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Study of BYL719 (Alpelisib) in Combination With Androgen Receptor Inhibitor (Enzalutamide) in Patients With Androgen Receptor (AR)-Positive and PTEN Positive Metastatic Breast Cancer

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ClinicalTrials.gov Identifier: NCT03207529
Recruitment Status : Not yet recruiting
First Posted : July 2, 2017
Last Update Posted : May 14, 2018
Sponsor:
Collaborators:
Novartis
Astellas Pharma Global Development, Inc.
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

There are 2 parts to this study: Part 1 (dose escalation) and Part 2 (dose expansion).

The goal of Part 1 of this clinical research study is to find the highest tolerable dose of alpelisib (also called BYL719) and enzalutamide that can be given to patients with breast cancer that is metastatic (has spread) and has come back after standard treatment or is intolerant to standard treatment.

The goal of Part 2 of this study is to learn if the dose of alpelisib and enzalutamide found in Part 1 can help to control the disease.

The safety of alpelisib when combined with enzalutamide will also be studied.

This is an investigational study. Alpelisib is not FDA approved or commercially available. It is currently being used for research purposes only. Enzalutamide is FDA approved and commercially available for the treatment of metastatic, castrate-resistant prostate cancer. It is considered investigational to use alpelisib and enzalutamide to treat metastatic breast cancer.

It is considered investigational to give alpelisib and enzalutamide together for breast cancer. The study doctor can explain how the study drugs are designed to work.

Up to 28 participants will be enrolled in this study. All will take part at MD Anderson.


Condition or disease Intervention/treatment Phase
Malignant Neoplasm of Breast Drug: Alpelisib Drug: Enzalutamide Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase Ib Study of BYL719 (Alpelisib) in Combination With Androgen Receptor Inhibitor (Enzalutamide) in Patients With Androgen Receptor (AR)-Positive and PTEN Positive Metastatic Breast Cancer
Estimated Study Start Date : June 2018
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Alpelisib + Enzalutamide

Dose Escalation Phase: Participants take Alpelisib at starting dose of 250 mg by mouth daily. Enzalutamide taken at 160 mg fixed dose by mouth daily.

Dose Expansion Phase: If any specific molecular subtype or other signals such as PIK3CA status among responder patients are observed, 10 additional patients enrolled with that specific characteristic (e.g., TNBC patients only, or patients with PIK3CA H1047R mutation only) as an expansion cohort at RP2D. Participants take the maximum tolerated dose (MTD) of Alpelisib that was tolerated during Dose Escalation Phase. All 10 patients enrolled in the dose-expansion cohort receive one-week single agent treatment with Alpelisib.

Enzalutamide taken at 160 mg fixed dose daily.

Study cycle is 28 days.

Drug: Alpelisib

Dose Escalation Phase: Participants take Alpelisib at starting dose of 250 mg by mouth daily.

Dose Expansion Phase: If any specific molecular subtype or other signals such as PIK3CA status among responder patients are observed, 10 additional patients enrolled with that specific characteristic (e.g., TNBC patients only, or patients with PIK3CA H1047R mutation only) as an expansion cohort at RP2D. Participants take the maximum tolerated dose (MTD) of Alpelisib that was tolerated during Dose Escalation Phase. All 10 patients enrolled in the dose-expansion cohort receive one-week single agent treatment with Alpelisib.

Other Name: BYL719

Drug: Enzalutamide
Dose Escalation and Expansion Phase: Enzalutamide taken at 160 mg fixed dose daily.
Other Names:
  • MDV3100
  • XTANDI




Primary Outcome Measures :
  1. Maximum Tolerated Dose of Alpelisib with Enzalutamide in Patients With Androgen Receptor (AR)-Positive and PTEN Positive Metastatic Breast Cancer [ Time Frame: 28 days ]
    MTD defined as the highest dose level at which 6 patients have been treated with at most 1 instance of dose limiting toxicity (DLT).


Secondary Outcome Measures :
  1. Profession-Free Survival (PFS) of Alpelisib with Enzalutamide in Patients With Androgen Receptor (AR)-Positive and PTEN Positive Metastatic Breast Cancer [ Time Frame: 16 weeks ]
    Profession-free survival (PFS) determined per RECIST version 1.1.

  2. Clinical Benefit Rate (CBR) of Alpelisib with Enzalutamide in Patients With Androgen Receptor (AR)-Positive and PTEN Positive Metastatic Breast Cancer [ Time Frame: 16 weeks ]
    Clinical benefit rate (CBR) determined per RECIST version 1.1.



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
Criteria

Inclusion Criteria:

  1. Patient is >/= 18 years old.
  2. Patient has signed the informed consent form prior to the performance of any screening procedures and is able to comply with protocol requirements.
  3. Patient has advanced or metastatic breast cancer that is refractory to at least one standard therapy or that has relapsed after standard therapy or that has no standard systemic therapy that increases survival by at least 3 months.
  4. Patient has metastatic breast cancer that is not suitable for surgery or radiation therapy for local disease control at the time of screening.
  5. Patient has disease that is hormone-receptor positive (ER and/or PR+, HER-2/neu -) or triple-negative (ER/PR/HER-2/neu -).
  6. Patient has an AR-positive and PTEN-positive tumor as determined by using Clinical Laboratory Improvement Amendments (CLIA) compliant assays to identify AR-positive and PTEN-positive disease (AR positivity is defined as >/= 1% of nuclear staining, PTEN positivity is defined as >0% of nuclear staining).
  7. Patient has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) </= 1 that the investigator believes is stable at the time of screening.
  8. Patient has adequate bone marrow and organ function as defined by the following laboratory values: o Absolute neutrophil count (ANC) >/= 1.0 x 10^9/L; Platelets>/= 100 x 10^9/L ; Hemoglobin >/= 9.0 g/dL ; Serum creatinine </= 1.5 x upper limit of normal (ULN) ; Total serum bilirubin </= 1.5 x ULN o Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) </= 2.5 x ULN ; Fasting plasma glucose (FPG) </= 140 mg/dL or </= 7.8 mmol/L
  9. Patient is able to swallow and retain oral medication and does not have any clinically significant gastrointestinal abnormalities that may alter drug absorption, such as malabsorption syndrome or major resection of the stomach or bowels.
  10. For dose-escalation cohort, patient has at least 1 measurable disease as defined by RECIST criteria (Version 1.1). For dose-expansion cohort, patient has at least 1 measurable disease as defined by RECIST criteria (Version 1.1) with a lesion larger than 1.5 cm that can be biopsied by core needle biopsy.
  11. For dose-escalation portion of study, patients must be refractory to or intolerant of existing therapies known to provide clinical benefit for their condition.
  12. Patient has a life expectancy of at least 3 months in the opinion of the investigator.

Exclusion Criteria:

  1. Patient has a known hypersensitivity to any of the excipients of BYL719 and/or enzalutamide.
  2. Patient has a known or suspected primary central nervous system (CNS) tumor or CNS tumor involvement or active leptomeningeal disease.
  3. Patient has a history of seizures or any condition that may predispose to seizures (e.g., prior cortical stroke, significant brain trauma) at any time in the past and/or a history of loss of consciousness or transient ischemic attack within 12 months of the cycle 1, day 1 visit.
  4. Patient has clinically manifest diabetes mellitus for the last 3 months or documented steroid-induced diabetes mellitus.
  5. Patient has a history of another malignancy within 2 years prior to starting study treatment, except for cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix.
  6. Patient has not recovered to CTCAE (Version 4.03) grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy.
  7. Patient has had any systemic therapy within 2 weeks prior to initiating study drug.
  8. Patient has participated in a prior investigational study within 3 weeks prior to initiating study drug.
  9. Patient has completed radiotherapy within 2 weeks prior to treatment initiation.
  10. Patient has any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with patient's safety, provision of informed consent, or compliance with the study procedures.
  11. Patient has known clinically significant cardiac disease or impaired cardiac function, such as: oCongestive heart failure requiring treatment (New York Heart Association grade >/= 2), LVEF < 50% as determined by MUGA scan or ECHO oHistory or current evidence of clinically significant cardiac arrhythmias, atrial fibrillation, and/or conduction abnormality, e.g., congenital long QT syndrome, high-grade/complete arteriovenous blockage oAcute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass graft, coronary angioplasty, or stenting) < 3 months prior to screening
  12. Patient has a QT interval adjusted by the Fridericia formula (QTcF) > 480 msec on screening ECG.
  13. Patient is currently receiving medication with a known risk of prolonging the QT interval or inducing torsades de pointes (TdP) and whose treatment cannot be either discontinued or switched to a different medication prior to starting treatment with the study drug.
  14. Patient has any prior use of PI3K inhibitors.
  15. Patient has any prior use of anti-androgen therapies.
  16. Patient is currently receiving warfarin or other Coumarin-derived anticoagulant for treatment, prophylaxis, or other reasons. Therapy with heparin, low molecular weight heparin, or fondaparinux is allowed.
  17. Patient is currently receiving treatment with drugs known to be strong inhibitors or inducers of isoenzymes CYP3A or CYP2C8. The patient must have discontinued strong inducers for at least 1 week and must have discontinued strong inhibitors before the start of the study treatment. Switching to a different medication prior to initiation of the trial treatment is allowed.
  18. Patient has impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral BYL719 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
  19. Patient has known positive serology for HIV.
  20. Patient has any other condition that would, in the investigators' judgment, preclude the patient's participation in the clinical study due to concerns about safety or compliance with clinical study procedures; e.g., infection/inflammation, intestinal obstruction, inability to swallow oral medication, social/psychological complications.
  21. Patient has a history of noncompliance to medical regimens or is unable to grant consent.
  22. Female patients of childbearing potential have positive urine or serum pregnancy test no more than 7 days prior to starting study drug.
  23. Female patients of childbearing potential are not willing to use highly effective contraception to prevent pregnancy or agree to abstain from heterosexual activity throughout the study. Highly effective contraception is defined as 1) Surgical birth control/sterilization (such as male vasectomy or female sterilization; 2) Birth control pills, injections, implants, or patches; 3) Intrauterine devices (IUDs); 4) Two barrier methods (male condom and female diaphragm, cervical cap, or sponge) in combination with a spermicide.
  24. Cont'd # 23 Highly effective contraception must be used by both sexes during the study and must be continued for 3 months after the last dose of study treatment. (Women of not childbearing potential: post-menopausal [age > 55 years with cessation of menses > 12 months or < 55 years but not spontaneous menses for at least 2 years or < 55 years and spontaneous menses within the past 1 year, but currently amenorrheic (eg, spontaneous or secondary to hysterectomy), and with postmenopausal gonadotropin levels (luteinizing hormone and follicle-stimulating hormone levels > 40 IU/L) or postmenopausal estradiol levels (< 5 ng/dL) or according to the definition of "postmenopausal range" for the laboratory involved] or who have had a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy).
  25. Female patients who are breast-feeding.

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 ClinicalTrials.gov identifier (NCT number): NCT03207529


Contacts
Contact: Meghan S. Karuturi, MD 713-792-2817 CR_Study_Registration@mdanderson.org

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Not yet recruiting
Houston, Texas, United States, 77030
Contact: Clinical Research Operations       CR_Study_Registration@mdanderson.org   
Sponsors and Collaborators
M.D. Anderson Cancer Center
Novartis
Astellas Pharma Global Development, Inc.
Investigators
Principal Investigator: Meghan S. Karuturi, MD M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03207529     History of Changes
Other Study ID Numbers: 2016-0538
First Posted: July 2, 2017    Key Record Dates
Last Update Posted: May 14, 2018
Last Verified: May 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Malignant neoplasm of breast
Metastatic breast cancer
Androgen receptor (AR)-positive and PTEN positive
Alpelisib
BY719
Enzalutamide
MDV3100
XTANDI

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