Overview

This trial is active, not recruiting.

Condition solid tumors
Treatments capecitabine, trastuzumab emtansine
Phase phase 2
Targets HER, HER2
Sponsor Hoffmann-La Roche
Start date December 2014
End date April 2018
Trial size 181 participants
Trial identifier NCT01702558, 2012-001547-46, MO28230

Summary

This multicenter study will assess the maximum tolerated dose of capecitabine in combination with Kadcyla (trastuzumab emtansine) in participants with HER2-positive mBC or HER2-positive LA/mGC using a Phase I design, followed by a randomized, open-label Phase II study to explore the efficacy and safety of the combination of Kadcyla and capecitabine compared with Kadcyla alone in mBC. The anticipated time on study treatment is until disease progression, intolerable toxicity, or withdrawal of consent.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Participants will receive a fixed dose of trastuzumab emtansine every 3 weeks. Capecitabine will be evaluated at different doses levels to determine the MTD. Treatment will continue until progression, withdrawal, death, physician decision, or study end.
capecitabine
In the Phase I component, participants will receive oral capecitabine twice daily at escalating doses up to 750 milligrams per meter squared (mg/m^2) to determine the MTD. In the Phase II component, capecitabine will be dosed at the MTD established in Phase I.
trastuzumab emtansine Kadcyla
Participants with breast cancer in the Phase I and II components will receive a dose of 3.6 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 3 weeks until disease progression, intolerable toxicity, withdrawal of consent. For participants with gastric cancer in the Phase I component, the dose will be 2.4 mg/kg via IV infusion every 3 weeks.
(Experimental)
Participants will receive a fixed dose of trastuzumab emtansine every 3 weeks. Capecitabine will be evaluated at different doses levels to determine the MTD. Treatment will continue until progression, withdrawal, death, physician decision, or study end.
capecitabine
In the Phase I component, participants will receive oral capecitabine twice daily at escalating doses up to 750 milligrams per meter squared (mg/m^2) to determine the MTD. In the Phase II component, capecitabine will be dosed at the MTD established in Phase I.
trastuzumab emtansine Kadcyla
Participants with breast cancer in the Phase I and II components will receive a dose of 3.6 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 3 weeks until disease progression, intolerable toxicity, withdrawal of consent. For participants with gastric cancer in the Phase I component, the dose will be 2.4 mg/kg via IV infusion every 3 weeks.
(Active Comparator)
Participants will be randomly assigned to receive trastuzumab emtansine until progression, withdrawal, death, physician decision, or study end.
trastuzumab emtansine Kadcyla
Participants with breast cancer in the Phase I and II components will receive a dose of 3.6 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 3 weeks until disease progression, intolerable toxicity, withdrawal of consent. For participants with gastric cancer in the Phase I component, the dose will be 2.4 mg/kg via IV infusion every 3 weeks.
(Experimental)
Participants will be randomly assigned to receive trastuzumab emtansine plus capecitabine until progression, withdrawal, death, physician decision, or study end.
capecitabine
In the Phase I component, participants will receive oral capecitabine twice daily at escalating doses up to 750 milligrams per meter squared (mg/m^2) to determine the MTD. In the Phase II component, capecitabine will be dosed at the MTD established in Phase I.
trastuzumab emtansine Kadcyla
Participants with breast cancer in the Phase I and II components will receive a dose of 3.6 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 3 weeks until disease progression, intolerable toxicity, withdrawal of consent. For participants with gastric cancer in the Phase I component, the dose will be 2.4 mg/kg via IV infusion every 3 weeks.

Primary Outcomes

Measure
Phase I (LA/mGC): Percentage of Participants with DLTs
time frame: Continuously during Cycle 1 (up to 3 weeks)
Phase I (mBC): Maximum Tolerated Dose (MTD) of Capecitabine when Combined with Trastuzumab Emtansine
time frame: Continuously during Cycle 1 (up to 3 weeks)
Phase I (mBC): Percentage of Participants with Dose-Limiting Toxicities (DLTs)
time frame: Continuously during Cycle 1 (up to 3 weeks)
Phase II (mBC): Percentage of Participants by Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
time frame: Baseline to progression, withdrawal, or study end; assessed at Baseline, Cycle 3 (up to 9 weeks), every 12 weeks until end of treatment (up to 4 years), up to 42 days after last dose (up to 4 years), every 3 to 6 months thereafter (up to 4 years overall)
Phase I (LA/mGC): MTD of Capecitabine when Combined with Trastuzumab Emtansine
time frame: Continuously during Cycle 1 (up to 3 weeks)

Secondary Outcomes

Measure
Phase I (LA/mGC): Percentage of Participants by BOR According to RECIST Version 1.1
time frame: Baseline to progression, withdrawal, or study end; assessed at Baseline, Cycle 3 (up to 9 weeks), every 12 weeks until end of treatment (up to 4 years), up to 42 days after last dose (up to 4 years), every 3 to 6 months thereafter (up to 4 years overall)
Phase I (LA/mGC): Percentage of Participants with AEs
time frame: Continuously during treatment (up to 4 years) and up to 28 days after last dose (up to 4 years overall)
Phase I (LA/mGC): Serum Concentration of Trastuzumab Emtansine
time frame: Pre-dose (0 h) and post-dose (0.5 h, 24 h, 7 days) from trastuzumab emtansine infusion given on Cycle 1 Day 2 and Cycle 2 Day 1; pre-dose (0 h) on Cycle 3 Day 1
Phase I (LA/mGC): Serum Concentration of Trastuzumab
time frame: Pre-dose (0 h) and post-dose (0.5 h, 24 h, 7 days) from trastuzumab emtansine infusion given on Cycle 1 Day 2 and Cycle 2 Day 1; pre-dose (0 h) on Cycle 3 Day 1
Phase I (LA/mGC): Plasma Concentration of DM1 (Component of Trastuzumab Emtansine)
time frame: Pre-dose (0 h) and post-dose (0.5 h, 24 h) from trastuzumab emtansine infusion given on Cycle 1 Day 2; post-dose (0.5 h, 24 h) from infusion given on Cycle 2 Day 1
Phase I (LA/mGC): Plasma Concentration of Capecitabine
time frame: Pre-dose (0 h) and post-dose (0.5, 1, 1.5, 2, 2.5, 4, 6 h) on Cycle 1 Day 1; pre-dose (0 h) and post-dose (0.5, 2, 6 h) on Cycle 1 Day 2; post-dose (0.5, 1, 1.5, 2, 2.5, 4, 6 h) on Cycle 2 Day 1
Phase I (LA/mGC): Plasma Concentration of 5-Fluorouracil (Metabolite of Capecitabine)
time frame: Pre-dose (0 h) and post-dose (0.5, 1, 1.5, 2, 2.5, 4, 6 h) on Cycle 1 Day 1; pre-dose (0 h) and post-dose (0.5, 2, 6 h) on Cycle 1 Day 2; post-dose (0.5, 1, 1.5, 2, 2.5, 4, 6 h) on Cycle 2 Day 1
Phase II (mBC): Duration of Response According to RECIST Version 1.1
time frame: Baseline to progression, withdrawal, or study end; assessed at Baseline, Cycle 3 (up to 9 weeks), every 12 weeks until end of treatment (up to 4 years), up to 42 days after last dose (up to 4 years), every 3 to 6 months thereafter (up to 4 years overall)
Phase II (mBC): Time to Progression According to RECIST Version 1.1
time frame: Baseline to progression, withdrawal, or study end; assessed at Baseline, Cycle 3 (up to 9 weeks), every 12 weeks until end of treatment (up to 4 years), up to 42 days after last dose (up to 4 years), every 3 to 6 months thereafter (up to 4 years overall)
Phase II (mBC): Time to Treatment Failure According to RECIST Version 1.1
time frame: Baseline to progression, withdrawal, or study end; assessed at Baseline, Cycle 3 (up to 9 weeks), every 12 weeks until end of treatment (up to 4 years), up to 42 days after last dose (up to 4 years), every 3 to 6 months thereafter (up to 4 years overall)
Phase II (mBC): Progression-Free Survival According to RECIST Version 1.1
time frame: Baseline to progression, withdrawal, or study end; assessed at Baseline, Cycle 3 (up to 9 weeks), every 12 weeks until end of treatment (up to 4 years), up to 42 days after last dose (up to 4 years), every 3 to 6 months thereafter (up to 4 years overall)
Phase II (mBC): Percentage of Participants with Complete or Partial Response, or Stable Disease Lasting at Least 6 Months, According to RECIST Version 1.1
time frame: Baseline to progression, withdrawal, or study end; assessed at Baseline, Cycle 3 (up to 9 weeks), every 12 weeks until end of treatment (up to 4 years), up to 42 days after last dose (up to 4 years), every 3 to 6 months thereafter (up to 4 years overall)
Phase II (mBC): Overall Survival
time frame: Baseline to progression, withdrawal, or study end; assessed continuously during treatment (up to 4 years), up to 42 days after last dose (up to 4 years), and every 3 to 6 months thereafter (up to 4 years overall)
Phase II (mBC): Percentage of Participants with AEs
time frame: Continuously during treatment (up to 4 years) and up to 28 days after last dose (up to 4 years overall)
Phase II (mBC): Time to Response According to RECIST Version 1.1
time frame: Baseline to progression, withdrawal, or study end; assessed at Baseline, Cycle 3 (up to 9 weeks), every 12 weeks until end of treatment (up to 4 years), up to 42 days after last dose (up to 4 years), every 3 to 6 months thereafter (up to 4 years overall)
Phase I (mBC): Percentage of Participants by BOR According to RECIST Version 1.1
time frame: Baseline to progression, withdrawal, or study end; assessed at Baseline, Cycle 3 (up to 9 weeks), every 12 weeks until end of treatment (up to 4 years), up to 42 days after last dose (up to 4 years), every 3 to 6 months thereafter (up to 4 years overall)
Phase I (mBC): Percentage of Participants with Adverse Events (AEs)
time frame: Continuously during treatment (up to 4 years) and up to 28 days after last dose (up to 4 years overall)
Phase I (mBC): Serum Concentration of Trastuzumab Emtansine
time frame: Pre-dose (0 hours [h]) and post-dose (0.5 h, 24 h, 7 days) from trastuzumab emtansine infusion given on Cycle 1 Day 2 and Cycle 2 Day 1; pre-dose (0 h) on Cycle 3 Day 1
Phase I (mBC): Serum Concentration of Trastuzumab
time frame: Pre-dose (0 h) and post-dose (0.5 h, 24 h, 7 days) from trastuzumab emtansine infusion given on Cycle 1 Day 2 and Cycle 2 Day 1; pre-dose (0 h) on Cycle 3 Day 1
Phase I (mBC): Plasma Concentration of Derivative of Maytansine (DM1, Component of Trastuzumab Emtansine)
time frame: Pre-dose (0 h) and post-dose (0.5 h, 24 h) from trastuzumab emtansine infusion given on Cycle 1 Day 2; post-dose (0.5 h, 24 h) from infusion given on Cycle 2 Day 1
Phase I (mBC): Plasma Concentration of Capecitabine
time frame: Pre-dose (0 h) and post-dose (0.5, 1, 1.5, 2, 2.5, 4, 6 h) on Cycle 1 Day 1; pre-dose (0 h) and post-dose (0.5, 2, 6 h) on Cycle 1 Day 2; post-dose (0.5, 1, 1.5, 2, 2.5, 4, 6 h) on Cycle 2 Day 1
Phase I (mBC): Plasma Concentration of 5-Fluorouracil (Metabolite of Capecitabine)
time frame: Pre-dose (0 h) and post-dose (0.5, 1, 1.5, 2, 2.5, 4, 6 h) on Cycle 1 Day 1; pre-dose (0 h) and post-dose (0.5, 2, 6 h) on Cycle 1 Day 2; post-dose (0.5, 1, 1.5, 2, 2.5, 4, 6 h) on Cycle 2 Day 1

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion Criteria: Metastatic Breast Cancer - Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 - Adequate blood cell count - Adequate liver, renal, and cardiac function - Life expectancy greater than or equal to (>/=) 12 weeks - Histologically or cytologically confirmed breast cancer - Confirmed HER2-positive disease, defined as immunohistochemistry (IHC) 3+ or in situ hybridization (ISH)-positive - mBC with at least one measurable lesion according to RECIST version 1.1 - Disease progression on at least one prior regimen containing trastuzumab and chemotherapy either separately or in combination; participants may be eligible to receive study therapy in first-line setting if trastuzumab and chemotherapy were given in the neoadjuvant/adjuvant setting - Recovered from previous treatments Locally Advanced/Metastatic Gastric Cancer - ECOG performance status of 0, 1, or 2 - Adequate blood cell count - Adequate liver, renal, and cardiac function - Life expectancy >/= 12 weeks - Histologically or cytologically confirmed LA/mGC - HER2-positive tumor (primary tumor or metastatic lesion), defined as either IHC 3+ or IHC 2+ and ISH-positive - Inoperable LA/mGC Exclusion Criteria: Metastatic Breast Cancer - Prior treatments before first study treatment: 1. Investigational therapy within 28 days or 5 half-lives, whichever is longest 2. Hormonal therapy within 14 days 3. Trastuzumab within 21 days - Prior treatment with trastuzumab emtansine or prior enrollment in a trastuzumab emtansine-containing study, regardless of whether the patient received trastuzumab emtansine - Prior treatment with capecitabine - History of severe or unexpected reactions to fluoropyrimidine or known hypersensitivity to fluorouracil - Related capecitabine contraindications 1. Treatment with sorivudine or chemically-related analogues 2. Rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption 3. Complete absence of dihydropyrimidine dehydrogenase (DPD) activity - History of intolerance or hypersensitivity to trastuzumab or murine proteins or any product component - History of exposure to high cumulative doses of anthracyclines - Brain metastases that are symptomatic or require radiation, surgery, or steroid therapy to control symptoms within 28 days before study drug - Current peripheral neuropathy of Grade >/=3 - History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other cancers with a similar outcome - Current unstable ventricular arrhythmia requiring treatment - History of symptomatic congestive heart failure (CHF) - History of myocardial infarction or unstable angina within 6 months prior to study drug - History of left ventricular ejection fraction (LVEF) less than (<) 40% or symptomatic CHF with previous trastuzumab treatment - Severe dyspnea at rest due to complications of advanced malignancy or currently requiring continuous oxygen therapy - Clinically significant malabsorption syndrome or inability to take oral medication - Current severe, uncontrolled systemic disease (such as clinically significant cardiovascular, pulmonary, or metabolic disease) - Major surgical procedure or significant traumatic injury within 28 days before enrollment or anticipation of the need for major surgery during study treatment - Current known active infection with human immunodeficiency virus (HIV) or hepatitis B or C - Lapatinib within 14 days before study drug Locally Advanced/Metastatic Gastric Cancer - Same as above, with addition of previous chemotherapy for advanced/metastatic disease (prior adjuvant/neoadjuvant therapy is allowed if at least 6 months has elapsed between completion of adjuvant/neoadjuvant therapy and enrollment into the study)

Additional Information

Official title Phase I Study of the Combination of Trastuzumab Emtansine (T-DM1) and Capecitabine in HER2-Positive Metastatic Breast Cancer and HER2-Positive Locally Advanced/Metastatic Gastric Cancer Patients, Followed by a Randomized, Open-Label Phase II Study of Trastuzumab Emtansine and Capecitabine Versus Trastuzumab Emtansine Alone in HER2-Positive Metastatic Breast Cancer
Trial information was received from ClinicalTrials.gov and was last updated in November 2016.
Information provided to ClinicalTrials.gov by Hoffmann-La Roche.