Ovarian CancerPhase 1/2NCT02431559
Phase 1/2 Study of Motolimod, Doxorubicin, and Durvalumab in Recurrent, Platinum-Resistant Ovarian Cancer
A Phase 1/2 study testing Durvalumab, Pegylated Liposomal Doxorubicin and Motolimod in people with Ovarian Cancer, run by Ludwig Institute for Cancer Research at 5 sites in 2 countries.
Trial summary
This is an ongoing Phase 1/2, open-label, multicenter, non-randomized study of MEDI4736 (durvalumab) in subjects with recurrent, platinum-resistant ovarian cancer who are scheduled to receive pegylated liposomal doxorubicin (PLD).The primary objective of Phase 1 is to determine the maximum tolerated dose (MTD) and… Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Ovarian Cancer
- What is being tested?
- Durvalumab, Pegylated Liposomal Doxorubicin and Motolimod
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 53 participants
- Where
- 5 sitesin 2 countries
- Study dates
- 2 Dec 2015to 10 Jun 2021
- Phase
- Phase 1/2
- 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
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Subjects must have had recurrent or persistent platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with measurable disease (as defined by the Response Evaluation Criteria in Solid Tumors [RECIST] 1.1.) after first or second line platinum-based chemotherapy, for which treatment with PLD was indicated. Platinum-based therapy was defined as treatment with carboplatin, cisplatin or another organoplatinum compound. Platinum-resistant was defined as having a platinum-free interval of < 12 months after first- or second-line platinum-based chemotherapy, or having disease progression while receiving second-line platinum-based chemotherapy.
- Subjects were allowed to have received, but were not required to have received:
- one additional cytotoxic regimen and/or poly adenosine diphosphate-ribose polymerase inhibitor for management of recurrent or persistent disease.
- biologic therapy (e.g., bevacizumab) as part of their primary treatment regimen or part of their treatment for management of recurrent or persistent disease.
- Histologic documentation of the original primary tumor.
- Documented radiographic disease progression < 12 months after the last dose of first- or second-line platinum-based chemotherapy.
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- Subjects in Phase 2 must have had disease amenable to biopsy and must have been willing to undergo pre- and post-treatment tumor biopsies. Optional for Phase 1.
- Note: archival tissue was requested for all subjects preferably from primary tumor site prior to cancer treatment; however, archival tissue was not a requirement for study entry.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Laboratory parameters for vital functions should have been in the normal range. Laboratory abnormalities that were not clinically significant were generally permitted, except for the following laboratory parameters, which must have been within the ranges specified, regardless of clinical significance:
- Hemoglobin: ≥ 9 g/dL
- Neutrophil count: ≥ 1.5 x 10^9/L
- Platelet count: ≥ 100,000/mm^3
- Serum creatinine: ≤ 1.5 x institutional upper limit of normal (ULN), or creatinine clearance ≥ 50 mL/min (by Cockcroft-Gault formula)
- Serum bilirubin: ≤ 1.2 mg/dL
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT): ≤ 2.5 x ULN
- Alkaline phosphatase: ≤ 2.5 x ULN
- Age ≥18 years.
- Able and willing to give valid written informed consent.
- Body weight > 30 kg.
Who cannot join
- Prior exposure to doxorubicin, PLD or any other anthracycline, motolimod and other toll-like receptor agonists, durvalumab or checkpoint inhibitors, such as anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1)/anti-programmed cell death ligand-1 (PD-L1) antibodies.
- Subjects with platinum-refractory disease, defined as disease progression while receiving first line platinum-based therapy.
- Clinically significant persistent immune-related adverse events following prior therapy.
- Subjects with history or evidence upon physical examination of central nervous system disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or, within 6 months prior to Day 1 of this study, history of cerebrovascular accident (stroke), transient ischemic attack or subarachnoid hemorrhage.
- Subjects with clinically significant cardiovascular disease. This included:
- Resistant hypertension.
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- Myocardial infarction or unstable angina within 6 months prior to Day 1 of the study.
- History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) or cardiac arrhythmias requiring anti-arrhythmic medications, except for atrial fibrillation that is well controlled with anti-arrhythmic medication.
- Baseline ejection fraction ≤ 50% as assessed by echocardiogram or multiple-gated acquisition.
- New York Heart Association Class II or higher congestive heart failure.
- Grade 2 or higher peripheral ischemia, except for brief (< 24 hours) episodes of ischemia managed non-surgically and without permanent deficit.
- History of pneumonitis or interstitial lung disease.
- Active, suspected or prior documented autoimmune disease (including inflammatory bowel disease, celiac disease, Wegner's granulomatosis, active Hashimoto's thyroiditis, rheumatoid arthritis, lupus, scleroderma and its variants, multiple sclerosis, myasthenia gravis). Vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger were permitted.
- Other malignancy within 2 years prior to Day 1 of the study, except for those treated with surgical intervention only.
- Subjects with clinical symptoms or signs of gastrointestinal obstruction and/or who required drainage gastrostomy tube and/or parenteral hydration or nutrition.
- Known immunodeficiency or human immunodeficiency virus, Hepatitis B or Hepatitis C positivity.
- History of severe allergic reactions to any unknown allergens or components of the study drugs.
- Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding disorders).
- Prior treatment in any other interventional clinical trial within 4 weeks prior to Day 1 of the study.
- Mental impairment that may have compromised compliance with the requirements of the study.
- Lack of availability for immunological and clinical follow-up assessment.
- Women of childbearing potential who were found to be pregnant as evidenced by positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) or nursing. NOTE: Pregnancy tests were not required for subjects who were not of childbearing potential as defined in #17.
- Female subjects of childbearing potential who were sexually active with a nonsterilized male partner must have used at least one highly effective method of contraception from screening, and must have agreed to continue using such precautions for 90 days after the final dose of investigational product (durvalumab). Male partners of a female subject must have used male condom plus spermicide throughout this period (from screening and for 90 days after subject's receipt of the final dose of investigational product). Cessation of birth control after this point should have been discussed with a responsible physician. Not engaging in sexual activity for the total duration of the trial and the drug washout period was an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method were not acceptable methods of birth control.
- Female subjects should have refrained from breastfeeding throughout the period described above.
- NOTE: For the standard of care, PLD (Doxil®, Caelyx®), the package insert advises females of reproductive potential to use effective contraception during and for 6 months after last treatment with the drug. Therefore, all subjects of childbearing potential on this study should have continued contraception use for 6 months after the last PLD administration.
- Females of childbearing potential were defined as those who were not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.
- Females were considered post-menopausal if they had been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements applied:
- Females < 50 years of age were considered post-menopausal if they had been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they had luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
- Females ≥ 50 years of age were considered post-menopausal if they had been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
- A highly effective method of contraception was defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. Note that some contraception methods were not considered highly effective (e.g., male or female condom with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral contraceptive pills).
- Any condition that, in the clinical judgment of the treating physician, was likely to prevent the subject from complying with any aspect of the protocol or that may have put the subject at unacceptable risk.
- Subjects must not have donated blood while on study and for at least 90 days following the last durvalumab treatment.
- History of allogeneic organ transplant.
Trial locations and contacts
5 sites in 2 countries.
5 sites in 2 countries
United States4 sites
Research Facility
Hilliard, Ohio, 43026
Research Facility
New York, New York, 10065
Research Facitlity
Phoenix, Arizona, 85016
Research Facility
Providence, Rhode Island, 02905
About this study
Official title: Phase 1/2 Study of Chemoimmunotherapy With Toll-like Receptor 8 Agonist Motolimod (VTX-2337) + Anti-PD-L1 Antibody MEDI4736 in Subjects With Recurrent, Platinum-Resistant Ovarian Cancer for Whom Pegylated Liposomal Doxorubicin is Indicated
This is an ongoing Phase 1/2, open-label, multicenter, non-randomized study of MEDI4736 (durvalumab) in subjects with recurrent, platinum-resistant ovarian cancer who are scheduled to receive pegylated liposomal doxorubicin (PLD).The primary objective of Phase 1 is to determine the maximum tolerated dose (MTD) and safety profile, with a secondary objective to evaluate the clinical efficacy as measured by progression-free survival (PFS) rate at 6 months (PFS-6). The primary objective of Phase 2 is the evaluation of clinical efficacy as measured by PFS-6. For both phases, secondary objectives include evaluation of clinical efficacy as measured by overall response rate, PFS, and overall survival (OS), safety and tolerability, and immunological responses.
Read the detailed description
In the completed Phase 1 part of the study, eligible subjects were enrolled using a standard 3 + 3 design to identify the MTD (i.e., the highest dose for which fewer than 33% of subjects experienced a dose-limiting toxicity [DLT]) of combination study treatment. All dose levels in Phase 1 included intravenous (IV) PLD (40 mg/m^2) in combination with subcutaneous (SC) motolimod (2.0 or 2.5 mg/m^2), using a starting dose of 3 mg/kg of IV durvalumab given every 2 weeks (Q2W) or 1500 mg of IV durvalumab given every 4 weeks (Q4W). All subjects in a cohort had their safety data reviewed for DLTs before proceeding with cohort expansion.
After completion of Phase 1 and determination of the durvalumab MTD to be carried forward into Phase 2, availability of data from another study (NCT01666444) indicated a lack of additive efficacy when motolimod was administered with PLD compared with PLD alone. As such, motolimod dosing was discontinued for all subjects in Study LUD2014-001 after completion of Phase 1. Subjects who had initiated treatment may have continued to receive PLD and durvalumab at their respective dose levels but must have discontinued motolimod. Thus, in the fully-accrued but ongoing Phase 2 portion of the study, subjects received only PLD (40 mg/m^2) in combination with durvalumab at the MTD determined in Phase 1 (1500 mg every 4 weeks [Q4W]).
Subjects are treated in the Core Study for an initial 12 cycles (28 days each) according to their treatment assignment. Durvalumab treatment may be extended for subjects who complete the Core Study with stable disease or better and upon agreement among the subject, Sponsor, and Investigator; extended durvalumab monotherapy may continue until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or other discontinuation criteria are met.
Subjects are followed on study for 90 days after the last drug administration and off study every 3 months for 3 years from the date of the first dose of study treatment.
- Conditions
- Ovarian Cancer
- Being tested
- Durvalumab, Pegylated Liposomal Doxorubicin, Motolimod
- Keywords
- Ovarian Cancer, Motolimod, Immunotherapy, PD-L1, MEDI4736, Pegylated, Liposomal, Doxorubicin, PLD, TLR-8, Durvalumab
- Medical subject headings
- Ovarian Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DurvalumabDrug
Also called MEDI4736
Durvalumab is administered as an IV infusion over 60 ± 5 minutes.
Pegylated Liposomal DoxorubicinDrug
Also called Doxil, Caelyx, Lipodox, PLD
PLD was administered as an IV infusion in accordance with local prescribing information.
MotolimodDrug
Also called VTX-2337
Motolimod was administered as an SC injection. Within 30 minutes prior to each dose of motolimod, subjects were administered 650-1000 mg acetaminophen by mouth to help mitigate potential adverse events (AEs) commonly associated with the administration of motolimod (e.g., fever, myalgia). On days with concurrent motolimod and durvalumab dosing, motolimod administration occurred 30-60 minutes after the end of the durvalumab infusion. After completion of Phase 1, a protocol amendment was implemented to remove motolimod dosing from the study.
| Study group | Role | What they receive |
|---|---|---|
| Phase 1, Dose Level 0a | Experimental | Subjects received PLD (40 mg/m^2 IV on Day 1 of every cycle) + durvalumab (3 mg/kg Q2W [equivalent to 450 mg Q4W] IV on Days 3 and 17 of every cycle) for up to 12 continuous 28-day cycles (Core Study), with extended durvalumab monotherapy permitted for subjects tolerating and benefiting from treatment. Prior to removal of motolimod from the study, subjects received motolimod (2.5 mg/m^2 SC) on Days 3, 10, and 17 of Cycles 1-3 and Days 3 and 17 of Cycles 4-12. Receives: Drug: Durvalumab; Drug: Pegylated Liposomal Doxorubicin; Drug: Motolimod |
| Phase 1, Dose Level 0b | Experimental | Subjects received PLD (40 mg/m^2 IV on Day 1 of every cycle) + durvalumab (1500 mg Q4W IV on Day 3 of every cycle) for up to 12 continuous 28-day cycles (Core Study), with extended durvalumab monotherapy permitted for subjects tolerating and benefiting from treatment. Prior to removal of motolimod from the study, subjects received motolimod (2.0 mg/m^2 SC) on Days 3, 10, and 17 of Cycles 1-3 and Day 3 of Cycles 4-12. Receives: Drug: Durvalumab; Drug: Pegylated Liposomal Doxorubicin; Drug: Motolimod |
| Phase 1, Dose Level +1 | Experimental | Subjects received PLD (40 mg/m^2 IV on Day 1 of every cycle) + durvalumab (1500 mg Q4W IV on Day 3 of every cycle) for up to 12 continuous 28-day cycles (Core Study), with extended durvalumab monotherapy permitted for subjects tolerating and benefiting from treatment. Prior to removal of motolimod from the study, subjects received motolimod (2.5 mg/m^2 SC) on Days 3, 10, and 17 of Cycles 1-3 and Day 3 of Cycles 4-12. Receives: Drug: Durvalumab; Drug: Pegylated Liposomal Doxorubicin; Drug: Motolimod |
| Phase 2 | Experimental | Subjects received the MTD determined in Phase 1 (Dose Level +1), comprising PLD (40 mg/m^2 IV on Day 1 of every cycle) + durvalumab (1500 mg Q4W IV on Day 3 of every cycle) for up to 12 continuous 28-day cycles (Core Study), with extended durvalumab monotherapy permitted for subjects tolerating and benefiting from treatment. Receives: Drug: Durvalumab; Drug: Pegylated Liposomal Doxorubicin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Subjects With Treatment-emergent Adverse Events (TEAEs)
The primary endpoint in Phase 1 and a secondary endpoint in Phase 2 is the safety/tolerability of study treatment. Toxicity is graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Adverse events (AEs) are reported based on clinical laboratory tests, vital signs, physical examinations, and any other medically indicated assessments, including subject interviews, from the time informed consent is signed through 90 days after the last dose of study treatment. Treatment-emergent AEs are those that occurred or worsened after administration of the first dose of study treatment.
Measured: Up to 3.05 years
Progression-free Survival Rate at 6 Months (PFS-6) by the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Estimated Using the Kaplan-Meier Method
PFS-6 according to RECIST 1.1 is the primary endpoint in Phase 2 and a secondary endpoint in Phase 1, where PFS is measured from the date of the first dose of study treatment to the date of earliest disease progression or to the date of death, if disease progression does not occur. Per RECIST 1.1, progressive disease (PD) is defined as a ≥ 20% increase in the sum of the longest diameter of target lesions (Eisenhauer et al 2009).
Measured: Up to 6 months for each subject
Secondary outcomes (8)
Number of Subjects With Best Overall Tumor Response by RECIST 1.1
Tumor responses were evaluated using appropriate imaging and categorized according to RECIST 1.1 at Screening (up to 14 days before the first dose of study treatment), every 3 cycles during study treatment, and during on-study follow-up approximately 3 months after the last disease assessment. Per RECIST 1.1, target lesions are categorized as follows: complete response (CR): disappearance of all target lesions; partial response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; PD: ≥ 20% increase in the sum of the longest diameter of target lesions; stable disease (SD): small changes that do not meet above criteria (Eisenhauer et al 2009).
Measured: Up to 36.6 months
Median PFS by RECIST 1.1 as Estimated Using the Kaplan-Meier Method
PFS is measured from the date of the first dose of study treatment to the date of earliest disease progression according to RECIST 1.1 or to the date of death, if disease progression does not occur. Per RECIST 1.1, PD is defined as a ≥ 20% increase in the sum of the longest diameter of target lesions (Eisenhauer et al 2009).
Measured: Up to 36.6 months
PFS-12 by RECIST 1.1 as Estimated Using the Kaplan-Meier Method
PFS is measured from the date of the first dose of study treatment to the date of earliest disease progression according to RECIST 1.1 or to the date of death, if disease progression does not occur. Per RECIST 1.1, PD is defined as a ≥ 20% increase in the sum of the longest diameter of target lesions (Eisenhauer et al 2009).
Measured: Up to 12 months for each subject
Number of Subjects With Best Overall Tumor Response by the Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)
Tumor responses were evaluated using appropriate imaging and categorized according to irRECIST at Screening (up to 14 days before the first dose of study treatment), every 3 cycles during study treatment, and during on-study follow-up approximately 3 months after the last disease assessment. Per irRECIST, measurable lesions are categorized as follows: irCR: Complete disappearance of all target lesions; irPR: ≥ 30% decrease from baseline in the total measurable tumor burden (TMTB); irPD: ≥ 20% increase from nadir in TMTB; irSD: not meeting above criteria (Bohnsack et al 2014).
Measured: Up to 36.6 months
PFS-6 by irRECIST as Estimated Using the Kaplan-Meier Method
PFS is measured from the date of the first dose of study treatment to the date of earliest disease progression according to irRECIST or to the date of death, if disease progression does not occur. Per irRECIST, irPD is defined as a ≥ 20% increase from nadir in the TMTB (Bohnsack et al 2014).
Measured: Up to 6 months for each subject
PFS-12 by irRECIST as Estimated Using the Kaplan-Meier Method
PFS is measured from the date of the first dose of study treatment to the date of earliest disease progression according to irRECIST or to the date of death, if disease progression does not occur. Per irRECIST, irPD is defined as a ≥ 20% increase from nadir in the TMTB (Bohnsack et al 2014).
Measured: Up to 12 months for each subject
Median PFS by irRECIST as Estimated Using the Kaplan-Meier Method
PFS is measured from the date of the first dose of study treatment to the date of earliest disease progression according to irRECIST or to the date of death, if disease progression does not occur. Per irRECIST, irPD is defined as a ≥ 20% increase from nadir in the TMTB (Bohnsack et al 2014).
Measured: Up to 36.6 months
Median Overall Survival (OS) as Estimated Using the Kaplan-Meier Method
After completion of treatment, all subjects are followed for survival every 3 months for up to 3 years following initiation of study treatment or or for subjects continuing treatment, completion of study treatment whichever was longer. OS is measured from the date of the first dose of study treatment to the date of death or last follow-up. Subjects lost to follow-up are censored on the date when they were last known to be alive.
Measured: Up to 36.6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 May 2015 (estimated)
- Study start2 Dec 2015
- Primary completion11 Dec 2018
- Study completion10 Jun 2021
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 (2)Papers the sponsor has linked to this study.
- Other trials for Ovarian CancerStudies of the same condition, open and under way.
- 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 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 53 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ludwig Institute for Cancer Research
- Sponsor type
- University, hospital or other
- Collaborators
- MedImmune LLC, Celgene, Cancer Research Institute, New York City
- Responsible party
- Sponsor
- Investigators
- George Coukos, MD, PhD, Study chair, University of Lausanne HospitalsBradley J Monk, MD, Study chair, Arizona Oncology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02431559
- Sponsor's protocol ID
- LUD2014-001
- Status last verified
- Oct 2022
- First submitted
- 27 Apr 2015
- Last updated
- 10 Oct 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
PubMed 19097774Bohnsack O, Hoos A, Ludajic K. Adaptation of the immune related response criteria: irRECIST. Ann Oncol. 2014 Sep;25(suppl 4):iv361-iv72 [Abstract 4958]. doi: 10.1093/annonc/mdu342.23.
Study at a glance
From the registry record, last updated by the sponsor on 10 Oct 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 1/2 Study of Chemoimmunotherapy With Toll-like Receptor 8 Agonist Motolimod (VTX-2337) + Anti-PD-L1 Antibody MEDI4736 in Subjects With Recurrent, Platinum-Resistant Ovarian Cancer for Whom Pegylated Liposomal Doxorubicin is Indicated
- ClinicalTrials.gov ID
- NCT02431559
- Acronym / sponsor ID
- LUD2014-001
- Conditions
- Ovarian Cancer
- Keywords
- Ovarian Cancer, Motolimod, Immunotherapy, PD-L1, MEDI4736, Pegylated, Liposomal, Doxorubicin
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 53 participants (actual)
- Lead sponsor
- Ludwig Institute for Cancer ResearchUniversity, hospital or other
- Collaborators
- MedImmune LLC, Celgene, Cancer Research Institute, New York City
- Study start
- 2 Dec 2015 (actual)
- Primary completion
- 11 Dec 2018 (actual)
- Study completion
- 10 Jun 2021 (actual)
- First posted
- 1 May 2015 (estimated)
- Results
- Posted 23 Sep 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is an ongoing Phase 1/2, open-label, multicenter, non-randomized study of MEDI4736 (durvalumab) in subjects with recurrent, platinum-resistant ovarian cancer who are scheduled to receive pegylated liposomal doxorubicin (PLD).The primary objective of Phase 1 is to determine the maximum tolerated dose (MTD) and safety profile, with a secondary objective to evaluate the clinical efficacy as measured by progression-free survival (PFS) rate at 6 months (PFS-6). The primary objective of Phase 2 is the evaluation of clinical efficacy as measured by PFS-6. For both phases, secondary objectives include evaluation of clinical efficacy as measured by overall response rate, PFS, and overall survival (OS), safety and tolerability, and immunological responses.
Detailed description
In the completed Phase 1 part of the study, eligible subjects were enrolled using a standard 3 + 3 design to identify the MTD (i.e., the highest dose for which fewer than 33% of subjects experienced a dose-limiting toxicity [DLT]) of combination study treatment. All dose levels in Phase 1 included intravenous (IV) PLD (40 mg/m^2) in combination with subcutaneous (SC) motolimod (2.0 or 2.5 mg/m^2), using a starting dose of 3 mg/kg of IV durvalumab given every 2 weeks (Q2W) or 1500 mg of IV durvalumab given every 4 weeks (Q4W). All subjects in a cohort had their safety data reviewed for DLTs before proceeding with cohort expansion.
After completion of Phase 1 and determination of the durvalumab MTD to be carried forward into Phase 2, availability of data from another study (NCT01666444) indicated a lack of additive efficacy when motolimod was administered with PLD compared with PLD alone. As such, motolimod dosing was discontinued for all subjects in Study LUD2014-001 after completion of Phase 1. Subjects who had initiated treatment may have continued to receive PLD and durvalumab at their respective dose levels but must have discontinued motolimod. Thus, in the fully-accrued but ongoing Phase 2 portion of the study, subjects received only PLD (40 mg/m^2) in combination with durvalumab at the MTD determined in Phase 1 (1500 mg every 4 weeks [Q4W]).
Subjects are treated in the Core Study for an initial 12 cycles (28 days each) according to their treatment assignment. Durvalumab treatment may be extended for subjects who complete the Core Study with stable disease or better and upon agreement among the subject, Sponsor, and Investigator; extended durvalumab monotherapy may continue until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or other discontinuation criteria are met.
Subjects are followed on study for 90 days after the last drug administration and off study every 3 months for 3 years from the date of the first dose of study treatment.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Phase 1, Dose Level 0a | Experimental | Drug: Durvalumab, Drug: Pegylated Liposomal Doxorubicin, Drug: MotolimodSubjects received PLD (40 mg/m^2 IV on Day 1 of every cycle) + durvalumab (3 mg/kg Q2W [equivalent to 450 mg Q4W] IV on Days 3 and 17 of every cycle) for up to 12 continuous 28-day cycles (Core Study), with extended durvalumab monotherapy permitted for subjects tolerating and benefiting from treatment. Prior to removal of motolimod from the study, subjects received motolimod (2.5 mg/m^2 SC) on Days 3, 10, and 17 of Cycles 1-3 and Days 3 and 17 of Cycles 4-12. |
| Phase 1, Dose Level 0b | Experimental | Drug: Durvalumab, Drug: Pegylated Liposomal Doxorubicin, Drug: MotolimodSubjects received PLD (40 mg/m^2 IV on Day 1 of every cycle) + durvalumab (1500 mg Q4W IV on Day 3 of every cycle) for up to 12 continuous 28-day cycles (Core Study), with extended durvalumab monotherapy permitted for subjects tolerating and benefiting from treatment. Prior to removal of motolimod from the study, subjects received motolimod (2.0 mg/m^2 SC) on Days 3, 10, and 17 of Cycles 1-3 and Day 3 of Cycles 4-12. |
| Phase 1, Dose Level +1 | Experimental | Drug: Durvalumab, Drug: Pegylated Liposomal Doxorubicin, Drug: MotolimodSubjects received PLD (40 mg/m^2 IV on Day 1 of every cycle) + durvalumab (1500 mg Q4W IV on Day 3 of every cycle) for up to 12 continuous 28-day cycles (Core Study), with extended durvalumab monotherapy permitted for subjects tolerating and benefiting from treatment. Prior to removal of motolimod from the study, subjects received motolimod (2.5 mg/m^2 SC) on Days 3, 10, and 17 of Cycles 1-3 and Day 3 of Cycles 4-12. |
| Phase 2 | Experimental | Drug: Durvalumab, Drug: Pegylated Liposomal DoxorubicinSubjects received the MTD determined in Phase 1 (Dose Level +1), comprising PLD (40 mg/m^2 IV on Day 1 of every cycle) + durvalumab (1500 mg Q4W IV on Day 3 of every cycle) for up to 12 continuous 28-day cycles (Core Study), with extended durvalumab monotherapy permitted for subjects tolerating and benefiting from treatment. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- Subjects must have had recurrent or persistent platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with measurable disease (as defined by the Response Evaluation Criteria in Solid Tumors [RECIST] 1.1.) after first or second line platinum-based chemotherapy, for which treatment with PLD was indicated. Platinum-based therapy was defined as treatment with carboplatin, cisplatin or another organoplatinum compound. Platinum-resistant was defined as having a platinum-free interval of < 12 months after first- or second-line platinum-based chemotherapy, or having disease progression while receiving second-line platinum-based chemotherapy.
- Histologic documentation of the original primary tumor.
- Documented radiographic disease progression < 12 months after the last dose of first- or second-line platinum-based chemotherapy.
- Subjects in Phase 2 must have had disease amenable to biopsy and must have been willing to undergo pre- and post-treatment tumor biopsies. Optional for Phase 1.
- Note: archival tissue was requested for all subjects preferably from primary tumor site prior to cancer treatment; however, archival tissue was not a requirement for study entry.
Key exclusion criteria (33 listed)
- Prior exposure to doxorubicin, PLD or any other anthracycline, motolimod and other toll-like receptor agonists, durvalumab or checkpoint inhibitors, such as anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1)/anti-programmed cell death ligand-1 (PD-L1) antibodies.
- Subjects with platinum-refractory disease, defined as disease progression while receiving first line platinum-based therapy.
- Clinically significant persistent immune-related adverse events following prior therapy.
- Subjects with history or evidence upon physical examination of central nervous system disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or, within 6 months prior to Day 1 of this study, history of cerebrovascular accident (stroke), transient ischemic attack or subarachnoid hemorrhage.
- Subjects with clinically significant cardiovascular disease. This included:
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 |
|---|---|---|
| DurvalumabAlso: MEDI4736Durvalumab is administered as an IV infusion over 60 ± 5 minutes. | Drug | Phase 1, Dose Level +1, Phase 1, Dose Level 0a, Phase 1, Dose Level 0b, Phase 2 |
| Pegylated Liposomal DoxorubicinAlso: Doxil, Caelyx, Lipodox, PLDPLD was administered as an IV infusion in accordance with local prescribing information. | Drug | Phase 1, Dose Level +1, Phase 1, Dose Level 0a, Phase 1, Dose Level 0b, Phase 2 |
| MotolimodAlso: VTX-2337Motolimod was administered as an SC injection. Within 30 minutes prior to each dose of motolimod, subjects were administered 650-1000 mg acetaminophen by mouth to help mitigate potential adverse events (AEs) commonly associated with the administration of motolimod (e.g., fever, myalgia). On days with concurrent motolimod and durvalumab dosing, motolimod administration occurred 30-60 minutes after the end of the durvalumab infusion. After completion of Phase 1, a protocol amendment was implemented to remove motolimod dosing from the study. | Drug | Phase 1, Dose Level +1, Phase 1, Dose Level 0a, Phase 1, Dose Level 0b |
Primary outcome
Number of Subjects With Treatment-emergent Adverse Events (TEAEs)
Time frame: Up to 3.05 years
The primary endpoint in Phase 1 and a secondary endpoint in Phase 2 is the safety/tolerability of study treatment. Toxicity is graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Adverse events (AEs) are reported based on clinical laboratory tests, vital signs, physical examinations, and any other medically indicated assessments, including subject interviews, from the time informed consent is signed through 90 days after the last dose of study treatment. Treatment-emergent AEs are those that occurred or worsened after administration of the first dose of study treatment.
Progression-free Survival Rate at 6 Months (PFS-6) by the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Estimated Using the Kaplan-Meier Method
Time frame: Up to 6 months for each subject
PFS-6 according to RECIST 1.1 is the primary endpoint in Phase 2 and a secondary endpoint in Phase 1, where PFS is measured from the date of the first dose of study treatment to the date of earliest disease progression or to the date of death, if disease progression does not occur. Per RECIST 1.1, progressive disease (PD) is defined as a ≥ 20% increase in the sum of the longest diameter of target lesions (Eisenhauer et al 2009).
8 secondary outcomes
Number of Subjects With Best Overall Tumor Response by RECIST 1.1
Time frame: Up to 36.6 months
Median PFS by RECIST 1.1 as Estimated Using the Kaplan-Meier Method
Time frame: Up to 36.6 months
PFS-12 by RECIST 1.1 as Estimated Using the Kaplan-Meier Method
Time frame: Up to 12 months for each subject
Number of Subjects With Best Overall Tumor Response by the Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)
Time frame: Up to 36.6 months
PFS-6 by irRECIST as Estimated Using the Kaplan-Meier Method
Time frame: Up to 6 months for each subject
PFS-12 by irRECIST as Estimated Using the Kaplan-Meier Method
Time frame: Up to 12 months for each subject
Median PFS by irRECIST as Estimated Using the Kaplan-Meier Method
Time frame: Up to 36.6 months
Median Overall Survival (OS) as Estimated Using the Kaplan-Meier Method
Time frame: Up to 36.6 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Oct 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 19097774Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
- BackgroundBohnsack O, Hoos A, Ludajic K. Adaptation of the immune related response criteria: irRECIST. Ann Oncol. 2014 Sep;25(suppl 4):iv361-iv72 [Abstract 4958]. doi: 10.1093/annonc/mdu342.23.
- Individual participant dataSharing planned: No
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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.
George Coukos, MD, PhD study chair
University of Lausanne Hospitals
Bradley J Monk, MD study chair
Arizona Oncology
5 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Durvalumab, Pegylated Liposomal Doxorubicin and Motolimod in people with Ovarian Cancer, run by Ludwig Institute for Cancer Research at 5 sites in 2 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 20 inclusion and 33 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: finished, as of the sponsor's last update on 10 Oct 2022. 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, Switzerland. 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 combined 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.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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 23 Sep 2019). 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?
Number of Subjects With Treatment-emergent Adverse Events (TEAEs) (time frame: Up to 3.05 years). 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 NCT02431559, which also lists 2 linked publications.
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 10 Oct 2022.