Clinical Trials /

Niraparib Plus Carboplatin in Patients With Homologous Recombination Deficient Advanced Solid Tumor Malignancies

NCT03209401

Description:

This is a multi-institutional Phase I dose-escalation and dose-expansion trial for patients with advanced, solid tumor malignancies who have pre-identified deleterious germline or somatic mutations in the homologous recombination deoxyribonucleic acid (DNA) repair pathway (HR deficient). The trial is designed to assess the efficacy and safety of niraparib plus carboplatin in patients with evidence of HRD. The primary endpoint will be identifying the recommended phase 2 dose (RP2D) and schedule of niraparib plus carboplatin, as well as establishing the anti-tumor efficacy of niraparib plus carboplatin as determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Niraparib Plus Carboplatin in Patients With Homologous Recombination Deficient Advanced Solid Tumor Malignancies
  • Official Title: Niraparib Plus Carboplatin in Patients With Homologous Recombination Deficient Advanced Solid Tumor Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 2017-0085
  • NCT ID: NCT03209401

Conditions

  • Solid Tumor, Adult
  • Homologous Recombination Deficiency

Interventions

DrugSynonymsArms
NiraparibMK-4827Niraparib and Carboplatin
CarboplatinParaplatinNiraparib and Carboplatin

Purpose

This is a multi-institutional Phase I dose-escalation and dose-expansion trial for patients with advanced, solid tumor malignancies who have pre-identified deleterious germline or somatic mutations in the homologous recombination deoxyribonucleic acid (DNA) repair pathway (HR deficient). The trial is designed to assess the efficacy and safety of niraparib plus carboplatin in patients with evidence of HRD. The primary endpoint will be identifying the recommended phase 2 dose (RP2D) and schedule of niraparib plus carboplatin, as well as establishing the anti-tumor efficacy of niraparib plus carboplatin as determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

Detailed Description

      This is a multi-institutional Phase I dose-escalation and dose-expansion trial for patients
      with advanced, solid tumor malignancies who have pre-identified deleterious germline or
      somatic mutations in the homologous recombination deoxyribonucleic acid (DNA) repair pathway
      (HR deficient). The trial is designed to assess the efficacy and safety of niraparib plus
      carboplatin in patients with evidence of HRD. The primary endpoint will be identifying the
      recommended phase 2 dose (RP2D) and schedule of niraparib plus carboplatin, as well as
      establishing the anti-tumor efficacy of niraparib plus carboplatin as determined by Response
      Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

      Patients will be pre-identified from participating centers as having either a germline
      deleterious mutation or tumor expression of a deleterious mutation in one of the genes listed
      below, as determined by Next-generation DNA sequencing (NGS) only, completed prior to
      enrollment in this protocol. Patients with advanced solid tumor malignancies with the
      presence of somatic or germline deleterious mutation in a gene(s) critical to DNA repair
      through homologous recombination, including but not limited to: ARID1A, ATM, ATRX, MRE11A,
      NBN, PTEN, RAD50/51/51B, BARD1, BLM, BRCA1, BRCA2, BRIP1, FANCA/C/D2/E/F/G/L, PALB2, WRN,
      CHEK2, CHEK1, BAP1, FAM175A, SLX4, MLL2 or XRCC, and who have an adequate performance status
      (PS), bone marrow, hepatic, and renal function as well as biopsiable and measurable disease
      will be screened for enrollment.

      Appropriate patients will be enrolled in a 3+3 alternating dose escalating fashion, to a
      maximum dose of niraparib of 300mg daily and a maximum dose of carboplatin area under the
      curve (AUC) of 4. The 3+3 schema will be employed to insure safety and tolerability. However,
      within any given cohort, a full contingent of 6 patients (assuming adequate tolerability)
      will be enrolled to capture a sufficient number of patients and samples for pharmacodynamic
      assessment of DNA damage.

      Once the RP2D and schedule are identified, a Phase Ib expansion cohort of 20 additional
      patients will be enrolled as a pilot subgroup to determine efficacy. Of the 20 patients in
      this Phase Ib cohort, no more than 10 patients will have underlying breast cancer; and
      additionally no more than 10 patients may harbor BRCA1 or BRCA2 mutations.

      To assess the efficacy of poly (ADP-ribose) polymerase (PARP) inhibition and the extent of
      DNA damage, patients will undergo serial tumor biopsies to measure DNA damage as quantified
      by levels of ᵞH2AX and RAD51 foci formation, as well as an assessment of PARP inhibitory
      activity. Tumor biopsies will also be used to assess the mechanisms of resistance to PARP
      inhibitor-based therapy.

      Assessment of safety including blood tests, clinic visits and exams will occur weekly at the
      start of therapy, then will transition to every 3-week clinic visits and exams at the
      beginning of cycle 4. For the Phase Ib portion, patients will undergo weekly lab work and
      clinic visits for cycle 1 only. The researchers hypothesize that in this HR deficient patient
      population, the addition of niraparib to carboplatin will lead to significant anti-tumor
      responses with acceptable toxicities.
    

Trial Arms

NameTypeDescriptionInterventions
Niraparib and CarboplatinExperimentalNiraparib will be administered orally, once daily for 21 days of each 21-day cycle in escalating doses depending on cohort patient is assigned to. Carboplatin will be administered via an injection on Day 2 of a given 21-day cycle. The dose a patient receives will depend on which cohort the patient is assigned to.
  • Niraparib
  • Carboplatin

Eligibility Criteria

        Inclusion Criteria:

          -  Patients PRE-identified as having either a germline deleterious mutation or tumor
             expression of a deleterious mutation) as determined by Next-generation DNA sequencing
             only, in at least one gene involved in DNA damage repair through homologous
             recombination including but not limited to: ARID1A, ATM, ATRX, MRE11A, NBN, PTEN,
             RAD50/51/51B, BARD1, BLM, BRCA1, BRCA2, BRIP1, FANCA/C/D2/E/F/G/L, PALB2, WRN, CHEK2,
             CHEK1, BAP1, FAM175A, SLX4, MLL2 or XRCC.

          -  Patients with somatic mutations will be PRE-identified as having a homologous
             recombination mutation based on NGS done in a CLIA certified, CAP tested and
             bioinformatics-validated testing lab PRIOR to enrollment in this current protocol. The
             testing may have been done at any time prior to enrollment. HOWEVER, if any patient
             has had NGS testing more than 3 months prior to enrollment, or if there has been
             intervening therapy, then a repeat NGS test must be done and the deleterious somatic
             mutation must be re-identified for inclusion.

          -  The determination of a deleterious mutation must be supported in the documentation
             included in the testing, and should include clinical, or pre-clinical literature to
             support the finding that a specific mutation results in impaired function of the gene,
             and thus impaired DNA repair through homologous recombination. Variants of unknown
             significance will not be eligible.

          -  Patients with germline deleterious mutations may have been identified at any time
             point prior to inclusion in the protocol and do NOT need to have this genetic testing
             repeated regardless of time frame and intervening therapy.

          -  Advanced, solid tumor malignancy that is amenable to biopsy. Patient must consent to 4
             mandatory biopsies during study

          -  Life expectancy of more than 3 months

          -  Age ≥ 18 years

          -  Measurable disease by RECIST v1.1 criteria (tumor ≥ 1 cm in longest diameter on axial
             image on computed tomography (CT) or magnetic resonance imaging (MRI) and/or lymph
             node(s) ≥ 1.5 cm in short axis on CT or MRI) on baseline imaging

          -  ECOG performance status (PS) of 0 to 1 (Table 10, Appendix A)

          -  Patients who have received and failed, or have been intolerant to, standard first line
             therapies known to confer clinical benefit. Patients who refuse standard therapy would
             also be eligible, as long as their refusal is documented.

          -  Patients with a standard 12-lead electrocardiogram (ECG) with the following parameters
             at screening (defined as the mean of the triplicate ECGs):

               1. QTc interval at screening < 481 msec

               2. Resting heart rate 50-90bpm

          -  Adequate hepatic, bone marrow, and renal function at the time of enrollment:

          -  Bone Marrow: Absolute neutrophil count (ANC) ≥ 1,500/mm3; Platelets ≥ 100,000/mm3;
             Hemoglobin ≥ 9.0 g/dL. Patients must be able to meet the criteria without transfusion
             or receipt of colony stimulating factors within 2 weeks before obtaining sample

          -  Renal function: Serum creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 50 mL/min/1.73
             m2

          -  Hepatic function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
             ≤ 2.5 × the upper normal limit of institution's normal range. Total bilirubin ≤ 1.5 ×
             the upper normal limit of institution's normal range. For subjects with liver
             metastases, AST and ALT < 5 × the upper normal limit of institution's normal range,
             and total bilirubin >1.5 - 3.0 x the upper normal limit of institution's normal range
             are acceptable as long as there is no persistent nausea, vomiting, right upper
             quadrant pain or tenderness, fever, rash, or eosinophilia

          -  Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) must be ≤ 2 X the upper
             limit of the institution's normal range and International Normalized Ratio (INR) < 2.

        Subjects on anticoagulation (such as coumadin) will be permitted to enroll as long as the
        INR is in the acceptable therapeutic range as determined by the investigator

          -  Patients may have received an unlimited number of prior therapies

          -  Patients must have fully recovered from all effects of surgery. Patients must have had
             at least two weeks after minor surgery and four weeks after major surgery before
             starting therapy. Minor procedures requiring conscious sedation such as endoscopies or
             mediport placement may only require a 24-hour waiting period, but this must be
             discussed with an investigator

          -  Women of childbearing potential must have a negative serum pregnancy test within 14
             days prior to initiation of treatment and/or postmenopausal women must be amenorrheic
             for at least 12 months to be considered of non-childbearing potential

          -  Patient is capable of swallowing pills whole

          -  Subject is capable of understanding and complying with parameters as outlined in the
             protocol and able to sign and date the informed consent, approved by the IRB, prior to
             the initiation of any screening or study-specific procedures

        Exclusion Criteria:

          -  Prior disease progression while receiving platinum chemotherapy or platinum
             chemotherapy within the last 6 months

          -  For patients who received platinum-based adjuvant chemotherapy, at least 6 months must
             have passed between the last dose of platinum-based therapy and the development of
             metastatic disease. For breast cancer patients, at least 12 months must have passed
             between the last dose of platinum-based therapy and the development of metastatic
             disease

          -  Prior PARP inhibitor-based therapy

          -  Known or suspected CNS metastases, unless at least one month has passed since last
             local CNS therapy and there is no evidence for recurrent or progressive CNS disease on
             follow up imaging. Participants may remain on steroids for CNS disease if they are
             taking a stable dose

          -  Active severe infection, or known chronic infection with HIV or hepatitis B virus
             (testing not required prior to enrollment)

          -  Patients with chronic Hepatitis C virus may be enrolled if there is no
             clinical/laboratory evidence of cirrhosis AND the patient's liver function tests fall
             within the parameters set in Section 3.2.8.3, Inclusion Criteria, Hepatic function

          -  Cardiovascular disease problems including unstable angina, therapy for
             life-threatening ventricular arrhythmia, or myocardial infarction, stroke, or
             congestive heart failure within the last 6 months. Additionally, patients must not
             have QT prolongation greater than or equal to 481 milliseconds

          -  Life-threatening visceral disease or other severe concurrent disease that would, in
             the investigator's judgment, cause unacceptable safety risks, contraindicate patient
             participation in the clinical study or compromise compliance with the protocol (e.g.
             chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral
             infections, etc.)

          -  Patient has impairment of gastrointestinal (GI) function or GI disease that may
             significantly alter the absorption of the study drugs (e.g., ulcerative diseases,
             uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel
             resection)

          -  Presence of a psychiatric illness or social situation that would limit compliance with
             study requirements

          -  Women who are pregnant or breastfeeding

          -  The subject must not have had diagnosis, detection, or treatment of another type of
             cancer ≤2 years prior to randomization (except basal or squamous cell carcinoma of the
             skin that has been definitively treated). Questions regarding the inclusion of
             individual subjects should be directed to the Principal Investigators, Dr. Isaacs and
             Dr. Pishvaian.

          -  Clinically significant peripheral neuropathy at the time of enrollment (defined in the
             NCI CTCAE v4.0) as grade 2 or greater neurosensory or neuromotor toxicity)

          -  Patients must not have had investigational therapy administered ≤4 weeks, or within a
             time interval less than at least 5 half-lives of the investigational agent, whichever
             is longer, prior to the first scheduled day of dosing in this study

          -  Patients must not have had radiotherapy encompassing >20% of the bone marrow

          -  Patients must not have a known hypersensitivity to the components of niraparib or the
             excipients

          -  Patients must not have had any known, persistent > Grade 2 toxicity from prior cancer
             therapy

          -  Patient must not have had any known, persistent (>4 weeks), ≥Grade 3 hematological
             toxicity or fatigue from prior cancer therapy

          -  Patients must not have current evidence of any condition, therapy, or laboratory
             abnormality (including active or uncontrolled myelosuppression [ie, anemia,
             leukopenia, neutropenia, thrombocytopenia]) that might confound the results of the
             study or interfere with the patient's participation for the full duration of the study
             treatment or that makes it not in the best interest of the patient to participate

          -  Patients must not be 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, or any psychiatric disorder that
             prohibits obtaining informed consent

          -  Patient must not have any known history of myelodysplastic syndrome (MDS)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Grade 3 and 4 toxicities
Time Frame:36 months
Safety Issue:
Description:Phase Ia Primary Endpoint - The number of grade 3 and 4 toxicities according to NCI CTCAE; Version 4.0 that occur after Cycle 1, Day 1 will be recorded at each study visit.

Secondary Outcome Measures

Measure:Median survival
Time Frame:36 months
Safety Issue:
Description:OS is defined by time from study enrollment till death from any cause
Measure:Median progression free survival
Time Frame:36 months
Safety Issue:
Description:PFS is defined as the time from study enrollment to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first
Measure:Disease control rate
Time Frame:36 months
Safety Issue:
Description:DCR is defined as the proportion of patients with a documented CR, PR, or SD at 4 months according to the RECIST version 1.1

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Georgetown University

Trial Keywords

  • Niraparib
  • Carboplatin

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