Ignite Creation Date:
2024-05-06 @ 10:14 AM
Last Modification Date:
2024-10-26 @ 12:27 PM
Study NCT ID:
NCT03209401
Status:
TERMINATED
Last Update Posted:
2024-02-05
First Post:
2017-07-03
Brief Title:
Niraparib Plus Carboplatin in Patients With Homologous Recombination Deficient Advanced Solid Tumor Malignancies
Sponsor:
Georgetown University
Organization:
Georgetown University
Study Overview
Official Title:
Niraparib Plus Carboplatin in Patients With Homologous Recombination Deficient Advanced Solid Tumor Malignancies
Status:
TERMINATED
Status Verified Date:
2024-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Lack of accrual
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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 v11 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 v11 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 genes critical to DNA repair through homologous recombination including but not limited to ARID1A ATM ATRX MRE11A NBN PTEN RAD505151B BARD1 BLM BRCA1 BRCA2 BRIP1 FANCACD2EFGL 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 33 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 33 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
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 genes critical to DNA repair through homologous recombination including but not limited to ARID1A ATM ATRX MRE11A NBN PTEN RAD505151B BARD1 BLM BRCA1 BRCA2 BRIP1 FANCACD2EFGL 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 33 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 33 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None