Circulating Tumor DNA Enriched, Genomically Directed Post-neoadjuvant Trial for Patients With Residual Triple Negative Breast Cancer

NCT ID: NCT04849364

Last Updated: 2025-05-31

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-08-24
• Study Completion Date: 2024-12-02

Brief Summary

This is a 3-arm study stratified by plasma ctDNA. Patients with residual TNBC disease after pre-operative therapy will be assigned to 1 of 3 Arms based on plasma ctDNA positivity and genomic marker(s).

Detailed Description

Participants that are plasma ctDNA positive with a genomic target will be assigned to one of the three groups in Arm 1 and receive genomically directed therapy.

• Arm 1a: DNA Repair pathway = talazoparib + capecitabine (CLOSED)
• Arm 1b: Immunotherapy pathway = pembrolizumab + capecitabine (CLOSED)
• Arm 1c: PI3K Pathway = inavolisib + capecitabine ---> +/- standard of care pembrolizumab
• Arm 1d: DNA Repair + Immunotherapy = talazoparib + capecitabine +/- standard of care pembrolizumab

Participants that are plasma ctDNA positive without a genomic target will be assigned to Arm 2 and receive capecitabine and pembrolizumab or treatment of physician's choice.

Participants that are plasma ctDNA negative will be assigned to Arm 3 and receive any of the following based on patient and physician decision: no therapy/observation, capecitabine and pembrolizumab or treatment of physician's choice.

Conditions

Breast Cancer; Triple Negative Breast Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm 1

Arm 1a: Patients who are ctDNA-positive and harbor a genomic target. DNA repair pathway = talazoparib + capecitabine (CLOSED)

Arm 1b: Patients who are ctDNA-positive and harbor a genomic target. Immunotherapy pathway = pembrolizumab + capecitabine (CLOSED)

Arm 1c: Patients who are ctDNA-positive and harbor a genomic target. PI3K Pathway = inavolisib + capecitabine ---> +/- standard of care pembrolizumab

Arm 1d: Patients who are ctDNA-positive and harbor a genomic target. DNA Repair + Immunotherapy = talazoparib + capecitabine +/- standard of care pembrolizumab

Group Type: EXPERIMENTAL

Capecitabine

Intervention Type: DRUG

Capecitabine 1000 mg/m2 BID Orally 14 days on and 7 days off Cycle = 21 days; Total of 8 cycles

Talazoparib

Intervention Type: DRUG

Talazoparib Cycle 1: 0.75 mg then Cycle 2-8: 1 mg Cycle = 21 days; Total of 8 cycles

Pembrolizumab

Intervention Type: DRUG

Per standard of care.

Inavolisib

Intervention Type: DRUG

Inavolisib Cycle 1: 6 mg then Cycle 2-8: 9mg Orally 21 days on Cycle = 21 days; Total of 8 cycles

Arm 2

Arm 2 subjects have plasma ctDNA positive but do not have a genomically driven treatment option. Treatment of physician's choice will be given with consideration for capecitabine and pembrolizumab. Dose, schedule and duration of treatment to be determined by treating physician.

Group Type: ACTIVE_COMPARATOR

Capecitabine

Intervention Type: DRUG

Capecitabine 1000 mg/m2 BID Orally 14 days on and 7 days off Cycle = 21 days; Total of 8 cycles

Pembrolizumab

Intervention Type: DRUG

Per standard of care.

Arm 3

Arm 3 subjects have plasma ctDNA negative. Treatment of patient and physician's choice will be given with consideration for capecitabine and pembrolizumab. Dose, schedule and duration of treatment to be determined by treating physician.

Group Type: ACTIVE_COMPARATOR

Capecitabine

Intervention Type: DRUG

Capecitabine 1000 mg/m2 BID Orally 14 days on and 7 days off Cycle = 21 days; Total of 8 cycles

Pembrolizumab

Intervention Type: DRUG

Per standard of care.

Interventions

Capecitabine

Capecitabine 1000 mg/m2 BID Orally 14 days on and 7 days off Cycle = 21 days; Total of 8 cycles

Intervention Type: DRUG

Talazoparib

Talazoparib Cycle 1: 0.75 mg then Cycle 2-8: 1 mg Cycle = 21 days; Total of 8 cycles

Intervention Type: DRUG

Pembrolizumab

Per standard of care.

Intervention Type: DRUG

Inavolisib

Inavolisib Cycle 1: 6 mg then Cycle 2-8: 9mg Orally 21 days on Cycle = 21 days; Total of 8 cycles

Intervention Type: DRUG

Other Intervention Names

Xeloda; Talzenna; Keytruda; GDC-0077

Eligibility Criteria

Inclusion Criteria

• Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or may be obtained separately.
• Age ≥ 18 years at the time of consent.
• ECOG Performance Status 0 or 1 within 28 days prior to study registration.
• Must have histologically or cytologically confirmed triple negative (ER-/PR-/HER2-) invasive breast cancer per pathology report. NOTE: ER and PR will be considered negative if ≤ 10% of cells stain weakly positive. HER2 will be considered negative if scored 0 or 1+ by immunohistochemistry (IHC) or 2+ by IHC associated with a fluorescence in situ hybridization (FISH) ratio of < 2.0 or < 6 copies per cell.
• Must have clinical stage I-III at diagnosis (AJCC 8th edition) based on initial evaluation by physical examination and/or breast imaging prior to neoadjuvant chemotherapy.
• Must have completed preoperative (neoadjuvant) chemotherapy for this index case. NOTE: Acceptable preoperative regimens include an anthracycline or a taxane, or both. Participants who received preoperative therapy as part of a clinical trial may enroll. Participants may not have received adjuvant chemotherapy after surgery prior to registration. Bisphosphonate use is allowed.
• Subjects who received pembrolizumab in the neoadjuvant setting are eligible and may continue treatment during the screening process. Subjects assigned to Arm 1 will require a 3 week wash out period prior to initiation of study treatment. Subjects may resume pembrolizumab to complete the planned year of therapy (17 cycles) after completion of study therapy based on investigator discretion. Subjects assigned to Arm 2 and Arm 3 may continue pembrolizumab treatment during the study based on investigator discretion. Total duration of pembrolizumab treatment should not be extended beyond 17 cycles.
• Must have significant residual invasive disease at the time of definitive surgery following preoperative chemotherapy. Significant residual disease is defined as at least one of the following:

• Residual invasive disease in the breast measuring at least 1 cm. The presence of DCIS without invasion does not qualify as residual disease in the breast.
• Any macroscopic, (≥ 2mm) residual, lymph node involvement regardless of primary tumor site involvement (includes no residual disease in the breast).
• Residual cancer burden (RCB) score 2 or 3.
• Must have completed definitive resection of primary tumor. Participants must begin assigned arm therapy no later than 96 days from the last local therapy. NOTE: Negative margins for both invasive and ductal carcinoma in situ (DCIS) are desirable, however participants with positive margins may enroll if the study site treatment team believes no further surgery is possible and participant has received radiotherapy. Participants with margins positive for lobular carcinoma in situ (LCIS) are eligible. Either mastectomy or breast conserving surgery (including lumpectomy or partial mastectomy) is acceptable.
• Breast Radiotherapy

• Radiotherapy is required for participants who underwent breast-conserving therapy, including lumpectomy or partial mastectomy unless deemed inappropriate by the treating provider.
• Post mastectomy radiation is at the discretion of the treating physician.
• If radiation was given prior to surgery, additional radiation after surgery is not required.
• In all cases participants must begin arm assigned therapy no later than 96 days from the last local therapy
• Any acute toxicity must have resolved to grade < 2 prior to starting arm specific therapy.
• Must consent to allow submission of blood and archived tumor tissue sample from definitive surgery for next generation sequencing of the tumor. Tumor block is preferred however 14 slides + 1H&E can be submitted if necessary. NOTE: Due to possible false positives, ctDNA should not be drawn before completing radiation or less than 14 days from surgery if radiation is not required.
• Adequate laboratory values must be obtained within 28 days prior to study registration.

• Hemoglobin (Hgb) ≥ 9.0 g/dL
• Platelets ≥ 100 K/mm3
• Absolute neutrophil count (ANC) ≥ 1.5 K/mm3
• Calculated creatinine clearance of ≥ 50 cc/min using the Cockcroft-Gault formula
• Bilirubin ≤ 1.5 ULN (except in participants with documented Gilbert's disease, who must have a total bilirubin ≤ 3.0 mg/dL)
• Aspartate aminotransferase (AST, SGOT) ≤ 2.5 ULN
• Alanine aminotransferase (ALT, SGPT) ≤ 2.5 ULN
• Women of childbearing potential and their partners and male subjects and their partners must be willing to use effective contraception (as outlined in protocol) from the time consent is signed until after protocol therapy discontinuation based on package insert or investigator brochure guidelines (See protocol for timeframes).
• Women of childbearing potential must have a negative urine or serum pregnancy test at screening and within 7 days prior to study registration. Women should be counseled regarding acceptable birth control methods to utilize. If prior to treatment after discussion with the subject it is felt by the treating physician there is a possibility the subject is pregnant a pregnancy test should be repeated. NOTE: Women are considered not of childbearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or they are postmenopausal for at least 12 consecutive months.
• Women must not be breastfeeding from the time of treatment initiation until the number of days after protocol therapy discontinuation based on package insert or investigator brochure guidelines (See protocol for timeframes).

-Adequate laboratory values must be obtained within 21 days prior to starting arm therapy.

• Fasting total glucose ≤ 126 mg/dL
• HbA1C ≤ 5.7%
• Cholesterol < 300 mg/dL; 10.34 mmol/L
• Triglycerides < 300 mg/dL; 3.42 mmol/L

Exclusion Criteria

• Clinically significant infections as judged by the treating physician.
• Stage IV (metastatic) disease, however no specific staging studies are required in the absence of symptoms or physical exam findings that would suggest distant disease.
• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial. NOTE: Patients without a known history of being HIV positive do not require testing at screening. Patients who are known to be HIV positive will require testing as described to be eligible for this trial. Testing should be considered standard of care.
• Patients with evidence of chronic hepatitis B virus (HBV) infection, with undetectable HBV viral load within 6 months of registration are eligible for this trial. They should be on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, the HCV viral load must be undetectable within 6 months of registration to be eligible for this trial. NOTE: Patients without a known history of being hepatitis positive do not require testing at screening. Patients who are known to be hepatitis positive will require testing as described to be eligible for this trial. Testing should be considered standard of care.
• Participants with unstable angina or a myocardial infarction within 12 months of study registration.
• Active second malignancy (except non-melanomatous skin cancer or incidental prostate cancer found on cystectomy): Active second malignancy is defined as a current need for cancer therapy or a high possibility (> 30%) of recurrence during the study. Previous contralateral breast cancer is allowable unless it meets "active" criteria as stated above.
• Inability to swallow pills.
• Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol, safety of participation, or interpretation of results. This includes significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome) or any other serious medical condition or abnormality in clinical laboratory tests that meet these criteria in the investigator's opinion.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to any of the study medications being used in this study.
• Treatment with any investigational agent within 30 days prior to study registration.

• Any concurrent ocular or intraocular condition (e.g., cataract or diabetic retinopathy) that, in the opinion of the investigator, would require medical or surgical intervention during the study period to prevent or treat vision loss that might result from that condition.
• Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of Type 1 diabetes.
• Active inflammatory (e.g., uveitis or vitritis) or infectious (e.g., conjunctivitis, keratitis, scleritis, or endophthalmitis) conditions in either eye or history of idiopathic or autoimmune-associated uveitis in either eye.
• Symptomatic active lung disease, including pneumonitis
• History of or active inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis). Patients currently receiving immunosuppressants for inflammatory bowel disease (e.g., sulfasalazine) are considered to have active disease and are therefore ineligible.
• Any active bowel inflammation (including diverticulitis)
• Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab therapy. Bisphosphonate and denosumab therapy for bone metastases or osteopenia/osteoporosis is allowed.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genentech, Inc.

INDUSTRY

Sponsor Role: collaborator

Pfizer

INDUSTRY

Sponsor Role: collaborator

Foundation Medicine

INDUSTRY

Sponsor Role: collaborator

Indiana University

OTHER

Sponsor Role: collaborator

Vera Bradley Foundation for Breast Cancer

OTHER

Sponsor Role: collaborator

Bryan Schneider, MD

OTHER

Sponsor Role: lead

Responsible Party

Bryan Schneider, MD

Sponsor-Investigator

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Bryan P Schneider, MD

Role: PRINCIPAL_INVESTIGATOR

Indiana University

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Georgetown University

Washington D.C., District of Columbia, United States

Memorial Healthcare System

Hollywood, Florida, United States

Miami Cancer Institute at Baptist Health, Inc.

Miami, Florida, United States

University of Chicago Medical Center

Chicago, Illinois, United States

Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Indianapolis, Indiana, United States

Summit Health

Berkeley Heights, New Jersey, United States

Novant Health Cancer Institute

Winston-Salem, North Carolina, United States

Mays Cancer Center at UT Health San Antonio

San Antonio, Texas, United States

University of Wisconsin

Madison, Wisconsin, United States

Froedtert and The Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Advocate Aurora Research Institute (Illinois)

Wauwatosa, Wisconsin, United States

Aurora Health Care

Wauwatosa, Wisconsin, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

HCRN BRE18-334

Identifier Type: -

Identifier Source: org_study_id