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A Randomized Study of Olaparib or Placebo in Patients With Surgically Removed Pancreatic Cancer Who Have a BRCA1, BRCA2 or PALB2 Mutation, The APOLLO Trial

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ClinicalTrials.gov Identifier: NCT04858334
Recruitment Status : Recruiting
First Posted : April 26, 2021
Last Update Posted : December 3, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial investigates how well the addition of olaparib following completion of surgery and chemotherapy works in treating patients with pancreatic cancer that has been surgically removed (resected) and has a pathogenic mutation in BRCA1, BRCA2, or PALB2. Olaparib 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.

Condition or disease Intervention/treatment Phase
Pancreatic Acinar Cell Carcinoma Pancreatic Adenosquamous Carcinoma Pancreatic Carcinoma Pancreatic Squamous Cell Carcinoma Resectable Pancreatic Acinar Cell Carcinoma Resectable Pancreatic Adenocarcinoma Resectable Pancreatic Adenosquamous Carcinoma Resectable Pancreatic Carcinoma Stage 0 Pancreatic Cancer AJCC v8 Stage I Pancreatic Cancer AJCC v8 Stage IA Pancreatic Cancer AJCC v8 Stage IB Pancreatic Cancer AJCC v8 Stage II Pancreatic Cancer AJCC v8 Stage IIA Pancreatic Cancer AJCC v8 Stage IIB Pancreatic Cancer AJCC v8 Drug: Olaparib Drug: Placebo Administration Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 152 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: APOLLO: A Randomized Phase II Double-Blind Study of Olaparib Versus Placebo Following Adjuvant Chemotherapy in Patients With Resected Pancreatic Cancer and a Pathogenic BRCA1, BRCA2 or PALB2 Mutation
Actual Study Start Date : April 29, 2021
Estimated Primary Completion Date : November 30, 2024
Estimated Study Completion Date : November 30, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Olaparib

Arm Intervention/treatment
Experimental: Arm I (olaparib)
Patients receive olaparib PO BID on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Olaparib
Given PO
Other Names:
  • AZD 2281
  • AZD-2281
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281

Placebo Comparator: Arm II (placebo)
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.
Drug: Placebo Administration
Given PO




Primary Outcome Measures :
  1. Improvement in relapse-free survival (RFS) [ Time Frame: From randomization to first documentation of disease recurrence (primary tumor relapse) or death, assessed from 22 months to 44 months ]
    Will demonstrate an improvement in the RFS from 22 months to 44 months (hazard ratio 0.5) in patients treated with olaparib after perioperative (neoadjuvant, adjuvant or a combination) chemotherapy compared to those treated with perioperative therapy alone.


Secondary Outcome Measures :
  1. RFS [ Time Frame: From randomization to first documentation of disease recurrence (primary tumor relapse) or death, assessed up to 5 years ]
    Will evaluate RFS in patients with olaparib after perioperative chemotherapy compared to those treated with perioperative therapy alone. Analysis will be largely exploratory. Within each arm any proportion endpoint (toxicity, mutation rate, etc.) will be estimable with a 95% confidence interval that will be no wider than 26 percentage points.

  2. Overall survival (OS) [ Time Frame: From randomization until 10 years after registration or until death, whichever comes first ]
    Analysis will be largely exploratory. Power for overall survival in particular will be limited. Within each arm any proportion endpoint (toxicity, mutation rate, etc.) will be estimable with a 95% confidence interval that will be no wider than 26 percentage points.

  3. Efficacy of olaparib after chemotherapy in patients with a pathogenic germline BRCA or PALB2 mutation [ Time Frame: Up to 10 years ]
    Will analyze the efficacy of olaparib after chemotherapy in patients with a pathogenic germline BRCA or PALB2 mutation compared to those with a somatic mutation.

  4. Differences in survival [ Time Frame: Up to 10 years ]
    Will analyze survival differences between patients who received neoadjuvant or perioperative chemotherapy compared to those who received adjuvant therapy alone.

  5. RFS in those who received =< 3 months of perioperative platinum chemotherapy compared to > 3 months of perioperative platinum chemotherapy [ Time Frame: From randomization to first documentation of disease recurrence (primary tumor relapse) or death, assessed up to 5 years ]
    Analysis will be largely exploratory. Within each arm any proportion endpoint (toxicity, mutation rate, etc.) will be estimable with a 95% confidence interval that will be no wider than 26 percentage points.

  6. OS in those who received =< 3 months of perioperative platinum chemotherapy versus > 3 months of perioperative platinum chemotherapy [ Time Frame: From randomization until 10 years after registration or until death, whichever comes first ]
    Analysis will be largely exploratory. Power for overall survival in particular will be limited. Within each arm any proportion endpoint (toxicity, mutation rate, etc.) will be estimable with a 95% confidence interval that will be no wider than 26 percentage points.

  7. RFS in those who received any platinum-based perioperative chemotherapy versus no platinum-based perioperative chemotherapy [ Time Frame: From randomization to first documentation of disease recurrence (primary tumor relapse) or death, assessed up to 5 years ]
    Analysis will be largely exploratory. Within each arm any proportion endpoint (toxicity, mutation rate, etc.) will be estimable with a 95% confidence interval that will be no wider than 26 percentage points.

  8. OS in those who received any platinum-based perioperative chemotherapy versus no platinum-based perioperative chemotherapy [ Time Frame: From randomization until 10 years after registration or until death, whichever comes first ]
    Analysis will be largely exploratory. Power for overall survival in particular will be limited. Within each arm any proportion endpoint (toxicity, mutation rate, etc.) will be estimable with a 95% confidence interval that will be no wider than 26 percentage points.


Other Outcome Measures:
  1. RFS and OS differences in patients who had R1 vs R0 resections [ Time Frame: At time of study enrollment ]
  2. RFS and OS differences in patients who had lymph node positivity at resection [ Time Frame: At time of study enrollment ]
  3. RFS and OS differences in patients who had elevated or rising CA 19-9 or CEA [ Time Frame: At time of study enrollment ]
    A cutoff of 35 will be used to determine elevated versus normal CA 19-9 (i.e., greater than 35 will be considered elevated), and the cutoff for CEA will be based on the treating institution's definition of the upper limit of normal. Univariate differences by marker status will be analyzed and Cox proportional hazards models will be fit, adjusting for other clinical and demographic factors that may be confounders.

  4. RFS and OS differences with those who had resectable disease at diagnosis [ Time Frame: Up to 10 years ]
    Will be compared to those who did not.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04858334


Locations
Show Show 309 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Kim A Reiss Binder ECOG-ACRIN Cancer Research Group
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04858334    
Other Study ID Numbers: NCI-2020-05659
NCI-2020-05659 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
EA2192 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
EA2192 ( Other Identifier: CTEP )
U10CA180820 ( U.S. NIH Grant/Contract )
First Posted: April 26, 2021    Key Record Dates
Last Update Posted: December 3, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Pancreatic Neoplasms
Carcinoma, Adenosquamous
Carcinoma, Acinar Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Neoplasms, Complex and Mixed
Olaparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents