Metastatic Breast Cancer
Conditions
Keywords
Xeloda, Capecitabine, BKM120, Lineberger Comprehensive Cancer Center, Metastatic, BYL719 Breast Cancer
Brief summary
This phase I study has been designed to establish the safety, tolerability and maximum tolerated dose (MTD) of four separate regimens for patients with metastatic breast cancer: dose- escalating BKM120 when combined with capecitabine (Arm A), with capecitabine and trastuzumab (Arm C), or with capecitabine and lapatinib (Arm D) and dose- escalating BEZ235 when combined with capecitabine (Arm B).
Detailed description
STUDY OBJECTIVES Primary Objectives * To determine the safety, DLT, and MTD of BKM120 when administered concomitantly with capecitabine in patients with metastatic breast cancer (ARM A) * To determine the safety, DLT, and MTD of BYL719 when administered concomitantly with capecitabine in patients with metastatic breast cancer (ARM B) * To determine the safety, DLT, and MTD of BKM120 when administered concomitantly with capecitabine and trastuzumab in patients with metastatic breast cancer (ARM C) * To determine the safety, DLT, and MTD of BKM120 when administered concomitantly with capecitabine and lapatinib in patients with metastatic breast cancer (ARM D) Secondary Objectives * To characterize the safety and tolerability of BKM120 in combination with capecitabine including acute and chronic toxicities * To characterize the safety and tolerability ofBYL719 in combination with capecitabine including acute and chronic toxicities * To characterize the safety and tolerability of BKM120 in combination with capecitabine and trastuzumab, including acute and chronic toxicities * To characterize the safety and tolerability of BKM120 in combination with capecitabine and lapatinib, including acute and chronic toxicities Exploratory Objectives * To obtain primary, archived paraffin-embedded tissues to evaluate intrinsic breast cancer subtype (i.e., HER2, luminal B, etc.) and other important predictive biomarkers (PI3K activating mutations, pAKT, p-mTOR), and explore correlations with therapeutic response to BKM120 or BYL719 in combination with capecitabine, with or without the addition of lapatinib or trastuzumab * To evaluate the PK profile of BKM120 with concomitant capecitabine * To examine other signaling pathway signatures * To examine drug effect in pre- and post-treatment core biopsy specimens (optional) from appropriate patients * To explore patient motivators for enrolling in early phase studies through patient interview Outline: This study is a four-arm multi-center, open-label phase I clinical trial testing the hypothesis that the addition of BKM120 to capecitabine (ARM A); the addition of BYL719 to capecitabine (ARM B); the addition of BKM120 to capecitabine plus trastuzumab (ARM C); or the addition of BKM120 to capecitabine plus lapatinib (ARM D) will be safe and tolerable as evidenced by the DLT seen. Following screening and informed consent, treatment will be initiated with one of the following: ARM A: BKM120 PO daily for 21 days (3 weeks) plus capecitabine PO BID for 2 weeks (no capecitabine is administered during the third week). ARM B: BYL719 PO BID for 21 days (3 weeks) plus capecitabine PO BID for 2 weeks (no capecitabine is administered during the third week of the cycle) ARM C: BKM120 PO daily for 21 days (3 weeks) plus capecitabine PO BID for 2 weeks (no capecitabine is administered during the third week) plus trastuzumab by intravenous infusion on Day 1 ARM D: BKM120 PO daily for 21 days (3 weeks) plus capecitabine PO BID for 2 weeks (no capecitabine is administered during the third week) plus lapatinib PO daily for 21 days. The consents are separate documents and the patient and the study team know ahead of time which Arm is open and enrolling and can therefore focus their discussion with the patient on that ARM. Cycles in each arm will be repeated every 3 weeks (21 days). Patients will continue on protocol-based therapy until progression, unacceptable toxicity, study withdrawal, or patient death.
Interventions
DRUGBMK120
BKM120 PO 50, 80 or 100mg every day for each day of each 21 day cycle. Number of cycles: until progression of disease; unacceptable toxicity, withdrawal or death.
DRUGCapecitabine
875-1250mg/m2 PO BID for two weeks followed by one week rest every three week cycle. Number of cycles: until progression of disease, unacceptable toxicity, withdrawal or death.
DRUGBYL719
BYL719 200mg PO BID for 21 days (3 weeks) in combination with capecitabine 1000 mg/m2 PO BID for 2 weeks
DRUGTrastuzumab
trastuzumab infusion on day 1 of each cycle.
DRUGLapatinib
lapatinib daily for 21 days in each cycle.
Sponsors
Novartis Pharmaceuticals
UNC Lineberger Comprehensive Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
PATIENT ELIGIBILITY Inclusion Criteria * Age ≥18 years (no upper age limit) * confirmed pathologic diagnosis of breast cancer which is metastatic and for which capecitabine is a reasonable treatment option * ARMS C & D: Histologically confirmed HER2+ breast cancer: IHC 3+ or fluorescence in situ hybridization \[FISH\] amplified; by clinical assay on either primary or metastatic tumor * Brain metastases permitted in Arms A and B if: * CNS-directed treatment has been given; * No CNS-directed therapy for the past 3 months, including glucocorticoids; AND * CNS disease has been clinically and radiographically stable for at least 8 weeks * Brain metastases permitted in Arms C and D if: * CNS-directed treatment has been given; * 4 weeks interval between whole brain radiation therapy and initiation of protocol-based therapy; * 2 weeks interval between stereotactic radiosurgery or gamma knife (or equivalent) and initiation of protocol-based therapy; * CNS disease has been clinically and radiographically stable for at least 4 weeks * In Arm C, if patient on glucocorticoids, must be on stable (4 weeks) dose of no more than 2 mg/day of dexamethasone or equivalent. * In Arms B and D, no steroids are allowed. * Measurable or non-measurable (but evaluable) disease as defined via RECIST 1.1 * No more than 4 prior chemotherapy regimens for metastatic disease for those in the dose-escalation cohorts. Prior trastuzumab and lapatinib are allowed for the HER2+ population. Once we reach the expanded RP2D cohorts, patients enrolled must have received ≤3 prior regimens * Patients enrolled in ARM C may remain on trastuzumab without a washout period * Patients enrolled in ARM D may remain on lapatinib without a washout period * Normal organ and marrow function as defined below: * Absolute neutrophil count ≥1,500/μL * Platelets ≥100,000/μL * Hemoglobin ≥8.5g/dL * ARMs A, C, D: Total bilirubin within normal range (or ≤1.5 X upper limit of normal (ULN) if liver metastases are present); or total bilirubin ≤3.0 x ULN with direct bilirubin within normal range in patients with Gilbert Syndrome. ARM B: Total 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) * ARMs A, C, D: AST(SGOT)/ALT(SGPT) within normal range (or ≤ 3.0X ULN if liver metastases are present) ARM B: AST(SGOT)/ALT(SGPT) ≤2.5X ULN or ≤ 5.0X ULN if liver metastases are present) * Serum creatinine ≤1.5 X ULN OR 24-hour creatinine clearance ≥60 mL/min * Amylase and lipase levels ≤ ULN * Left Ventricular Ejection Fraction ≥ 50% by ECHO or MUGA * Total calcium (corrected for serum albumin) within normal limits (bisphosphonate use for malignant hypercalcemia control is not allowed; the use of denosumab(Xgeva®) is permitted) * Magnesium levels \>lower limit of normal * ARM A: Fasting plasma glucose ≤120 mg/dL (6.7 mmol/L) ARM B: Fasting plasma glucose \<140 mg/dL (7.8) mmol/L); HbA1c ≤ 8% ARMS C and D: Fasting plasma glucose ≤150 mg/dL * INR ≤2 * Life expectancy ≥12 weeks * ECOG performance status 0-2 (Karnofsky \>60%) * Time since the last dose of prior therapy to treat underlying malignancy: * Cytotoxic chemotherapy or endocrine therapy: ≥ the duration of the most recent cycle of the previous regimen (with a minimum of 3 weeks for all, except 6 weeks for nitrosourea, mitomycin-C) * Biologic therapy (e.g., antibodies): ≥4 weeks * ≥5 X half-life of a small molecule therapeutic * ≥4 weeks interval between whole brain radiation therapy and initiation of protocol-based therapy for ARM C or D patient with stable brain metastases; * ≥2 weeks interval between stereotactic radiosurgery (SRS) or gamma knife (or equivalent) and initiation of protocol-based therapy for ARM C or D patient with stable brain metastases * Patients enrolled in ARM C may remain on trastuzumab without a washout period * Patients enrolled in ARM D may remain on lapatinib without a washout period -Adults of reproductive potential must be able and agree to use appropriate contraception. Double barrier contraceptives must be used throughout the trial by both sexes.. * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study. Women assigned to ARMS AC and D must use highly effective contraception for 16 weeks after stopping treatment. Women assigned to ARM A must continue contraceptive measures for 4 weeks after stopping treatment. Women assigned to ARM B must continue contraceptive measures for 5 weeks after stopping treatment. The highly effective contraception is defined as either: * True abstinence: When this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. * Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. * Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female subjects on the study, the vasectomized male partner should be the sole partner for that patient. * Use of a combination of any two of the following (a+b): 1. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 2. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel /film/cream/vaginal suppository * For ARMs A, C and D, oral contraception (OC), injected or implanted hormonal methods are not allowed as BKM120 and potentially decreases the effectiveness of hormonal contraceptives. For ARM B, oral contraceptives, injected or implanted hormonal methods are not allowed as the sole method of contraception, as BYL719 has not been characterized with respect to its potential to interfere with the PK and/or the effectiveness of OCs. * Recovered from all reversible toxicities related to their previous treatment (other than alopecia) to ≤grade 1 or baseline
Exclusion criteria
Subjects meeting any of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose | two years | Maximum Tolerated Dose (MTD) will be the highest does at which less than or equal to 1 out of 6 patients have experienced a dose limiting toxicity (DLT) |
| Dose limiting toxicity (DLT) | two years | Dose-limiting toxicities (DLT) will be defined per NCI Common Terminology Criteria for Adverse Events version 4 (CTCAE v4) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response | two years | Objective response is measured by assessing the tumor response using Recist 1.1 criteria |
| Best Overall Response | two years | The best overall response is defined as the best response achieved across all time points prior to progression (for example, a patient who has SD at first assessment, PR at second assessment, and PD on last assessment has a best overall response of PR). |
Countries
United States
Outcome results
None listed