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

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.

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.

Eligibility Criteria:
Inclusion Criteria:

1. 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.
2. Histologic documentation of the original primary tumor.
3. Documented radiographic disease progression \< 12 months after the last dose of first- or second-line platinum-based chemotherapy.
4. 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.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. 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
7. Age ≥18 years.
8. Able and willing to give valid written informed consent.
9. Body weight \> 30 kg.

Exclusion Criteria:

1. 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.
2. Subjects with platinum-refractory disease, defined as disease progression while receiving first line platinum-based therapy.
3. Clinically significant persistent immune-related adverse events following prior therapy.
4. 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.
5. Subjects with clinically significant cardiovascular disease. This included:

   1. Resistant hypertension.
   2. Myocardial infarction or unstable angina within 6 months prior to Day 1 of the study.
   3. 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.
   4. Baseline ejection fraction ≤ 50% as assessed by echocardiogram or multiple-gated acquisition.
   5. New York Heart Association Class II or higher congestive heart failure.
   6. Grade 2 or higher peripheral ischemia, except for brief (\< 24 hours) episodes of ischemia managed non-surgically and without permanent deficit.
6. History of pneumonitis or interstitial lung disease.
7. 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.
8. Other malignancy within 2 years prior to Day 1 of the study, except for those treated with surgical intervention only.
9. Subjects with clinical symptoms or signs of gastrointestinal obstruction and/or who required drainage gastrostomy tube and/or parenteral hydration or nutrition.
10. Known immunodeficiency or human immunodeficiency virus, Hepatitis B or Hepatitis C positivity.
11. History of severe allergic reactions to any unknown allergens or components of the study drugs.
12. Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding disorders).
13. Prior treatment in any other interventional clinical trial within 4 weeks prior to Day 1 of the study.
14. Mental impairment that may have compromised compliance with the requirements of the study.
15. Lack of availability for immunological and clinical follow-up assessment.
16. 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.
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).
18. 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.
19. Subjects must not have donated blood while on study and for at least 90 days following the last durvalumab treatment.
20. History of allogeneic organ transplant.