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

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ClinicalTrials.gov Identifier: NCT04849364
Recruitment Status : Recruiting
First Posted : April 19, 2021
Last Update Posted : January 13, 2023
Sponsor:
Collaborators:
Genentech, Inc.
Pfizer
Foundation Medicine
Indiana University
Epic Sciences
Vera Bradley Foundation for Breast Cancer Research
Information provided by (Responsible Party):
Bryan Schneider, MD, Hoosier Cancer Research Network

Tracking Information
First Submitted Date  ICMJE April 13, 2021
First Posted Date  ICMJE April 19, 2021
Last Update Posted Date January 13, 2023
Actual Study Start Date  ICMJE August 24, 2021
Estimated Primary Completion Date January 31, 2029   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 13, 2021)
2 year Disease Free Survival (DFS) ARM 1 [ Time Frame: 2 year ]
DFS is defined as the duration of time from arm assignment to time of a DFS event, defined as local failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-invasive), or death from any cause.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 13, 2021)
  • 2 year Disease Free Survival (DFS) in ARM 2 [ Time Frame: 2 years ]
    DFS is defined as the duration of time from arm assignment to time of a DFS event, defined as local failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-invasive), or death from any cause.
  • 2 year Disease Free Survival (DFS) in ARM 3 [ Time Frame: 2 years ]
    DFS is defined as the duration of time from arm assignment to time of a DFS event, defined as local failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-invasive), or death from any cause.
  • Overall Disease Free Survival (DFS) [ Time Frame: 2 years ]
    Comparison of overall DFS in Arms 1, 2, 3; defined as the duration of time from arm assignment to time of a DFS event, defined as local failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-invasive), or death from any cause
  • Overall Distant Disease Free Survival (DDFS) [ Time Frame: 2 years ]
    DDFS is defined as the duration of time from arm assignment to time of recurrence of breast cancer outside the breast and/or death from any cause.
  • 1 year Disease Free Survival (DFS) [ Time Frame: 1 year ]
    DFS is defined as the duration of time from arm assignment to time of a DFS event, defined as local failure (invasive), regional failure, distant failure, contralateral breast cancer (invasive or non-invasive), or death from any cause
  • 5 year Overall Survival (OS) [ Time Frame: 5 years ]
    Overall survival is defined as the time from date of treatment start until death from any cause.
  • Frequency and Severity of Adverse Events [ Time Frame: 1 year ]
    Adverse events will be assessed using CTCAE criteria v5
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Circulating Tumor DNA Enriched, Genomically Directed Post-neoadjuvant Trial for Patients With Residual Triple Negative Breast Cancer
Official Title  ICMJE A Phase II Circulating Tumor DNA Enriched, Genomically Directed Post-neoadjuvant Trial for Patients With Residual Triple Negative Breast Cancer (PERSEVERE)
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 = atezolizumab + capecitabine
  • Arm 1c: PI3K Pathway = inavolisib + capecitabine ---> atezolizumab
  • Arm 1d: DNA Repair + Immunotherapy = talazoparib + atezolizumab + capecitabine

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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Breast Cancer
  • Triple Negative Breast Cancer
Intervention  ICMJE
  • Drug: Capecitabine
    Capecitabine 1000 mg/m2 BID Orally 14 days on and 7 days off Cycle = 21 days; Total of 8 cycles
    Other Name: Xeloda
  • Drug: Talazoparib
    Talazoparib Cycle 1: 0.75 mg then Cycle 2-8: 1 mg Cycle = 21 days; Total of 8 cycles
    Other Name: Talzenna
  • Drug: Atezolizumab
    Atezolizumab 1200 mg IV over 1 hour Cycle = 21 days; Total of 9 cycles
    Other Name: Tecentriq
  • Drug: Inavolisib
    Inavolisib Cycle 1: 6 mg then Cycle 2-8: 9mg Orally 21 days on Cycle = 21 days; Total of 8 cycles
    Other Name: GDC-0077
  • Other: Treatment of Choice
    Treatment of patient and physician's choice will be given with strong consideration for capecitabine given the data from CREATE-X and KEYNOTE 522. Dose, schedule and duration of treatment to be determined by treating physician.
    Other Name: Xeloda
Study Arms  ICMJE
  • Experimental: 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 = atezolizumab + capecitabine

    Arm 1c: Patients who are ctDNA-positive and harbor a genomic target. PI3K Pathway = inavolisib + capecitabine ---> atezolizumab

    Arm 1d: Patients who are ctDNA-positive and harbor a genomic target. DNA Repair + Immunotherapy = talazoparib + atezolizumab + capecitabine

    Interventions:
    • Drug: Capecitabine
    • Drug: Talazoparib
    • Drug: Atezolizumab
    • Drug: Inavolisib
  • Active Comparator: 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/or pembrolizumab. Dose, schedule and duration of treatment to be determined by treating physician.
    Intervention: Other: Treatment of Choice
  • Active Comparator: Arm 3
    Arm 3 subjects have plasma ctDNA negative. Treatment of patient and physician's choice will be given with consideration for capecitabine and/or pembrolizumab. Dose, schedule and duration of treatment to be determined by treating physician.
    Intervention: Other: Treatment of Choice
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 13, 2021)
197
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 31, 2034
Estimated Primary Completion Date January 31, 2029   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

General 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 21 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 receiving pembrolizumab 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 assigned to Arm 2 and Arm 3 may continue pembrolizumab treatment during the study based on investigator discretion.
  • 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, 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 84 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.
    • 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 84 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 21 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 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).

Inclusion Criteria for Patients Assigned to Arm 1c ONLY -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

General Exclusion Criteria

  • Clinically significant infections as judged by the treating physician. NOTE: For participants who are exhibiting symptoms consistent with COVID-19 or have tested positive using a test consistent with the institutional standard of care, enrollment and protocol treatment should not be initiated until resolution of symptoms as per investigator discretion.
  • 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.
  • History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computerized tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
  • History of interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections (pneumocystis pneumonia or cytomegalovirus pneumonia).
  • History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) or active bowel inflammation (e.g., diverticulitis).
  • History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus (SLE), rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with the following are eligible:

    • history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone
    • controlled Type 1 diabetes mellitus on a stable insulin dosing regimen
    • eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g. patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:

      • rash must cover less than 10% of body surface area
      • disease is well controlled prior to arm assignment and only requires low potency topical steroids
      • no acute exacerbations of underlying condition within the previous 12 months (not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral steroids).
  • Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, mycophenolate and anti-tumor necrosis factor [TNF] agents) within 2 weeks prior to arm assignment, or anticipated requirement for systemic immunosuppressive medications during the trial. Patients who have received acute, low dose, systemic immunosuppressant medications (e.g. one-time dose of dexamethasone) may be enrolled in the study. The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g. fludrocortisone) for patients with orthostatic hypotension, and low dose supplemental corticosteroids (<10 mg prednisone or equivalent) for adrenocortical insufficiency are allowed. Patients with a history of allergic reaction to IV contrast requiring steroid pre-treatment should have screening and subsequent tumor assessments performed using magnetic resonance imaging (MRI).
  • 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.
  • Prior history of stem cell or solid organ transplantation.
  • 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.

Exclusion Criteria for Patients Assigned to Arm 1c ONLY

-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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Bryan P Schneider, MD 317-948-3885 bpschnei@iu.edu
Contact: Milena Petkov 317-634-5842 ext 40 mpetkov@hoosiercancer.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04849364
Other Study ID Numbers  ICMJE HCRN BRE18-334
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Bryan Schneider, MD, Hoosier Cancer Research Network
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Bryan Schneider, MD
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Genentech, Inc.
  • Pfizer
  • Foundation Medicine
  • Indiana University
  • Epic Sciences
  • Vera Bradley Foundation for Breast Cancer Research
Investigators  ICMJE
Principal Investigator: Bryan P Schneider, MD Indiana University
PRS Account Hoosier Cancer Research Network
Verification Date January 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP