PRIMARY OBJECTIVE:
I. To evaluate the progression free survival (PFS) of advanced pancreatic cancer patients with germline BRCA1 or BRCA2 mutations treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy.
SECONDARY OBJECTIVES:
I. To evaluate the safety and tolerability associated with the combination of olaparib + pembrolizumab versus (vs.) olaparib alone as maintenance therapy.
II. To evaluate the overall survival (OS) of patients treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy.
III. To evaluate the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, including confirmed and unconfirmed, complete and partial response, of patients treated with olaparib + pembrolizumab compared to olaparib alone, in the subset of patients with measurable disease.
IV. To evaluate the duration of response (DoR) by RECIST 1.1 in patients treated with olaparib + pembrolizumab compared to olaparib alone.
BANKING OBJECTIVE:
I. To bank tissue and blood specimens for future correlative studies.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive olaparib orally (PO) twice daily (BID) on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 19, patients receive olaparib PO BID on days 1-42 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive olaparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Patients undergo computed tomography (CT) scan or magnetic resonance imaging (MRI), tumor biopsy and blood sample collection throughout the study.
After completion of study treatment, patients are followed for 30 days and every 6 months for 3 years from the date of randomization.
Inclusion Criteria:
- Patients must have a histologic or cytologic diagnosis of pancreatic adenocarcinoma.
Patients with neuroendocrine tumors, acinar cell and adenosquamous carcinomas are
excluded. All disease must be assessed and documented on the Baseline Tumor Assessment
Form
- Patients must have one of the following mutations: germline mutation in BRCA 1 or 2
that was tested in a Clinical Laboratory Improvement Act (CLIA) certified lab defined
as positive and/or deleterious (that is, pathogenic or likely pathogenic variant).
(NOTE: Patients with tumor somatic mutations are not eligible)
- Patients must have metastatic disease and received first line platinum-based
chemotherapy (i.e. fluorouracil, irinotecan, leucovorin and oxaliplatin [FOLFIRINOX],
leucovorin calcium, 5-fluorouracil, and oxaliplatin [FOLFOX], gemcitabine +
nab-paclitaxel + cisplatin or gemcitabine + cisplatin)
- Patients must have had a CT or MRI showing stable or responding disease on first line
platinum-based chemotherapy within 30 days prior to registration
- Patients with known human immunodeficiency virus (HIV)-infection are eligible
providing they are on effective anti-retroviral therapy and have undetectable viral
load at their most recent viral load test and within 6 months prior to registration
- Patients with history of chronic hepatitis B virus (HBV) infection must have
undetectable HBV viral load within 30 days prior to registration
- 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 must have an
undetectable HCV viral load within 30 days prior to registration
- Patients must have received at least 16 weeks of first line platinum-based
chemotherapy for metastatic disease. Patients may have also received one cycle of
treatment (no more than 4 weeks) with gemcitabine + nab-paclitaxel while waiting for
germline test results, prior to platinum-based therapy
- Patients' last chemotherapy treatment must be within 30 days prior to registration
- Patients must have resolved or stable =< grade 1 toxicity from prior administration of
another investigational drug and/or prior anti-cancer treatment, excluding neuropathy
and alopecia
- Patients must not have a known hypersensitivity to olaparib or any of the excipients
of the product
- Patients must not be planning to receive strong or moderate CYP3A inhibitors or
inducers while on olaparib treatment. Patients receiving strong or moderate CYP3A
inhibitors must discontinue use at least 2 weeks prior to receiving olaparib. Patients
receiving strong or moderate CYP3A inducers must discontinue use at least 5 weeks
prior to receiving olaparib. Medications should be checked using a frequently updated
medical reference for a list of drugs to avoid
- Patients must not have received live vaccines within 42 days prior to randomization
and must not be planning to receive live virus or live bacterial vaccines while
receiving study treatment and during the 30 day follow up period. Examples of live
vaccines include, but are not limited to, the following: measles, mumps, rubella,
chicken pox, shingles, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed
virus vaccines and are allowed; however, intranasal influenza vaccines (e.g.,
Flu-Mist) are live attenuated vaccines, and are not allowed. Coronavirus disease 2019
(COVID-19) messenger ribonucleic acid (mRNA) vaccine is allowed
- Patients must not have had prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2
agent, or any other immune checkpoint inhibitors
- Patients must not have had prior therapy with PARP inhibitors
- Patients must not have had a prior diagnosis of immunodeficiency or receiving systemic
steroid therapy (defined as >= 10 mg prednisone or equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of trial treatment
- Zubrod performance status of 0-1
- Patients must be >= 18 years old
- Patients must have a complete medical history and physical exam within 28 days prior
to registration
- Absolute neutrophil count >= 1.5 x 10^3/uL (within 14 days of registration)
- Platelets >= 100 x 10^3/uL (within 14 days of registration)
- Total bilirubin =< 1.5 institutional upper limit of normal (ULN) (within 14 days of
registration)
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x institutional
ULN (within 14 days of registration)
- Albumin >= 3.0 g/dL (within 14 days of registration)
- Hemoglobin >= 9.0 g/dL (within 14 days of registration)
- Creatinine clearance (Cockcroft _Gault) > 50 mg/dL (within 14 days of registration)
- Participants must have a serum creatinine =< the institutional (I)ULN OR measured OR
calculated creatinine clearance >= 50 mL/min using the following Cockcroft-Gault
Formula. This specimen must have been drawn and processed within 14 days prior to
registration
- Patients must have CA19-9 obtained within 42 days prior to registration
- Patients must be able to swallow and retain oral medications and have no known
gastrointestinal disorders likely to interfere with absorption of the study medication
- Participants with a prior or concurrent malignancy whose natural history or treatment
(in the opinion of the treating physician) does not have the potential to interfere
with the safety or efficacy assessment of the investigational regimen are eligible for
this trial provided it does not require concurrent therapy
- Participants must not be pregnant or nursing due to the possibility of harm to the
fetus or nursing infant from this treatment regimen. Women of childbearing potential
must have a negative urine or serum pregnancy test within 28 days prior to
registration. Women/men of reproductive potential must have agreed to use an effective
contraceptive method for the course of the study through 6 months after the last dose
of study medication. A woman is considered to be of "reproductive potential" if she
has had menses at any time in the preceding 12 consecutive months. In addition to
routine contraceptive methods, "effective contraception" also includes heterosexual
celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy
prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal
ligation. However, if at any point a previously celibate participant chooses to become
heterosexually active during the time period for use of contraceptive measures, he/she
is responsible for beginning contraceptive measures. Should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately
- Patients must not have a history of (non-infectious) pneumonitis that required
steroids or current pneumonitis
- Patients must not have an active infection requiring systemic therapy
- Patients must not have active autoimmune disease that has required systemic treatment
in 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 must be offered the opportunity to participate in specimen banking of
formalin-fixed paraffin-embedded (FFPE) tissue and whole blood. If a patient is unable
to submit archival tissue, should the patient need to undergo a standard of care
biopsy per National Comprehensive Cancer Network (NCCN) guidelines, patients must then
be offered the opportunity to submit the fresh tumor tissue from that biopsy. With
participant consent, specimens must be collected and submitted via the Southwest
Oncology Group (SWOG) Specimen Tracking System
- Patients must be informed of the investigational nature of this study and must sign
and give informed consent in accordance with institutional and federal guidelines. For
participants with impaired decision making capabilities, legally authorized
representatives may sign and give informed consent on behalf of study participants in
accordance with applicable federal, local, and Canada Industrial Relations Board
(CIRB) regulations
- As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has been
entered in the system