Taselisib and Anti-HER2 Therapy in Treating Patients with Advanced HER2+ Breast Cancer
This phase Ib trial studies the side effects and best dose of taselisib when given with anti-human epidermal growth factor receptor 2 (HER2) therapies in treating patients with HER2 positive (HER2+) breast cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment. Taselisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as trastuzumab emtansine, pertuzumab, and trastuzumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Estrogen can cause the growth of breast cancer cells. Antihormone therapy, such as fulvestrant, may lessen the amount of estrogen made by the body. It is not yet known whether taselisib works better when given together with trastuzumab emtansine, pertuzumab, and trastuzumab, or with pertuzumab, trastuzumab, paclitaxel, and fulvestrant in treating patients with breast cancer.
Inclusion Criteria
- Participants must have histologically or cytologically confirmed breast cancer, with diagnosed or suspected metastatic, inoperable locally advanced breast cancer, or inoperable locally recurrent breast cancer for which standard curative or palliative measures do not exist or are no longer effective
- Participants must have histologically confirmed HER2+ invasive breast cancer (immunohistochemistry [IHC] 3+ and/or fluorescence in situ hybridization [FISH] positive [HER2/chromosome 17 centromere [CEP17] >= 2 and/or > 6 HER2 gene copies per nucleus]); note: central confirmation of HER2 status is not required
- Measurable or non-measurable disease per RECIST version (v)1.1
- Prior therapy - prior trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine (T-DM1) are allowed; patients who have received prior therapy with taselisib (GDC-0032) or BYL-719 are excluded; there is no limit on the number of prior lines of therapy
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- Absolute neutrophil count >= 1,500/mm^3 (within 14 days of planned protocol therapy start)
- Platelets >= 100,000/mm^3 (within 14 days of planned protocol therapy start)
- Total bilirubin < 1.5 X institutional upper limit of normal; for patients with Gilbert syndrome, the direct bilirubin should be within the institutional normal range (within 14 days of planned protocol therapy start)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 X institutional upper limit of normal (within 14 days of planned protocol therapy start)
- Serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance >= 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation (within 14 days of planned protocol therapy start)
- Fasting glucose =< 120 mg/dL and hemoglobin A1c (HbA1c) < 7% (within 14 days of planned protocol therapy start)
- Left ventricular ejection fraction >= 50%, as determined by multigated acquisition (MUGA) or echocardiogram within 30 days prior to protocol registration
- Women of childbearing potential (including those who have had a tubal ligation) must have a documented negative pregnancy test within 14 days prior to planned initiation of taselisib; women of childbearing potential and men with partners of childbearing potential must be willing to use one highly effective form on nonhormonal contraception or two effective forms of non-hormonal contraception by the patient and/or partner and continue its use for the duration of the study treatment and for 7 months after the last dose of study treatment
- Ability to understand and the willingness to sign a written informed consent document
- For the expansion portion of the study: patients must have tissue that is amenable to biopsy and must be willing to undergo research biopsy; patients who undergo an attempted research biopsy procedure for the purpose of this protocol, and in whom inadequate tissue is obtained, are not required to undergo a repeat biopsy in order to continue on protocol
- For Cohort E only: Patients must have histologically confirmed HER2+ (IHC 3+ and/or FISH positive [HER2/CEP17 >= 2 and/or > 6 HER2 gene copies per nucleus]) and hormone receptor positive (estrogen receptor [ER]+ and/or progesterone receptor [PR]+ >= 1%), metastatic breast cancer
- For Cohort E only: patients must be postmenopausal (use of a gonadotropin-releasing hormone [GnRH] agonist while on the study is permitted to achieve postmenopausal status)
Exclusion Criteria
- Participants who have had anti-cancer therapy within 2 weeks prior to entering the study or those who have not recovered from acute adverse events due to agents administered more than 2 weeks earlier; palliative radiation to bony metastases >= 2 weeks prior to study entry is allowed; use of GnRH agonist therapy, such as leuprorelin, at the time of study entry is not exclusionary and participants can continue the GnRH agonist therapy while on study
- Prior treatment with a phosphatidylinositol 3 (PI3)-kinase, v-akt murine thymoma viral oncogene homolog 1 (AKT) or mammalian target of rapamycin (mTOR) inhibitor in which the patient experienced a grade >= 3 drug-related adverse event or otherwise would be at increased risk for additional PI3K-related toxicity
- Participants who are currently receiving any other investigational agents; treatment with an investigational agent within 2 weeks prior to planned initiation of study therapy is allowed provided that any drug-related toxicity has completely resolved
- Major surgical procedure within 4 weeks prior to planned initiation of study therapy
- Significant traumatic injury within 3 weeks prior to planned initiation of study therapy
- Participants with central nervous system (CNS) metastases are eligible (treated or untreated), provided they meet all of the following criteria: * Disease outside the CNS is present * No evidence of progression in CNS metastases within 4 months of planned initiation of study therapy for patients with untreated CNS metastases * No history of intracranial hemorrhage or spinal cord hemorrhage * Not requiring anti-convulsants or corticosteroids for symptomatic control * Minimum of 2 weeks between completion of CNS radiotherapy and cycle 1 day 1 and recovery from significant toxicity
- History of allergic reactions or hypersensitivity attributed to compounds of similar chemical or biologic composition to the taselisib drug formulation or other agents used in this study
- Participants receiving any medications or substances that are inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; as part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
- Malabsorption syndrome or other condition that would interfere with enteral absorption
- Active small or large intestine inflammation such as Crohn’s disease or ulcerative colitis
- Type 1 or 2 diabetes requiring anti-hyperglycemic medication (e.g. metformin, glipizide, insulin)
- Leptomeningeal disease as the only manifestation of the current malignancy
- Congenital long QT syndrome or corrected QT interval (QTc) > 500 msec
- Active congestive heart failure or ventricular arrhythmia requiring medication
- Uncontrolled ascites requiring weekly large-volume paracentesis for 2 consecutive weeks prior to initiation of study treatment
- Active infection requiring intravenous (IV) antibiotics
- Patients requiring any daily supplemental oxygen
- Uncontrolled hypomagnesemia, hypokalemia or hypocalcemia, defined as values below the lower limit of normal (LLN) for the institution despite adequate electrolyte supplementation or management
- Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab therapy
- Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
- Grade >= 2 peripheral neuropathy
- Any other diseases, active or uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, pulmonary dysfunction, metabolic dysfunction, psychiatric illness/social situations, physical examination finding, or clinical laboratory finding that would limit compliance with study requirements
- Women of childbearing potential (< 1 year amenorrheic) or sexually active males who are not employing adequate contraception (or practicing complete abstinence); female patients of childbearing potential must commit to using a reliable and appropriate method of contraception until at least 7 months after the end of last dose of study treatment; male patients with a partner of childbearing potential must agree to use a barrier method of contraception (condom) in addition to having their partner use another contraceptive method during the trial and for 7 months after the last dose of study treatment; examples of reliable and appropriate methods of contraception include hormonal implants, oral contraceptives, intra-uterine devices, or a barrier method used in conjunction with spermicidal jelly
- Pregnant women and women who are lactating; breastfeeding should be discontinued if the mother is treated with taselisib
- Known human immunodeficiency virus (HIV) infection
- Inability or unwillingness to swallow pills
- For Cohort E only: prior treatment with fulvestrant is prohibited
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02390427.
PRIMARY OBJECTIVES:
I. To determine the maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of taselisib in combination with trastuzumab emtansine (T-DM1) in participants with HER2+ breast cancer.
II. To determine the MTD and RP2D of taselisib in combination with T-DM1 and pertuzumab in participants with HER2+ breast cancer.
III. To determine the MTD and RP2D of taselisib in combination with trastuzumab and pertuzumab in participants with HER2+ breast cancer.
IV. To determine the MTD and RP2D of taselisib in combination with trastuzumab, pertuzumab and paclitaxel in participants with HER2+ breast cancer.
SECONDARY OBJECTIVES:
I. Occurrence of adverse events (AE) and serious adverse events (SAE) experienced during treatment with taselisib in combination with anti-HER2 therapy(ies) and/or paclitaxel, defined using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
II. Occurrence of dose delays or hold defined as a delay or hold of one of the study agents for more than 7 days.
III. Occurrence of dose reductions, defined as any dose reduction associated with toxicity.
IV. Reasons for study discontinuation.
V. Occurrence of death.
VI. Additionally, the pharmacokinetics (PK) of taselisib when given in combination with anti-HER2 therapy(ies) and/or paclitaxel will be assessed from plasma concentrations of taselisib following once daily (QD) or every other day (QOD) dosing in each cohort.
VII. Clinical benefit rate (CBR) that will be defined as complete response (CR) + partial response (PR) + stable disease (SD) >= 6 months (using Response Evaluation Criteria in Solid Tumors [RECIST] 1.1).
VIII. Progression-free survival (PFS) that will be defined as the time from the date of the first dose of study treatment until the date of first documentation of progressive disease (PD) or death from any cause (whichever occurs first).
IX. Overall survival (OS) that will be defined as the time from the date of the first dose of study treatment until the date of death from any cause.
CORRELATIVE OBJECTIVES:
I. To determine the proportion of patients with PIK3CA gene mutations and loss of PTEN expression in archival tissue.
II. To determine the proportion of patients with PIK3CA gene in circulating tumor deoxyribonucleic acid (DNA) (ctDNA) from blood obtained at study baseline.
III. To determine concordance of PIK3CA mutations and PTEN status between primary tumor and distant metastasis.
IV. To determine concordance of PIK3CA mutation status assessed in circulating free tumor DNA and distant metastasis specimens (i.e. liquid and solid biopsies).
V. To explore the impact of PIK3CA mutation status on response to taselisib-containing regimens in this study.
OUTLINE: This is a dose-escalation study of taselisib. Patients are assigned to 1 of 5 treatment cohorts.
COHORT A: Patients receive taselisib orally (PO) QD on days 1-21 and trastuzumab emtansine intravenously (IV) over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
COHORT B: Patients receive taselisib PO QOD or QD on days 1-21, pertuzumab IV over 30-60 minutes on day 1, and trastuzumab emtansine IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
COHORT C: Patients receive taselisib PO QD on days 1-21, pertuzumab IV over 30-60 minutes on day 1, and trastuzumab IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
COHORT D: Patients receive taselisib PO QD on days 1-21, pertuzumab IV over 30-60 minutes on day 1, trastuzumab IV over 30-90 minutes on day 1, and paclitaxel IV over 30-180 minutes on days 1, 8, and 15. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
COHORT E: Patients receive taselisib PO QD on days 1-21, pertuzumab IV over 30-60 minutes on day 1, trastuzumab IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also receive fulvestrant intramuscularly (IM) on day 1 of course 1 and every 28 days thereafter.
After completion of study treatment, patients are followed up every 4 months.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorOtto Metzger
- Primary ID15-024
- Secondary IDsNCI-2015-00627, ML29407
- ClinicalTrials.gov IDNCT02390427