PRIMARY OBJECTIVE:
I. To determine the relapse-free survival (RFS)-benefit from the addition of a maintenance
olaparib following completion of chemotherapy in patients with resected pancreatic carcinoma
and a pathogenic germline or somatic mutation in BRCA1, BRCA2 or PALB2.
SECONDARY OBJECTIVES:
I. To evaluate RFS in patients with olaparib after perioperative chemotherapy compared to
those treated with perioperative therapy alone among patients who received prior
platinum-based perioperative chemotherapy.
II. To evaluate overall survival (OS) in patients treated with olaparib after adjuvant
chemotherapy compared to those treated with adjuvant treatment alone.
III. To analyze the efficacy of olaparib after chemotherapy in patients with a pathogenic
germline BRCA or PALB2 mutation compared to those with a somatic mutation.
IV. To analyze survival differences between patients who received neoadjuvant or
perioperative chemotherapy compared to those who received adjuvant therapy alone.
V. To analyze RFS and OS differences in those who received =< 3 months of perioperative
platinum chemotherapy compared to those who received > 3 months of perioperative platinum
chemotherapy.
VI. To analyze RFS and OS differences in those who received any platinum-based perioperative
chemotherapy compared to no-platinum based perioperative chemotherapy.
EXPLORATORY OBJECTIVES:
I. To analyze RFS and OS differences in patients who had R1 versus (vs) R0 resections, lymph
node positivity at resection, and/or elevated or rising CA 19-9 or CEA at time of study
enrollment in the post-operative setting.
II. To analyze RFS and OS differences with those who had resectable disease at diagnosis
compared to those who did not.
III. To analyze RFS and OS differences in those with gBRCA1 mutations compared to those with
gBRCA2 mutations and gPALB2 mutations.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive olaparib orally (PO) twice daily (BID) on days 1-28. Treatment
repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable
toxicity.
ARM II: Patients receive placebo PO BID on days 1-28. Treatment repeats every 28 days for 12
cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, every 4 months for
year 1, then every 6 months for years 2-10.
Inclusion Criteria:
- STEP 0 (PRE-REGISTRATION) INCLUSION CRITERIA
- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0-2
- Patient must have a diagnosis of pancreatic cancer and have successfully undergone a
curative intent surgical resection and must have no evidence of recurrent disease as
determined by the investigator
- NOTE: This includes patients with adenocarcinoma, acinar carcinoma, squamous cell
carcinoma adenosquamous and variants thereof. Patients with neuroendocrine tumors
are excluded from enrolling
- Patient must be planning to receive, be receiving or be within 8 weeks of having
completed at least three combined months (i.e., 12 weeks) of perioperative
(neoadjuvant, adjuvant or a combination of both) systemic, multi-agent chemotherapy.
Patients may have had up to 6 months of perioperative systemic therapy as deemed
appropriate by their primary treating medical team (patients can have received
radiation or chemoradiation in addition to this 6 month course)
- Patient must have a known pathogenic or likely pathogenic germline or somatic mutation
in BRCA1, BRCA2, or PALB2, as determined by a Clinical Laboratory Improvement
Amendments (CLIA) certified or equivalently-accredited laboratory. Mutations must be
considered pathogenic or likely pathogenic by a reference database such as ClinVar or
OncoKb.org
- STEP 1 (RANDOMIZATION) INCLUSION CRITERIA
- Patient must have met the eligibility criteria outlined above
- Patient must have undergone at least 3 combined months (i.e., 12 weeks) of
perioperative (neoadjuvant, adjuvant or a combination of both) systemic, multi-agent
chemotherapy. Patients may have had up to 6 months of perioperative systemic therapy
as deemed appropriate by their primary treating medical team (patients can have
received radiation or chemoradiation in addition to this 6 months course)
- Central expert reviewer must have determined the patient eligible for randomization
after review of local genetic testing reports
- If mutation in BRCA1, BRCA2 or PALB2 was identified in tumor tissue and the patient
has not previously undergone germline testing, the patient must agree to undergo
germline testing
- Patient must not have previously had evidence of progressive pancreatic cancer while
receiving platinum-based therapy
- Patient must be >= 21 days (three weeks) from their last treatment (including
chemotherapy or radiotherapy) but =< 56 days (eight weeks) from their last treatment.
Patients who have received neoadjuvant and/or adjuvant radiotherapy are eligible
- Patient must have recovered from any adverse events due to prior anti-cancer therapy
(i.e., have no residual toxicities > grade 1 with the exception of alopecia and/or
neuropathy)
- Leukocytes >= 3,000/mcL (obtained =< 14 days prior to randomization)
- Absolute neutrophil count >= 1,500/mcL (obtained =< 14 days prior to randomization)
- Platelets >= 100,000/mcL (obtained =< 14 days prior to randomization)
- Hemoglobin >= 10.0 g/dL with no blood transfusion in the past 28 days (obtained =< 14
days prior to randomization)
- Total bilirubin =< institutional upper limit of normal (ULN) except in patients with
Gilbert's syndrome. Patients with Gilbert's syndrome may enroll if direct bilirubin =<
2.5 ULN of the direct bilirubin (obtained =< 14 days prior to randomization)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 institutional ULN (obtained =< 14 days prior to randomization)
- Creatinine =< institutional ULN OR calculated Cockcroft Gault creatinine clearance >
50 mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney function
values, no lower than 30 mL/min/1.73 m^2 (obtained =< 14 days prior to randomization)
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- 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
- Patient must have the ability to understand the willingness to sign a written informed
consent document, or have legally authorized representative provide authorization to
participate
Exclusion Criteria:
- STEP 1 (RANDOMIZATION) EXCLUSION CRITERIA
- Patient must have no evidence of recurrent or metastatic pancreatic cancer at the time
of randomization as documented by baseline scans obtained =< 4 weeks prior to
randomization
- Patient must not be receiving any other investigational agents at the time of
randomization and while on protocol treatment
- Patient must not have any history of allergic reactions attributed to compounds of
similar chemical or biological composition to olaparib
- Patient must not have any personal history of myelodysplastic syndrome (MDS) or acute
myeloid leukemia (AML). Patients with myelodysplastic syndrome/acute myeloid leukemia
or with features suggestive of MDS/AML.
- Patient must not have any uncontrolled gastrointestinal disorder that would, in the
opinion of the investigator, interfere with the ingestion or absorption of olaparib
- Patient must not be pregnant or breast-feeding due the potential harm to an unborn
fetus and possible risk for adverse events in nursing infants with the treatment
regimens being used. All patients of childbearing potential must have a blood test or
urine study within 14 days prior to randomization to rule out pregnancy. A patient of
childbearing potential is defined as anyone, regardless of sexual orientation or
whether they have undergone tubal ligation, who meets the following criteria: 1) has
achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral
oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer
therapy does not rule out childbearing potential) for at least 24 consecutive months
(i.e., has had menses at any time in the preceding 24 consecutive months)
- Patients of childbearing potential and sexually active patients must not expect to
conceive or father children by using accepted and effective method(s) of contraception
or abstaining from sexual intercourse for the duration of their participation in the
study and for 6 months after the last dose of protocol treatment. Patients must also
not donate sperm while on protocol treatment and for 6 months after the last dose of
protocol treatment. Patients must also not breast-feed while on protocol treatment and
for 3 months after the last dose of protocol treatment
- Patient must not have resting electrocardiogram (ECG) indicating uncontrolled,
potentially reversible cardiac conditions, as judged by the investigator (e.g.
unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure,
corrected QT (QTc) prolongation > 500 ms, electrolyte disturbances, etc.) or have
congenital long QT syndrome
- Concomitant use of known potent CYP3A4/5 inhibitors such as ketoconazole,
itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and
nelfinavir is prohibited
- Patients who are being actively treated for an ongoing concurrent malignancy are
ineligible, with the exception of those receiving adjuvant hormone therapies and those
receiving topical therapies for skin cancers
- Patient must not have, in the opinion of the investigator, any other concurrent
medical condition that would prevent the patient from complying with the study
procedures
- Patient must not be considered a poor medical risk due to a serious, uncontrolled
medical disorder, non-malignant systemic disease or active, uncontrolled infection.
Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent
(within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable
spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral
lung disease on high resolution computed tomography (HRCT) scan or any psychiatric
disorder that prohibits obtaining informed consent
- Patient must not have had major surgery within 2 weeks prior to randomization and
patients must have recovered from any effects of any major surgery
