Viewing Study NCT01989546



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Last Modification Date: 2024-10-26 @ 11:15 AM
Study NCT ID: NCT01989546
Status: COMPLETED
Last Update Posted: 2021-02-23
First Post: 2013-11-16

Brief Title: Pilot Trial of BMN 673 an Oral PARP Inhibitor in Patients With Advanced Solid Tumors and Deleterious BRCA Mutations
Sponsor: National Cancer Institute NCI
Organization: National Institutes of Health Clinical Center CC

Study Overview

Official Title: Pilot Trial of BMN 673 an Oral PARP Inhibitor in Patients With Advanced Solid Tumors and Deleterious BRCA Mutations
Status: COMPLETED
Status Verified Date: 2021-02
Last Known Status: None
Delayed Posting: No
If Stopped, Why?: Not Stopped
Has Expanded Access: False
If Expanded Access, NCT#: N/A
Has Expanded Access, NCT# Status: N/A
Acronym: None
Brief Summary: Background

The poly ADP-ribose polymerase PARP family of enzymes is critical for maintaining genomic stability by regulating a variety of deoxyribonucleic acid DNA damage repair mechanisms
Talazoparib BMN 673 is a PARP inhibitor with greater in vitro activity than any other PARP inhibitor currently in development BMN 673 has been shown to cause single-agent synthetic lethality in breast cancer 1 and breast cancer 2 BRCA12- and phosphatase and tensin homolog PTEN-deficient cell lines and has potent antitumor activity in animal models of tumors harboring mutations in DNA repair pathways
BMN 673 is showing promising single-agent activity in patients with advanced ovarian and breast cancer harboring deleterious BRCA mutations
This pilot study will evaluate the pharmacodynamic effects of BMN 673 on DNA damage and apoptosis markers in tumor biopsy tissue

Primary Objective

-Determine the pharmacodynamic effect of BMN 673 in tumor biopsies from patients with advanced ovarian breast or other solid tumor and deleterious BRCA mutations

Secondary Objectives

Determine the response rate Complete Response CR Partial Response PR of treatment with BMN 673 in patients with advanced ovarian or primary peritoneal carcinoma and deleterious BRCA mutations
Determine the response rate CR PR of treatment with BMN 673 in patients with advanced breast carcinoma and deleterious BRCA mutations
Determine the response rate CR PR of treatment with BMN 673 in patients with advanced solid tumor other than breast or ovarian and deleterious BRCA mutations

Eligibility

Adult patients with documented deleterious BRCA 1 or 2 mutations with histologically confirmed ovarian primary peritoneal breast prostate pancreas gastric or other solid tumor whose disease has progressed following at least one standard therapy or who have no acceptable standard treatment options
No major surgery radiation or chemotherapy within 4 weeks prior to study enrollment and recovered from toxicities of prior therapies to at least eligibility levels
Age greater than or equal to 18 years of age Eastern Cooperative Oncology Group ECOG performance status less than equal to 2
Adequate organ function
Willingness to undergo tumor biopsies

Study Design

BMN 673 will be administered orally each day in 28-day cycles
Dosing will be at the established recommended Phase II dose of 1000 mcgday each day for

28 days
We plan to accrue a total of 12 evaluable patients per cohort for a total of 36 patients To allow for some patients who will not be evaluable the accrual ceiling is 42 patients
Tumor biopsies will be mandatory at baseline pre-dose and then approximately 3-6 hours post BMN 673 on day 8 An optional tumor biopsy may also be collected at time of disease progression

SCHEMA

BMN 673 is administered orally each day in 28-day cycles
Tumor biopsies will be performed at baseline pre-treatment and 3-6 hrs post dose on cycle 1 day 8 An optional tumor biopsy may also be collected at time of disease progression Tumor biopsies will be evaluated for protease activated receptor PAR levels DNA damage response markers such as H2AX Variant Histone H2AX cleaved caspase 3 excision repair cross-complementing group 1 ERCC1 pNbs1 XPF RAD51 and pT1989ATR and as indicators of ataxia telangiectasia and Rad3-related protein ATRataxia telangiectasia mutated ATM activation Checkpoint kinase 1 chk1 and Checkpoint kinase 2 chk2
Blood samples for circulating tumor cells CTC analyses will be collected at baseline pre-treatment on cycle 1 day 13-6 hours post dose on cycle 1 day 8 3-6 hours post dose and on cycle 2 day 1 3-6 hours post dose
Blood samples for pharmacokinetic PK analysis will be collected on cycle 1 day 1 pre-dose and 05 1 2 3 4 68 and 24 hours post-dose on cycle 1 day 8 3-6 hours post dose and on cycle 2 day 1 pre-dose and 3-6 hours post dose
Detailed Description: Background

The poly ADP-ribose polymerase PARP family of enzymes is critical for maintaining genomic stability by regulating a variety of deoxyribonucleic acid DNA damage repair mechanisms
Talazoparib BMN 673 is a PARP inhibitor with greater in vitro activity than any other PARP inhibitor currently in development Talazoparib BMN 673 has been shown to cause single-agent synthetic lethality in breast cancer 1 and breast cancer 2 BRCA12- and phosphatase and tensin homolog PTEN-deficient cell lines and has potent antitumor activity in animal models of tumors harboring mutations in DNA repair pathways
Talazoparib BMN 673 is showing promising single-agent activity in patients with advanced ovarian and breast cancer harboring deleterious BRCA mutations
This pilot study will evaluate the pharmacodynamic effects of talazoparib BMN 673 on DNA damage and apoptosis markers in tumor biopsy tissue

Primary Objective

-Determine the pharmacodynamic effect of talazoparib BMN 673 in tumor biopsies from patients with advanced ovarian breast or other solid tumor and deleterious BRCA mutations

Secondary Objectives

-Determine the response rate Complete Response CR Partial Response PR of treatment with talazoparib BMN 673 in patients with deleterious BRCA mutations

Eligibility

Adult patients with documented deleterious BRCA 1 or 2 mutations with histologically confirmed ovarian primary peritoneal breast prostate pancreas gastric or other solid tumor whose disease has progressed following at least one standard therapy or who have no acceptable standard treatment options
No major surgery radiation or chemotherapy within 4 weeks prior to study enrollment and recovered from toxicities of prior therapies to at least eligibility levels
Age greater than or equal to 18 years of age Eastern Cooperative Oncology Group ECOG performance status less than equal to 2
Adequate organ function
Willingness to undergo tumor biopsies

Study Design

Talazoparib BMN 673 will be administered orally each day in 28-day cycles
Dosing will be at the established recommended Phase II dose of 1000 microgramday each day for 28 days
To meet the primary pharmacodynamic endpoint of the trial we plan to accrue a total of 12 patients with matched evaluable baseline and day 8 biopsies To allow for some patients whose biopsies will not be evaluable ie will contain 5 tumor content the accrual ceiling is 24 patients The number of patients evaluable for objective response while relevant to the secondary objective of the trial will not be considered in determining completion of accrual
Tumor biopsies will be mandatory at baseline pre-dose and then approximately 3-6 hours post talazoparib BMN 673 on day 8 One optional tumor biopsy may also be collected either on day 1 - 2 days of the cycle following any restaging at which a 10-19 increase in tumor volume is observed according to Response Evaluation Criteria in Solid Tumors RECIST criteria if the patient has been on study for at least 4 cycles or at time of disease progression

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
Secondary IDs
Secondary ID Type Domain Link
14-C-0015 None None None