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)

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