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Phase II Trial of the PARP Inhibitor Niraparib and PD-1 Inhibitor Dostarlimab in Patients With Advanced Cancers With Active Progressing Brain Metastases (STARLET)

Recruiting
18 years of age
Both
Phase 2

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Overview

To learn if the combination of niraparib and dostarlimab can help to control advanced cancer that has spread to the brain.

Description

Primary Objective:

--To determine the intracranial objective response rate (ORR) of niraparib in combination with dostarlimab in patients with brain metastases.

Secondary Objectives:

  • To determine the duration of intracranial response (DoR) of niraparib in combination with dostarlimab in patients with brain metastases.
  • To determine the intracranial ORR, defined as assessed by RANO-BM and iRANO.
  • To assess the systemic antitumor activity of niraparib in combination with dostarlimab in patients with brain metastases as defined by ORR, CBR (Stable Disease [SD]>6m+CR+PR), progression free survival (PFS) and overall survival (OS).
  • Evaluate the safety and tolerability of niraparib in combination with dostarlimab in patients with brain metastases.

Explorative Objectives:

  • To assess predictive and pharmacodynamic (PD) markers of response.
  • To assess the immune-related effects of niraparib and dostarlimab.
  • To evaluate the effects of niraparib and dostarlimab on steroid, cranial radiation, and opiate pain medication use and seizure reduction.
  • To assess ctDNA in cerebrospinal fluid (CSF) in all participants, and explore relationship to matched blood and tissue samples, when available.
  • To explore biomarkers of response and resistance in CSF.
  • To evaluate niraparib and dostarlimab concentrations or pharmacokinetics (PK)
  • To screen for the presence of dostarlimab anti-drug antibodies (ADA)

Eligibility

Inclusion Criteria:

  1. Age ≥ 18 years old. 2. Participant must have brain metastasis and either
  2. Advanced BRCA1/2m cancer 2. Advanced HRR-aberrant, non-BRCA1/2m cancer 3. Advanced small cell lung cancer 4. Advanced non-small cell lung cancer 5. Advanced Triple Negative Breast Cancer 3. In cohorts 1 and 2, subjects will be eligible for this study based on the presence of actionable aberrations in one or more of the following HRR genes: BRCA1/2, ATM; BRIP1; CDK12; CHEK1; CHEK2; FANCL; PALB2; RAD51; RAD51B; RAD51C; RAD51D; RAD52; RAD54L, or other related genes at the discretion of the principal investigator in consultation with the MD Anderson Cancer Center Institute for Personalized Cancer Therapy Precision Oncology Decision Support (PODS) group. Variant interpretation for actionability will be performed by PODS.
  3. Any prior SRS to brain lesions or prior excision must have occurred ≥1 week before the start of dosing for this study. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
  4. Patients must have had at least one prior line of systemic therapy directed at their malignancy.
  5. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
  6. Adequate organ function as described below: (Note: CBC test should be obtained without transfusion or receipt of colony-stimulating factors in the 2 weeks before obtaining).

Hematological • Absolute neutrophil count (ANC) ≥1,500 /mcL

• Platelets ≥ 100,000 / mcL

• Hemoglobin ≥ 9.0 g/dL

        • Serum creatinine ≤1.5xULN OR Measured or calculated creatinine clearance ≥50 mL/min for
        participants.
        Hepatic
          -  Serum total bilirubin ≤1.5xULN OR Direct bilirubin ≤1 x ULN for subjects with total
             bilirubin levels ≥1.5xULN ) (if associated with liver metastases or Gilbert's disease,
             ≤2.5 x ULN)
          -  Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x ULN (if associated
             with liver metastases, ≤5 x ULN) Coagulation
          -  International Normalized Ratio (INR) or Prothrombin Time (PT) and Activated Partial
             Thromboplastin Time (aPTT) ≤1.5xULN, unless subject is receiving anticoagulant
             therapy.
             8. Participant must have at least one measurable brain metastasis (tumor diameter of
             0.5-3 cm by mRECIST on magnetic resonance imaging [MRI]) for which all of the
             following criteria have to be met: asymptomatic (no neurologic signs or symptoms),
             unirradiated, not requiring immediate local intervention (surgery or radiosurgery),
             and not requiring systemic glucocorticoid therapy within 10 days prior to study
             treatment initiation. Patient may have other metastatic lesions which can have had
             irradiation.
             9. Patients must have archival systemic tumor tissue available at screening. Patients
             who do not have tissue specimens available may undergo a biopsy during the screening
             period. Acceptable samples include core-needle biopsies for deep systemic tumor tissue
             or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or
             mucosal lesions. Representative formalin-fixed paraffin-embedded (FFPE) tumor
             specimens in paraffin blocks (blocks are preferred) OR at least 4 unstained slides,
             with an associated pathology report, for testing of tumor PD-L1 expression. Tumor
             tissue should be of good quality based on total and viable tumor content.
             10. Female participant has a negative serum pregnancy test within 3 days prior to
             taking study treatment if of childbearing potential and agrees use a highly effective
             method of contraception (< 1% failure rate with low user dependency) from screening
             through 180 days after the last dose of study treatment or is of nonchildbearing
             potential. Nonchildbearing potential is defined as follows (by other than medical
             reasons):
          -  Patients who are ≥45 years of age and who have not had menses for >1 year or 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. See Section 4.4 for a list of
             acceptable birth control methods. 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.
          -  Participant must agree to not breastfeed during the study or for 180 days after the
             last dose of study treatment.
             11. Male participants are eligible to participate if they agree to the following
             during the treatment period and for at least 180 days after the last dose of study
             treatment:
          -  Refrain from donating sperm plus, either:
          -  Be abstinent from sexual activity as their preferred and usual lifestyle (abstinent on
             a long-term and persistent basis) and agree to remain abstinent or
          -  Must agree to use a male condom (and should also be advised of the benefit for a
             female partner to use a highly effective method of contraception as a condom may break
             or leak) 12. Participant must have signed and dated an IRB/IEC approved written
             informed consent form in accordance with regulatory and institutional guidelines. This
             must be obtained before the performance of any protocol related procedures that are
             not part of normal subject care. Hence, participants must have the ability to
             understand and the willingness to sign the approved written informed consent document.
             13. Participant must be willing and able to comply with scheduled visits, treatment
             schedule, laboratory testing, and other requirements of the study.
        Exclusion Criteria:
          1. Participant must not be simultaneously receiving interventional anticancer treatment.
          2. Participant must not have contraindications to MRI (implanted metal device or foreign
             bodies) or MRI contrast (insufficient renal function or allergy).
          3. A history of / or suffers from claustrophobia or subject feels unable to lie flat and
             still on their back for the required period of time in an MRI or PET/CT scanner.
          4. Participant must not have symptomatic or untreated spinal cord compression.
          5. Participant must not have evidence of leptomeningeal disease.
          6. Participant must not have previously received a combination of PARP inhibitor and
             PD-1/L1inhibitor. Participant must not have previously received equivalent of full
             dose single agent PARPi. Prior therapy with PD-1/L1-inhibitor is permitted.
          7. For participants choosing optional CSF collection via lumbar puncture: no medical
             contraindication to lumbar puncture may be present (including severe coagulopathy,
             radiographic concern for impending herniation or obstructive hydrocephalus, or soft
             tissue infection at puncture site, as outlined in MD Anderson institutional policy).
             LP may be deferred if at any time the treating physician determines that it would be
             unsafe to perform this procedure due to the characteristics of the brain metastases
             (eg. size, associated edema, etc).
          8. Participant must not have had major surgery ≤ 3 weeks prior to initiating protocol
             therapy and participant must have recovered from any surgical effects.
          9. Participant must not have received systemic anticancer therapy ≤2 weeks prior to
             initiating protocol therapy.
         10. Previous systemic radiation therapy encompassing >20% of the bone marrow (but not
             encompassing the CNS) within 2 weeks
         11. Previous stereotactic or highly conformal radiotherapy within 1 week before the start
             of dosing for this study, whole brain radiotherapy within 2 weeks.
         12. Participant must not have a known hypersensitivity to niraparib and dostarlimab
             components or excipients.
         13. Participants with an inactive, known or suspected autoimmune disease. Subjects with
             type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin
             disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment,
             or conditions not expected to recur in the absence of an external trigger are
             permitted to enroll.
         14. Participant must not have a history of interstitial lung disease.
         15. Participants with a major medical, neurologic or psychiatric condition who are judged
             as unable to fully comply with study therapy or assessments should not be enrolled.
         16. Participant has a history of a second malignancy, unless potentially curative
             treatment has been completed with no evidence of malignancy for 2 years.
         17. Patients with prostate cancer are excluded from this trial.
         18. Participant has a known history of active hepatitis B or hepatitis C. Prior treated
             hepatitis B or C with undetectable viral load may be enrolled.
         19. Participants who have a known history of HIV positive and are on effective
             anti-retroviral therapy with documented undetectable viral load and CD4 count ≥350
             within 6 months of the first dose of study treatment are eligible.
         20. Participants unable to undergo contrast enhanced brain MRI.
         21. Participants unable to swallow pills or have significant gastrointestinal disease
             which would preclude the adequate oral absorption of medications.
         22. Patients who have received live vaccines within 30 days of study entrance.
         23. Patients with uncontrolled high blood pressure (HTN >140/90).
         24. Patients with prior diagnosis of MDS or AML.

Study details

Brain Metastases

NCT05700721

M.D. Anderson Cancer Center

14 June 2024

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