Niraparib Plus Carboplatin in Patients With Homologous Recombination Deficient Advanced Solid Tumor Malignancies
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|ClinicalTrials.gov Identifier: NCT03209401|
Recruitment Status : Recruiting
First Posted : July 6, 2017
Last Update Posted : May 21, 2019
|Condition or disease||Intervention/treatment||Phase|
|Solid Tumor, Adult Homologous Recombination Deficiency||Drug: Niraparib Drug: Carboplatin||Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||146 participants|
|Intervention Model:||Sequential Assignment|
|Intervention Model Description:||
The Phase Ia portion of the trial will be conducted in a 3+3 design, enrolling patients in cohorts of 3 patients each to insure safety and tolerability.
There will be a Phase Ib expansion cohort including 20 patients to further assess the efficacy of niraparib plus carboplatin, using the RP2D and schedule from Phase Ia.
|Masking:||None (Open Label)|
|Official Title:||Niraparib Plus Carboplatin in Patients With Homologous Recombination Deficient Advanced Solid Tumor Malignancies|
|Actual Study Start Date :||October 13, 2017|
|Estimated Primary Completion Date :||July 2020|
|Estimated Study Completion Date :||July 2022|
Experimental: Niraparib and Carboplatin
Niraparib 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.
an oral PARP inhibitor
Other Name: MK-4827
a platinum-based injection
Other Name: Paraplatin
- Grade 3 and 4 toxicities [ Time Frame: 36 months ]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.
- Anti-tumor efficacy by overall response rate [ Time Frame: 36 months ]Phase Ib Primary Endpoint - ORR is defined as the proportion of patients whose best overall response recorded during the treatment is either complete response or partial response according to the RECIST v1.1.
- Median survival [ Time Frame: 36 months ]OS is defined by time from study enrollment till death from any cause
- Median progression free survival [ Time Frame: 36 months ]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
- Disease control rate [ Time Frame: 36 months ]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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03209401
|United States, District of Columbia|
|Lombardi Comprehensive Cancer Center||Recruiting|
|Washington, District of Columbia, United States, 20057|
|Contact: Stephanie Wagner, RN 202-687-9782 firstname.lastname@example.org|
|Principal Investigator: Claudine Isaacs, MD|
|Study Chair:||Claudine Isaacs, MD||Lombardi Comprehensive Cancer Center|