Estrogen Receptor NegativePhase 1/2NCT02457910
Taselisib and Enzalutamide in Treating Patients With Androgen Receptor Positive Triple-Negative Metastatic Breast Cancer
A Phase 1/2 study testing Biomarker Analysis, Enzalutamide and Pharmacological Study in people with Estrogen Receptor Negative and Estrogen Receptor Positive, run by Vanderbilt-Ingram Cancer Center at 12 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Estrogen Receptor Negative, Estrogen Receptor Positive, HER2/Neu Negative
- What is being tested?
- Biomarker Analysis, Enzalutamide and Pharmacological Study
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 12 sitesUnited States
- Study dates
- Jun 2015to 8 Aug 2022
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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 cycle 1, day 1 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)
- international normalized ratio (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
Who cannot join
- 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
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- 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
Trial locations and contacts
12 sites in 1 country.
12 sites in 1 country
United States12 sites
University of Michigan
Ann Arbor, Michigan
John Hopkins University
Baltimore, Maryland, 21218
University of Alabama, Birmingham
Birmingham, Alabama, 35249
Dana Farber Cancer Institute
Boston, Massachusetts, 02115
University of North Carolina
Chapel Hill, North Carolina, 27599
University of Chicago
Chicago, Illinois, 60637
Baylor Breast Center
Houston, Texas, 77030
Indiana University
Indianapolis, Indiana, 47405
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, 37232
University of Pittsburgh
Pittsburgh, Pennsylvania, 15260
Mayo Clinic
Rochester, Minnesota, 55905
Georgetown University
Washington D.C., District of Columbia, 20007
About this study
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
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.
Read the detailed description
PRIMARY OBJECTIVES:
- To determine the safety and tolerability of taselisib given in combination with enzalutamide: Assessment of dose limiting toxicities (DLTs) during the first 4 weeks of treatment (cycle 1). (Phase Ib) II. To determine the safety and tolerability of taselisib given in combination with enzalutamide: Determination of the maximally tolerated dose (MTD) of taselisib given in combination with enzalutamide. (Phase Ib) III. To evaluate the efficacy, as measured by clinical benefit rate (CBR), of enzalutamide + taselisib in patients with androgen receptor positive (AR+) triple negative (TN) metastatic breast cancer (MBC). (Phase II)
SECONDARY OBJECTIVES:
- To determine the progression free survival (PFS) of enzalutamide + taselisib in patients with AR+ TN MBC.
II. To assess the pharmacokinetics (PKs) of taselisib and enzalutamide in patients with AR+ TN MBC.
TERTIARY OBJECTIVES:
- To explore predictors of biomarker response and mechanisms of resistance based on exploratory analysis of tumor tissue obtained through biopsies.
II. Levels of phosphatase and tensin homolog (PTEN) expression by immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qPCR).
III. Presence of mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene.
IV. Human epidermal growth factor receptor 2 (HER2) (IHC, fluorescence in situ hybridization [FISH]) and estrogen receptor (ER)/progesterone receptor (PR) levels (IHC) in tumor biopsy from a metastatic site.
- Levels of mitogen-activated protein kinase kinase (MEK) activity measured by phosphorylated extracellular-signal-regulated kinases (p-ERK1/2) (IHC) and phosphorylated p-ribosomal protein S6 (S6) (S235/236 and S240/244) at baseline and upon progression of disease.
VI. Levels of phosphorylated v-akt murine thymoma viral oncogene homolog 1 (p-AKT) (IHC) at baseline and upon progression of disease.
VII. Gene expression profiling to assign a triple negative subtype. VIII. Whole exome deoxyribonucleic acid (DNA)-sequencing (seq) on DNA isolated at baseline and upon progression.
IX. Plasma for circulating tumor DNA (ctDNA) analysis to assess PIK3CA mutation status in response and resistance.
- To assess the predictive effects of PIK3CA mutations and PTEN loss on PFS and CBR.
XI. To evaluate the ability of multi-parametric magnetic resonance imaging (MRI) performed early in therapy to predict both biological and clinical response.
OUTLINE: This is a phase Ib, dose-escalation study of taselisib followed by a randomized phase II study.
PHASE IB: Patients receive taselisib orally (PO) once daily (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.
PHASE II: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive taselisib PO QD and enzalutamide as in Phase Ib. 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.
ARM II: 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.
After completion of study treatment, patients are followed up for 30 days and then every 3 months for 3 years.
- Conditions
- Estrogen Receptor Negative, Estrogen Receptor Positive, HER2/Neu Negative, Progesterone Receptor Negative, Progesterone Receptor Positive, Stage IV Breast Cancer
- Being tested
- Biomarker Analysis, Enzalutamide, Pharmacological Study, Taselisib
- Medical subject headings
- Breast Neoplasms, Triple Negative Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Biomarker AnalysisOther
Correlative studies
EnzalutamideDrug
Also called MDV3100, Xtandi
Given PO
Correlative studies
TaselisibDrug
Also called GDC-0032
Given PO
| Study group | Role | What they receive |
|---|---|---|
| Taselisib 2 mg | Experimental | 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. Receives: Other: Biomarker Analysis; Drug: Enzalutamide; Other: Pharmacological Study; Drug: Taselisib |
| Enzalutamide | Active comparator | 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 receive Enzalutamide + Taselisib Receives: Other: Biomarker Analysis; Drug: Enzalutamide; Other: Pharmacological Study |
| Taselisib 4 mg | Experimental | 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. Receives: Other: Biomarker Analysis; Drug: Enzalutamide; Other: Pharmacological Study; Drug: Taselisib |
| Taselisib 6 mg | Experimental | 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. Receives: Other: Biomarker Analysis; Drug: Enzalutamide; Other: Pharmacological Study; Drug: Taselisib |
| Taselisib 8 mg | Experimental | 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. Receives: Other: Biomarker Analysis; Drug: Enzalutamide; Other: Pharmacological Study; Drug: Taselisib |
| Enzalutamide + Taselisib | Experimental | Patients receive enzalutamide PO QD starting on day 1 of cycle 1, and will receive Taselisib PO QD starting on day 1 of cycle 2. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Receives: Other: Biomarker Analysis; Drug: Enzalutamide; Other: Pharmacological Study; Drug: Taselisib |
| Cross-Over | Experimental | Upon progression of disease, patients on the enzalutamide only arm will be allowed to crossover to enzalutamide + taselisib (must begin no later than 21 days after the clinic visit at which disease progression is determined) Enzalutamide and Taselisib will be taken PO QD Receives: Other: Biomarker Analysis; Drug: Enzalutamide; Other: Pharmacological Study; Drug: Taselisib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Clinical Benefit Rate (CBR) - Phase II
CBR is defined as the proportion of patients with a best response of complete response (CR), partial response (PR), or (SD) stable disease per RECIST criteria 1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition, the sum must also demonstrate an absolute increase of at least 5 mm. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. It is calculated as the mean of binomial distribution.
Measured: At 16 weeks
Maximum Tolerated Dose (MTD) of Taselisib Combined With 160mg Enzalutamide - Phase I
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.
Measured: 4 weeks
Secondary outcomes (2)
Overall Progression-Free Survival (PFS) of Patients Treated With Enzalutamide and Taselisib
The PFS time is defined as the time from treatment start to progression or death (whichever comes first), and those alive without progression were censored at the last date of follow up. PFS will be estimated using the Kaplan-Meier method. The median with 95% confidence intervals will be reported.
Measured: Time from course 1, day 1 until objective tumor progression, assessed up to 3 years
Pharmacokinetic Profile
Pharmacokinetic sampling will occur in the phase Ib portion and in 10 patients in the phase II portion
Measured: Approximately 4 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 May 2015 (estimated)
- Study startJun 2015
- Primary completionDec 2018
- Study completion8 Aug 2022
Why it stopped: Interim analysis - toxicity
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Estrogen Receptor NegativeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt-Ingram Cancer Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI), Translational Breast Cancer Research Consortium, Conquer Cancer Foundation, Genentech, Inc.
- Responsible party
- Principal investigator, Vandana Abramson, Vanderbilt-Ingram Cancer Center
- Investigators
- Vandana Abramson, MD, Principal investigator, Vanderbilt University/Ingram Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02457910
- Sponsor's protocol ID
- VICC BRE 1374
- Other IDs
- NCI-2015-00795, GO28972, TBCRC 032, VICC BRE 1374, P30CA068485
- Status last verified
- Aug 2022
- First submitted
- 21 May 2015
- Last updated
- 22 Aug 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 22 Aug 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02457910
- Acronym / sponsor ID
- VICC BRE 1374
- Conditions
- Estrogen Receptor Negative, Estrogen Receptor Positive, HER2/Neu Negative, Progesterone Receptor Negative, Progesterone Receptor Positive, Stage IV Breast Cancer
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Interim analysis - toxicity
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Vanderbilt-Ingram Cancer CenterUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI), Translational Breast Cancer Research Consortium, Conquer Cancer Foundation, Genentech, Inc.
- Study start
- Jun 2015 (actual)
- Primary completion
- Dec 2018 (actual)
- Study completion
- 8 Aug 2022 (actual)
- First posted
- 29 May 2015 (estimated)
- Results
- Posted 7 May 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
PRIMARY OBJECTIVES:
- To determine the safety and tolerability of taselisib given in combination with enzalutamide: Assessment of dose limiting toxicities (DLTs) during the first 4 weeks of treatment (cycle 1). (Phase Ib) II. To determine the safety and tolerability of taselisib given in combination with enzalutamide: Determination of the maximally tolerated dose (MTD) of taselisib given in combination with enzalutamide. (Phase Ib) III. To evaluate the efficacy, as measured by clinical benefit rate (CBR), of enzalutamide + taselisib in patients with androgen receptor positive (AR+) triple negative (TN) metastatic breast cancer (MBC). (Phase II)
SECONDARY OBJECTIVES:
- To determine the progression free survival (PFS) of enzalutamide + taselisib in patients with AR+ TN MBC.
II. To assess the pharmacokinetics (PKs) of taselisib and enzalutamide in patients with AR+ TN MBC.
TERTIARY OBJECTIVES:
- To explore predictors of biomarker response and mechanisms of resistance based on exploratory analysis of tumor tissue obtained through biopsies.
II. Levels of phosphatase and tensin homolog (PTEN) expression by immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qPCR).
III. Presence of mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene.
IV. Human epidermal growth factor receptor 2 (HER2) (IHC, fluorescence in situ hybridization [FISH]) and estrogen receptor (ER)/progesterone receptor (PR) levels (IHC) in tumor biopsy from a metastatic site.
- Levels of mitogen-activated protein kinase kinase (MEK) activity measured by phosphorylated extracellular-signal-regulated kinases (p-ERK1/2) (IHC) and phosphorylated p-ribosomal protein S6 (S6) (S235/236 and S240/244) at baseline and upon progression of disease.
VI. Levels of phosphorylated v-akt murine thymoma viral oncogene homolog 1 (p-AKT) (IHC) at baseline and upon progression of disease.
VII. Gene expression profiling to assign a triple negative subtype. VIII. Whole exome deoxyribonucleic acid (DNA)-sequencing (seq) on DNA isolated at baseline and upon progression.
IX. Plasma for circulating tumor DNA (ctDNA) analysis to assess PIK3CA mutation status in response and resistance.
- To assess the predictive effects of PIK3CA mutations and PTEN loss on PFS and CBR.
XI. To evaluate the ability of multi-parametric magnetic resonance imaging (MRI) performed early in therapy to predict both biological and clinical response.
OUTLINE: This is a phase Ib, dose-escalation study of taselisib followed by a randomized phase II study.
PHASE IB: Patients receive taselisib orally (PO) once daily (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.
PHASE II: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive taselisib PO QD and enzalutamide as in Phase Ib. 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.
ARM II: 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.
After completion of study treatment, patients are followed up for 30 days and then every 3 months for 3 years.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 7
| Arm | Type | Receives |
|---|---|---|
| Taselisib 2 mg | Experimental | Other: Biomarker Analysis, Drug: Enzalutamide, Other: Pharmacological Study, Drug: TaselisibPatients 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. |
| Enzalutamide | Active comparator | Other: Biomarker Analysis, Drug: Enzalutamide, Other: Pharmacological StudyPatients 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 receive Enzalutamide + Taselisib |
| Taselisib 4 mg | Experimental | Other: Biomarker Analysis, Drug: Enzalutamide, Other: Pharmacological Study, Drug: TaselisibPatients 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. |
| Taselisib 6 mg | Experimental | Other: Biomarker Analysis, Drug: Enzalutamide, Other: Pharmacological Study, Drug: TaselisibPatients 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. |
| Taselisib 8 mg | Experimental | Other: Biomarker Analysis, Drug: Enzalutamide, Other: Pharmacological Study, Drug: TaselisibPatients 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. |
| Enzalutamide + Taselisib | Experimental | Other: Biomarker Analysis, Drug: Enzalutamide, Other: Pharmacological Study, Drug: TaselisibPatients receive enzalutamide PO QD starting on day 1 of cycle 1, and will receive Taselisib PO QD starting on day 1 of cycle 2. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
| Cross-Over | Experimental | Other: Biomarker Analysis, Drug: Enzalutamide, Other: Pharmacological Study, Drug: TaselisibUpon progression of disease, patients on the enzalutamide only arm will be allowed to crossover to enzalutamide + taselisib (must begin no later than 21 days after the clinic visit at which disease progression is determined) Enzalutamide and Taselisib will be taken PO QD |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (31 listed)
- 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
Key exclusion criteria (26 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Biomarker AnalysisCorrelative studies | Other | Cross-Over, Enzalutamide, Enzalutamide + Taselisib, Taselisib 2 mg, Taselisib 4 mg, Taselisib 6 mg, Taselisib 8 mg |
| EnzalutamideAlso: MDV3100, XtandiGiven PO | Drug | Cross-Over, Enzalutamide, Enzalutamide + Taselisib, Taselisib 2 mg, Taselisib 4 mg, Taselisib 6 mg, Taselisib 8 mg |
| Pharmacological StudyCorrelative studies | Other | Cross-Over, Enzalutamide, Enzalutamide + Taselisib, Taselisib 2 mg, Taselisib 4 mg, Taselisib 6 mg, Taselisib 8 mg |
| TaselisibAlso: GDC-0032Given PO | Drug | Cross-Over, Enzalutamide + Taselisib, Taselisib 2 mg, Taselisib 4 mg, Taselisib 6 mg, Taselisib 8 mg |
Primary outcome
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 per RECIST criteria 1.1. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition, the sum must also demonstrate an absolute increase of at least 5 mm. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. It is calculated as the mean of binomial distribution.
Maximum Tolerated Dose (MTD) of Taselisib Combined With 160mg Enzalutamide - 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.
2 secondary outcomes
Overall Progression-Free Survival (PFS) of Patients Treated With Enzalutamide and Taselisib
Time frame: Time from course 1, day 1 until objective tumor progression, assessed up to 3 years
Pharmacokinetic Profile
Time frame: Approximately 4 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Aug 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Vanderbilt-Ingram Cancer Center, Find a Clinical TrialLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Vandana Abramson, MD principal investigator
Vanderbilt University/Ingram Cancer Center
12 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Biomarker Analysis, Enzalutamide and Pharmacological Study in people with Estrogen Receptor Negative and Estrogen Receptor Positive, run by Vanderbilt-Ingram Cancer Center at 12 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 31 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 22 Aug 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 12 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 7 May 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Clinical Benefit Rate (CBR) - Phase II (time frame: At 16 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Aug 2022.