APOLLO: A Randomized Phase II Double-Blind Study of Olaparib Versus Placebo Following Curative Intent Therapy in Patients With Resected Pancreatic Cancer and a Pathogenic BRCA1, BRCA2 or PALB2 Mutation
A
Anita Turk, MD
Primary Investigator
Overview
This phase II trial investigates how well the addition of olaparib following completion ofurgery and chemotherapy works in treating patients with pancreatic cancer that has beenurgically removed (resected) and has a pathogenic mutation in BRCA1, BRCA2, or PALB2.b is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA)
when it becomes damaged. Blocking PARP may help keep tumor cells from repairing their damaged
DNA, causing them to die. PARP inhibitors are a type of targeted therapy.
Description
PRIMARY OBJECTIVE:
I. To determine the relapse-free survival (RFS)-benefit from the addition of a maintenanceb following completion of chemotherapy in patients with resected pancreatic carcinomad 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 tohose treated with perioperative therapy alone among patients who received priorum-based perioperative chemotherapy.
II. To evaluate overall survival (OS) in patients treated with olaparib after adjuvanthemotherapy 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 orve chemotherapy compared to those who received adjuvant therapy alone.
V. To analyze RFS and OS differences in those who received =< 3 months of perioperativeum chemotherapy compared to those who received > 3 months of perioperative platinumhemotherapy.
VI. To analyze RFS and OS differences in those who received any platinum-based perioperativehemotherapy 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, lymphde positivity at resection, and/or elevated or rising CA 19-9 or CEA at time of studyhe post-operative setting.
II. To analyze RFS and OS differences with those who had resectable disease at diagnosisd 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. Treatmentvery 28 days for 12 cycles in the absence of disease progression or unacceptabley. Patients also undergo computed tomography (CT) scans/magnetic resonance imaging
(MRI) and collection of blood throughout the study.
ARM II: Patients receive placebo PO BID on days 1-28. Treatment repeats every 28 days for 12ycles in the absence of disease progression or unacceptable toxicity. Patients also undergo
CT scans/MRI and collection of blood throughout the study.
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.
Eligibility
You may be eligible for this study if you meet the following criteria:
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Conditions:
Pancreatic Acinar Cell Carcinoma, Pancreatic Adenosquamous Carcinoma, Pancreatic Squamous Cell Carcinoma, Resectable Pancreatic Acinar Cell Carcinoma, Resectable Pancreatic Adenocarcinoma, Resectable Pancreatic Adenosquamous Carcinoma, Resectable Pancreatic Carcinoma
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Age: 18 Years
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Gender: All
Inclusion Criteria:
- STEP 0 (PRE-REGISTRATION) INCLUSION CRITERIA
- Patient must be >= 18 years of age on day of consent
- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of2
- Patient must have a diagnosis of pancreatic cancer and have successfully undergone aurative intent surgical resection and must have no evidence of recurrent disease asdetermined by the investigator
- NOTE: This includes patients with adenocarcinoma, acinar carcinoma, squamous celldenosquamous and variants thereof. Patients with neuroendocrine tumorsuded from enrolling
- Patient must (1) be planning to receive, (2) be receiving or (3) have received at
least three combined months (i.e., 12 weeks) of perioperative (neoadjuvant, adjuvantbination of both) systemic, multi-agent chemotherapy. Patients may have had up6 months of perioperative systemic therapy as deemed appropriate by their primaryg medical team (patients can have received radiation or chemoradiation inddition to this 6 month course)
- Patient must be no more than 12 weeks from their most recent treatment (this may behemotherapy, radiotherapy or surgery)
- Patient must have a known pathogenic or likely pathogenic germline or somatic mutationBRCA1, BRCA2, or PALB2, as determined by a Clinical Laboratory ImprovementAmendments (CLIA) certified or equivalently-accredited laboratory. Mutations must bedered pathogenic or likely pathogenic by a reference database such as ClinVar orKb.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) ofve (neoadjuvant, adjuvant or a combination of both) systemic, multi-agenthemotherapy. Patients may have had up to 6 months of perioperative systemic therapydeemed appropriate by their primary treating medical team (patients can haveved radiation or chemoradiation in addition to this 6 months course)
- Central expert reviewer must have determined the patient eligible for randomizationview of local genetic testing reports
- If mutation in BRCA1, BRCA2 or PALB2 was identified in tumor tissue and the patienthas not previously undergone germline testing, the patient must agree to undergogermline testing
- Patient must have no evidence of recurrent or metastatic pancreatic cancer at the timedomization as documented by baseline scans obtained =< 4 weeks prior to Step 1domization
- Patient must not have previously had evidence of progressive pancreatic cancer whileving platinum-based therapy
- Patient must be >= 21 days (three weeks) from their last treatment (includinghemotherapy radiotherapy or surgery) but =< 84 days (twelve weeks) from their lasthe time of Step 1 randomization. Patients who have received neoadjuvantd/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/oruropathy)
- Patient must not be receiving any other investigational agents at the time of Step 1domization and while on protocol treatment
- Patient must not have any history of allergic reactions attributed to compounds ofhemical or biological composition to olaparib
- Patient must not have any personal history of myelodysplastic syndrome (MDS) or acuteyeloid leukemia (AML). Patients with myelodysplastic syndrome/acute myeloid leukemiawith features suggestive of MDS/AML.
- Patient must not have any uncontrolled gastrointestinal disorder that would, in thehe investigator, interfere with the ingestion or absorption of olaparib
- Patient must not be pregnant or breast-feeding due the potential harm to an unbornus and possible risk for adverse events in nursing infants with the treatmentgimens being used. All patients of childbearing potential must have a blood test orurine study within 14 days prior to Step 1 randomization to rule out pregnancy. Ahildbearing potential is defined as anyone, regardless of sexualwhether they have undergone tubal ligation, who meets the following: 1) has achieved menarche at some point, 2) has not undergone a hysterectomybilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrheawing cancer therapy does not rule out childbearing potential) for at least 24utive months (i.e., has had menses at any time in the preceding 24 consecutivehs)
- Patients must not expect to conceive or father children by using accepted andve method(s) of contraception or by abstaining from sexual intercourse for theduration of their participation in the study and for 6 months after the last dose ofd for 3 months after the last dose of. Patients must also not donate sperm while ond for 3 months after the last dose of protocol treatment.Patients must also not breast-feed while on protocol treatment and for 1 month afterhe last dose of protocol treatment
- Leukocytes >= 3,000/mcL (obtained =< 28 days prior to Step 1 randomization)
- Absolute neutrophil count >= 1,500/mcL (obtained =< 28 days prior to Step 1domization)
- Platelets >= 100,000/mcL (obtained =< 28 days prior to Step 1 randomization)
- Hemoglobin >= 9.0 g/dL with no blood transfusion in the past 28 days (obtained =< 28days prior to Step 1 randomization)
- Total bilirubin =< 1.5 institutional upper limit of normal (ULN) except in patientswith Gilbert's syndrome. Patients with Gilbert's syndrome may enroll if directbilirubin =< 2.5 x ULN of the direct bilirubin (obtained =< 28 days prior to Step 1domization)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])=< 2.5 institutional ULN (obtained =< 28 days prior to Step 1 randomization)
- Creatinine =< 1.5 institutional ULN OR calculated Cockcroft Gault creatinine clearance> 50 mL/min/1.73 m^2 (obtained =< 28 days prior to Step 1 randomization)
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviralherapy 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 virald must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treatedd cured. For patients with HCV infection who are currently on treatment, they aregible if they have an undetectable HCV viral load
- Patient must not have resting electrocardiogram (ECG) indicating uncontrolled,y reversible cardiac conditions, as judged by the investigator (e.g.unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure,d QT [QTc] prolongation > 500 ms, electrolyte disturbances, etc.) or havegenital long QT syndrome
- Concomitant use of known potent CYP3A4/5 inhibitors such as ketoconazole,zole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin andvir is prohibited
- Patients who are being actively treated for an ongoing concurrent malignancy aregible, with the exception of those receiving adjuvant hormone therapies and thoseving topical therapies for skin cancers
- Patient must not have, in the opinion of the investigator, any other concurrentdical condition that would prevent the patient from complying with the studydures
- Patient must not be considered a poor medical risk due to a serious, uncontrolleddical disorder, non-malignant systemic disease or active, uncontrolled infection.ude, but are not limited to, uncontrolled ventricular arrhythmia, recent(within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstabled compression, superior vena cava syndrome, extensive interstitial bilateralung disease on high resolution computed tomography (HRCT) scan or any psychiatricdisorder that prohibits obtaining informed consent
- Patient must have the ability to understand the willingness to sign a written informeddocument, or have legally authorized representative provide authorization to
- Patient must not have had major surgery within 2 weeks prior to Step 1 randomizationd patients must have recovered from any effects of any major surgery
Updated on
29 Apr 2024.
Study ID: NCI-2020-05659
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