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Taselisib and Enzalutamide in Treating Patients With Androgen Receptor Positive Triple-Negative Metastatic Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02457910
Recruitment Status : Active, not recruiting
First Posted : May 29, 2015
Last Update Posted : August 1, 2018
National Cancer Institute (NCI)
Translational Breast Cancer Research Consortium
Conquer Cancer Foundation
Genentech, Inc.
Information provided by (Responsible Party):
Vandana Abramson, Vanderbilt-Ingram Cancer Center

Brief Summary:
This partially randomized phase Ib/II trial studies the side effects and best dose of taselisib when given together with enzalutamide and to see how well they work in treating patients with androgen receptor positive triple-negative breast cancer that has spread to other places in the body. Taselisib is a PI3K inhibitor. The PI3K pathway is involved is cancer growth. Androgen may cause the growth of tumor cells. Enzalutamide may stop the growth of tumor cells by blocking the androgen receptor from working. Giving taselisib with enzalutamide may be a better treatment for patients with breast cancer.

Condition or disease Intervention/treatment Phase
Estrogen Receptor Negative Estrogen Receptor Positive HER2/Neu Negative Progesterone Receptor Negative Progesterone Receptor Positive Stage IV Breast Cancer Triple-Negative Breast Carcinoma Other: Biomarker Analysis Drug: Enzalutamide Other: Pharmacological Study Drug: Taselisib Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 73 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib/II Trial of Taselisib (GDC-0032), a PI3K Inhibitor, in Combination With Enzalutamide in Patients With Androgen Receptor Positive Triple Negative Metastatic Breast Cancer
Study Start Date : June 2015
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Arm I (taselisib, enzalutamide)
Patients receive taselisib PO QD on days 1-28 and enzalutamide PO QD on days 9-28 of course 1 and days 1-28 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing unacceptable toxicity due to enzalutamide may continue to receive taselisib.
Other: Biomarker Analysis
Correlative studies

Drug: Enzalutamide
Given PO
Other Names:
  • MDV3100
  • Xtandi

Other: Pharmacological Study
Correlative studies

Drug: Taselisib
Given PO
Other Name: GDC-0032

Active Comparator: Arm II (enzalutamide)
Patients receive enzalutamide PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients may crossover to Arm I.
Other: Biomarker Analysis
Correlative studies

Drug: Enzalutamide
Given PO
Other Names:
  • MDV3100
  • Xtandi

Other: Pharmacological Study
Correlative studies

Drug: Taselisib
Given PO
Other Name: GDC-0032

Primary Outcome Measures :
  1. Clinical Benefit Rate (CBR) - Phase II [ Time Frame: At 16 weeks ]
    CBR is defined as the proportion of patients with a best response of complete response (CR), partial response (PR), or (SD) stable disease. This will be studied using a Simon two-stage design.

  2. Maximum Tolerated Dose (MTD) - Phase I [ Time Frame: 4 weeks ]
    defined as the highest dose tested in which a dose limiting toxicity is experienced by 0 out of 3 or 1 out of 6 patients among the dose levels. Dose limiting toxicity will be graded according to the National Cancer Institute CTCAE version 4.0.

Secondary Outcome Measures :
  1. Overall Progression-Free Survival (PFS) [ Time Frame: Time from course 1, day 1 until objective tumor progression, assessed up to 3 years ]
    The overall PFS data for the patients at the dose recommended for phase II will be estimated using the Kaplan-Meier method with 95% confidence intervals.

  2. Overall response rate (ORR) [ Time Frame: Up to 3 years ]
    The ORR and corresponding 95% confidence intervals will be calculated at the dose recommended for phase II.

  3. Cmax, the peak plasma concentration of taselisib after administration of taselisib [ Time Frame: 0-4 hours pre-dose and 1, 3, and 6 hours post-administration (course 1, day 8 of phase Ib) ]
    Plasma samples may be used for exploratory analysis to evaluate potential taselisib-related metabolites and/or exploratory biomarker development.

  4. Cmax, the peak plasma concentration of taselisib and enzalutamide after administration of both drugs [ Time Frame: 0-4 hours (hrs) pre-dose, 1, 3, and 6 hrs post-administration (course 2, day 15); 0-4 hrs pre-dose, 3 hrs post-administration (course 4, day 1), 0-4 hrs pre-dose, 2-4 hrs post administration (course 1, day 8, course 2 day 15, course 4 day 1 of phase II) ]
    Plasma samples may be used for exploratory analysis to evaluate potential taselisib-related metabolites and/or exploratory biomarker development.

Other Outcome Measures:
  1. Changes in biopsy analysis (including proliferation, mitosis, apoptosis, genomic instability, levels of PTEN, PI3KCA mutational analysis, HER2 and ER/PR levels, levels of MEK and AKT) [ Time Frame: Baseline up to 3 years ]
    Biopsy analysis will be performed in conjunction with the Pathology and Tissue Informatics Core to assess baseline, therapy-induced changes and status upon progression.

  2. Changes in RNA-seq analysis [ Time Frame: Baseline up to 3 years ]
    RNA-seq will be performed on all biopsies to assign a triple negative subtype and define mutations present in the tumors both at baseline and upon progression of the disease.

  3. Treatment-induced changes in gene expression analysis [ Time Frame: Baseline to up to 10 days of treatment ]
    Ribonucleic acid (RNA)-seq will be performed on all biopsies to determine baseline and treatment-induced changes in gene expression after 5-10 days of therapy.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients must provide informed written consent
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Clinical stage IV invasive mammary carcinoma
  • For phase 1b: HER2 negative, as defined for phase II; any ER/PR (negative or positive) can be enrolled in the phase 1b portion
  • For phase II: ER negative (defined as expression of ER in =< 1% cells), PR negative (defined as expression of PR in =< 1% cells), HER2 negative (acceptable methods of HER2 analysis include IHC [0, 1+], fluorescence in situ hybridization [FISH] with HER2/centromere on chromosome 17 [CEN17] ratio < 2, and/or chromogenic in situ hybridization [CISH] with HER2/CEN-17 ratio < 2), as previously documented by histological analysis
  • Androgen receptor positivity, defined as >= 10% of tumor cell nuclei with immunoreactivity for AR on central review at Vanderbilt
  • Measurable or bone-only evaluable disease; measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension by Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1, with radiologic scans within 21 days of day 1, cycle 1
  • Any number of prior therapies as long as patients have adequate performance status and meet all other eligibility criteria
  • Prior treatment with anti-androgens other than enzalutamide is acceptable
  • Phase 1b only: Formalin-fixed paraffin embedded blocks (FFPB) or fresh frozen tissue from the original diagnosis or the metastatic setting should be located; tissue must be submitted with 3 weeks of study initiation
  • Phase II only: Biopsy of a metastatic lesion in patients with reasonably accessible metastatic lesions (chest wall, skin, subcutaneous tissue, lymph nodes, skin, breast, bones, lung, and liver metastases); if a reasonably accessible metastatic lesion is not available, the patient may go on study provided that archived tissue is available; however, if a reasonably accessible site is available for biopsy, the patient must agree to biopsy; any patients not undergoing biopsy must be approved for study enrollment by the Protocol Chair; biopsies may be done with local anesthesia or intravenous conscious sedation, according to institutional guidelines; if a biopsy requires general anesthesia, then it is only allowed if acquisition of tissue is clinically indicated, and excess tissue may be collected for research purposes; patients without sites available for biopsy must have available tissue (archived formalin-fixed paraffin embedded blocks [FFPB] or fresh frozen tissue from original diagnosis or metastatic setting) for correlative studies; tissue needs to be located and available at the time of registration (tissue needs to be submitted within 3 weeks of study initiation)
  • Patients must have adequate hematologic, hepatic, and renal function. All tests must be obtained within 28 days of starting treatment. Labs are to be repeated on C1D1 and must still meet eligibility. These include:
  • Absolute neutrophil count (ANC) >= 1500/mm^3
  • Platelet count >= 75,000/mm^3
  • Hemoglobin (HgB) >= 9 g/dL
  • Creatinine =< 1.5 X upper limits of normal (ULN)
  • INR ≤2
  • Total serum bilirubin =< 1.5 x ULN (in patients with known Gilbert syndrome, a total bilirubin =< 3.0 x ULN, with direct bilirubin =< 1.5 x ULN)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (or =< 5.0 x ULN if hepatic metastases are present)
  • For patients without known type II diabetes, the following is required at screening:

    • Fasting plasma glucose =< 160 mg/dL (7.49 mmol/L) and glycosylated hemoglobin (HbA1c) < 7.5 % or International Federation of Clinical Chemistry (IFCC) < 53 mmol/mol
  • For patients with type II diabetes receiving only oral anti-hyperglycemic therapy (patients receiving insulin are not eligible), the following are required at screening:

    • HbA1c < 8.5 % or IFCC < 69.4 mmol/mol
    • Stable regimen of oral anti-hyperglycemic therapy without insulin usage for at least 3 weeks prior to first study treatment
    • Fasting plasma glucose levels =< 160 mg/dL (8.88 mmol/L) and no hypoglycemia (blood sugar [BS] < 60) during home monitoring for at least 1 week prior to study entry
  • Patients must be able to swallow and retain oral medication
  • For patients who are not postmenopausal or surgically sterile (absence of ovaries and/or uterus), agreement to remain abstinent or to use two adequate methods of contraception (e.g., condoms, diaphragm, vasectomy/vasectomized partner, tubal ligation), during the treatment period and for at least 30 days after the last dose of study treatment or 3 months after discontinuation of taselisib and/or enzalutamide, whichever is longer; hormone based oral contraceptives are not allowed on study; postmenopausal is defined as:

    • Age >= 60 years
    • Age =< 60 years and amenorrheic for 12 months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression; or follicle stimulating hormone and estradiol in the postmenopausal range
  • Patients may have received radiation therapy to painful bone metastases or areas of impending bone fracture as long as radiation therapy is completed >= 2 weeks prior to day 1 of cycle 1 of treatment; patients who have received prior radiotherapy must have recovered from toxicity (=< grade 1) induced by this treatment; baseline radiologic scans must be obtained after completion of radiation
  • Patients must complete all screening assessments

Exclusion Criteria:

  • Any kind of malabsorption syndrome significantly affecting gastrointestinal function, including history of Crohn's disease or inflammatory bowel disease
  • Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, hormonal therapy, biologic therapy) other than the ones specified in the protocol; patients must have discontinued the above cancer therapies for 1 week prior to the first dose of study medication, as well as recovered to baseline from toxicity induced by previous treatments; any investigational drugs should be discontinued 2 weeks prior to the first dose of study medication and radiotherapy must have been completed >= 2 weeks prior to initiation of study drug (cycle 1, day 1)
  • Prior use of PI3K or Akt inhibitors in the metastatic setting for the treatment of cancer; these include, but are not limited to: taselisib, GDC-0941, GDC-0980, BEZ235, BKM120, LY294002, PIK-75, TGX-221, XL147, XL765, SF1126, PX-866, D-87503, D-106669, GSK615, CAL101; patients who have received PI3K/Akt inhibitors previously for < 4 weeks will be eligible
  • Prior treatment with enzalutamide
  • Current or previously treated brain metastasis or active leptomeningeal disease; head imaging is required during screening in all patients to exclude the presence of central nervous system (CNS) metastatic disease
  • History of seizure or any condition that may predispose to seizure; history of loss of consciousness or transient ischemic attack within 12 months before day 1
  • Pregnant or lactating women
  • Insulin-dependent diabetes; patients with type II diabetes must meet the inclusion criteria outlined above
  • Uncontrolled intercurrent illness including, but not limited to:

    • Ongoing or active infection requiring parenteral antibiotics
    • Impairment of lung function (chronic obstructive pulmonary disease [COPD] > grade 2, lung conditions requiring oxygen therapy) or current dyspnea at rest
    • Symptomatic congestive heart failure (class III or IV of the New York Heart Association classification for heart disease)
    • Known left ventricular ejection fraction (LVEF) < 50%
    • Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months
    • Uncontrolled hypertension (systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mm Hg, found on two consecutive measurements separated by a 1 or 2-week period despite adequate medical support)
    • Clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or requires treatment [National Cancer Institute-Common Terminology Criteria for Adverse Events, version 4.0, grade 3])
    • Corrected QT using the Fridericia correction formula (QTcF) >= 480 msec on screening electrocardiogram (EKG)
    • Known history of QT/correct QT (QTc) prolongation or Torsades de Pointes (TdP)
    • ST depression or elevation of >= 1.5 mm in 2 or more leads
    • Diarrhea of any cause >= Common Terminology Criteria for Adverse Events (CTCAE) grade 2
    • Active autoimmune disease that is not controlled by nonsteroidal or steroidal (< 10 mg of prednisone per day) anti-inflammatory drugs or active inflammatory disease, including small or large intestine inflammation such as active Crohn's disease or ulcerative colitis, which requires immunosuppressive therapy
    • Psychiatric illness/social situations that would compromise patient safety or limit compliance with study requirements including maintenance of a compliance/pill diary
    • Known history of chronic liver disease including cirrhosis, current alcohol abuse, or infection with hepatitis B virus or hepatitis C virus (active or carrier) or renal failure
    • Known history of chronic pancreatitis
    • Conditions that affect lymphocyte counts, such as human immunodeficiency virus (HIV) infection or immunosuppressive therapy
  • Use of prohibited drugs

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02457910

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United States, Alabama
University of Alabama, Birmingham
Birmingham, Alabama, United States, 35249
United States, District of Columbia
Georgetown University
Washington, District of Columbia, United States, 20007
United States, Illinois
University of Chicago
Chicago, Illinois, United States, 60637
United States, Indiana
Indiana University
Indianapolis, Indiana, United States, 47405
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37232
United States, Texas
Baylor Breast Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Vanderbilt-Ingram Cancer Center
National Cancer Institute (NCI)
Translational Breast Cancer Research Consortium
Conquer Cancer Foundation
Genentech, Inc.
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Principal Investigator: Vandana Abramson, MD Vanderbilt University/Ingram Cancer Center

Additional Information:
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Responsible Party: Vandana Abramson, Principal Investigator, Vanderbilt-Ingram Cancer Center Identifier: NCT02457910     History of Changes
Other Study ID Numbers: VICC BRE 1374
NCI-2015-00795 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
VICC BRE 1374 ( Other Identifier: Vanderbilt-Ingram Cancer Center )
P30CA068485 ( U.S. NIH Grant/Contract )
First Posted: May 29, 2015    Key Record Dates
Last Update Posted: August 1, 2018
Last Verified: July 2018

Additional relevant MeSH terms:
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Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs