PRIMARY OBJECTIVES:
I. Measure objective response rate (RR) to guadecitabine and pembrolizumab in subjects with
recurrent platinum resistant ovarian cancer (OC).
SECONDARY OBJECTIVES:
I. Measure progression free survival (PFS) for the combination of guadecitabine and
pembrolizumab.
II. Progression free survival (PFS). III. Measure clinical benefit rate (CBR) for the
combination of guadecitabine and pembrolizumab.
IV. Measure toxicity profiles to the combination of guadecitabine and pembrolizumab.
TERTIARY OBJECTIVES:
I. NY-ESO-1 and MAGE antigens' promoter methylation (pyrosequencing) and messenger
ribonucleic acid (mRNA) expression levels (quantitative reverse transcriptase-polymerase
chain reaction [RT-PCR]) will be measured before and after treatment in deoxyribonucleic acid
(DNA) (plasma and/or tumor biopsies) and ribonucleic acid (RNA) (tumor biopsies),
respectively.
II. Cytokine response (IFN gamma IL2, IL6, IL10, TNF alpha) will be measured in plasma by
enzyme-linked immunosorbent assay (ELISA).
III. Measure LINE 1 methylation in DNA extracted from peripheral blood mononuclear cells
(PBMCs) (measured on days 1 and 5 of cycles 1 and 2).
IV. Expression of the PD-L1 ligand will be measured by immunohistochemistry (IHC) in archival
tumors.
V. Tumor infiltrating lymphocytes (TILs) will be quantified in tumor biopsies before and
after treatment (IHC).
OUTLINE:
Patients receive guadecitabine subcutaneously (SC) on days 1-4 and pembrolizumab
intravenously (IV) over 30 minutes on day 5. Courses repeat every 21 days in the absence of
disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, every 6 weeks for 1
year, and then every 9 weeks and, once a subject experiences confirmed disease progression or
starts a new anticancer therapy, every 3 months thereafter.
Inclusion Criteria:
- Patients must have a histological or cytological evidence/confirmation of recurrent
epithelial ovarian cancer, primary peritoneal carcinomatosis, or fallopian tube cancer
- Patients must have measurable disease according to Response Evaluation Criteria in
Solid Tumors (RECIST) 1.1 within 28 days prior to registration
- Prior therapy allowed:
- At least one and no more than 3 platinum based chemotherapy regimens
- Up to 2 non-platinum, cytotoxic regimen
- There is no limit on use of prior biological therapies (hormonal or targeted
therapy)
- NOTE: Prior immunotherapy is not allowed
- Patients must exhibit an Eastern Cooperative Oncology Group (ECOG), performance status
of 0-1 within 14 days prior to registration
- Demonstrate adequate organ function as defined below; all screening labs to be
obtained within 14 days prior to treatment initiation:
- Absolute neutrophil count (ANC) >= 1,500/mcL
- Platelets >= 100,000/mcL
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (without transfusion or growth factor
support/erythropoietin [EPO] dependency)
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated
creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine
levels > 1.5 X institutional ULN
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
ULN OR =< 5 X ULN for subjects with liver metastases
- Albumin >= 2.5 mg/dL
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants
- Activated partial thromboplastin time (aPTT) =< 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
- Be willing to allow the use of archival formalin-fixed paraffin-embedded tumor tissue
for correlative analyses
- Note: The archived tumor tissue specimens may be from prior surgery or from prior
diagnostic biopsy of primary or metastatic tumor specimen; unavailability of
archived tissue will not render subject ineligible for study
- Be willing and able to undergo a core or excisional tumor biopsy according to
institutional standards (guided visually or by computed tomography [CT] or
ultrasound), paracentesis, or thoracentesis for tumor cells
- Note: This is to be done prior to treatment at cycle 1 day 1 (C1D1) and
post-treatment (cycle 2 day 8), if this is clinically and safely feasible to do
so; this will allow the use of this freshly obtained tissue for correlative
analyses in the study
- Females of child-bearing potential (FOCBP) must agree to use adequate contraception
prior to registration, for the duration of study participation, and for 120 days
following completion of therapy; should a female patient become pregnant or suspect
she is pregnant while participating in this study, she should inform her treating
physician immediately
- NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a
tubal ligation, or remaining celibate by choice) who meets the following
criteria:
- Has not undergone a hysterectomy or bilateral oophorectomy
- Has had menses at any time in the preceding 12 consecutive months (and
therefore has not been naturally postmenopausal for > 12 months)
- FOCBP must have a negative pregnancy test within 7 days prior to registration on study
- Patients must have the ability to understand and the willingness to sign a written
informed consent prior to registration on study
Exclusion Criteria:
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 14 days prior to registration or who has not recovered (i.e., =< grade 1 or at
baseline) from adverse events due to a previously administered agent
- NOTE: Subjects with =< grade 2 neuropathy are an exception to this criterion and
may qualify for the study
- NOTE: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting therapy
- Has had a prior anti-cancer monoclonal antibody (mAb) within 28 days prior to
registration or who has not recovered (i.e., =< grade 1 or at baseline) from adverse
events due to agents administered more than 4 weeks earlier
- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 28 days registration
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment
- Has a known additional malignancy that is progressing or requires active treatment;
exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer
- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis; subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least 28 days prior
to registration and any neurologic symptoms have returned to baseline), have no
evidence of new or enlarging brain metastases, and are not using steroids for at least
7 days prior to trial treatment; this exception does not include carcinomatous
meningitis which is excluded regardless of clinical stability
- Has active autoimmune disease 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
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent; please
contact the principal investigator for further clarification if needed
- Hypersensitivity to pembrolizumab or any of its excipients
- Has a known history of active TB (Bacillus tuberculosis)
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
infection
- Has a known history of hepatitis B and/or hepatitis C infection
- Has known history of, or any evidence of active, non-infectious pneumonitis
- Has an active infection requiring systemic therapy within 3 days of registration
(NOTE: except for uncomplicated urinary tract infection [UTI])
- Has a 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
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial
- Has received a live vaccine within 30 days of planned start of study therapy
- Note: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)
are live attenuated vaccines, and are not allowed
- Female patients who are pregnant or nursing, or expecting to conceive within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment; subjects should not breast
feed within 120 days of completing the trial
- 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
