LCI-BRE-MTN-NIR-001:Ph I Study of Niraparib in Combo With Standard Chemo in Metastatic Trip Neg Breast Cancer

Phase 1

Withdrawn

• Conditions: Breast Cancer
• Interventions: Drug: Niraparib; Drug: Paclitaxel; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Carboplatin; Drug: Pegfilgrastim

• Registration Number: NCT04762901
• Lead Sponsor: Wake Forest University Health Sciences

Brief Summary

This is an open-label, two-stage, multi-arm Phase 1 study designed to evaluate the safety and preliminary efficacy of combining niraparib with four standard chemotherapy regimens used to treat TNBC.

Detailed Description

Niraparib is an oral, selective poly ADP ribose polymerase (PARP)-1 and PARP-2 inhibitor. A strategy of combining a PARP inhibitor, as a chemopotentiator, with chemotherapy is a promising approach in the treatment of triple-negative breast cancer. This study will evaluate the combination of niraparib with several standard chemotherapy regimens used to treat breast cancer to determine a recommended Stage 2 dose (RS2D) of chemotherapy regimens with niraparib. Stage 1 will be conducted in subjects with metastatic TNBC and will include 4 chemotherapy treatment arms in escalating dose levels (Arm 1: doxorubicin + cyclophosphamide (AC) every 14 days with pegfilgrastim (or biosimilar) for 4 cycles followed by AC every 21 days; Arm 2: AC every 21 days; Arm 3: weekly paclitaxel; Arm 4: weekly paclitaxel + carboplatin every 21 days), each combined with oral daily niraparib. Treatment will continue until disease progression, unacceptable toxicity, or subject withdrawal.Stage 2 will be conducted in subjects with non-metastatic TNBC. Subjects will receive neoadjuvant chemotherapy with either AC every 14 days (Arm 1A) or every 21 days (Arm 2A) at the RS2D of chemotherapy combined with oral daily niraparib from Stage 1. Treatment will continue for 4 cycles.

Study Timeline

• Study First Submitted: 2021-01-17
• Study First Submitted QC: 2021-02-16
• Study First Posted: 2021-02-21
• Study Start: 2021-04-01
• Status Verified: 2021-05
• Last Update Submitted: 2022-04-20
• Last Update Posted: 2022-04-26
• Primary Completion: 2026-01
• Study Completion: 2026-01

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Stage 2 Arm 1	Pegfilgrastim	Niraparib 100 mg orally once daily, Doxorubicin and Cyclophosphamide (AC) IV every 14 days with pegfilgrastim (or biosimilar) for 4 cycles
Stage 1 Arm 3	Paclitaxel	Niraparib 100 mg orally once daily, Paclitaxel IV Days 1, 8, 15, and 22 every 28 days
Stage 1 Arm 1	Niraparib	Niraparib 100 mg orally once daily, Doxorubicin and Cyclophosphamide (AC) IV every 14 days with pegfilgrastim (or biosimilar) for 4 cycles, followed by AC IV every 21 days
Stage 1 Arm 1	Doxorubicin	Niraparib 100 mg orally once daily, Doxorubicin and Cyclophosphamide (AC) IV every 14 days with pegfilgrastim (or biosimilar) for 4 cycles, followed by AC IV every 21 days
Stage 1 Arm 1	Pegfilgrastim	Niraparib 100 mg orally once daily, Doxorubicin and Cyclophosphamide (AC) IV every 14 days with pegfilgrastim (or biosimilar) for 4 cycles, followed by AC IV every 21 days
Stage 1 Arm 1	Cyclophosphamide	Niraparib 100 mg orally once daily, Doxorubicin and Cyclophosphamide (AC) IV every 14 days with pegfilgrastim (or biosimilar) for 4 cycles, followed by AC IV every 21 days
Stage 1 Arm 2	Niraparib	Niraparib 100 mg orally once daily, Doxorubicin and Cyclophosphamide (AC) IV every 21 days
Stage 1 Arm 2	Doxorubicin	Niraparib 100 mg orally once daily, Doxorubicin and Cyclophosphamide (AC) IV every 21 days
Stage 1 Arm 2	Cyclophosphamide	Niraparib 100 mg orally once daily, Doxorubicin and Cyclophosphamide (AC) IV every 21 days
Stage 1 Arm 4	Paclitaxel	Niraparib 100 mg orally once daily, Paclitaxel IV Days 1, 8, and 15 every 21 days and carboplatin IV every 21 days
Stage 1 Arm 3	Niraparib	Niraparib 100 mg orally once daily, Paclitaxel IV Days 1, 8, 15, and 22 every 28 days
Stage 1 Arm 4	Niraparib	Niraparib 100 mg orally once daily, Paclitaxel IV Days 1, 8, and 15 every 21 days and carboplatin IV every 21 days
Stage 1 Arm 4	Carboplatin	Niraparib 100 mg orally once daily, Paclitaxel IV Days 1, 8, and 15 every 21 days and carboplatin IV every 21 days
Stage 2 Arm 1	Cyclophosphamide	Niraparib 100 mg orally once daily, Doxorubicin and Cyclophosphamide (AC) IV every 14 days with pegfilgrastim (or biosimilar) for 4 cycles
Stage 2 Arm 1	Niraparib	Niraparib 100 mg orally once daily, Doxorubicin and Cyclophosphamide (AC) IV every 14 days with pegfilgrastim (or biosimilar) for 4 cycles
Stage 2 Arm 2	Doxorubicin	Niraparib 100 mg orally once daily, Doxorubicin and Cyclophosphamide (AC) IV every 21 days
Stage 2 Arm 1	Doxorubicin	Niraparib 100 mg orally once daily, Doxorubicin and Cyclophosphamide (AC) IV every 14 days with pegfilgrastim (or biosimilar) for 4 cycles
Stage 2 Arm 2	Cyclophosphamide	Niraparib 100 mg orally once daily, Doxorubicin and Cyclophosphamide (AC) IV every 21 days
Stage 2 Arm 2	Niraparib	Niraparib 100 mg orally once daily, Doxorubicin and Cyclophosphamide (AC) IV every 21 days

Primary Outcome Measures

Name	Time	Method
Stage 1 - Evaluate dose-limiting toxicities (DLT) separately for Arms 1, 2, 3, and 4 and establish recommended Stage 2 dose of chemotherapy in combination with niraparib	up to 28 days	The DLT variable will be determined for each subject as a binary variability indicating whether or not subject experienced a protocol-defined DLT.
Stage 2 - Assess clinically significant toxicities separately for Arms 1 and 2 after RS2D of niraparib is determined.	up to 84 days	The clinically significant toxicity variable will be determined for each subject as a binary variable indicating whether or not the subject experienced a niraparib-related dose delay of at least 28 days or a Grade 3 or higher niraparib-related non-hematologic toxicity.

Secondary Outcome Measures

Name	Time	Method
Stage 1 - Objective response rate (ORR)	up to 30 days post-treatment discontinuation	Objective response will be determined for each subject in Stage 1 as a binary variable indicating whether or not the subject achieved a best overall response of CR or PR
Stage 1 - Duration of response (DoR)	up to 5 years post-treatment discontinuation	Duration of Response (DoR) will be determined for subjects in Stage 1 who experience a PR or better and is defined as the duration of time from the first assessment that determined a CR or PR to the date of the first occurrence of progressive disease or death.
Stage 1 - Clinical benefit rate (CBR)	up to 30 days post-treatment discontinuation	Clinical benefit will be determined for each subject in Stage 1 as a binary variable indicating whether or not the subject achieved a best overall response of CR, PR, or SD
Stage 1 - Progression free survival (PFS)	up to 5 years post-treatment discontinuation	PFS will be determined for all subjects in Stage 1 and is defined as the duration of time from enrollment to the first occurrence of either progressive disease or death.
Stage 1 - Overall survival (OS)	up to 5 years post-treatment discontinuation	Overall survival is defined as the duration of time from enrollment to the date of death from any cause.
Stage 1 - Cumulative incidence of secondary malignancies including MDS	up to 5 years post-treatment discontinuation	Secondary malignancies (including MDS) will be defined as a time to event endpoint and will be calculated from the date of enrollment.
Stage 1 - Overall safety profile - Adverse Events of Special Interest (AESIs)	up to 30 days post-treatment discontinuation	The AESI variable will be determined for each subject as a binary variability indicating whether or not subject experienced a protocol-defined AESI.
Stage 1 - Overall safety profile - Adverse Events (AEs)	up to 30 days post-treatment discontinuation	The AE variable will be determined for each subject as a binary variability indicating whether or not subject experienced an AE per CTCAE V5.0.
Stage 1 - Overall safety profile - Death on Study Therapy	up to 30 days post-treatment discontinuation	The death of study therapy variable will be determined for each subject as a binary variability indicating whether or not subject experienced a Grade 5 event.
Stage 1 - Overall safety profile - Complete Blood Count with Differential (CBCD)	up to 30 days post-treatment discontinuation	The CBCD variable will be collected quantitatively for each subject.
Stage 1 - Overall safety profile - Comprehensive Metabolic Profile (CMP)	up to 30 days post-treatment discontinuation	The CMP variable will be collected quantitatively for each subject.
Stage 2 - Cumulative incidence of secondary malignancies including MDS	up to 5 years post-treatment discontinuation	Secondary malignancies (including MDS) will be defined as a time to event endpoint and will be calculated from the date of enrollment.
Stage 2 - Overall safety profile - Death on Study Therapy	up to 4 weeks post-surgery	The death of study therapy variable will be determined for each subject as a binary variability indicating whether or not subject experienced a Grade 5 event.
Stage 2 - Overall safety profile - Complete Blood Count with Differential (CBCD)	up to 4 weeks post-surgery	The CBCD variable will be collected quantitatively for each subject.
Stage 2 - Overall safety profile - Comprehensive Metabolic Profile (CMP)	up to 4 weeks post-surgery	The CMP variable will be collected quantitatively for each subject.
Stage 2 - Pathologic complete response (pCR)	up to 4 weeks post-surgery	Pathologic complete response (pCR) will be determined for each subject in Stage 2 as a binary variable indicating whether the subject experiences a pCR to neoadjuvant therapy.
Stage 2 - Overall safety profile - Adverse Events of Special Interest (AESIs)	up to 4 weeks post-surgery	The AESI variable will be determined for each subject as a binary variability indicating whether or not subject experienced a protocol-defined AESI.
Stage 2 - Overall safety profile - Adverse Events (AEs)	up to 4 weeks post-surgery	The AE variable will be determined for each subject as a binary variability indicating whether or not subject experienced an AE per CTCAE V5.0.
Stage 2 - Clinical complete response (cCR)	up to 4 weeks post-surgery	Clinical complete response (cCR) will be determined for each subject in Stage 2 as a binary variable indicating whether the subject experiences a cCR to neoadjuvant therapy.
Stage 2 - Overall survival	up to 5 years post-treatment discontinuation	Overall survival is defined as the duration of time from enrollment to the date of death from any cause.
Stage 2 - Relapse-free survival	up to 5 years post-treatment discontinuation	RFS will be determined for all subjects in Stage 2 and is defined as the duration of time from enrollment to the first occurrence of either disease progression prior to surgery, disease relapse after surgery, or death.
Stage 2 - Overall safety profile - Serious Adverse Events (SAEs)	up to 4 weeks post-surgery	The SAE variable will be determined for each subject as a binary variability indicating whether or not subject experienced a protocol-defined SAE.