Clinical Trials /

Niraparib and Dostarlimab for Treatment of Germline or Somatic BRCA1/2 and PALB2 Mutated Metastatic Pancreatic Cancer

NCT04493060

Description:

This phase II trial studies how well niraparib and dostarlimab work in treating patients with germline or somatic BRCA1/2 and PALB2 mutated pancreatic cancer that has spread to other places in the body (metastatic). Niraparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as dostarlimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving niraparib and dostarlimab may kill more tumor cells.

Related Conditions:
  • Pancreatic Ductal Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Niraparib and Dostarlimab for Treatment of Germline or Somatic BRCA1/2 and PALB2 Mutated Metastatic Pancreatic Cancer
  • Official Title: Phase II Study of Niraparib and TSR-042 in Patients With Germline or Somatic BRCA1/2 and PALB2-Related Pancreatic Cancer

Clinical Trial IDs

  • ORG STUDY ID: MC1841
  • SECONDARY ID: NCI-2020-05352
  • SECONDARY ID: MC1841
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT04493060

Conditions

  • Metastatic Pancreatic Ductal Adenocarcinoma
  • Stage IV Pancreatic Cancer AJCC v8

Interventions

DrugSynonymsArms
DostarlimabANB011, Immunoglobulin G4, Anti-programmed Cell Death Protein 1 (PDCD1) (Humanized Clone ABT1 Gamma4-chain), Disulfide with Humanized Clone ABT1 Kappa-chain, Dimer, TSR 042, TSR-042, TSR042Treatment (niraparib, dostarlimab)
NiraparibMK-4827, MK4827Treatment (niraparib, dostarlimab)

Purpose

This phase II trial studies how well niraparib and dostarlimab work in treating patients with germline or somatic BRCA1/2 and PALB2 mutated pancreatic cancer that has spread to other places in the body (metastatic). Niraparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as dostarlimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving niraparib and dostarlimab may kill more tumor cells.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine antitumor activity as measured by disease control rate at 12 weeks (DCR12) as
      assessed using immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST) in
      select homologous recombination repair (HRR) deficient pancreatic cancer patients with HRR
      deficiency (defined as mutations in BRCA 1/ 2, or PALB2).

      SECONDARY OBJECTIVES:

      I. To assess adverse events according to the current National Cancer Institute (NCI) Common
      Terminology Criteria for Adverse Events (CTCAE) and other safety parameters.

      II. To assess the time to next treatment (TTNT), objective response rate (ORR), time to and
      duration of response and duration of confirmed stable disease according to iRECIST.

      III. To assess progression-free survival. IV. To assess overall survival.

      CORRELATIVE RESEARCH OBJECTIVES:

      I. To assess germline deoxyribonucleic acid (DNA) and serum markers of immune response.

      II. To determine changes in circulating tumor DNA (ctDNA) profile after therapy with a PARP
      inhibitor (i) and a PD-1 inhibitor.

      III. To study mechanisms of resistance in ctDNA profile after therapy with a PARPi and a PD-1
      inhibitor.

      IV. To assess the tumor microenvironment for immune related changes (immune infiltration,
      PD-L1 and PD-1 expression, tumor-infiltrating lymphocytes [TIL]).

      V. To assess genetic profile of the tumor pre- and post-treatment. VI. To determine changes
      in the cytokine profile pre- and post-treatment.

      OUTLINE:

      Patients receive niraparib orally (PO) once daily (QD) on days 1-21. Patients also receive
      dostarlimab intravenously (IV) over 30 minutes on day 1 every 3 weeks (Q3W) for cycles 1-4
      and every 6 weeks (Q6W) for subsequent cycles. Cycles repeat every 21 days for up to 2 years
      in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, every 3 months
      until progressive disease (PD), and then every 6 months for up to 5 years after registration.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (niraparib, dostarlimab)ExperimentalPatients receive niraparib PO QD on days 1-21. Patients also receive dostarlimab IV over 30 minutes on day 1 Q3W for cycles 1-4 and Q6W for subsequent cycles. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Dostarlimab
  • Niraparib

Eligibility Criteria

        Inclusion Criteria:

          -  Presence of either a germline deleterious mutation or somatic deleterious mutation in
             any one of the genes in our proposed gene-panel as determined by any of the
             commercially available or institutional testing platforms. Note: The somatic mutation
             could be either on a tissue-based test or the circulating tumor DNA (ctDNA)-based
             assay. The 6 genes that would determine eligibility would be: BRCA1/2, PALB2, BRAD1,
             RAD51c, RAD51d

          -  Provide written informed consent

          -  Histological/cytological confirmation of diagnosis of metastatic pancreatic ductal
             adenocarcinoma

          -  At least one but no more than two prior lines of systemic therapy for metastatic
             disease (maintenance therapy is not considered a line of treatment)

               -  Note: Patients who have not had any prior chemotherapy can refuse chemotherapy
                  and be considered eligible. This refusal and their reason for refusal would have
                  to be documented

          -  Received a platinum agent as part of first or second line treatment (unless
             contraindicated)

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Serum creatinine =< 1.5 x upper limit of normal (ULN) or estimated glomerular
             filtration rate (eGFR) >= 60mL/min using the Cockcroft-Gault Equation (=< 14 days
             prior to registration)

          -  Hemoglobin >= 9.0 g/dL (=< 14 days prior to registration)

          -  Absolute neutrophil count >= 1500/uL (=< 14 days prior to registration:)

          -  Platelets >= 100x10^9/L (=< 14 days prior to registration)

          -  Total bilirubin =< 1.5 x ULN, (2.0 x ULN for subjects with Gilbert's disease) (=< 14
             days prior to registration:)

          -  Aspartate transaminase (AST) and alanine transaminase (ALT) =< 2.5x ULN (for subjects
             with hepatic metastases =< 5 x ULN) (=< 14 days prior to registration). Note: One time
             repeat testing to meet eligibility is allowed. If more testing is required, discuss
             with principal investigator (PI)

          -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
             patient is receiving anticoagulant therapy as long as PT or partial thromboplastin
             (PTT) is within therapeutic range of intended use of anticoagulants. Activated partial
             thromboplastin time (aPTT) =< 1.5 x ULN unless patient is receiving anticoagulant
             therapy as long as PT or PTT is within therapeutic range of intended use of
             anticoagulants (=< 14 days prior to registration)

          -  Evaluable or measurable disease per iRECIST

          -  Life expectancy of >= 3 months

          -  Willingness to consent to translational studies

          -  Willingness to undergo repeat biopsies of tumor lesions amenable to biopsy

               -  Note: While biopsies are mandatory, subjects are allowed to participate if no
                  lesions are amenable to biopsy, or if biopsy is not possible due to safety

          -  Willingness to not donate blood during the study or for 90 days after the last dose of
             study treatment

          -  Willingness to not breastfeed during the study or for 90 days after the last dose of
             study treatment

          -  Negative pregnancy test done =< 7 days prior to registration, for persons of
             childbearing potential only

        Exclusion Criteria:

          -  Known hypersensitivity to any component of study treatments (either niraparib and/or
             TSR-042 or similar medications)

          -  Prior treatment with the combination of PARP inhibition and immunotherapy (either
             CTLA-4 or anti-PD1/PD-L1 therapies). Prior treatment consisting of monotherapy with
             either PARP inhibitors and/or with immunotherapy are allowed. Treatment with PARPi or
             PD1 inhibitor as the most recent treatment prior to enrollment is not allowed

          -  Patient experienced >= grade 3 immune-related adverse events (AE) with prior
             immunotherapy, with the exception of non-clinically significant lab abnormalities

          -  Radiotherapy =< 2 weeks prior to first study treatment or radionuclide treatment =< 4
             weeks of first study treatment

          -  Live attenuated vaccine administration within 30 days prior to registration and/or
             expected during study period

          -  Known brain metastases, uncontrolled seizure disorder, or active neurologic disease
             which in the opinion of the investigator would impede participation within the trial.
             Subjects with treated brain metastases are allowed to enroll

          -  Allogeneic bone marrow transplantation or high-dose chemotherapy requiring
             hematopoietic stem cell rescue

          -  Received a transfusion (platelets or red blood cells) =< 4 weeks prior to registration

               -  NOTE: patients are also deemed ineligible if they have received a transfusion =<
                  4 weeks prior to first dose of niraparib

          -  Received colony-stimulating factors (eg, granulocyte colony-stimulating factor,
             granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) =< 4
             weeks prior to registration

               -  NOTE: patients are also deemed ineligible if they have received
                  colony-stimulating factors =< 4 weeks prior to first dose of niraparib

          -  Known grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy
             that persisted > 4 weeks and was related to the most recent treatment

          -  Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)

          -  =< 4 weeks since receiving treatment with another investigational drug, or anti-cancer
             therapy, or within a time interval less than at least 5 half-lives of the
             investigational agent (whichever is shorter), or insufficient recovery (to the
             judgement of the investigator) from adverse events due to such a previously
             administered agent, except for alopecia prior to initiating protocol therapy.
             Bisphosphonate therapy and Receptor activator of nuclear factor kappa-Β ligand (RANKL)
             inhibitors are not considered anti-cancer therapy

          -  Inadequate recovery from toxicity and/or complications from previous interventions,
             including due to major surgery to the judgement of the investigator. Minor surgery
             allowed up to 3 weeks from registration

          -  Primary or secondary immunodeficiency, including immunosuppressive disease, and
             immunosuppressive doses of corticosteroids (e.g., prednisone > 20 mg per day during 2
             weeks prior to first study treatment) or other immunosuppressive medications at dose
             levels that to the judgement of the investigator would preclude participation within
             the past 4 weeks prior to registration. Subjects with human immunodeficiency virus
             (HIV) who are stable on highly active antiretroviral therapy (HAART) will not be
             excluded

          -  Participant has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg]
             reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [qualitative]
             is detected)

          -  Pregnant or lactating

          -  Clinically significant, active, bacterial infections that, to the judgement of the
             investigator makes it undesirable for the subject to participate in the study

          -  Persons of childbearing potential (POCBP) or those capable of causing pregnancy whose
             sexual partners are POCBP who are unwilling or unable to use an effective method of
             contraception for at least 1 month prior to study entry, for the duration of the
             study, and for at least 180 days after the last dose of study drug. Nonchildbearing
             potential is defined as follows (by other than medical reasons):

               -  >= 45 years of age and has not had menses for > 1 year

               -  Patients who have been amenorrhoeic for < 2 years without history of a
                  hysterectomy and oophorectomy must have a follicle stimulating hormone value in
                  the postmenopausal range upon screening evaluation

               -  Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation.
                  Documented hysterectomy or oophorectomy must be confirmed with medical records of
                  the actual procedure or confirmed by an ultrasound. Tubal ligation must be
                  confirmed with medical records of the actual procedure, otherwise the patient
                  must be willing to use an adequate barrier method throughout the study, starting
                  with the screening visit through 180 days after the last dose of study treatment.
                  Information must be captured appropriately within the site's source documents.
                  Note: Abstinence is acceptable if this is the established and preferred
                  contraception for the patient

          -  History or active TB (Bacillus tuberculosis) that in the investigators opinion would
             preclude participation within the study

          -  Any gastro-intestinal conditions that to the judgement of the investigator would
             interfere with the absorption of niraparib

          -  Active, known or suspected unstable auto-immune disease, are excluded from this study.
             Exceptions to this criteria are all auto-immune disease that have remained stable
             within the past 3 months on corticosteroids (=< prednisone 20 mg or equivalent) prior
             to first study treatment are allowed to enroll

               -  Note: Paraneoplastic disease as a cause of auto-immune phenomenon will not be
                  considered as auto-immune disease and are allowed to enroll

          -  Evidence of serious uncontrolled medical disorder, active infection or mental disorder
             that, to the judgement of the investigator, makes it undesirable for the subject to
             participate in the study or that would jeopardize compliance with the protocol.
             Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent
             (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable
             spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that
             prohibits obtaining informed consent

          -  Prior malignancy which required active systemic treatment within 2 years prior to
             first study treatment. Exceptions are: successfully treated squamous cell carcinoma of
             the skin, superficial bladder cancer, and in situ carcinoma of the cervix. Since
             patients with BRCA 1/2 or PALB2 can have other tumors, as long as they have been
             definitively treated, it would not be considered an exclusion
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease control rate at 12 weeks (DCR12)
Time Frame:At 12 weeks
Safety Issue:
Description:Will be assessed using the standard immune-modified Response Evaluation Criteria in Solid Tumors (iRECIST) criteria.

Secondary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:Up to 5 years
Safety Issue:
Description:The confirmed response rate (by iRECIST ) will be assessed.
Measure:Time to next treatment (TTNT)
Time Frame:From the end of study treatment to receiving the next treatment, assessed up to 5 years
Safety Issue:
Description:TTNT will be estimated using the Kaplan-Meier method.
Measure:Overall survival (OS)
Time Frame:From study entry to death from any cause, assessed up to 5 years
Safety Issue:
Description:OS will be estimated using the Kaplan-Meier method.
Measure:Time to and duration of confirmed response
Time Frame:From the first documented date of confirmed response (complete response [CR] or partial response [PR]) to the date at which progression is first documented, assessed up to 5 years
Safety Issue:
Description:Will be assessed using the Kaplan-Meier method.
Measure:Progression-free survival (PFS)
Time Frame:From study entry to the first of either disease progression or death from any cause, assessed up to 5 years
Safety Issue:
Description:PFS will be estimated using the Kaplan-Meier method.
Measure:Incidence of adverse events (AEs)
Time Frame:Up to 5 years
Safety Issue:
Description:The maximum grade for each type of adverse event will be summarized using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The frequency and percentage of grade 3+ adverse events will be estimated. Will also assess AEs at least possibly related to treatment as well.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Mayo Clinic

Last Updated

July 27, 2020