A Phase 1 Study of CC-486 as a Single Agent and in Combination With Carboplatin or ABI-007 in Subjects With Relapsed or Refractory Solid Tumors

A Phase 1 Study of CC-486 as a Single Agent and in Combination With Carboplatin or ABI-007 in Subjects With Relapsed or Refractory Solid Tumors

The purpose of the study is to evaluate the safety and to define the Maximal Tolerated Dose (MTD) or the Maximal Administered Dose (MAD) of oral azacitidine as a single agent and in combination with carboplatin (CBDCA) or paclitaxel protein bound particles (ABI-007,ABX) in subjects with relapsed or refractory solid tumors.

Inclusion Criteria:

1. Men and women, 18 years or older at the time of signing the Informed Consent Document (ICD).

2. Understand and voluntarily sign an ICD prior to any study-related assessments or procedures are conducted.

3. Able to adhere to the study visit schedule and other protocol requirements.

4. With histological or cytological confirmation of advanced unresectable solid tumors, including those who have progressed on (or not been able to tolerate) standard anticancer therapy, or for whom no other effective therapy exists, or for who declines standard therapy.

5. Consent to screening tumor biopsy (for accessible tumors when appropriate [optional in Part 1, mandatory in Part 2]).

6. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.

7. The following laboratory values:

   • Absolute neutrophil count (ANC) ≥ 1.5 X 10^9/L
   • Hemoglobin (Hgb) ≥90 g/L
   • Platelets (plt) ≥ 100 x 10^9/L
   • Potassium within normal range, or correctable with supplements;
   • AST and ALT ≤2.5 x Upper Limit Normal (ULN) or ≤5.0 x ULN if liver tumor is present;
   • Serum total bilirubin ≤ 1.5 x ULN
   • Serum creatinine ≤ 1.5 x ULN, or 24-hr clearance ≥ 60ml/min; and
   • Negative serum pregnancy test within 7 days before starting study treatment in females of childbearing potential (FCBP)

8. Females of child-bearing potential {defined as a sexually mature women who

   • has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or,

   • has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months} must

     • agree to the use of a physician- approved contraceptive method (oral, injectable, or implantable hormonal contraceptive ; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) while on oral azacitidine and for 3 months following the last dose of study medication; and
     • have a negative serum pregnancy test during screening

9. Male subjects with female partner of childbearing potential must agree to the use of a physician-approved contraceptive method throughout the course of the study to avoid fathering a child during the course of the study and for 6 months following the last dose of oral azacitidine.

The criteria below are in addition to or supersede the Part 1 inclusion criteria above:

1. With histological or cytological confirmation of relapsed or refractory advanced unresectable solid tumors as listed below for each Arm, including those who have progressed on or were unable to tolerate standard anti-cancer therapy.

   • Arm A: CC-486 plus CBDCA:
   • Relapsed or refractory urothelial carcinoma of the bladder, renal pelvis, ureter, or urethra (mixed histologies are permitted provided a component of urothelial carcinoma is present)
   • Epithelial ovarian, fallopian tube, or primary peritoneal carcinoma
   • Arm B: CC-486 plus ABI-007:
   • NSCLC
   • Pancreatic carcinoma
   • Arm C: CC-486 single agent:
   • Virally-associated tumors - tumor types known to be driven by Epstein-Barr Virus (EBV), Human Papilloma Virus (HPV), and Merkel cell carcinoma of the skin (MC Polomavirus)
   • Nasopharyngeal carcinoma (a minimum of 5 subjects)
   • Cervical carcinoma
   • Anal carcinoma
   • Merkel cell carcinoma (MCC)
   • Note: Hepatitis B virus (HBV) and Hepatitis C virus (HCV)-associated tumors (hepatocellular cancers) are not eligible.
   • Note: Head and neck squamous cell cancers (HNSCC) must have HPV-positive status documented to be eligible

2. Subjects with documented liver metastases must have serum albumin ≥ 3 g/dL;

3. Sites of disease (primary or metastatic) that are, in the opinion of the investigator, accessible for biopsy without undue risk to the subject

4. Consent to tumor biopsy at screening (prior to the first dose of CC-486) and at Cycle 1 Day 15.

5. Measurable disease according to RECIST v1.1.

Exclusion Criteria:

1. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
2. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
3. Any condition that confounds the ability to interpret data from the study.
4. Symptomatic central nervous system metastases. Subjects with brain metastases that have been previously treated and are stable for 6 weeks are allowed.
5. Known acute or chronic pancreatitis.
6. Any peripheral neuropathy ≥ NCI CTCAE grade 2.
7. Persistent diarrhea or malabsorption ≥ NCI CTCAE grade 2, despite medical management.
8. Impaired ability to swallow oral medication.
9. Unstable angina, significant cardiac arrythmia, or New York Heart Association (NYHA) class 3 or 4 congestive heart failure.
10. Prior systemic cancer-directed treatments or investigational modalities ≤ 5 half lives or 4 weeks, whichever is shorter, prior to starting study drug or who have not recovered from side effects of such therapy. (except alopecia).
11. Major surgery ≤ 2 weeks prior to starting a study drug or who have not recovered from side effects of such therapy.
12. Pregnant or breast feeding.
13. Known Human Immunodeficiency Virus (HIV) infection.
14. Known chronic hepatitis B or C virus (HBV/HCV) infection, unless this is a comorbidity in subjects with HCV.
15. Liver metastases with serum albumin < 3 g/dL.
16. Other prior cancers within previous 5 years except adequately treated in situ carcinoma cervix, or basal, or squamous carcinoma of the skin.
17. Subjects with > 4 prior systemic chemotherapy regimens will require approval by the Celgene Medical Monitor prior to enrollment. A regimen is defined as >/= 2 cycles of systemic anti-cancer therapy containing 1 or more agents in the following classes: topoisomerase 1 or 2 inhibitors, platinum salts, alkylating agents, tubulin inhibitors, anti-metabolites or vinca alkaloids.