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Title A Phase 1 Study to Evaluate the Safety and Tolerability of MEDI4736 as Monotherapy or in Combination with Tremelimumab with or without Azacitidine in Subjects with Myelodysplastic Syndrome after Treatment with Hypomethylating Agents

IRB MEDI1917

CC 17-514

Hospital Main Campus

Phase Phase 1

Disease Myelodisplastic Syndrome (MDS)

Drug Durvalumab

Description

Primary Objective

• The primary objective is to determine the recommended dose of MEDI4736 monotherapy and MEDI4736 in combination with tremelimumab with or without azacitidine; and assess the safety and tolerability of MEDI4736 monotherapy and MEDI4736 in combination with azacitidine in subjects with low, intermediate-1, intermediate-2 or high risk MDS who have progressed during MEDI4736 monotherapy, and MEDI4736 in combination with tremelimumab with or without azacitidine in subjects with intermediate-2/high risk MDS.

Secondary Objectives

• To evaluate the clinical outcome per International Working Group (IWG) 2006 MDS response criteria (Cheson et al, 2006) of MEDI4736 with or without azacitidine, and MEDI4736 in combination with tremelimumab with or without azacitidine in subjects with MDS.
• To evaluate the PK of MEDI4736 and tremelimumab following treatment in subjects with MDS.
• To determine the immunogenicity of MEDI4736 and tremelimumab following treatment in subjects with MDS.
• To evaluate the effect of MEDI4736 with or without azacitidine, and MEDI4736 in combination with tremelimumab with or without azacitidine on patient-reported outcomes (PROs).

Exploratory Objectives

• To evaluate the relationships between gene expression, gene methylation, and protein expression patterns within the bone marrow and periphery at baseline after hypomethylating agents and during treatment with MEDI4736 with or without azacitidine, and MEDI4736 in combination with tremelimumab with or without azacitidine and clinical response to treatment.
• To examine the validity of cellular biomarkers in the periphery to correlate with response/outcome following MEDI4736 with or without azacitidine, and MEDI4736 in combination with tremelimumab with or without azacitidine.
• To evaluate circulating soluble proteins (that may include but are not limited to cell-free DNA, immunoregulatory cytokines, chemokines, cancer biomarkers, and antibodies against host and tumor antigens) in the periphery to assess the baseline immune status of subjects as they relate to other disease states, as well as changes in response to treatment with MEDI4736 with or without azacitidine, and MEDI4736 in combination with tremelimumab with or without azacitidine and clinical outcome.

Inclusion Criteria

1. Age ≥ 18 years at the time of screening
2. Must have one of the following diagnoses:
   • Pathologically confirmed MDS (< 20% blasts in bone marrow, peripheral blood, or both) at the time of referral for trial: low, intermediate-1, intermediate-2 or high risk by IPSS for MEDI4736 monotherapy (Part 1) and intermediate-2 or high risk by IPSS for MEDI4736 combination therapy (Part 2)
   • Secondary MDS (defined as MDS developing in a subject with an antecedent hematologic disorder or any subject with prior chemotherapy or radiation exposure)
   • Chronic myelomonocytic leukemia subjects are excluded
3. Available unstained archived bone marrow sample to allow for biomarker analyses (optional)
4. All MDS subjects are required to have failed to respond, relapsed after an initial response, or be unable to tolerate hypomethylating agents 5-azacitidine or decitabine as the most recent treatment received prior to enrollment on study
   • Failure to respond is defined as failing to achieve a CR, PR or HI after at least 4 cycles of hypomethylating therapy; these subjects could have received other therapies or not, but must have received hypomethylating monotherapy as the most recent treatment received prior to enrollment on study
5. ECOG performance status of 0-2
6. Adequate organ function, as defined below:
   • Total bilirubin ≤ 1.5 x ULN except subjects with documented Gilbert's syndrome (> 3 x ULN), who must have a baseline total bilirubin ≤ 3.0 mg/dL
   • ALT and AST ≤ 2.5 x ULN;
   • Serum creatinine ≤ 2.0 mg/dL
7. Willingness to provide consent for bone marrow samples. Bone marrow samples will be required for all subjects at the time of screening and at the end of treatment (EOT) as described in Section 4.3.1.1
8. Written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the US obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations)
9. Females of childbearing potential who are sexually active with a nonsterilized male partner must use a highly effective method of contraception from the time of screening, and must agree to continue using such precautions for 90 days (MEDI4736 monotherapy) or 180 days (MEDI4736 combination therapy) after the final dose of investigational product. Cessation of contraception after this point should be discussed with a responsible physician. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however, occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of periods.
   • Females of childbearing potential are defined as those who are not surgically sterile (ie, have not undergone bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal (defined as 12 months with no menses without an alternative medical cause)A highly effective method of contraception is defined as one that results in a low failure rate (ie, less than 1% per year) when used consistently and correctly. The acceptable methods of contraception are described in Table 4.1.2-1. Note that some contraception methods are not considered highly effective (eg, 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)
10. Nonsterilized males who are sexually active with a female partner of childbearing potential must use a highly effective method of contraception (see Table 4.1.2-1) from screening through 90 days (MEDI4736 monotherapy) or 180 days (MEDI4736 combination therapy) after receipt of the final dose of investigational product. In addition, they must refrain from sperm donation for 90 days (MEDI4736 monotherapy) or 180 days (MEDI4736 combination therapy) after the final dose of investigational product. Not engaging in sexual activity for the total duration of the trial and the drug washout periods is an acceptable practice; however, occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Male subjects should refrain from sperm donation throughout these periods. Female partners of a male subject must use a highly effective method of contraception throughout these periods.

Exclusion Criteria

1. Concurrent enrollment in another clinical study, unless in a follow-up period or it is an observational study
2. Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormones for non-cancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable
3. Subjects must not have received hematopoietic growth factors, within 21 days of beginning the study, and should have recovered from all toxicities of prior therapies
4. Inaspirable bone marrow (subjects enrolled in Part 2)
5. Exposure to any of the following within 28 days of receiving the first dose of study treatment:
   • Thrombopoiesis-stimulating agents (eg, romiplostim, eltrombopag, interleukin [IL]-11; only for subjects receiving MEDI4736 combination therapy in Part 2)
   • Any hematopoietic growth factors (erythropoiesis-stimulating agents and other RBC hematopoietic growth factors [eg, IL-3]; only for subjects receiving MEDI4736 combination therapy in Part 2)
   • Any chemotherapy, radiotherapy or iron chelation therapy
   • Any investigational agents within 28 days prior or 5 half-lives (whichever is longer) of initiating study treatment
6. Received any prior mAb against CTLA-4, PD-1, or PD-L1 (including MEDI4736)
7. History of hematopoietic or organ transplantation
8. Subjects who have had clinical evidence of central nervous system (CNS) or pulmonary leukostasis or CNS leukemia
9. Major surgery (as defined by the investigator) within 28 days prior to first dose of MEDI4736 or still recovering from prior surgery. Local procedures (eg, placement of a systemic port, core needle biopsy, and prostate biopsy) are allowed if completed at least 24 hours prior to the administration of the first dose of study treatment
10. Any toxicity from prior therapy that has not been completely resolved to baseline at the time of consent. Subjects with NCI CTCAE v4.03 Grade 1 or 2 toxicities that are deemed stable or irreversible can be enrolled on a case-by-case basis with prior consultation and agreement with the medical monitor
11. Current or prior use of immunosuppressive medication within 14 days prior to the first dose of MEDI4736. The following are exceptions to this criterion:
    • Intranasal, inhaled, topical or local steroid injections (eg, intra-articular injection)
    • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent
    • Steroids as premedication for hypersensitivity reactions (eg, computed tomography [CT] scan premedication)
12. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis, Crohn's disease], diverticulitis with the exception of a prior episode that has resolved or diverticulosis, celiac disease, irritable bowel disease, or other serious gastrointestinal chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener's syndrome [granulomatosis with polyangiitis]; 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:
    • Subjects with vitiligo or alopecia
    • Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
    • Subjects with psoriasis not requiring systemic treatment
13. History of primary immunodeficiency
14. Known positive for human immunodeficiency virus (HIV), chronic or active hepatitis B or active hepatitis A or C
15. Receipt of live, attenuated vaccine within 30 days prior to the first dose of MEDI4736 (NOTE: Subjects, if enrolled, should not receive live vaccine during the study and 30 days after the last dose of MEDI4736)
16. Females who are pregnant, lactating, or intend to become pregnant during the participation to the study
17. Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, current pneumonitis, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs from MEDI4736, or compromise the ability of the subject to give written informed consent
18. Other invasive malignancy within 2 years except for noninvasive malignancies such as cervical carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma of the skin, or ductal carcinoma in situ of the breast that has been surgically cured
19. Known allergy or hypersensitivity to study drug formulations
20. Any condition that, in the opinion of the investigator or sponsor, would interfere with evaluation of the investigational product or interpretation of subject safety or study results