Clinical Trials /

A Study of Pembrolizumab and Olaparib for People With Metastatic Pancreatic Ductal Adenocarcinoma and Homologous Recombination Deficiency or Exceptional Treatment Response to Platinum-Based Therapy

NCT04666740

Description:

The study researchers think that combining the drugs pembrolizumab and olaparib (POLAR) may help people with this disease because pembrolizumab activates the immune system to fight cancer, and olaparib destroys cancer cells by preventing them from repairing damage to the genetic information that helps them survive and grow. The study researchers are doing this study to find out whether combining these drugs may be a more effective treatment for this cancer than taking olaparib alone.

Related Conditions:
  • Pancreatic Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Pembrolizumab and Olaparib for People With Metastatic Pancreatic Ductal Adenocarcinoma and Homologous Recombination Deficiency or Exceptional Treatment Response to Platinum-Based Therapy
  • Official Title: A Phase 2 Trial to Evaluate the Safety and Antitumor Activity of Pembrolizumab and OLApaRib (POLAR) Maintenance for Patients With Metastatic Pancreatic Ductal Adenocarcinoma and Homologous Recombination Deficiency and/or Exceptional Treatment Response to Platinum-Based Therapy

Clinical Trial IDs

  • ORG STUDY ID: 20-481
  • NCT ID: NCT04666740

Conditions

  • Metastatic Pancreatic Ductal Adenocarcinoma
  • Homologous Recombination Deficiency (HRD)

Interventions

DrugSynonymsArms
PembrolizumabCohort A: Core HRD
OlaparibCohort A: Core HRD

Purpose

The study researchers think that combining the drugs pembrolizumab and olaparib (POLAR) may help people with this disease because pembrolizumab activates the immune system to fight cancer, and olaparib destroys cancer cells by preventing them from repairing damage to the genetic information that helps them survive and grow. The study researchers are doing this study to find out whether combining these drugs may be a more effective treatment for this cancer than taking olaparib alone.

Trial Arms

NameTypeDescriptionInterventions
Cohort A: Core HRDExperimentalPatients with either pathogenic germline or somatic alterations of 3 core homologous recombination-genes (HR-genes) - (BRCA1/2, or PALB2) who have stable or responding disease on first-line or second-line platinum therapy in two consecutive imaging assessments over at least 4 months are eligible for inclusion in Cohort A.
  • Pembrolizumab
  • Olaparib
Cohort B: Non core HRDExperimentalPatients with either pathogenic somatic or germline non-core 14 HR-gene alterations (ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, RTEL1) who have stable or responding disease on first-line or second-line platinum therapy in two consecutive imaging assessments over at least 4 months are eligible for inclusion in Cohort B.
  • Pembrolizumab
  • Olaparib
Cohort C: Platinum sensitiveExperimentalPatients without any of the above HR-gene alterations included in Cohort A and B who have platinum-sensitivity, which is defined as a partial response (PR) or complete response (CR) for the best overall response (BOR) during at least 4 months on platinumbased therapy. Variants of unknown significance of candidate HR-genes from Cohort A or B will be eligible for Cohort C if they meet the partial response to platinum criterion.
  • Pembrolizumab
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          1. This is an on-platinum maintenance trial either in a first-line or second-line
             setting.

             Participants must have either stable disease or responding disease on current
             first-line or second-line platinum treatment for metastatic disease.

          2. Male or female patients with cytologically or histologically confirmed metastatic
             pancreas adenocarcinoma with homologous recombination gene alterations or platinum
             sensitivity. Patients will be assigned to cohorts based on their genetic alterations
             and clinical response. Patient stratification to different Cohorts will be in the
             order of more canonical homologous recombination-gene (HR-gene) order. For example,
             patients who meet criteria for both A and B Cohorts, they will be assigned to Cohort
             A, not B. Cohorts will be defined as following by CLIA-approved NGS or MSK-IMPACT Part
             A or C:

               -  Cohort A: Patients with either pathogenic germline or somatic alterations of 3
                  core HR-genes (BRCA1/2, or PALB2) who have stable or responding disease on
                  first-line or second-line platinum therapy in two consecutive imaging assessments
                  over at least 4 months are eligible for inclusion in Cohort A.

               -  Cohort B: Patients with either pathogenic somatic or germline non-core 14 HR-gene
                  alterations (ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN,
                  RAD50, RAD51, RAD51C, RTEL1) who have stable or responding disease on first-line
                  or second-line platinum therapy in two consecutive imaging assessments over at
                  least 4 months are eligible for inclusion in Cohort B.

               -  Cohort C: Patients without any of the above HR-gene alterations included in
                  Cohort A and B who have platinum-sensitivity, which is defined as a partial
                  response (PR) or complete response (CR) for the best overall response (BOR)
                  during at least 4 months on platinumbased therapy. Variants of unknown
                  significance of candidate HR-genes from Cohort A or B will be eligible for Cohort
                  C if they meet the partial response to platinum criterion.

               -  Variants of unknown significance (VUS) or benign polymorphisms of above 17
                  HR-genes from Cohort A and B are considered non-pathogenic and will be excluded
                  from cohort A or B. However, if the participant demonstrates platinum
                  sensitivity, patient can be considered eligible for Cohort C.

          3. A recurrence after curative surgery is eligible if the recurrence is > 6 months after
             the last date of adjuvant therapy and the participant has at least stable or
             responding disease on platinum therapy and meet the above genomic or platinum
             sensitivity criteria.

          4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 .

          5. Patients must have normal organ and bone marrow function measured within 28 days prior
             to administration of study treatment as defined as below:

               -  Absolute neutrophil count (ANC) ≥1500/μL

               -  Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La

               -  Platelets ≥100 000/μL

               -  Total bilirubin ≤ 2 × ULN

               -  AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for if liver metastases)

               -  Creatinine ≤2 × ULN

          6. Patients with measurable disease and/or non-measurable or no evidence of disease
             assessed at baseline by CT (or MRI where CT is contraindicated) are eligible.

          7. Postmenopausal or evidence of non-childbearing status for women of childbearing
             potential: negative urine or serum pregnancy test. Postmenopausal is defined as:

               -  Amenorrhoeic for 1 year or more following cessation of exogenous hormonal
                  treatments

               -  Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the
                  postmenopausal range for women under 50

               -  Radiation-induced oophorectomy with last menses >1 year ago

               -  Chemotherapy-induced menopause with >1-year interval since last menses

               -  Surgical sterilization (bilateral oophorectomy or hysterectomy)

        Exclusion Criteria:

          1. Disease progression on either a first-line or the second-line platinum for metastatic
             PDAC.

          2. Patients with a second (or more) primary cancer, EXCEPTIONS: adequately treated
             nonmelanoma skin cancer, curatively treated in-situ cancer of the cervix, Ductal
             Carcinoma in Situ (DCIS), stage 1 grade 1 endometrial carcinoma, or other solid
             tumours including lymphomas curatively treated and with no evidence of disease for ≥ 2
             years prior to study entry, are eligible.

          3. Resting EKG with QTC ≥ 450 msec detected on 2 or more time points within a 24-hour
             period or family history of long QT syndrome. If EKG demonstrates QTC ≥ 450 msec,
             patient will only be eligible if repeat EKG demonstrates QTC ≤ 450 msec.

          4. Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features
             suggestive of MDS/AML.

          5. Previous allogeneic bone marrow transplant.

          6. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence
             of brain metastases is not required for eligibility. The patient can receive a stable
             dose of corticosteroids before and during the study as long as the steroids were
             started at least 4 weeks prior to treatment and the steroid dose is < 10 mg/day.
             Patients with spinal cord compression unless considered to have received definitive
             treatment for this and evidence of clinically stable disease for 28 days.

          7. Patients unable to swallow orally administered medication and patients with
             gastrointestinal disorders likely to interfere with absorption of the study
             medication.

          8. A diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in
             dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study drug.

          9. Immunocompromised patients, e.g., patients who are known to be serologically positive
             for human immunodeficiency virus (HIV).

         10. Patients with known active hepatitis (i.e. Hepatitis B or C).

               1. Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen
                  (HBsAg) result. Patients with a past or resolved HBV infection (defined as the
                  presence of hepatitis B core antibody and absence of HBsAg) are eligible.

               2. Patients positive for hepatitis C virus (HCV) antibody are eligible only if
                  polymerase chain reaction is negative for HCV RNA.

               3. Has a known history of active TB (Bacillus tuberculosis).

         11. Any prior treatment with any PARP inhibitor, including olaparib.

         12. Any previous treatment with any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

         13. Patients with any recent investigational agents are not eligible unless at least 2
             weeks or 5 half-lives of investigational agent prior to the first dose of study
             treatment have passed.

         14. Live vaccines within 30 days prior to the first dose of study treatment and while
             participating in the study are not permitted. Examples of live vaccines include, but
             are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow
             fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are
             generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.

         15. Active autoimmune disease that has required systemic treatment in the past 2 years is
             not permitted (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.

         16. Palliative radiotherapy must have been completed 14 or more days before Cycle 1 Day 1.

         17. If participant received major surgery within 4 weeks before screening, they must have
             recovered adequately from the toxicity and/or complications from the intervention
             prior to starting study treatment.

         18. Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or
             baseline. Participants with ≤Grade 2 neuropathy may be eligible. Participants with
             ≤Grade 2 alopecia may be eligible as well.

         19. Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin,
             clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
             saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.
             ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
             period prior to starting is 2 weeks.

         20. Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin,
             rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or
             moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout
             period prior to starting is 5 weeks for enzalutamide or phenobarbital and 3 weeks for
             other agents.
      
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:6 months
Safety Issue:
Description:PFS is defined as the time from the initiation of study treatment to radiographic progression or death.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:6 months
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • Pembrolizumab
  • OLApaRib (POLAR)
  • 20-481

Last Updated

December 17, 2020