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Testing the Addition of Pembrolizumab, an Immunotherapy Cancer Drug to Olaparib Alone as Therapy for Patients With Pancreatic Cancer That Has Spread With Inherited BRCA Mutations

NCT04548752

Description:

This phase II trial studies whether adding pembrolizumab to olaparib (standard of care) works better than olaparib alone in treating patients with pancreatic cancer with germline BRCA1 or BRCA2 mutations that has spread to other places in the body (metastatic). BRCA1 and BRCA2 are human genes that produce tumor suppressor proteins. These proteins help repair damaged deoxyribonucleic acid (DNA) and, therefore, play a role in ensuring the stability of each cell's genetic material. When either of these genes is mutated, or altered, such that its protein product is not made or does not function correctly, DNA damage may not be repaired properly. As a result, cells are more likely to develop additional genetic alterations that can lead to some types of cancer, including pancreatic cancer. 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. Olaparib is an inhibitor of PARP, a protein that helps repair damaged DNA. Blocking PARP may help keep tumor cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. The addition of pembrolizumab to the usual treatment of olaparib may help to shrink tumors in patients with metastatic pancreatic cancer with BRCA1 or BRCA2 mutations.

Related Conditions:
  • Pancreatic Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of Pembrolizumab, an Immunotherapy Cancer Drug to Olaparib Alone as Therapy for Patients With Pancreatic Cancer That Has Spread With Inherited BRCA Mutations
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-06838
  • SECONDARY ID: NCI-2020-06838
  • SECONDARY ID: S2001
  • SECONDARY ID: S2001
  • SECONDARY ID: U10CA180888
  • NCT ID: NCT04548752

Conditions

  • Metastatic Pancreatic Adenocarcinoma
  • Stage IV Pancreatic Cancer AJCC v8

Interventions

DrugSynonymsArms
OlaparibAZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Arm A (olaparib, pembrolizumab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Arm A (olaparib, pembrolizumab)

Purpose

This phase II trial studies whether adding pembrolizumab to olaparib (standard of care) works better than olaparib alone in treating patients with pancreatic cancer with germline BRCA1 or BRCA2 mutations that has spread to other places in the body (metastatic). BRCA1 and BRCA2 are human genes that produce tumor suppressor proteins. These proteins help repair damaged deoxyribonucleic acid (DNA) and, therefore, play a role in ensuring the stability of each cell's genetic material. When either of these genes is mutated, or altered, such that its protein product is not made or does not function correctly, DNA damage may not be repaired properly. As a result, cells are more likely to develop additional genetic alterations that can lead to some types of cancer, including pancreatic cancer. 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. Olaparib is an inhibitor of PARP, a protein that helps repair damaged DNA. Blocking PARP may help keep tumor cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. The addition of pembrolizumab to the usual treatment of olaparib may help to shrink tumors in patients with metastatic pancreatic cancer with BRCA1 or BRCA2 mutations.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (olaparib, pembrolizumab)ExperimentalPatients 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.
  • Olaparib
  • Pembrolizumab
Arm B (olaparib)Active ComparatorPatients receive olaparib PO BID on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Olaparib

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)

          -  Hemoglobin >= 9.0 g/dL

          -  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. 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

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:Up to 3 years
Safety Issue:
Description:Primary analysis of PFS will be conducted in all eligible patients according to the intent-to-treat principle using a log rank test stratified by first line chemotherapy, performance status and disease status after first line platinum-based treatment. Distributions of PFS by treatment arm will be estimated using the method of Kaplan-Meier.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 3 years
Safety Issue:
Description:Will utilize the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 for toxicity and serious adverse event reporting.
Measure:Overall survival
Time Frame:Up to 3 years
Safety Issue:
Description:Distributions of overall survival in each arm will be estimated using the method of Kaplan-Meier and compared using the stratified log-rank test.
Measure:Overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST)
Time Frame:Up to 3 years
Safety Issue:
Description:Measured per RECIST 1.1. ORR will be estimated in the subset of patients with measurable disease. Assuming 90% of patients (n=35 per arm) will present with measurable disease, ORR can be estimated to within 18% (95% confidence interval) and will be compared by treatment arm using logistic regression.
Measure:ORR per Immune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST)
Time Frame:Up to 3 years
Safety Issue:
Description:Measured per iRECIST. ORR will be estimated in the subset of patients with measurable disease. Assuming 90% of patients (n=35 per arm) will present with measurable disease, ORR can be estimated to within 18% (95% confidence interval) and will be compared by treatment arm using logistic regression.
Measure:Duration of response (DoR)
Time Frame:Up to 3 years
Safety Issue:
Description:Distributions of DoR in each arm will be estimated using the method of Kaplan-Meier and compared using the stratified log-rank test.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

May 28, 2021