Testing the Addition of Pembrolizumab, an Immunotherapy Cancer Drug to Olaparib Alone as Therapy for Patients With Pancreatic Cancer That Has Spread With Unhealthy Tumor Suppressor Genes

Randomized Phase II Clinical Trial of Olaparib + Pembrolizumab vs. Olaparib Alone as Maintenance Therapy in Metastatic Pancreatic Cancer Patients With Germline BRCA1 or BRCA2 Mutations

Sponsors

Lead Sponsor: National Cancer Institute (NCI)

Source National Cancer Institute (NCI)
Brief Summary

This phase II trial investigates how well pembrolizumab and olaparib work in treating patients with pancreatic cancer with germline BRCA1 or BRCA2 mutations that has spread to other places in the body (metastatic). PARPs are proteins that help repair deoxyribonucleic acid (DNA) mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. The addition of pembrolizumab to the usual treatment of olaparib may help to shrink the tumors in patients with pancreatic cancer.

Detailed Description

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 overall response rate (ORR) by immune RECIST, 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.

V. 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. 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. 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. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for 30 days and every 6 months for 3 years from the date of randomization.

Overall Status Not yet recruiting
Start Date December 9, 2020
Completion Date March 31, 2025
Primary Completion Date March 31, 2025
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Progression-free survival (PFS) Up to 3 years
Secondary Outcome
Measure Time Frame
Incidence of adverse events Up to 3 years
Overall survival Up to 3 years
Overall response rate (ORR) Up to 3 years
ORR Up to 3 years
Duration of response (DoR) Up to 3 years
Enrollment 88
Condition
Intervention

Intervention Type: Drug

Intervention Name: Olaparib

Description: Given PO

Intervention Type: Biological

Intervention Name: Pembrolizumab

Description: Given IV

Arm Group Label: Arm A (olaparib, pembrolizumab)

Eligibility

Criteria:

Inclusion Criteria:

- Patient 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)

- Patient 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], or gemcitabine + cisplatin)

- Patients must have had a computed tomography (CT) or magnetic resonance imaging (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 but no more than 24 weeks of first line platinum-based therapy for metastatic disease

- 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

- Zubrod performance status of 0-1

- Patients must have a complete medical history and physical exam within 28 days prior to registration

- Absolute neutrophil count >= 1,500/mcL (within 14 days of registration)

- Platelets >= 100,000/mcL (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)

- Creatinine =< 1.5 mg/dl (within 14 days of registration)

- Albumin >= 3.0 (within 14 days of 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

- 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

- 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

Exclusion Criteria:

- 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

- 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

- Participants must not be pregnant or nursing due to the possibility of harm to the fetus or nursing infant from this treatment regimen. 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

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Vincent Chung Principal Investigator Southwest Oncology Group
Verification Date

September 2020

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Arm A (olaparib, pembrolizumab)

Type: Experimental

Description: Patients receive olaparib PO BID on days 1-21 and pembrolizumab IV over 30 minutes on day 1. 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. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.

Label: Arm B (olaparib)

Type: Active Comparator

Description: Patients receive olaparib PO BID on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patient Data Yes
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov