Clinical trial NCT01702558: 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)
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Breast Cancer
Gastric Cancer
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2012-10-08
Enrollment: 182
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This multicenter study will assess the maximum tolerated dose (MTD) of capecitabine in combination with Kadcyla (trastuzumab emtansine) in participants with HER2-positive mBC or HER2-positive LA/mGC using a Phase 1 design, followed by a randomized, open-label Phase 2 part to explore the efficacy and safety of the combination of Kadcyla and capecitabine compared with Kadcyla alone in participants with mBC. The anticipated time on study treatment is until disease progression, intolerable toxicity, withdrawal of consent, or study end.


Eligibility 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 v1.1
* 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
* Participant must have 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 longer
  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)

Primary outcomes:
measure: Phase 1 (mBC): Percentage of Participants With Dose-Limiting Toxicities (DLTs)
timeFrame: Continuously during Cycle 1 (up to 3 weeks)
measure: Phase 1 (mBC): Maximum Tolerated Dose (MTD) of Capecitabine When Combined With Trastuzumab Emtansine (3.6 mg/kg Every 3 Weeks)
timeFrame: Continuously during Cycle 1 (up to 3 weeks)
measure: Phase 2 (mBC): Percentage of Participants With Best Overall Response (BOR) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
timeFrame: Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)
measure: Phase 1 (LA/mGC): Percentage of Participants With DLTs
timeFrame: Continuously during 3 weeks
measure: Phase 1 (LA/mGC): MTD of Capecitabine When Combined With Trastuzumab Emtansine (2.4 mg/kg QW)
timeFrame: Continuously during 3 weeks
Secondary outcomes:
measure: Phase 1 (mBC): Percentage of Participants With BOR as Assessed by the Investigator According to RECIST v1.1
timeFrame: Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 3.5 years overall)
measure: Phase 1 (mBC): Serum Concentration of Trastuzumab Emtansine
timeFrame: Pre-trastuzumab emtansine dose (0 hour [h]) on Day 1 Cycle 2; 15-30 minutes (min) after end of trastuzumab emtansine infusion (maximum infusion duration = 90 min) on Day 2 Cycle 1 and Day 1 Cycle 2 (cycle length=21 days)
measure: Phase 1 (mBC): Serum Concentration of Trastuzumab
timeFrame: Pre-trastuzumab emtansine dose (0 h) on Day 1 Cycle 2; 15-30 min after end of trastuzumab emtansine infusion (maximum infusion duration = 90 min) on Day 2 Cycle 1 and Day 1 Cycle 2 (cycle length=21 days)
measure: Phase 1 (mBC): Maximum Observed Plasma Concentration (Cmax) of Capecitabine
timeFrame: Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1
measure: Phase 1 (mBC): Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC[0-inf]) of Capecitabine
timeFrame: Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1
measure: Phase 1 (mBC): Plasma Terminal Half-Life (t1/2) of Capecitabine
timeFrame: Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1
measure: Phase 1 (mBC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)
timeFrame: Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1
measure: Phase 1 (mBC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)
timeFrame: Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1
measure: Phase 1 (mBC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)
timeFrame: Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1
measure: Phase 2 (mBC): Time to Response (TTR) as Assessed by the Investigator According to RECIST v1.1
timeFrame: Baseline until first documentation of confirmed PR or CR, whichever occurred first (up to approximately 2.5 years overall)
measure: Phase 2 (mBC): Duration of Response (DoR) as Assessed by the Investigator According to RECIST v1.1
timeFrame: From the documentation of response until PD, death, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)
measure: Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1
timeFrame: Baseline until PD, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)
measure: Phase 2 (mBC): Time to Progression (TTP) as Assessed by the Investigator According to RECIST v1.1
timeFrame: Baseline until PD, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)
measure: Phase 2 (mBC): Percentage of Participants With Treatment Failure as Assessed by the Investigator According to RECIST v1.1
timeFrame: Baseline until treatment failure, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)
measure: Phase 2 (mBC): Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST v1.1
timeFrame: Baseline until treatment failure, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)
measure: Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1 or Death From Any Cause
timeFrame: Baseline until PD, death from any cause, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)
measure: Phase 2 (mBC): Progression-Free Survival (PFS) as Assessed by the Investigator According to RECIST v1.1
timeFrame: Baseline until PD, death from any cause, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)
measure: Phase 2 (mBC): Percentage of Participants With Clinical Benefit as Assessed by the Investigator According to RECIST v1.1
timeFrame: Baseline until clinical benefit response, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)
measure: Phase 2 (mBC): Percentage of Participants Who Died of Any Cause
timeFrame: Baseline until death or study end whichever occurred first (up to approximately 2.5 years overall)
measure: Phase 2 (mBC): Overall Survival (OS)
timeFrame: Baseline until death or study end whichever occurred first (up to approximately 2.5 years overall)
measure: Phase 1 (LA/mGC): Percentage of Participants With BOR as Assessed by the Investigator According to RECIST v1.1
timeFrame: Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 1.5 years overall)
measure: Phase 1 (LA/mGC): Serum Concentration of Trastuzumab Emtansine
timeFrame: Pre-trastuzumab emtansine dose (0 h) on Day 1 Cycle 2; 15-30 min after end of trastuzumab emtansine infusion (maximum infusion duration = 90 min) on Day 2 Cycle 1 and Day 1 Cycle 2 (cycle length=21 days)
measure: Phase 1 (LA/mGC): Serum Concentration of Trastuzumab
timeFrame: Pre-trastuzumab emtansine dose (0 h) on Day 1 Cycle 2; 15-30 min after end of trastuzumab emtansine infusion (maximum infusion duration = 90 min) on Day 2 Cycle 1 and Day 1 Cycle 2 (cycle length=21 days)
measure: Phase 1 (LA/mGC): Cmax of Capecitabine
timeFrame: Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1
measure: Phase 1 (LA/mGC): AUC(0-inf) of Capecitabine
timeFrame: Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1
measure: Phase 1 (LA/mGC): t1/2 of Capecitabine
timeFrame: Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1
measure: Phase 1 (LA/mGC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)
timeFrame: Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1
measure: Phase 1 (LA/mGC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)
timeFrame: Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1
measure: Phase 1 (LA/mGC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)
timeFrame: Pre-capecitabine dose (0 h) and 0.5, 1, 1.5, 2, 2.5, 4, and 6 h post-capecitabine dose on Day 1 Cycle 1
Other outcomes:
Locations:
city: Caba
country: Argentina
facility: Fundacion Investigar
city: La Rioja
country: Argentina
facility: Centro Oncologico Riojano Integral (CORI)
city: Curitiba
country: Brazil
facility: Hospital Erasto Gaertner
state: PR
city: Ribeirao Preto
country: Brazil
facility: Instituto Oncologico de Ribeirao Preto - INORP
state: SP
city: Sao Jose do Rio Preto
country: Brazil
facility: Faculdade de Medicina de Sao Jose do Rio Preto - FAMERP*X*
state: SP
city: Sao Paulo
country: Brazil
facility: Instituto do Cancer do Estado de Sao Paulo - ICESP
state: SP
city: Vancouver
country: Canada
facility: British Columbia Cancer Agency (Bcca) - Vancouver Cancer Centre
state: British Columbia
city: Angers
country: France
facility: ICO Paul Papin; Oncologie Medicale.
city: Lyon
country: France
facility: Centre Leon Berard; Departement Oncologie Medicale
city: Marseille
country: France
facility: Institut Paoli Calmettes; Oncologie Medicale
city: Paris
country: France
facility: Institut Curie; Oncologie Medicale
city: Saint Herblain
country: France
facility: Ico Rene Gauducheau; Oncologie
city: Berlin
country: Germany
facility: Charité-Universitätsm. Berlin; Med. Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunolo.
city: Bielefeld
country: Germany
facility: Onkologische Schwerpunktpraxis Bielefeld; Haemotologie & Internistische onkologie
city: Düsseldorf
country: Germany
facility: Heinrich-Heine Universitätsklinik Düsseldorf
city: Fulda
country: Germany
facility: Klinik Fulda, Medizinisches Versorgungszentrum Osthessen GmbH
city: Marburg
country: Germany
facility: Philipps-Universität Marburg; Klinik für Innere Med.; Schwerpunkt Hämatologie/Onkologie/Immunologie
city: München
country: Germany
facility: Klinikum rechts der Isar der TU München; III. Medizinischen Klinik (Hämatologie/Onkologie)
city: München
country: Germany
facility: Klinikum rechts der Isar der TU München; Klinik und Poliklinik für Frauenheilkunde
city: Athens
country: Greece
facility: Alexandras General Hospital of Athens; Oncology Department
city: Heraklion
country: Greece
facility: Univ General Hosp Heraklion; Medical Oncology
city: Patras
country: Greece
facility: University Hospital of Patras Medical Oncology
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Irccs Fondazione g. PASCALE;U.O.C. Oncologia Medica Senologica
state: Campania
city: Milano
country: Italy
facility: Istituto Europeo Di Oncologia
state: Lombardia
city: Candiolo
country: Italy
facility: Fondazione Del Piemonte Per L'oncologia Ircc Di Candiolo; Dipartimento Oncologico
state: Piemonte
city: Pontedera
country: Italy
facility: Azienda usl 5 Di Pisa-Ospedale Di Pontedera;U.O. Oncologia
state: Toscana
city: Lisboa
country: Portugal
facility: Hospital da Luz; Departamento de Oncologia Medica
city: Lisboa
country: Portugal
facility: Hospital de Santa Maria; Servico de Oncologia Medica
city: Porto
country: Portugal
facility: IPO do Porto; Servico de Oncologia Medica
city: Ivanovo
country: Russian Federation
facility: Ivanovo Regional Oncology Dispensary
city: Moscow
country: Russian Federation
facility: Blokhin Cancer Research Center; Combined Treatment
city: Moscow
country: Russian Federation
facility: City Clinical Oncology Hospital
city: Saint-Petersburg
country: Russian Federation
facility: S-Pb clinical scientific practical center of specialized kinds of medical care (oncological)
city: St Petersburg
country: Russian Federation
facility: City Oncology Dispensary
city: UFA
country: Russian Federation
facility: Bashkirian Republican Clinical Oncology Dispensary
city: Belgrade
country: Serbia
facility: Institute for Oncology and Radiology of Serbia; Medical Oncology
city: Nis
country: Serbia
facility: Clinical Centre Nis, Clinic for Oncology
city: Bratislava
country: Slovakia
facility: Narodny Onkologicky Ustav; Oddelenie klinickej onkologie A
city: Trencin
country: Slovakia
facility: Fakultna nemocnica Trencín; Onkologicke odd.
city: Barcelona
country: Spain
facility: Hospital Univ Vall d'Hebron; Servicio de Oncologia
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Cortes J, Dieras V, Lorenzen S, Montemurro F, Riera-Knorrenschild J, Thuss-Patience P, Allegrini G, De Laurentiis M, Lohrisch C, Oravcova E, Perez-Garcia JM, Ricci F, Sakaeva D, Serpanchy R, Sufliarsky J, Vidal M, Irahara N, Wohlfarth C, Aout M, Gelmon K. Efficacy and Safety of Trastuzumab Emtansine Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Phase 1 and Randomized Phase 2 Trial. JAMA Oncol. 2020 Aug 1;6(8):1203-1209. doi: 10.1001/jamaoncol.2020.1796.