Study of Pembrolizumab With or Without CC-486 in Patients With Platinum-resistant Ovarian Cancer

Conditions:Ovarian Cancer, Cancer
Therapuetic Areas:Oncology
Age Range:18 - Any
Start Date:December 20, 2016
End Date:December 2019
Contact:John Glaspy, MD

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Phase II Randomized Study of Pembrolizumab With or Without Epigenetic Modulation With CC-486 in Patients With Platinum-resistant Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer

The purpose of the study is to determine the optimal dose of CC-486 (oral azacitidine) in
combination with pembrolizumab for the treatment of platinum-resistant/refractory Epithelial
Ovarian Cancer (EOC).

This is an open-label, non-randomized, four-cohort study, in which intravenous pembrolizumab
will be combined with 4 different schedules of administration of CC-486 (oral azacitidine),
for the treatment of platinum-resistant/refractory (EOC). This is also a futility trial for
the strategy to combine pembrolizumab and CC-486 in EOC. Eligible subjects will be treated in
one of four cohorts of combined oral CC-486 and intravenous pembrolizumab (200 mg intravenous
(IV) every 3 weeks in all cohorts) to evaluate the safety of each combination schedule and to
have preliminary data on their efficacy. The primary objective is to establish the optimal
dosing schedule for comparison with pembrolizumab alone.

Subjects will be assigned to a treatment cohort in the order they are enrolled in the study.
In all subjects, tumor tissue will be obtained via image-guided core biopsy at study entry
and 6 weeks after commencing treatment with CC-486. A cohort will remain open to accrual
until five subjects treated on that cohort have completed two CC-486 cycles and have had the
first post-baseline tumor burden assessment and both tumor biopsies performed and adequate
paired tissue obtained. At least 5 evaluable subjects per cohort will be accrued over an
estimated period of approximately 24 months.

Subjects will be treated in the assigned cohort until progressive disease based on
Immune-Related Response Evaluation Criteria In Solid Tumors (irRECIST), unacceptable
toxicity, consent withdrawal or the Investigator concludes that it is in the subject´s best
interest to discontinue. Once 5 subjects in each cohort are considered evaluable for
response, toxicity and treatment responses will be analyzed for each of the four cohorts and
an optimal schedule will be selected.

This study includes mandatory tumor core biopsies for biomarkers research and mandatory whole
blood sampling for deoxyribonucleic acid (DNA) methylation analyses.

Inclusion Criteria:

- Signed and dated informed consent document obtained prior to initiation of any
study-specific procedure and treatment (by the subject or a legally acceptable
representative as per the local regulations).

- Women ≥ 18 years old

- Histologically confirmed Epitheilial Ovarian Cancer (EOC), Fallopian Tube Cancer (FTC)
or Primary Peritoneal Cancer (PPC).

- Received debulking surgery and preoperative and/or postoperative platinum-based
frontline chemotherapy (intravenous and/or intraperitoneal) for the treatment of

- Documented platinum-resistant or platinum-refractory disease. Platinum-resistant
disease is defined as progression within < 6 months from completion of a minimum of 4
platinum frontline therapy cycles in the pre or postoperative setting (the date should
be calculated from the last administered dose of platinum agent). Platinum-refractory
is defined as disease that has recurred/progressed while receiving platinum-based
frontline therapy.

- Measurable disease according to Immune-Related Response Evaluation Criteria In Solid
Tumors (irRECIST)

- Indication of systemic treatment for the relapsed EOC, FTC or PPC.

- Subjects must have a tumor lesion that is amenable to an image-guided core biopsy and
willingness to undergo two biopsies (baseline and 6 weeks after first dose of study

- Eastern Cooperative Oncology Group (ECOG) Performance status (PS) 0 or 1.

- Expected survival of more than 6 months.

- Adequate organ function within 7 days prior to enrollment, as defined by the following

- Absolute neutrophils count (ANC) ≥ 1.5 x 10E9/L, platelets ≥ 100 x 10E9/L,
hemoglobin > 9 g/dL (without transfusion or erythropoiesis stimulating agents'

- Serum creatinine ≤ 1.5 x upper limit of normal (ULN).

- Total serum bilirubin ≤ 1.5 x ULN regardless of liver involvement secondary to
tumor. Higher levels are acceptable if these can be attributed to active
hemolysis or ineffective erythropoiesis.

- Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) < 2.0 x
ULN or ≤ 5 X ULN for subjects with liver metastases.

- International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or PTT is within
therapeutic range of intended use of anticoagulants

- Partial Thromboplastin Time (PTT) or Activated Partial Thromboplastin Time (aPTT)
≤ 40 seconds unless subject is receiving anticoagulant therapy as long as PT or
PTT is within therapeutic range of intended use of anticoagulants.

- For women of childbearing potential, negative serum pregnancy test within 7 days of

- Women of childbearing potential must agree to use acceptable methods of birth control
starting with the screening visit and up to 120 days after the last dose of study
treatment. Recommendation is for 2 effective contraceptive methods during the study.
Adequate forms of contraception are double-barrier methods (condoms with spermicidal
jelly or foam and diaphragm with spermicidal jelly or foam), oral depo provera, or
injectable contraceptives, intrauterine devices, and tubal ligation.

- Willingness and ability to comply with scheduled visits, treatment plan, laboratory
tests, and other trial procedures.

Exclusion Criteria:

- Non-epithelial ovarian cancers, including malignant mixed Müllerian tumors.

- Ovarian tumors with low malignant potential (i.e. borderline tumors).

- Relapse/progression based solely on elevation of CA-125, in absence of measurable
disease, according to irRECIST criteria.

- More than 2 prior treatment regimens for the platinum-resistant/refractory relapsed
EOC, FTC, or PTC, defined as investigational, chemotherapy, hormonal, biologic, or
targeted therapy.

- Any concurrent or previous malignancy within 5 years prior to enrollment except for
adequately and radically treated basal or squamous skin cancer, or carcinoma in situ
of the cervix, or other non-invasive/in-situ neoplasm. A subject with previous history
of invasive malignancy (other than adequately and radically treated basal or squamous
skin cancer or carcinomas in situ) is eligible provided that she has been disease free
for more than 5 years.

- Brain metastases (even if treated and/or stable), spinal cord compression,
carcinomatous meningitis, or leptomeningeal disease.

- Prior systemic anticancer therapy within 4 weeks prior to enrollment or who has not
recovered (i.e. ≤ Grade 1 or baseline grade) from adverse events due to a previously
administered agent

- Prior treatment with a monoclonal antibody within 4 weeks prior to enrollment or who
has not recovered (i.e. ≤ Grade 1 or baseline grade) from adverse events due to agents
administered more than 4 weeks earlier.

- Diagnosis of immunosuppression or receiving systemic steroid therapy or any other form
of immunosuppressive therapy within 7 days prior to enrollment . The use of
physiologic doses of corticosteroids may be approved after consultation with the

- Active autoimmune disease or history of autoimmune disease or syndrome that has
required systemic treatment in the past 2 years (i.e. with use of disease modifying
agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g.
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or
pituitary insufficiency, etc.) is not considered a form of systemic treatment.
Subjects with vitiligo or resolved childhood asthma/atopy will not be excluded.

- Received live vaccines within 30 days prior to enrollment

- Current or prior history of myelodysplastic syndrome, leukemia or clinically
significant (as per Investigator judgment) bone marrow failure.

- Uncontrolled systemic fungal, bacterial or viral infection at time of enrollment
(defined as ongoing signs/symptoms related the infection without improvement despite
appropriate antibiotics, antiviral therapy and/or other treatment).

- Known history of active TB (Bacillus Tuberculosis).

- Known HIV infection or known history of Hepatitis B or known positivity for active
Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA [qualitative] is detected).

- Known history of non-infectious pneumonitis that required steroids or has current
pneumonitis (infectious or non-infectious).

- Significant active cardiac disease within 6 months prior to enrollment, including but
not limited to New York Heart Association class 4 cardiac heart failure, unstable
angina, myocardial infarction

- History or current evidence of any condition, therapy, or laboratory abnormality that
might confound the results of the trial, interfere with the subject's participation
for the full duration of the trial, or is not in the best interest of the subject to
participate, in the opinion of the treating Investigator. Is or has an immediate
family member (e.g. spouse, parent/legal guardian, sibling or child) who is
investigational site or sponsor staff directly involved with this trial, unless
prospective Institutional Review Board (IRB) approval (by chair or designee) is given
allowing exception to this criterion for a specific subject.

- Any contraindication to oral agents or significant nausea and vomiting, malabsorption,
or significant small bowel resection that, in the opinion of the Investigator, would
preclude adequate absorption.

- Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial.

- Prior treatment with any anti-Programmed Death (PD)-1, or PD-L1 or PD-L2 agent; or
with azacitidine (any formulation) or any other hypomethylating agent; or with
anti-cytoplasmic (CD) 137, or anti-cytotoxic T-Lymphocyte Associated Protein (CTLA)-4
antibody (including ipilimumab) or any other antibody or drug specifically targeting
T-cell co-stimulation or checkpoint pathways.

- Known or suspected hypersensitivity to azacitidine, pembrolizumab or the excipients of
any of the study drugs (including mannitol). Known or suspected hypersensitivity to
monoclonal antibodies.

- Currently participating and receiving study therapy or has participated in a study of
an investigational agent and received study therapy or used an investigation device
within 4 weeks prior to enrollment .

- Pregnant or lactating women or is expecting to conceive children or breastfeed within
the projected duration of the trial, starting with the screening visit through 120
days after the last dose of trial treatment.
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