Talazoparib Before Standard Therapy in Treating Patients With Invasive, BRCA-Mutated Breast Cancer

Sponsor
M.D. Anderson Cancer Center (Other)
Overall Status
Completed
CT.gov ID
NCT02282345
Collaborator
National Cancer Institute (NCI) (NIH)
36
1
1
85.7
0.4

Study Details

Study Description

Brief Summary

This phase II trial studies the side effects of talazoparib when given before standard therapy in treating patients with breast cancer that has spread to nearby healthy tissue and has a mutation in a breast cancer, early onset (BRCA) gene. Talazoparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth, and may be especially effective in patients with BRCA mutations. It is not yet known whether adding talazoparib before standard treatment is safe in treating patients with BRCA mutated breast cancer.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. To evaluate the feasibility of using talazoparib prior to initiating standard neoadjuvant therapies.

  2. To evaluate the toxicity profile in women taking talazoparib in the neoadjuvant setting.

SECONDARY OBJECTIVES:
  1. To provide first estimate of clinical response to talazoparib in the neoadjuvant setting in a pilot trial setting.

  2. To evaluate biomarkers of therapy efficacy as well as initiate patient derived xenograft (PDX) models: targeted or whole exome sequencing for BRCA pathway mutations and other somatic and germline alterations; ribonucleic acid (RNA) sequencing; evaluation of changes in immune response; transcriptional profile to assess triple negative breast cancer (TNBC) subtype, BRCA-ness signature and putative PARP sensitivity predictors; functional proteomics with reverse phase protein array (RPPA); generate PDX models and mammosphere cultures from patient derived tumors; PTEN, gamma-H2A histone family, member x (gamma-H2A.X), Ki-67 and cleaved caspase 3 by immunohistochemistry (IHC).

OUTLINE:

Patients receive talazoparib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then proceed to the standard of care therapy of the treating physician's choice.

After completion of study treatment, patients are followed up until the day after definitive breast surgery.

Study Design

Study Type:
Interventional
Actual Enrollment :
36 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Pilot Study of Talazoparib as a Neoadjuvant Study in Patients With a Diagnosis of Invasive Breast Cancer and a Deleterious BRCA Mutation
Actual Study Start Date :
Apr 16, 2015
Actual Primary Completion Date :
Apr 26, 2018
Actual Study Completion Date :
Jun 7, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (talazoparib)

Patients receive talazoparib PO QD on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then proceed to the standard of care therapy of the treating physician's choice. This arm was concluded early after 13 patients. An expansion arm of 20 patients was opened in August 2016 to include at least 4 and up to 6 cycles of talazoparib, followed by surgery to estimate residual cancer burden after therapy with single-agent talazoparib.

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Talazoparib
Given PO
Other Names:
  • BMN 673
  • BMN-673
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Overall Pathological Complete Response (pCR) [Up to 6 months]

      Pathologic response was documented using the Residual Cancer Burden (RCB) Calculator. Residual cancer burden by ICR will be reported as a categorical variable with four classes (categories) RCB 0 (pCR) which correlates to no invasive disease in breast and lymph, I (minimal RCB), II (moderate RCB), and III (extensive RCB). Up to two fine needle aspirates (FNAs) will also be obtained at each time point for a total of up to 6 FNA's for the trial, which will be used for the patient derived xenograft models. Pre-study biopsies, as well as biopsies within 7 days prior to the completion of 2 months of talazoparib will be collected via diagnostic imaging. During the expansion phase of this trial, ultrasounds will be obtained every 2 cycles (+/- 1 week). Therapy will be discontinued if the Physician or PI indicates clinically significant progression of disease.

    2. Number of Participants With Grade 4 Toxicities [up to 6 months]

      To assess the toxicity profile of women taking single agent Talazoparib prior to surgery. If greater than 33% of the patients enrolled have either a grade 4 toxicity possibly, probably, or definitely related to the treatment as attributed by the Principal Investigator, or requires a delay in treatment for greater than 4 weeks due to toxicity.

    Secondary Outcome Measures

    1. Median Clinical Response to Single Agent Talazoparib [2 months]

      Imaging was the primary measures response with tumor volume shrinkage after 2 months of Talazoparib prior to proceeding with standard chemotherapy for all participants. The clinical response to Talazoparib in the neoadjuvant setting in a pilot trial setting.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Signed written informed consent

    • Histologically confirmed primary invasive adenocarcinoma of the breast with the size of the primary tumor being at least 1 cm on imaging by either mammography, ultrasound or breast magnetic resonance imaging (MRI)

    • Negative human epidermal growth factor receptor 2 (HER-2)/neu- disease defined as patients with fluorescence in situ hybridization (FISH) ratio < 2.0 or < 6.0 HER2 gene copies per nucleus, and IHC staining scores of 0, 1+, or 2+

    • No treatment for current primary invasive adenocarcinoma of the breast such as irradiation, chemotherapy, immunotherapy, investigational therapy or surgery; previous treatment for breast and/or ovarian cancer with chemotherapy, endocrine therapy, surgery and radiation are allowed if >= 3 years prior to current diagnosis and there is no clinical evidence of metastatic disease

    • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

    • Baseline multi gated acquisition scan (MUGA) or echocardiogram scans with left ventricular ejection fraction (LVEF) of > 50%

    • Absolute neutrophil count (ANC) >= 1,500/uL

    • Platelets >= 100,000/uL

    • Hemoglobin (Hgb) >= 9 g/dL

    • Creatinine clearance > 50 ml/min

    • Total bilirubin =< 1.5 X upper limit of normal (ULN)

    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 X ULN

    • Negative serum or urine pregnancy test for women within 7 days of receiving the first dose of the study medication for women of childbearing potential; women will be considered not of childbearing potential and exempt from pregnancy testing if they are either a) older than 50 and amenorrheic for at least 12 consecutive months following cessation of all exogenous hormonal treatments, or b) have documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation

    • Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of investigational product; men on study also must be using contraception

    • Identified deleterious mutation in BRCA 1 or 2 genes (this does not include variants of uncertain significance)

    • Eligible to receive standard of care chemotherapy and/or surgery based upon standard practices or institutional guidelines

    Exclusion Criteria:
    • Women who are pregnant (including positive pregnancy test at enrollment or prior to study drug administration) or breast-feeding

    • Disease free of prior malignancy for < 3 years with the exception of curatively treated basal carcinoma of the skin or carcinoma in situ of the cervix

    • Any other previous antitumor therapies for the current cancer event

    • Has had major surgery within 21 days before cycle 1 day 1

    • Gastrointestinal tract disease or defect with associated malabsorption syndrome

    • Uncontrolled inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)

    • Myocardial infarction within 6 months before starting therapy, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medication

    • Serious intercurrent infections or non-malignant medical illness that are uncontrolled or the control of which may be jeopardized by this therapy

    • Psychiatric disorders or other conditions rendering the subject incapable of complying with the requirements of the protocols

    • Unable to take oral medications

    • Known to be human immunodeficiency virus positive

    • Known active hepatitis C virus, or known active hepatitis B virus

    • Concurrent disease or condition that would interfere with study participation or safety, such as any of the following:

    • Active, clinically significant infection either grade > 2 by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.03 or requiring the use of parenteral anti-microbial agents within 14 days before day 1 of study drug

    • Clinically significant bleeding diathesis or coagulopathy, including known platelet function disorders

    • Non-healing wound, ulcer, or bone fracture

    • Known hypersensitivity to any of the components of talazoparib

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 M D Anderson Cancer Center Houston Texas United States 77030

    Sponsors and Collaborators

    • M.D. Anderson Cancer Center
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Jennifer K Litton, M.D. Anderson Cancer Center

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    M.D. Anderson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT02282345
    Other Study ID Numbers:
    • 2014-0045
    • NCI-2015-00335
    • 2014-0045
    First Posted:
    Nov 4, 2014
    Last Update Posted:
    Jul 6, 2022
    Last Verified:
    Jun 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details All participants were recruited from the breast medical oncology clinic at MD Anderson Cancer Center
    Pre-assignment Detail 36 participants signed the consent, 3 participants were inevaluable
    Arm/Group Title Talazoparib (2 Months) Expansion Arm Talazoparib (6 Months) + Surgery
    Arm/Group Description Talazoparib was administered as single-agent oral dose of 1 mg per day for six cycles (each cycle was 28 days) for 2 months followed by standard of care chemotherapy. Talazoparib will be administered orally at 1 mg per day for at least 4 and up to 6 cycles. Each cycle will consist of 28 days (+/-3 days) followed by surgery or standard of care chemotherapy.
    Period Title: Overall Study
    STARTED 13 20
    COMPLETED 13 19
    NOT COMPLETED 0 1

    Baseline Characteristics

    Arm/Group Title Talazoparib - (2 Months) Expansion Arm (Talazoparib (6 Months) + Surgery) Total
    Arm/Group Description Talazoparib was administered as single-agent oral dose of 1 mg per day for six cycles (each cycle was 28 days) for 2 months followed by standard of care chemotherapy. Talazoparib will be administered orally at 1 mg per day for at least 4 and up to 6 cycles. Each cycle will consist of 28 days (+/-3 days) followed by surgery or standard of care chemotherapy. Total of all reporting groups
    Overall Participants 13 20 33
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    40
    38
    38
    Sex: Female, Male (Count of Participants)
    Female
    13
    100%
    20
    100%
    33
    100%
    Male
    0
    0%
    0
    0%
    0
    0%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    3
    23.1%
    5
    25%
    8
    24.2%
    Not Hispanic or Latino
    10
    76.9%
    15
    75%
    25
    75.8%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    1
    7.7%
    3
    15%
    4
    12.1%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    4
    30.8%
    5
    25%
    9
    27.3%
    White
    5
    38.5%
    7
    35%
    12
    36.4%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    3
    23.1%
    5
    25%
    8
    24.2%
    Region of Enrollment (participants) [Number]
    United States
    13
    100%
    20
    100%
    33
    100%
    Number of Participants with Breast Cancer Gene and 2 (BRCA1/2) Mutations at Baseline (Count of Participants)
    BRCA1
    10
    76.9%
    16
    80%
    26
    78.8%
    BRCA2
    3
    23.1%
    4
    20%
    7
    21.2%
    Clinical stage (Count of Participants)
    I
    2
    15.4%
    5
    25%
    7
    21.2%
    II
    9
    69.2%
    12
    60%
    21
    63.6%
    III
    2
    15.4%
    3
    15%
    5
    15.2%
    Histology (Count of Participants)
    Ductal
    12
    92.3%
    18
    90%
    30
    90.9%
    Metaplastic
    1
    7.7%
    1
    5%
    2
    6.1%
    Metaplastic chondrosarcomatous
    0
    0%
    1
    5%
    1
    3%
    Chemotherapy regimen used (Count of Participants)
    AC followed or preceded by weekly taxol
    13
    100%
    0
    0%
    13
    39.4%
    Addition of carboplatin to weekly taxol
    6
    46.2%
    0
    0%
    6
    18.2%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Overall Pathological Complete Response (pCR)
    Description Pathologic response was documented using the Residual Cancer Burden (RCB) Calculator. Residual cancer burden by ICR will be reported as a categorical variable with four classes (categories) RCB 0 (pCR) which correlates to no invasive disease in breast and lymph, I (minimal RCB), II (moderate RCB), and III (extensive RCB). Up to two fine needle aspirates (FNAs) will also be obtained at each time point for a total of up to 6 FNA's for the trial, which will be used for the patient derived xenograft models. Pre-study biopsies, as well as biopsies within 7 days prior to the completion of 2 months of talazoparib will be collected via diagnostic imaging. During the expansion phase of this trial, ultrasounds will be obtained every 2 cycles (+/- 1 week). Therapy will be discontinued if the Physician or PI indicates clinically significant progression of disease.
    Time Frame Up to 6 months

    Outcome Measure Data

    Analysis Population Description
    1 patient did not go to surgery but went to chemotherapy for suspected progression
    Arm/Group Title Talazoparib (2 Months) +(SOC) Chemotherapy Expansion Arm Talazoparib (6 Months) + Surgery
    Arm/Group Description Talazoparib was administered as single-agent oral dose of 1 mg per day for six cycles (each cycle was 28 days) for 2 months followed by standard of care (SOC) chemotherapy. Talazoparib will be administered orally at 1 mg per day for at least 4 and up to 6 cycles. Each cycle will consist of 28 days (+/-3 days) followed by surgery or standard of care chemotherapy.
    Measure Participants 13 20
    Residual Cancer Burden 0
    7
    53.8%
    10
    50%
    Residual Cancer Burden I
    3
    23.1%
    2
    10%
    Residual cancer Burden II
    3
    23.1%
    5
    25%
    Residual Cancer Burden III
    0
    0%
    2
    10%
    2. Primary Outcome
    Title Number of Participants With Grade 4 Toxicities
    Description To assess the toxicity profile of women taking single agent Talazoparib prior to surgery. If greater than 33% of the patients enrolled have either a grade 4 toxicity possibly, probably, or definitely related to the treatment as attributed by the Principal Investigator, or requires a delay in treatment for greater than 4 weeks due to toxicity.
    Time Frame up to 6 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Talazoparib - (2 Months) + (SOC) Chemotherapy. Expansion Arm (Talazoparib (6 Months) + Surgery)
    Arm/Group Description Talazoparib was administered as single-agent oral dose of 1 mg per day for six cycles (each cycle was 28 days) for 2 months followed by standard of care (SOC)chemotherapy. Talazoparib will be administered orally at 1 mg per day for at least 4 and up to 6 cycles. Each cycle will consist of 28 days (+/-3 days) followed by surgery or standard of care chemotherapy.
    Measure Participants 13 20
    Count of Participants [Participants]
    0
    0%
    1
    5%
    3. Secondary Outcome
    Title Median Clinical Response to Single Agent Talazoparib
    Description Imaging was the primary measures response with tumor volume shrinkage after 2 months of Talazoparib prior to proceeding with standard chemotherapy for all participants. The clinical response to Talazoparib in the neoadjuvant setting in a pilot trial setting.
    Time Frame 2 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Talazoparib (2 Months)
    Arm/Group Description Talazoparib was administered as single-agent oral dose of 1 mg per day for six cycles (each cycle was 28 days) for 2 months followed by standard of care (SOC) chemotherapy.
    Measure Participants 13
    Median (95% Confidence Interval) [percentage of tumor volume shrinkage]
    88

    Adverse Events

    Time Frame Adverse events were monitored from date of consent to date patients started new treatment, an average of 1 year
    Adverse Event Reporting Description
    Arm/Group Title Talazoparib (2 Months) Expansion Arm Talazoparib (6 Months) + Surgery
    Arm/Group Description Talazoparib was administered as single-agent oral dose of 1 mg per day for six cycles (each cycle was 28 days) for 2 months followed by standard of care chemotherapy. Talazoparib will be administered orally at 1 mg per day for at least 4 and up to 6 cycles. Each cycle will consist of 28 days (+/-3 days) followed by surgery or standard of care chemotherapy.
    All Cause Mortality
    Talazoparib (2 Months) Expansion Arm Talazoparib (6 Months) + Surgery
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/13 (0%) 0/20 (0%)
    Serious Adverse Events
    Talazoparib (2 Months) Expansion Arm Talazoparib (6 Months) + Surgery
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/13 (0%) 1/20 (5%)
    Blood and lymphatic system disorders
    Thrombocytopenia 0/13 (0%) 1/20 (5%)
    Other (Not Including Serious) Adverse Events
    Talazoparib (2 Months) Expansion Arm Talazoparib (6 Months) + Surgery
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 9/13 (69.2%) 15/20 (75%)
    Blood and lymphatic system disorders
    Anemia 9/13 (69.2%) 15/20 (75%)
    Leukopenia 8/13 (61.5%) 0/20 (0%)
    Neutropenia (decreased ANC) 7/13 (53.8%) 7/20 (35%)
    Thrombocytopenia 5/13 (38.5%) 1/20 (5%)
    Hyperbilirubinemia 2/13 (15.4%) 0/20 (0%)
    Hypomagnesemia 2/13 (15.4%) 3/20 (15%)
    Hypokalemia 1/13 (7.7%) 1/20 (5%)
    Decreased white blood cells 8/13 (61.5%) 12/20 (60%)
    Neutropenia 7/13 (53.8%) 7/20 (35%)
    Hyperglycemia 0/13 (0%) 5/20 (25%)
    Hypophosphatemia 0/13 (0%) 1/20 (5%)
    Hyperphoshatemia 0/13 (0%) 1/20 (5%)
    Eye disorders
    Eye redness/pain 1/13 (7.7%) 0/20 (0%)
    Gastrointestinal disorders
    Mucositis/mouth sore 5/13 (38.5%) 0/20 (0%)
    Nausea 7/13 (53.8%) 15/20 (75%)
    GI disorder (stomach cramps/pain) 3/13 (23.1%) 0/20 (0%)
    Constipation 2/13 (15.4%) 2/20 (10%)
    Dry mouth 1/13 (7.7%) 0/20 (0%)
    Vomiting 0/13 (0%) 3/20 (15%)
    Flatulence 0/13 (0%) 1/20 (5%)
    General disorders
    Fatigue 7/13 (53.8%) 14/20 (70%)
    Pain 0/13 (0%) 5/20 (25%)
    Pain in breast 0/13 (0%) 4/20 (20%)
    Increased transaminases 4/13 (30.8%) 4/20 (20%)
    Increased Phosphorous 0/13 (0%) 1/20 (5%)
    Infections and infestations
    Sinusitis 0/13 (0%) 2/20 (10%)
    Investigations
    Elevated ALT/AST 4/13 (30.8%) 0/20 (0%)
    Increased Creatinine 0/13 (0%) 1/20 (5%)
    Metabolism and nutrition disorders
    Hyperkalemia 1/13 (7.7%) 1/20 (5%)
    Musculoskeletal and connective tissue disorders
    Myalgia 1/13 (7.7%) 0/20 (0%)
    Nervous system disorders
    Dizziness 8/13 (61.5%) 6/20 (30%)
    Headache 3/13 (23.1%) 2/20 (10%)
    Memory impairment 2/13 (15.4%) 0/20 (0%)
    Neuropathy 1/13 (7.7%) 0/20 (0%)
    Anxiety 0/13 (0%) 1/20 (5%)
    Renal and urinary disorders
    Urinary tract infection 0/13 (0%) 3/20 (15%)
    Increased Blood Urea Nitrogen (BUN) 0/13 (0%) 1/20 (5%)
    Reproductive system and breast disorders
    Vaginal Bleeding 0/13 (0%) 1/20 (5%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnea 3/13 (23.1%) 5/20 (25%)
    Bronchitis 0/13 (0%) 1/20 (5%)
    Skin and subcutaneous tissue disorders
    Alopecia 2/13 (15.4%) 11/20 (55%)
    Nail discoloration 1/13 (7.7%) 0/20 (0%)
    Rash 1/13 (7.7%) 0/20 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Jennifer Litton,VP, Clinical Research, VP Clinical Research
    Organization UT MD Anderson Cancer Center
    Phone (713) 792-2817
    Email jlitton@mdanderson.org
    Responsible Party:
    M.D. Anderson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT02282345
    Other Study ID Numbers:
    • 2014-0045
    • NCI-2015-00335
    • 2014-0045
    First Posted:
    Nov 4, 2014
    Last Update Posted:
    Jul 6, 2022
    Last Verified:
    Jun 1, 2022