PRIMARY OBJECTIVES:
I. To determine whether olaparib plus tremelimumab has adequate safety in the study
population. (Safety Lead-in Trial Components) II. To compare the progression-free survival
(PFS) duration of olaparib monotherapy versus olaparib plus tremelimumab in women with
recurrent, platinum sensitive ovarian, primary peritoneal, or fallopian tube cancer. (Phase
II Trial Component)
SECONDARY OBJECTIVES:
I. To compare the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1 in women with recurrent, platinum sensitive ovarian, primary peritoneal or
fallopian tube cancer treated with either olaparib monotherapy or olaparib plus tremelimumab.
II. To compare the overall survival (OS) of women with recurrent, platinum sensitive ovarian,
primary peritoneal or fallopian tube cancer treated with either olaparib monotherapy or
olaparib plus tremelimumab.
EXPLORATORY OBJECTIVES:
I. To explore whether conditions in the tumor microenvironment (as measured by gene
expression signature in archived tumor samples) identify patients that benefit from combined
olaparib and tremelimumab immunotherapy.
II. To explore whether mutations in BRCA1/2 genes or other evidence of homologous repair
deficiency (HRD+) is prognostic and/or predictive of response to combined olaparib and
tremelimumab immunotherapy.
III. To explore associations between PD1 expression in the tumor microenvironment and outcome
and changes in circulating leukocyte populations.
IV. To explore the correlation between tumor mutational burden and response to olaparib and
tremelimumab immunotherapy.
V. To explore the impact of olaparib and tremelimumab versus olaparib monotherapy on
circulating leukocyte subsets via exploration of the immunomodulatory effects of PARP
inhibition and the added impact of CTLA4 blockade in this patient population.
VI. To explore cytokine/chemokine levels using a multiplex immunoassay (Olink) and correlate
these levels with clinical endpoints.
VII. To use cell-free deoxyribonucleic acid (DNA) to assess BRCA mutation status as a
mechanism of acquired resistance to prior PARP inhibition and to compare with treatment
efficacy.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive olaparib orally (PO) twice daily (BID) in the absence of disease
progression or unacceptable toxicity.
ARM II: Patients receive olaparib as in Arm I. Patients also receive tremelimumab
intravenously (IV) over 60 minutes on day 1. Cycles of tremelimumab repeat every 4 weeks for
4 doses and then every 12 weeks for up to 2 years total in the absence of disease progression
or unacceptable toxicity.
After completion of study treatment, patients are followed up monthly for 3 months, then
every 3 months for 2 years, followed by every 6 months for 3 years.
Inclusion Criteria:
- Patients must have platinum-sensitive, recurrent high-grade serous or high-grade
endometrioid (grade 3) ovarian, primary peritoneal, or fallopian tube cancer. Patients
with other histologies are also eligible, provided that the patient has a known
deleterious germline or somatic BRCA1 or BRCA2 mutation identified through testing at
a clinical laboratory. Submission of BRCA testing results (germline and/or somatic) is
required for all patients.
- Platinum-sensitive disease defined as no clinical or radiographic evidence of disease
recurrence for > 6 months (or 182 days) after last receipt of platinum-based therapy.
The date should be calculated from the last administered dose of platinum therapy.
- Patients must have had response (complete or partial) to their prior line of platinum
therapy and cannot have had progression through prior platinum-based therapy.
- Patients must have RECIST 1.1 measurable disease. Patients with biochemical recurrence
based on CA125 levels alone are not eligible.
- Prior therapy:
- Prior chemotherapy must have included a first-line platinum-based regimen with or
without consolidation chemotherapy.
- Prior bevacizumab therapy as a component of frontline or recurrent treatment is
permitted.
- Patients may have received an unlimited number of platinum-based therapies in the
recurrent setting.
- Patients may have received up to one non-platinum-based line of therapy in the
recurrent setting. Prior hormonal therapy will not be counted as this
non-platinum-based line.
- Prior treatment with a PARP inhibitor:
- Patients may not have had a prior PARP inhibitor in the recurrent setting.
- Prior use of a PARP inhibitor in the upfront maintenance setting is allowed
for women with a confirmed BRCA1 or BRCA2 germline or somatic mutation.
- Women who received a PARP inhibitor for maintenance therapy in the frontline
setting must have received at least one other chemotherapy regimen for
recurrence prior to enrolling on this trial.
- Patients who demonstrated disease progression while on a PARP inhibitor are
excluded.
- Prior hormonal-based therapy for ovarian, primary peritoneal, or fallopian tube
cancer is acceptable.
- Body weight > 30 kg.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
- Absolute neutrophil count (ANC) >= 1,500/mcl (within 14 days prior to enrollment)
- Platelets >= 100,000/mcl (within 14 days prior to enrollment)
- Hemoglobin >= 10 g/dL (within 14 days prior to enrollment)
- Note: blood transfusions are not permitted within 28 days prior to enrollment
- Creatinine =< 1.5 x institutional/laboratory upper limit of normal (ULN) (within 14
days prior to enrollment)
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 14 days
prior to enrollment)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 times
institutional ULN (within 14 days prior to enrollment)
- Adequately controlled thyroid function, with no symptoms of thyroid dysfunction and
thyroid stimulating hormone (TSH) within normal limits. Thyroid replacement therapy is
permitted to achieve a TSH within normal limits.
- Patients must be able to swallow and retain oral medications and not have
gastrointestinal illnesses that would preclude absorption of olaparib as judged by the
treating physician.
- Evidence of post-menopausal status or negative urinary or serum pregnancy test for
pre-menopausal patients. Women will be considered post-menopausal if they have been
amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply:
- Women < 50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
- Women >= 50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses > 1 year ago, had
chemotherapy-induced menopause with last menses > 1 year ago, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
hysterectomy).
- Administration of study drugs (olaparib, tremelimumab) may have an adverse effect
on pregnancy and poses a risk to the human fetus, including embryo-lethality.
Women of childbearing potential (WOCBP) must agree to use two (2) highly
effective forms of contraception from up to 14 days prior to enrollment (for oral
contraceptives), during treatment, and for 6 months after the last dose of study
medication.
- Life expectancy >= 12 weeks.
- Patients with brain metastases are eligible if follow-up brain imaging after central
nervous system (CNS)-directed therapy shows no evidence of progression. Imaging
studies must have been completed no later than 14 days prior to enrollment. In
addition, patients must have been successfully weaned off steroid support. Patients
should not have received steroids for the treatment of brain metastases within 14 days
prior to enrollment.
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- The patient or a legally authorized representative must provide study-specific
informed consent prior to study entry and, for patients treated in the United States
(U.S.), authorization permitting release of personal health information.
Exclusion Criteria:
- Active infection requiring antibiotic therapy (except for uncomplicated urinary tract
infections), including tuberculosis.
- Known clinically significant liver disease, including active viral, alcoholic, or
other hepatitis; and cirrhosis. For patients with evidence of chronic hepatitis B
virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy,
if indicated. Patients with a history of hepatitis C virus (HCV) infection must have
been treated and cured. For patients with HCV infection who are currently on
treatment, they are eligible if they have an undetectable HCV viral load.
- Hormonal therapy directed at treatment for the cancer must be discontinued at least 28
days prior to enrollment. Hormone replacement therapy for symptom management is
permitted.
- Any other therapy directed at treating the cancer including chemotherapy,
biologic/targeted agents, and immunologic agents, unless discontinued at least 28 days
prior to enrollment.
- Any radiation therapy unless discontinued at least 28 days prior to enrollment.
- Major surgical procedure within 28 days prior to enrollment.
- Current or prior use of immunosuppressive medication within 14 days before enrollment.
The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (i.e.
intra-articular injection)
- Systemic corticosteroids at physiologic doses not to exceed 10mg/day of
prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (i.e. computed
tomography [CT] scan contrast allergy premedication).
- Patients with 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.
- Patients with autoimmune disease (e.g., psoriasis, extensive atopic dermatitis,
severe asthma, inflammatory bowel disease [IBD], multiple sclerosis [M.S.],
uveitis, vasculitis) requiring concurrent use of any systemic immunosuppressants
or steroids are excluded from the study. Patients with vitiligo, mild,
intermittent asthma requiring only occasional beta-agonist inhaler use, or mild
localized eczema are eligible.
- Any patient with an allogeneic (allo)-transplant of any kind is excluded,
including xenograft heart valve.
- Chronic use of immune-suppressive drugs (i.e. systemic corticosteroids) for the
management of cancer or non-cancer related illnesses (i.e. chronic obstructive
pulmonary disease [COPD]).
- Note: ongoing steroid use for the management of brain metastases is not
permitted.
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to olaparib or tremelimumab.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirements, substantially increase
risk of incurring adverse events (AEs) or compromise the ability of the patient to
give written informed consent.
- Subjects must not have evidence of bowel obstruction on imaging or symptoms consistent
with a bowel obstruction. Additional workup to rule this out is not required.
- Known potent CYP3A4 inhibitors or inducers must be discontinued prior to starting
treatment.
- Symptoms associated with toxicities (> Common Terminology Criteria for Adverse Event
[CTCAE version (v) 5.] grade 2) caused by prior cancer therapy, excluding alopecia,
vitiligo, and the laboratory values defined in the inclusion criteria.
- Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis
after consultation with the Study Chair.
- Patients who are receiving any other investigational agent.
- Resting electrocardiogram (ECG) with corrected QT interval (QTc) > 470 msec on two or
more time points within a 24-hour period, or a family history of long QT syndrome. If
an initial ECG is within normal limits, a repeat ECG is not required.
- Patients who have previously received anti-CTLA-4 antibody therapy.
- Blood transfusions are not permitted within 28 days prior to study enrollment.
- Patients must not have signs or symptoms suggestive of myelodysplastic syndrome or
acute myeloid leukemia.
- Pregnant or lactating patients
- Receipt of live attenuated vaccines within 30 days of enrollment. Note: patients, if
enrolled, should not receive live vaccines while receiving study treatment and up to
30 days after the last treatment dose. Inactivated vaccines are permitted.
