DLT is classified per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and defined as any of the following events occurring after first dose of study intervention and judged not to be related to underlying disease or any previous or concomitant medication. Grade (Gr) >=3 non-hematologic toxicity with exception of Nausea, vomiting and diarrhea lasting =<3 days in once per FD; Worsening of preexisting tumor pain associated with tumor lesions for which participant was irradiated in context of this study; Evidence of treatment-related hepatocellular injury for >3 days in the once per FD; Any occurrence of Hy's law; Gr 4 neutropenia lasting for >5 days, Gr 4 thrombocytopenia or Gr 4 anemia that was unexplained by underlying disease; Any toxicity related to study treatment that caused participant to interrupt treatment for not to be able to be treated within 24 hours of the scheduled treatment time.
Measured: Baseline up to 4 weeks (including 2 weeks of treatment and 2 weeks of the follow-up period)
Secondary outcomes (25)
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Grade >=3 Adverse Events (AEs), Serious TEAEs and Deaths According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 4.03 (CTCAE V4.03)
An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was 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. TEAEs are events with start date on or after the date of first dose of study treatment and up to and including 30 days after the last dose of study treatment, or events with start date prior to the date of first dose of study treatment, and worsened in severity or become serious during treatment. TEAEs include both Serious TEAEs and non-serious TEAEs.
Measured: Baseline up to 749 days
Number of Participants With Grade 3 or Higher Laboratory Abnormalities Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE)
The laboratory assessment included measurements hematology and biochemistry parameters. It had been graded according to NCI-CTCAE version 4.03 into Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (Life-threatening) and Grade 5 = death. Participants with grade 3 or higher were reported.
Measured: Baseline up to Day 44
Number of Participants With Abnormalities in Vital Signs
Vital signs assessment included blood pressure, pulse rate, body temperature, respiratory rate, and body weight. Notably abnormal vital signs were: Blood pressure: systolic blood pressure >= 140 millimeter of mercury (mmHg) \& diastolic blood pressure >=90 mmHg on treatment; Pulse rate >100 beats/min; Body temperature >= 38 degree Celsius (°C) on treatment; Respiratory rate >= 20 breaths/min; Weight (kilogram) > +/-20% from baseline. Number of Participants with abnormalities in vital signs were reported.
Measured: Baseline up to 379 days
Number of Participants With Abnormalities in Physical Examination Reported as Adverse Events (AEs)
Number of participants with any clinically significant abnormalities in physical examination reported as adverse events with National Cancer Institute Common Terminology Criteria (NCI-CTC) Grade >=3 were presented.
Measured: Baseline up to 379 days
Number of Participants With Abnormal Change From Baseline in Electrocardiogram (ECG)
The 12-lead ECG was recorded after the participant was in semi-supine position for at least 5 minutes. The ECG was obtained using a Holter recorder. Number of Participants with abnormal change from baseline in ECG were reported.
Measured: Baseline up to 15 days
Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
BOR was determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). BOR is defined as the best response of any of the complete response (CR), 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% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. SD=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Measured: Time from randomization to 964 days
Progression-Free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator
PFS is defined as the time (in months) from first administration of M3541 until the first date of progressive disease (PD) or death due to any cause. PFS was assessed as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). PD was defined as at least a 20% 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 and unequivocal progression of non-target lesions. Participants with neither disease progression nor death were censored at the last date of the last tumor assessment that confirmed that their disease had not progressed. Participant wise data reported for this outcome measure.
Measured: From first dose of study drug to disease progression or death from any cause, assessed up to 964 days
Maximum Observed Plasma Concentration (Cmax) of M3541
Cmax was obtained directly from the plasma concentration versus time curve.
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3541
Dose normalized was calculated as Cmax obtained directly from the concentration versus time curve divided by dose.
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Time to Reach Maximum Observed Plasma Concentration (Tmax) of M3541
Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Apparent Terminal Half-Life (t1/2) of M3541
Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination.
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Area Under Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Sampling Time Point (AUC[0-last]) of M3541
AUC(0-last) is defined as the area under the concentration-time curve from dosing (time 0) to the time of the last measured concentration. AUC(0-last) will be estimated using the Linear Up Log Down calculation method.
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Dose Normalized Area Under the Concentration-Time Curve From Time Zero to the Last Quantifiable Sampling Time Point (AUC[0-last]/Dose) of M3541
The Dose normalized AUC from time zero to the last sampling time (0-last) at which the concentration is at or above the lower limit of quantification. Normalized using the actual dose, using the formula AUC0-last/Dose.
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Area Under the Concentration-Time Curve From Time Zero to 6 Hour Postdose (AUC[0-6h]) of M3541
Area under the drug concentration-time curve from 0 to 6 hour post dosing for M3541. AUC0-6 was calculated according to the mixed log-linear trapezoidal rule.
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of M3541
AUC0-inf is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time.
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Dose Normalized Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]/Dose) of M3541
Dose normalized was calculated as area under the plasma concentration-time curve from time zero to 8 h postdose divided by dose.
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Oral Clearance (CL/F) of M3541
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. CL/f = Dose /AUC0-inf. Predicted AUC0-inf should be used.
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Oral Clearance at Steady-State (CLss/F) of M3541
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Apparent Volume of Distribution During Terminal Phase (Vz/F) of M3541
The Vz/f was defined as the theoretical volume in which the total amount of required to uniformly distribute to produce the desired plasma concentration. Apparent volume of distribution after oral dose (Vz/F) was influenced by the fraction absorbed. The Vz/f was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz/f=Dose/AUC(0-inf)* Lambda(z).
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Apparent Volume of Distribution at Steady-State (Vss/F) of M3541
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss/f after oral dose was influenced by the fraction absorbed.
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Accumulation Ratio for Area Under Plasma Concentration-Time Curve From Time Zero to 6 Hour (Racc[AUC0-6]) of M3541
The accumulation ratio to assess the increase in exposure via AUC0-6h. Racc(AUC0-6h)= (AUC0-6h after multiple dose) / (AUC0-6h after single dose).
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Accumulation Ratio for Maximum Observed Plasma Concentration (Racc[Cmax])
The accumulation ratio is to assess the increase in maximum concentration with multiple dosing. Racc(Cmax) = (Cmax after multiple dose)/ (Cmax after single dose).
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Pre-dose Plasma Concentration (Ctrough) of M3541
Ctrough is the concentration prior to study drug administration.
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Minimum Observed Plasma Concentration (Cmin) of M3541
Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve.
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Average Plasma Concentration (Cavg) of M3541
Cavg was defined as average plasma concentration.
Measured: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Jul 2017
- Study start6 Sep 2017
- Primary completion2 Sep 2019
- Study completion27 Apr 2020
Why it stopped: The study was terminated early per sponsor decision to halt further development of M3541 due to pharmaceutical and PK/pharmacodynamics properties that precluded further clinical development.
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 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
- Model description
- Subsequent cohorts of patients treated at different dose levels.
- Masking
- None (open label)
- Enrolment
- 15 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
- NCT03225105
- Sponsor's protocol ID
- MS200770_0001
- Status last verified
- Jan 2023
- First submitted
- 19 Jul 2017
- Last updated
- 22 Nov 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Waqar SN, Robinson C, Olszanski AJ, Spira A, Hackmaster M, Lucas L, Sponton L, Jin H, Hering U, Cronier D, Grinberg M, Seithel-Keuth A, Diaz-Padilla I, Berlin J. Phase I trial of ATM inhibitor M3541 in combination with palliative radiotherapy in patients with solid tumors. Invest New Drugs. 2022 Jun;40(3):596-605. doi: 10.1007/s10637-022-01216-8. Epub 2022 Feb 12.
PubMed 35150356
Study at a glance
From the registry record, last updated by the sponsor on 22 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I, Open-label, Uncontrolled, Multicenter, Dose-escalation Study of M3541 in Combination With Palliative Radiotherapy in Subjects With Solid Tumors
- ClinicalTrials.gov ID
- NCT03225105
- Acronym / sponsor ID
- MS200770_0001
- Conditions
- Solid Tumors
- Keywords
- Solid Tumors, M3541, Palliative radiotherapy, Adenosine triphosphate-competitive inhibitor
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The study was terminated early per sponsor decision to halt further development of M3541 due to pharmaceutical and PK/pharmacodynamics properties that precluded further clinical development.
- Enrolment
- 15 participants (actual)
- Lead sponsor
- EMD Serono Research & Development Institute, Inc.Industry (pharma, biotech, devices)
- Collaborators
- Merck KGaA, Darmstadt, Germany
- Study start
- 6 Sep 2017 (actual)
- Primary completion
- 2 Sep 2019 (actual)
- Study completion
- 27 Apr 2020 (actual)
- First posted
- 21 Jul 2017 (actual)
- Results
- Posted 22 Nov 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This dose-escalation study evaluated the safety, tolerability, pharmacokinetic (PK), pharmacodynamic, and explore antitumor activity of M3541 in combination with fractionated palliative radiotherapy (RT) in participants with solid tumors with malignant lesions in the thorax, abdominal cavity, head and neck region, or extremities likely to benefit from palliative RT.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 4
- Model description
- Subsequent cohorts of patients treated at different dose levels.
| Arm | Type | Receives |
|---|---|---|
| M3541 50 mg + RT | Experimental | Drug: M3541, Radiation: Palliative Radiotherapy (RT)Participants received 50 milligrams (mg) M3541 orally once per fraction day (FD) in combination with palliative radiotherapy (RT) administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10, for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). |
| M3541 100 mg + RT | Experimental | Drug: M3541, Radiation: Palliative Radiotherapy (RT)Participants received 100 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). |
| M3541 200 mg + RT | Experimental | Drug: M3541, Radiation: Palliative Radiotherapy (RT)Participants received 200 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). |
| M3541 300 mg + RT | Experimental | Drug: M3541, Radiation: Palliative Radiotherapy (RT)Participants received 300 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Participants must have solid tumors with malignant lesions in the thorax, abdominal cavity, head and neck region, or extremities (any histology) likely to benefit from palliative radiotherapy; participants requiring palliative RT for lesions in the spine or lesions adjacent to the spinal cord are excluded from this study
- Eastern Cooperative Oncology Group performance status (ECOG PS) =< 2
- Life expectancy >= 3 months
- Adequate hematologic, hepatic, and renal function
- Agree to use highly effective contraception (that is, methods with a failure rate of less than 1 percent per year) if the participant is male or a female of childbearing potential (female partners of childbearing potential of male participants must also agree to use highly effective contraception)
Key exclusion criteria (10 listed)
- Use of other anticancer therapy within 15 days before the first dose of M3541 administration and should not be within the "at risk follow-up period" for that specific anticancer therapy. The use of any investigational agent is not allowed within 28 days before the first dose of M3541
- Residual toxicity due to previous anticancer therapy with no return to baseline or =< Grade 1 (except alopecia) according to Common Terminology Criteria for Adverse Events (CTCAE) v4.03
- Extensive prior RT on more than 30 percent of bone marrow reserves (by Investigator judgment), or prior bone marrow/stem cell transplantation within 5 years before study start
- Prior RT to the same region that would be irradiated in this study
- Participants at increased risk for radiation toxicities, such as known collagen vascular disease (example, scleroderma, Sjogren's disease, etc) or other inherited radiation hypersensitivity syndromes (example, Gorlin syndrome, Fanconi anemia, ataxia-telangiectasia, etc.)
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 |
|---|---|---|
| M3541Participants received M3541 orally once per fraction day (FD) for two consecutive calendar weeks (that is, Monday through Friday, with Saturday and Sunday as M3541 holidays). | Drug | M3541 100 mg + RT, M3541 200 mg + RT, M3541 300 mg + RT, M3541 50 mg + RT |
| Palliative Radiotherapy (RT)Participants received RT dose of 30 Gray (Gy) given in 10 fractions (3 Gy given per fraction day) administered over two consecutive calendar weeks (that is, Monday through Friday, with Saturday and Sunday as RT holidays). | Radiation | M3541 100 mg + RT, M3541 200 mg + RT, M3541 300 mg + RT, M3541 50 mg + RT |
Primary outcome
M3541 50 mg + 100 mg + 200 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs)
Time frame: Baseline up to 5 weeks (including 2 weeks of treatment and 3 weeks of follow-up period)
DLT is classified per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and defined as any of the following events occurring after first dose of study intervention and judged not to be related to underlying disease or any previous or concomitant medication. Grade (Gr) >=3 non-hematologic toxicity with exception of Nausea, vomiting and diarrhea lasting =<3 days in once per FD; Worsening of preexisting tumor pain associated with tumor lesions for which participant was irradiated in context of this study; Evidence of treatment-related hepatocellular injury for >3 days in the once per FD; Any occurrence of Hy's law; Gr 4 neutropenia lasting for >5 days, Gr 4 thrombocytopenia or Gr 4 anemia that was unexplained by underlying disease; Any toxicity related to study treatment that caused participant to interrupt treatment for not to be able to be treated within 24 hours of the scheduled treatment time.
M3541 300 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs)
Time frame: Baseline up to 4 weeks (including 2 weeks of treatment and 2 weeks of the follow-up period)
DLT is classified per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and defined as any of the following events occurring after first dose of study intervention and judged not to be related to underlying disease or any previous or concomitant medication. Grade (Gr) >=3 non-hematologic toxicity with exception of Nausea, vomiting and diarrhea lasting =<3 days in once per FD; Worsening of preexisting tumor pain associated with tumor lesions for which participant was irradiated in context of this study; Evidence of treatment-related hepatocellular injury for >3 days in the once per FD; Any occurrence of Hy's law; Gr 4 neutropenia lasting for >5 days, Gr 4 thrombocytopenia or Gr 4 anemia that was unexplained by underlying disease; Any toxicity related to study treatment that caused participant to interrupt treatment for not to be able to be treated within 24 hours of the scheduled treatment time.
25 secondary outcomes
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Grade >=3 Adverse Events (AEs), Serious TEAEs and Deaths According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 4.03 (CTCAE V4.03)
Time frame: Baseline up to 749 days
Number of Participants With Grade 3 or Higher Laboratory Abnormalities Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE)
Time frame: Baseline up to Day 44
Number of Participants With Abnormalities in Vital Signs
Time frame: Baseline up to 379 days
Number of Participants With Abnormalities in Physical Examination Reported as Adverse Events (AEs)
Time frame: Baseline up to 379 days
Number of Participants With Abnormal Change From Baseline in Electrocardiogram (ECG)
Time frame: Baseline up to 15 days
Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Time frame: Time from randomization to 964 days
Progression-Free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator
Time frame: From first dose of study drug to disease progression or death from any cause, assessed up to 964 days
Maximum Observed Plasma Concentration (Cmax) of M3541
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3541
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Time to Reach Maximum Observed Plasma Concentration (Tmax) of M3541
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Apparent Terminal Half-Life (t1/2) of M3541
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Area Under Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Sampling Time Point (AUC[0-last]) of M3541
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Dose Normalized Area Under the Concentration-Time Curve From Time Zero to the Last Quantifiable Sampling Time Point (AUC[0-last]/Dose) of M3541
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Area Under the Concentration-Time Curve From Time Zero to 6 Hour Postdose (AUC[0-6h]) of M3541
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of M3541
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Dose Normalized Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]/Dose) of M3541
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Oral Clearance (CL/F) of M3541
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Oral Clearance at Steady-State (CLss/F) of M3541
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Apparent Volume of Distribution During Terminal Phase (Vz/F) of M3541
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Apparent Volume of Distribution at Steady-State (Vss/F) of M3541
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Accumulation Ratio for Area Under Plasma Concentration-Time Curve From Time Zero to 6 Hour (Racc[AUC0-6]) of M3541
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Accumulation Ratio for Maximum Observed Plasma Concentration (Racc[Cmax])
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Pre-dose Plasma Concentration (Ctrough) of M3541
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Minimum Observed Plasma Concentration (Cmin) of M3541
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Average Plasma Concentration (Cavg) of M3541
Time frame: Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Nov 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 35150356Waqar SN, Robinson C, Olszanski AJ, Spira A, Hackmaster M, Lucas L, Sponton L, Jin H, Hering U, Cronier D, Grinberg M, Seithel-Keuth A, Diaz-Padilla I, Berlin J. Phase I trial of ATM inhibitor M3541 in combination with palliative radiotherapy in patients with solid tumors. Invest New Drugs. 2022 Jun;40(3):596-605. doi: 10.1007/s10637-022-01216-8. Epub 2022 Feb 12.
- Trial Awareness and Transparency websiteLink provided by the sponsor.
- US Medical Information website, Medical ResourcesLink provided by the sponsor.
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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
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing M3541 and Palliative Radiotherapy (RT) in people with Solid Tumors, run by EMD Serono Research & Development Institute, Inc. at 5 sites in United States.
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 6 inclusion and 10 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 22 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in United States. 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 22 Nov 2023). 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?
M3541 50 mg + 100 mg + 200 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs) (time frame: Baseline up to 5 weeks (including 2 weeks of treatment and 3 weeks of follow-up period)). The study lists 2 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 NCT03225105, 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 22 Nov 2023.