A Study to Determine the Efficacy of the Combination of Daratumumab (DARA) Plus Durvalumab (DURVA) (D2) in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM)

MEDI4736-MM-005 (FUSION MM-005): A Phase 2, Multicenter, Single-Arm, Study to Determine the Efficacy for the Combination of Durvalumab (DURVA) Plus Daratumumab (DARA) (D2) in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM) That Have Progressed While on Current Treatment Regimen Containing Daratumumab.

This is a single-arm, multicenter, Phase 2 study to evaluate the efficacy and safety of the combination regimen of daratumumab plus durvalumab (D2). The study will consist of 2 parts; Part 1 has a 2-stage design while Part 2 consists of an expansion phase. Subjects will receive intravenous (IV) DARA at 16 mg/kg on the same dosing schedule (weekly [QW], every 2 weeks [Q2W] or every 4 weeks [Q4W] of each 28-day cycle) received on their last prior therapy containing DARA. The dosing schedule for DARA may be adjusted during the course of the study as outlined in the protocol. Subjects will also receive IV DURVA at 1500 mg on Day 2 (Cycle 1) and on Day 1 (Cycles ≥ 2) of each 28-day treatment cycle.

Indication:

This study will include subjects that have relapsed and refractory multiple myeloma (RRMM) after treatment with at least 3 prior antimyeloma therapies, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD®) or after development of double-refractoriness to a both a PI and an IMiD.

The most recent multiple myeloma (MM) treatment regimen should contain daratumumab (DARA) and subjects must have progressed on DARA while on this regimen. Stage 1 A cohort of 18 subjects will be enrolled to determine the preliminary efficacy of DARA plus DURVA. Once the 18 subjects have been enrolled, an interim analysis for futility purpose will be conducted to determine if the study can proceed to Stage 2.

Early Safety Monitoring Once 6 subjects have been enrolled and completed the first treatment cycle in Stage 1 of this study, the enrollment continuity would depend on the availability of safety data from the on-going Phase 2 study (MEDI4736-MM-003) of DARA and DURVA in previously DARA-naïve patients.

• If MEDI4736-MM-003 safety data are available and the tolerability profile of DARA plus DURVA has been determined to be adequate, then enrollment will continue as planned in Stage 1 without an early safety monitoring review of the data.
• If safety data are not available enrollment in this study will be paused for a review of the safety profile of DARA plus DURVA by a Dose Review Team (DRT), using the data from the first 6 patients.
• If ≥ 1 of the first 6 patients experiences a dose-limiting toxicity (DLT), the study will be halted for review and a change in the dosing regimen may be implemented.
• The DRT will consist of the Celgene Medical Monitor, Celgene lead Safety Physician, Celgene biostatistician, other Celgene functional area representatives, as appropriate, study specific consultants (MD/PhD), and site investigator and/or designees who have enrolled subjects to the study.
• All available safety and, if applicable, PK/(pharmacodynamic) Pd, biomarker, and preliminary efficacy data will be reviewed and can be considered in the DRT's decisions.
• A DRT meeting will be held to review all data and make decisions regarding continuity of the study.

Dose-limiting Toxicity

Dose-limiting toxicities (DLTs) may be evaluated during the DLT evaluation period for the initial 6 patients in Part 1 of the study. The DLT evaluation period will be defined as the first treatment cycle. Subjects are considered evaluable for assessment of DLT if they:

• Receive at least 1 dose of study treatments and experience a DLT OR
• Receive 1 dose of DURVA, 4 doses of DARA and complete the safety follow-up through the end of the DLT evaluation period.

Grading of DLTs will be according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03.

A DLT will be defined as below:

Hematologic DLT

1. Grade 4 neutropenia observed for greater than 5 days duration
2. Grade 3 neutropenia associated with fever (≥ 38.5 °C) of any duration.
3. Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding, or any requirement for platelets transfusion.
4. Any other Grade 4 hematologic toxicity that does not resolve to subject's pretreatment baseline level within 72 hours
5. Grade 4 anemia, unexplained by underlying disease. Non-hematologic DLT

a. Any nonhematological toxicity ≥ Grade 3 except for alopecia and nausea controlled by medical management b. Any treatment interruption greater than 2 weeks due to an AE. While the rules for adjudicating DLTs in the context of dose escalation are specified above, an AE not listed above may be defined as a DLT after consultation with the Sponsor and investigators, based on the emerging safety profile.

Stage 2 If 3 or more subjects achieved a response (PR or better) out of the 18 subjects at the end of Stage 1, an additional 32 subjects will be enrolled to evaluate the safety and efficacy of DARA plus DURVA.

Part 2: Expansion Upon completion of Part 1, if at least 9 subjects achieve a response (PR or better) out of a total of 50 subjects and it is determined to further confirm the efficacy and safety of DARA plus DURVA, an additional 70 subjects may be enrolled.

An Independent Response Adjudication Committee (IRAC) will be set up for this trial to review study data. The IRAC will determine tumor response to therapy and to confirm the time of disease progression (PD) (if disease progressed) at scheduled or unscheduled visits for each subject.

The safety and efficacy of the study will be monitored by an independent Data Monitoring Committee (DMC) who are not involved in the trial conduct. The DMC will meet up and review study data at pre specified intervals throughout the trial.

In the event that the trial is halted for early safety monitoring, evaluation of the emerging safety data from the initial 6 patients enrolled in Part 1 will be performed by the Dose Review Team (DRT).

Safety data will be monitored by the Celgene Medical Monitor and Safety Physician on an ongoing basis throughout the study. Should a significant safety issue be identified, the DMC will be convened to make a recommendation as to the future conduct of the study.

The decision to discontinue a subject, which will not be delayed or refused by the Sponsor, remains the responsibility of the treating physician. However, prior to discontinuing a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting documents for review and discussion.

The study will be conducted in compliance with the International Council on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements.

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

1. Subject received at least 3 prior anti-myeloma regimens including a proteasome inhibitor (PI) and an immunomodulatory agent or is double-refractory to a PI and an immunomodulatory agent.

   • Induction, bone marrow transplant with or without maintenance therapy is considered one regimen.
   • Refractory is defined as disease that is nonresponsive on therapy, or progresses within 60 days of last therapy. Nonresponsive disease is defined as either failure to achieve minimal response or development of progressive disease while on therapy.
   • For subjects who received more than 1 regimen containing a PI their disease must be refractory to the most recent PI containing regimen.
   • For subjects who received more than 1 regimen containing a immunomodulatory agent their disease must be refractory to the most recent immunomodulatory agent containing regimen.

2. All subjects must have failed Daratumumab (DARA) either as a single agent or in combination on last Multiple myeloma (MM) therapy. Failure is defined as disease progression(PD) on DARA either as a single agent or in combination.

3. Subject has measurable disease defined as:

   1. M-protein (serum protein electrophoresis (sPEP) or urine protein electrophoresis (uPEP): sPEP ≥ 0.5 g/dL or uPEP ≥ 200 mg/24 hours) and/or
   2. Light chain MM without measurable disease in the serum or the urine: serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio

4. Subject achieved a response (minimal response [MR] or better) to at least 1 prior treatment regimen.

5. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 2 or less.

6. Subject's toxicities resulting from previous therapy (including peripheral neuropathy) have resolved or stabilized to ≤ Grade 1.

7. Subject is at least 18 years of age the time of signing the informed consent form (ICF).

8. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.

9. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.

10. Females of childbearing potential (FCBP) must:

    a. Have 2 negative pregnancy tests as verified by the investigator prior to starting study treatment. This applies even if the subject practices true abstinence from heterosexual contact.

    i. Negative serum pregnancy test at screening ii. Negative serum or urine pregnancy test (investigator's discretion) within 72 hours prior to starting study treatment (Cycle 1, Day 1), and before beginning each subsequent cycle of treatment, and after end of study treatment.

    b. Either practice true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, effective contraception without interruption (eg, oral, inject able, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; true abstinence; or vasectomized partner), 28 days prior to starting study treatment, during the study therapy (including dose interruptions), and for at least 90 days after discontinuation of study treatment.

    c. Agree to abstain from breastfeeding during study participation and for at least 90 days after the last dose of Daratumumab (DARA) or Durvalumab (DURVA), whichever is later.

    d. Refrain from egg cell donation for at least 90 days after the final dose of DURVA or DARA, whichever is later.

11. Male subjects must:

    1. Either practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 90 days following study treatment discontinuation, even if he has undergone a successful vasectomy.
    2. Refrain from sperm donation for at least 90 days after the final dose of DURVA or DARA, whichever is later.

Exclusion Criteria:

The presence of any of the following will exclude a subject from enrollment:

1. Subject has had prior exposure to anti-CTLA-4, anti-PD-1 (Programmed cell death-1), anti-PD-L1 (Programmed death-ligand 1) Monoclonal antibody (mAbs), or cancer vaccines

2. Subject has received autologous stem cell transplantation (ASCT) within 12 weeks before the date of randomization.

3. History of organ or allogeneic stem cell transplantation

4. Subject received any of the following within the last 14 days of initiating study treatment:

   1. Plasmapheresis
   2. Major surgery (as defined by the investigator)
   3. Radiation therapy other than local therapy for myeloma associated bone lesions
   4. Use of any systemic anti-myeloma drug therapy (except for DARA either alone or in combination with other agents given with it)

5. Subject received prior treatment with a monoclonal antibody within 5 half-lives of initiating study treatment, other than DARA.

6. Subject is receiving concurrent chemotherapy or biologic or hormonal therapy for cancer treatment. Note: Concurrent use of hormones for noncancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable.

7. Subject has any of the following laboratory abnormalities:

   1. Absolute neutrophil count (ANC) < 1,000/µL
   2. Platelet count: < 75,000/µL (it is not permissible to transfuse a subject to reach this level)
   3. Hemoglobin < 8 g/dL (< 4.9 mmol/L) (it is not permissible to transfuse a subject to reach this level)
   4. Creatinine clearance (CrCl) < 45 mL/min (calculated using the Cockcroft-Gault formula or directly calculated from the 24-hour urine collection method)
   5. Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L)
   6. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × upper limit of normal (ULN)
   7. Serum total bilirubin > 1.5 × upper limit of normal (ULN) or > 3.0 mg/dL for subjects with documented Gilbert's syndrome

8. Subject has clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS MM

9. Subject has known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal. Note that forced expiratory testing (FEV1) is required for subjects suspected of having COPD and subjects must be excluded if FEV1 is < 50% of predicted normal.

10. Subject has known moderate or severe persistent asthma within the past 2 years or uncontrolled asthma of any classification. Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.

11. Subject has plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or amyloidosis

12. Subject has nonsecretory MM

13. Subject has known allergy or hypersensitivity to study drug formulations

14. Subject has active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis, Crohn's disease], diverticulitis, celiac disease, irritable bowel disease, or other serious gastrointestinal chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener syndrome; myasthenia gravis; Graves' disease; rheumatoid arthritis, hypophysitis, uveitis, etc) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:

    1. Subjects with vitiligo or alopecia.
    2. Subjects with hypothyroidism (eg, following Hashimoto's disease) stable on hormone replacement.
    3. Psoriasis not requiring systemic treatment.

15. Subject has history of primary immunodeficiency

16. Subject is positive for human immunodeficiency virus (HIV-1), chronic or active hepatitis B or active hepatitis A or C.

17. Subject has received live, attenuated vaccine within 30 days prior to the first dose of DURVA (NOTE: Subjects, if enrolled, should not receive live vaccine during the study and through 30 days after the last dose of DURVA)

18. Subject is currently using or has used immunosuppressive medication within 14 days prior to the first study dose of study treatment. The following are exceptions to this criterion:

    1. Intranasal, topical, inhaled, or local steroid injections (eg, intra-articular injection).
    2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent.
    3. Steroids as premedication for hypersensitivity reactions (eg, infusion-related reactions, computed tomography [CT] scan premedication).

19. Subject has any one of the following:

    1. Clinically significant abnormal Electrocardiogram (ECG) finding at screening
    2. Congestive heart failure (New York Heart Association Class III or IV)
    3. Myocardial infarction within 12 months prior to starting study treatment
    4. Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris

20. Subject has prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years with the exception of the following noninvasive malignancies:

    1. Basal cell carcinoma of the skin
    2. Squamous cell carcinoma of the skin
    3. Carcinoma in situ of the cervix
    4. Carcinoma in situ of the breast
    5. Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative

21. Subject is a female who is pregnant, nursing, or breastfeeding, or who intends to become pregnant during the participation in the study.

22. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study

23. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study

24. Subject has any condition that confounds the ability to interpret data from the study