Phase 1/2 Study of Motolimod, Doxorubicin, and Durvalumab in Recurrent, Platinum-Resistant Ovarian Cancer

NCT02431559 | Completed Phase 1 Results FDA Drug

• 1 other identifier: LUD2014-001
• Study Type: interventional
• Target: 53
• Locations: 2 countries
• Sites: 5

Brief 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 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.

Conditions

Ovarian Cancer

Keywords

Ovarian Cancer; Motolimod; Immunotherapy; PD-L1; MEDI4736; Pegylated; Liposomal; Doxorubicin; PLD; TLR-8; Durvalumab

Outcome Measures

Primary Outcomes (2)

• 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.

  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).

  Up to 6 months for each subject

Secondary Outcomes (8)

• Number of Subjects With Best Overall Tumor Response by RECIST 1.1

  Up to 36.6 months

• Median PFS by RECIST 1.1 as Estimated Using the Kaplan-Meier Method

  Up to 36.6 months

• PFS-12 by RECIST 1.1 as Estimated Using the Kaplan-Meier Method

  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)

  Up to 36.6 months

• PFS-6 by irRECIST as Estimated Using the Kaplan-Meier Method

  Up to 6 months for each subject

Study Arms (4)

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.

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.

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.

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.

Drug: Durvalumab; Drug: Pegylated Liposomal Doxorubicin

Interventions

Durvalumab DRUG

Durvalumab is administered as an IV infusion over 60 ± 5 minutes.

Also known as: MEDI4736

Phase 1, Dose Level +1; Phase 1, Dose Level 0a; Phase 1, Dose Level 0b; Phase 2

Pegylated Liposomal Doxorubicin DRUG

PLD was administered as an IV infusion in accordance with local prescribing information.

Also known as: Doxil, Caelyx, Lipodox, PLD

Phase 1, Dose Level +1; Phase 1, Dose Level 0a; Phase 1, Dose Level 0b; Phase 2

Motolimod DRUG

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.

Also known as: VTX-2337

Phase 1, Dose Level +1; Phase 1, Dose Level 0a; Phase 1, Dose Level 0b

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Ludwig Institute for Cancer Research: lead
• MedImmune LLC: collaborator
• Celgene: collaborator
• Cancer Research Institute, New York City: collaborator

Study Sites (5)

Research Facitlity

Phoenix, Arizona, 85016, United States

Location

Research Facility

New York, New York, 10065, United States

Location

Research Facility

Hilliard, Ohio, 43026, United States

Location

Research Facility

Providence, Rhode Island, 02905, United States

Location

Research Facility

Lausanne, 1011, Switzerland

Location

Related Publications (2)

• 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.

  PMID: 19097774 BACKGROUND

• Bohnsack 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.

  BACKGROUND

MeSH Terms

Conditions

Ovarian Neoplasms

Interventions

durvalumab; liposomal doxorubicin; 1-dodecylpyridoxal; VTX-2337

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders

Results Point of Contact

• Title: Jonathan Skipper PhD
• Organization: Ludwig Institute for Cancer Research

jskipper@lcr.org

(212) 450-1539

Study Officials

• George Coukos, MD, PhD

  University of Lausanne Hospitals

  STUDY CHAIR

• Bradley J Monk, MD

  Arizona Oncology

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 27, 2015
• First Posted: May 1, 2015
• Study Start: December 2, 2015
• Primary Completion: December 11, 2018
• Study Completion: June 10, 2021
• Last Updated: October 10, 2022
• Results First Posted: September 23, 2019

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1); US (4)