MC# 19-20 - An Open Label, Randomized Sequence, Multicenter, Single Crossover Study to Assess the Relative Bioavailability and Bioequivalence of Niraparib Tablet Formulation Compared to Niraparib Capsule Formulation in Patients with Advanced Solid Tumors

  • Agent(s): Niraparib
  • Disease Type(s): Solid Tumors that benefit from PARP inhibitor
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Small Molecule
  • Molecular Target(s): PARP-1, PARP-2

Mechanism of Action

Niraparib binds to and inhibits the activity of PARP-1 and -2, thereby inhibiting PARP-1 and -2-mediated DNA repair, enhancing the accumulation of DNA strand breaks, promoting genomic instability and resulting in apoptosis.

Purpose

In this study, the sponsor and investigators want to learn:

  • How different forms of niraparbi can be given with an acceptable level of side effects
  • About the safety and tolerability of the different forms of niraparib
  • How much of niraparib is absorbed into the blood and how fast it is removed for each form
Inclusion Criteria

PK Phase:

  1. Patient is capable of understanding the written informed consent, provides signed and witnessed written informed consent, and agrees to comply with protocol requirements.
  2. Patient has histologically or cytologically confirmed diagnosis of metastatic or locally advanced solid tumors that have failed to respond to standard therapy, has progressed despite standard therapy, or for which no standard therapy exists, and who may benefit from treatment with a PARP inhibitor as assessed by the Investigator.  Patients with lymphoma are eligible.  Patients with primary CNS malignancy are eligible provided they do not have new or progressive signs or symptoms, and are not requiring steroid dose exceeding the equivalent of 10 mg of prednisone daily.
  3. Patient is at least 18 years of age.
  4. Patient has an ECOG performance status of 0 to 2.
  5. Patient has adequate organ function as defined below (Note: CBC should be obtained without transfusion or receipt of CSFs, erythropoietin stimulating agents or platelet- stimulating agents within 2 weeks before first dose):
    • Absolute neutrophil count ≥ 1,500/µL
    • Platelets ≥ 100,000/µL
    • Hemoglobin ≥ 9 g/dL (5.6 mM)
    • Serum creatinine ≤ 1.5 × the upper limit of normal (ULN) or a calculated creatinine clearance ≥ 60 mL/min using the Cockcroft-Gault equation or 24-hour urine creatinine clearance
    • Total bilirubin ≤ 1.5 × ULN except in patients with Gilbert’s syndrome.  Patients with Gilbert’s syndrome may enroll if direct bilirubin ≤ 1.5 × ULN of the direct bilirubin.
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN unless liver metastases are present, in which case, they must be ≤ 5 × ULN
  6. Patient has recovered to Grade 1 toxicity from prior cancer therapy (a patient with Grade 2 neuropathy or Grade 2 alopecia or Grade 2 hypothyroidism on a stable dose of thyroid replacement is an exception to this criterion and may qualify for this study).  For patients with hematologic, renal, or hepatic toxicity from prior therapy, inclusion criterion #5 should be applied to determined eligibility.
  7. Patient is able to take oral medications
  8. Female patient meets the following criteria:
    • Patient (of childbearing potential) is not breastfeeding, has a negative serum pregnancy test within 72 hours prior to taking study drug and agrees to abstain from activities that could result in pregnancy from Screening through 180 days after the last dose of study drug, or is of non-childbearing potential.  Note: A urine pregnancy test may be performed if the serum pregnancy test is not available before dosing.
    • Female patient is of non-childbearing potential (other than medical reasons) as defined by the following:
      • ≥45 years of age and has not had menses for >1 year)
      • Amenorrheic for <2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon Screening evaluation
      • Had undergone a hysterectomy, bilateral oophorectomy, or tubal ligation.  Documented hysterectomy, oophorectomy, or tubal ligation must be confirmed in the medical records; otherwise the patient must be willing to use highly effective contraception throughout the study starting from the Screening visit through 180 days after the last dose of study drug.  Information must be captured appropriately within the site’s source documents.  Note: Abstinence is acceptable if this is the established and preferred contraception method for the patient.
  9. Male patient agrees to use an adequate method of contraception and not donate sperm starting with the first dose of study drug through 90 days after the last dose of study drug.  ​Note: Abstinence is acceptable if this is the established and preferred contraception method for the patient.

Extension Phase:

  1. Patient has an ECOG performance status of 0 to 2
  2. Patient has adequate organ function as defined below  (Note: CBC should be obtained without transfusion or receipt of CSFs, erythropoietin stimulating agents or platelet stimulating factors within 2 weeks before first dose):
    • Absolute neutrophil count ≥ 1,500/µL
    • Platelets ≥ 100,000/µL
    • Hemoglobin ≥ 9 g/dL (5.6 mM)
    • Serum creatinine ≤ 1.5 × the ULN or a calculated creatinine clearance ≥ 60 mL/min using the Cockcroft-Gault equation or 24-hour urine creatinine clearance
    • Total bilirubin ≤ 1.5 × ULN except in patients with Gilbert’s syndrome.  Patients with Gilbert’s syndrome may enroll if direct bilirubin ≤ 1.5 × ULN of the direct bilirubin.
    • AST and ALT ≤ 2.5 × ULN unless liver metastases are present, in which case, they must be ≤5 × ULN
  3. Female patient meets the following criteria:
    • Patient (of childbearing potential) is not breastfeeding, has a negative serum pregnancy test within 72 hours prior to taking study drug and agrees to abstain from activities that could result in pregnancy from Screening through 180 days after the last dose of study drug, or is of non-childbearing potential.  Note: A urine pregnancy test may be performed if the serum pregnancy test is not available before dosing.
    • Female patient of non-childbearing potential (other than medical reasons) is defined by the following:
      • ≥45 years of age and has not had menses for >1 year)
      • Amenorrheic for <2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon Screening evaluation
      • Had undergone a hysterectomy, bilateral oophorectomy, or tubal ligation. Documented hysterectomy, oophorectomy, or tubal ligation must be confirmed in the medical records; otherwise the patient must be willing to use highly effective contraception throughout the study, starting from the Screening visit through 180 days after the last dose of study drug.  Information must be captured appropriately within the site’s source documents.  Note: Abstinence is acceptable if this is the established and preferred contraception method for the patient.
  4. Male patient agrees to use an adequate method of contraception and not donate sperm starting with the first dose of study drug through 90 days after the last dose of study drug.  Note: Abstinence is acceptable if this is the established and preferred contraception method for the patient.
Exclusion Criteria

PK Phase:

  1. Patient has a known hypersensitivity to the components of niraparib or excipients
  2. Patient has a known diagnosis of immunodeficiency  (Note: Patients with splenectomy are allowed).
  3. Patient has symptomatic uncontrolled brain or leptomeningeal metastases.  To be considered “controlled,” the patient must have undergone treatment (e.g., radiation or chemotherapy) at least 1 month prior to study entry.  The patient must not have any new or progressive signs or symptoms related to the central nervous system disease and must be taking ≤10 mg of prednisone or equivalent per day or no steroids.
  4. Patient underwent major surgery within 3 weeks of starting the study or patient has not recovered from any effects of any major surgery
  5. Patient is considered a poor medical risk due to a serious, uncontrolled medical disorder; nonmalignant systemic disease; or active, uncontrolled infection.  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, uncontrolled hypertension, active uncontrolled coagulopathy, bleeding disorder, or any psychiatric disorder that prohibits obtaining informed consent.
  6. Female patient is pregnant or is expecting to conceive children while receiving study drug or for up to 180 days after the last dose of study drug. Male patient is expecting to donate sperm or father children while receiving study drug or for up to 90 days after the last dose of study drug.
    • Female patient is breastfeeding or is expecting to breastfeed within 30 days of receiving final dose of study drug (women should not breastfeed or store breastmilk for use, during treatment and for 30 days after receiving the final dose of study treatment)
  7. Patient has a known history of myelodysplastic syndrome or acute myeloid leukemia
  8. Patient is unable to refrain from any intake of grapefruit or grapefruit juice within 7 days of the first administration of niraparib until 2 days post-dose.  (Does not apply for Extension Phase.)
  9. Patient is currently taking any of the following P-glycoprotein (P-gp) inhibitors: amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, cyclosporine, diltiazem, dronedarone, erythromycin, felodipine, itraconazole, ketoconazole, lopinavir and ritonavir, quercetin, quinidine, ranolazine, ticagrelor, and verapamil, unless the dose and regimen has been stable for at least 14 days prior to first dose and will not change during PK periods 1 and 2.  (Does not apply for Extension Phase.)
  10. Patient taking proton pump inhibitors, antacids, or histamine 2 blockers unless the dose and regimen is stable for at least 14 days prior to first dose and will not change during PK periods 1 and 2.  Patients must hold these therapies starting within 8 hours prior to study drug administration until 9 hours after study drug administration.  (Does not apply for Extension Phase.)
  11. Patient has gastric, gastro-esophageal or esophageal cancer; patient is unable to swallow orally administered medication; or patient has gastrointestinal disorders or significant gastrointestinal resection likely to interfere with the absorption of niraparib
  12. Patient has known active hepatic disease (known hepatic cirrhosis, hepatitis B surface antigen-positive status, or suspected active hepatitis C infection)
  13. Patient has a past or current history of chronic alcohol use (3 or more drinks per day for the 30 days prior to the Screening Visit) or dependence or is unable to abstain from alcohol for the duration of the study
  14. Patient has had a prior cytotoxic therapy or anticancer monoclonal antibodies (mAbs) within 14 days prior to start of PK phase.  For targeted small anti-cancer molecules (e.g., tyrosine kinase inhibitors), the required washout is 5 half-lives of the start of PK phase.  Certain hormonal agents are allowed and do not require washout.  For hormonal agents not listed, the Site must consult with the Sponsor regarding allowing patient on study.  There is no required washout for palliative radiation.
  15. Patient has significant pleural effusion or ascites that is expected to require drainage during the PK Phase.  (Does not apply for Extension Phase.)

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT03329001

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Re: MC# 19-20