A Combination Study of Kadcyla (Trastuzumab Emtansine) and Capecitabine in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Metastatic Breast Cancer (mBC) or HER2-Positive Locally Advanced/Metastatic Gastric Cancer (LA/mGC)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01702558
First received: October 4, 2012
Last updated: July 1, 2016
Last verified: July 2016
  Purpose
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.

Condition Intervention Phase
Solid Tumors
Drug: Capecitabine
Drug: Trastuzumab emtansine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Phase I (LA/mGC): Percentage of Participants with DLTs [ Time Frame: Continuously during Cycle 1 (up to 3 weeks) ] [ Designated as safety issue: Yes ]
  • Phase I (mBC): Maximum Tolerated Dose (MTD) of Capecitabine when Combined with Trastuzumab Emtansine [ Time Frame: Continuously during Cycle 1 (up to 3 weeks) ] [ Designated as safety issue: Yes ]
  • Phase I (mBC): Percentage of Participants with Dose-Limiting Toxicities (DLTs) [ Time Frame: Continuously during Cycle 1 (up to 3 weeks) ] [ Designated as safety issue: Yes ]
  • 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) ] [ Designated as safety issue: No ]
  • Phase I (LA/mGC): MTD of Capecitabine when Combined with Trastuzumab Emtansine [ Time Frame: Continuously during Cycle 1 (up to 3 weeks) ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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) ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]

Enrollment: 181
Study Start Date: December 2012
Estimated Study Completion Date: April 2018
Estimated Primary Completion Date: April 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase I: Locally Advanced/Metastatic Gastric Cancer Cohort
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.
Drug: 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.
Drug: Trastuzumab emtansine
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.
Other Name: Kadcyla
Experimental: Phase I: Metastatic Breast Cancer Cohort
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.
Drug: 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.
Drug: Trastuzumab emtansine
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.
Other Name: Kadcyla
Active Comparator: Phase II: Kadcyla
Participants will be randomly assigned to receive trastuzumab emtansine until progression, withdrawal, death, physician decision, or study end.
Drug: Trastuzumab emtansine
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.
Other Name: Kadcyla
Experimental: Phase II: Kadcyla + Capecitabine
Participants will be randomly assigned to receive trastuzumab emtansine plus capecitabine until progression, withdrawal, death, physician decision, or study end.
Drug: 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.
Drug: Trastuzumab emtansine
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.
Other Name: Kadcyla

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01702558

  Show 45 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01702558     History of Changes
Other Study ID Numbers: MO28230  2012-001547-46 
Study First Received: October 4, 2012
Last Updated: July 1, 2016
Health Authority: Spain: Ministry of Health

Additional relevant MeSH terms:
Stomach Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Capecitabine
Ado-trastuzumab emtansine
Trastuzumab
Maytansine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators

ClinicalTrials.gov processed this record on July 28, 2016