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)

NCT01702558 | Terminated Phase 2 Results

• 2 other identifiers: MO282302012-001547-46
• Study Type: interventional
• Target: 182
• Locations: 12 countries
• Sites: 40

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.

Conditions

Breast Cancer; Gastric Cancer

Outcome Measures

Primary Outcomes (5)

• Phase 1 (mBC): Percentage of Participants With Dose-Limiting Toxicities (DLTs)

  A DLT was defined as any one of the following study treatment related toxicities: Uncomplicated Grade 4 thrombocytopenia that does not recover before Day 21; thrombocytopenia complicated with clinically significant bleeding requiring medical intervention; Grade 4 neutropenia lasting more than (\>) 7 consecutive days; febrile neutropenia with absolute neutrophil count (ANC) less than (\<) 1000 cells/millimeter cube (mm\^3); Grade greater than or equal to (\>/=) 3 diarrhea or Grade 3 hand-foot syndrome (in absence of dihydropyrimidine dehydrogenase \[DPD\] deficiency only for DL 1); any other Grade \>/=3 toxicity prohibiting start of Cycle 2; Grade 2 toxicity requiring treatment interruption for \>14 days (\>7 days for DL 1); for DL -1 only: \<14 full doses of capecitabine; Cycle 2 dose level \<100 percent (%).

  Continuously during Cycle 1 (up to 3 weeks)

• Phase 1 (mBC): Maximum Tolerated Dose (MTD) of Capecitabine When Combined With Trastuzumab Emtansine (3.6 mg/kg Every 3 Weeks)

  MTD was defined as the dose level for which the probability of DLT is equal to a protocol-specified target probability. A DLT was defined as any one of the following study treatment related toxicities: Uncomplicated Grade 4 thrombocytopenia that does not recover before Day 21; thrombocytopenia complicated with clinically significant bleeding requiring medical intervention; Grade 4 neutropenia lasting \>7 consecutive days; febrile neutropenia with ANC \<1000 cells/mm\^3; Grade \>/=3 diarrhea or Grade 3 hand-foot syndrome (in absence of DPD deficiency only for DL 1); any other Grade \>/=3 toxicity prohibiting start of Cycle 2; Grade 2 toxicity requiring treatment interruption for \>14 days (\>7 days for DL 1); for DL -1 only: \<14 full doses of capecitabine; Cycle 2 dose level \<100%.

  Continuously during Cycle 1 (up to 3 weeks)

• 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)

  Tumor response was assessed by the investigator according to RECIST v1.1. BOR was defined as percentage of participants with a complete response (CR) or partial response (PR) that was confirmed by repeat assessments \>/=4 weeks after initial documentation. CR was defined as the disappearance of all target lesions (TLs) and non-TLs; short axis (SA) reduction to \<10 millimeters (mm) for nodal TLs/non-TLs; and no new lesions. PR was defined as \>/=30% decrease in sum of diameters (SoD) of TLs, taking as reference the baseline SoD; no progression in non-TLs; and no new lesions. The 90% confidence Interval (CI) was computed using Clopper-Pearson approach.

  Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

• Phase 1 (LA/mGC): Percentage of Participants With DLTs

  A DLT was defined as any one of the following study treatment related toxicities: Uncomplicated Grade 4 thrombocytopenia that does not recover before Day 21; thrombocytopenia complicated with clinically significant bleeding requiring medical intervention; Grade 4 neutropenia lasting \>7 consecutive days; febrile neutropenia with ANC \<1000 cells/mm\^3; Grade \>/=3 diarrhea or Grade 3 hand-foot syndrome; any other Grade \>/=3 toxicity prohibiting start of Cycle 2; Grade 2 toxicity requiring treatment interruption for \>14 days; \<14 full doses of capecitabine; Cycle 2 dose level \<100%.

  Continuously during 3 weeks

• Phase 1 (LA/mGC): MTD of Capecitabine When Combined With Trastuzumab Emtansine (2.4 mg/kg QW)

  MTD was defined as the dose level for which the probability of DLT is equal to a protocol-specified target probability. A DLT was defined as any one of the following study treatment related toxicities: Uncomplicated Grade 4 thrombocytopenia that does not recover before Day 21; thrombocytopenia complicated with clinically significant bleeding requiring medical intervention; Grade 4 neutropenia lasting \>7 consecutive days; febrile neutropenia with ANC \<1000 cells/mm\^3; Grade \>/=3 diarrhea or Grade 3 hand-foot syndrome; any other Grade \>/=3 toxicity prohibiting start of Cycle 2; Grade 2 toxicity requiring treatment interruption for \>14 days; \<14 full doses of capecitabine; Cycle 2 dose level \<100%.

  Continuously during 3 weeks

Secondary Outcomes (29)

• Phase 1 (mBC): Percentage of Participants With BOR as Assessed by the Investigator According to RECIST v1.1

  Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 3.5 years overall)

• Phase 1 (mBC): Serum Concentration of Trastuzumab Emtansine

  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)

• Phase 1 (mBC): Serum Concentration of Trastuzumab

  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)

• Phase 1 (mBC): Maximum Observed Plasma Concentration (Cmax) of Capecitabine

  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

• Phase 1 (mBC): Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC[0-inf]) of Capecitabine

  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

Study Arms (4)

Phase 1 (mBC) Cohort 1: T-DM1 + Capecitabine

EXPERIMENTAL

In Phase 1, Cohort 1 participants (with mBC) will receive trastuzumab emtansine (T-DM1) at a dose of 3.6 milligrams per kilogram (mg/kg) via intravenous (IV) infusion (on Day 1 \[on Day 2 for Cycle 1\] of each 21-day cycle) along with capecitabine at de-escalating dose levels (starting from 750 milligrams per meter squared \[mg/m\^2\]) via tablet orally twice daily on Days 1-14 of each 21-day cycle until unacceptable toxicity, withdrawal of consent, disease progression (PD), death, or study end.

Drug: Capecitabine; Drug: Trastuzumab emtansine (T-DM1)

Phase 1 (LA/mGC) Cohort 2: T-DM1 + Capecitabine

EXPERIMENTAL

In Phase 1, Cohort 2 participants (with LA/mGC) will receive trastuzumab emtansine at a dose of 2.4 mg/kg via IV infusion on Day 1 (on Day 2 of first week) of every week along with capecitabine at MTD (determined in Cohort 1) via tablet orally twice daily on Days 1-14 followed by a 7-day rest period, in each 21-day cycle until unacceptable toxicity, withdrawal of consent, PD, death, or study end.

Drug: Trastuzumab emtansine (T-DM1); Drug: Capecitabine

Phase 2 (mBC): T-DM1 + Capecitabine

ACTIVE COMPARATOR

In Phase 2, participants (with mBC) who will be randomized to this group, will receive trastuzumab emtansine at a dose of 3.6 mg/kg via IV infusion on Day 1 of each 21-day cycle along with capecitabine at MTD via tablet orally twice daily on Days 1-14 of each 21-day cycle until unacceptable toxicity, withdrawal of consent, PD, death, or study end.

Drug: Trastuzumab emtansine (T-DM1); Drug: Capecitabine

Phase 2 (mBC): T-DM1

EXPERIMENTAL

In Phase 2, participants (with mBC) who will be randomized to this group, will receive trastuzumab emtansine at a dose of 3.6 mg/kg via IV infusion on Day 1 of each 21-day cycle until investigator-assessed PD, unacceptable toxicity, withdrawal of consent, death, or study end.

Drug: Trastuzumab emtansine (T-DM1)

Interventions

Capecitabine DRUG

Capecitabine will be administered at de-escalating doses (starting from 750 mg/m\^2) to determine the MTD.

Also known as: Xeloda

Phase 1 (mBC) Cohort 1: T-DM1 + Capecitabine

Trastuzumab emtansine (T-DM1) DRUG

Trastuzumab emtansine will be administered at a dose of 3.6 mg/kg via IV infusion every 3 weeks.

Also known as: Kadcyla,, RO5304020

Phase 1 (mBC) Cohort 1: T-DM1 + Capecitabine; Phase 2 (mBC): T-DM1; Phase 2 (mBC): T-DM1 + Capecitabine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Metastatic Breast Cancer
• Prior treatments before first study treatment:
• Investigational therapy within 28 days or 5 half-lives, whichever is longer
• Hormonal therapy within 14 days
• 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
• Treatment with sorivudine or chemically-related analogues
• Rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (40)

Fundacion Investigar

CABA, C1025ABI, Argentina

Location

Centro Oncologico Riojano Integral (CORI)

La Rioja, F5300COE, Argentina

Location

Hospital Erasto Gaertner

Curitiba, Paraná, 81520-060, Brazil

Location

Instituto Oncologico de Ribeirao Preto - INORP

Ribeirão Preto, São Paulo, 14025-270, Brazil

Location

Faculdade de Medicina de Sao Jose do Rio Preto - FAMERP*X*

São José do Rio Preto, São Paulo, 15090-000, Brazil

Location

Instituto do Cancer do Estado de Sao Paulo - ICESP

São Paulo, São Paulo, 01246-000, Brazil

Location

British Columbia Cancer Agency (Bcca) - Vancouver Cancer Centre

Vancouver, British Columbia, V5Z 4E6, Canada

Location

ICO Paul Papin; Oncologie Medicale.

Angers, 49055, France

Location

Centre Leon Berard; Departement Oncologie Medicale

Lyon, 69373, France

Location

Institut Paoli Calmettes; Oncologie Medicale

Marseille, 13273, France

Location

Institut Curie; Oncologie Medicale

Paris, 75231, France

Location

Ico Rene Gauducheau; Oncologie

Saint-Herblain, 44805, France

Location

Charité-Universitätsm. Berlin; Med. Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunolo.

Berlin, 10117, Germany

Location

Onkologische Schwerpunktpraxis Bielefeld; Haemotologie & Internistische onkologie

Bielefeld, 33604, Germany

Location

Heinrich-Heine Universitätsklinik Düsseldorf

Düsseldorf, 40225, Germany

Location

Klinik Fulda, Medizinisches Versorgungszentrum Osthessen GmbH

Fulda, 36043, Germany

Location

Philipps-Universität Marburg; Klinik für Innere Med.; Schwerpunkt Hämatologie/Onkologie/Immunologie

Marburg, 35043, Germany

Location

Klinikum rechts der Isar der TU München; III. Medizinischen Klinik (Hämatologie/Onkologie)

München, 81675, Germany

Location

Klinikum rechts der Isar der TU München; Klinik und Poliklinik für Frauenheilkunde

München, 81675, Germany

Location

Alexandras General Hospital of Athens; Oncology Department

Athens, 115 28, Greece

Location

Univ General Hosp Heraklion; Medical Oncology

Heraklion, 711 10, Greece

Location

University Hospital of Patras Medical Oncology

Pátrai, 265 04, Greece

Location

Istituto Nazionale Tumori Irccs Fondazione g. PASCALE;U.O.C. Oncologia Medica Senologica

Napoli, Campania, 80131, Italy

Location

Istituto Europeo Di Oncologia

Milan, Lombardy, 20141, Italy

Location

Fondazione Del Piemonte Per L'oncologia Ircc Di Candiolo; Dipartimento Oncologico

Candiolo, Piedmont, 10060, Italy

Location

Azienda usl 5 Di Pisa-Ospedale Di Pontedera;U.O. Oncologia

Pontedera, Tuscany, 56025, Italy

Location

Hospital da Luz; Departamento de Oncologia Medica

Lisbon, 1500-650, Portugal

Location

Hospital de Santa Maria; Servico de Oncologia Medica

Lisbon, 1649-035, Portugal

Location

IPO do Porto; Servico de Oncologia Medica

Porto, 4200-072, Portugal

Location

Ivanovo Regional Oncology Dispensary

Ivanovo, 153040, Russia

Location

Blokhin Cancer Research Center; Combined Treatment

Moscow, 115478, Russia

Location

City Clinical Oncology Hospital

Moscow, 143423, Russia

Location

S-Pb clinical scientific practical center of specialized kinds of medical care (oncological)

Saint Petersburg, 197758, Russia

Location

City Oncology Dispensary

Saint Petersburg, Russia

Location

Bashkirian Republican Clinical Oncology Dispensary

Ufa, 450054, Russia

Location

Institute for Oncology and Radiology of Serbia; Medical Oncology

Belgrade, 11000, Serbia

Location

Clinical Centre Nis, Clinic for Oncology

Niš, 18000, Serbia

Location

Narodny Onkologicky Ustav; Oddelenie klinickej onkologie A

Bratislava, 833 10, Slovakia

Location

Fakultna nemocnica Trencín; Onkologicke odd.

Trenčín, 911 71, Slovakia

Location

Hospital Univ Vall d'Hebron; Servicio de Oncologia

Barcelona, 08035, Spain

Location

Related Publications (1)

• 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.

  PMID: 32584367 DERIVED

MeSH Terms

Conditions

Breast Neoplasms; Stomach Neoplasms

Interventions

Capecitabine; Ado-Trastuzumab Emtansine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Maytansine; Macrolides; Lactones; Organic Chemicals; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Trastuzumab; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

The sponsor decided to terminate the study after 70% of participants had experienced a PFS event. Participants were allowed to continue treatment by enrolling into study NCT00781612 or by moving to commercial drug, depending on their country.

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 4, 2012
• First Posted: October 8, 2012
• Study Start: December 3, 2012
• Primary Completion: May 31, 2017
• Study Completion: May 31, 2017
• Last Updated: January 22, 2021
• Results First Posted: April 8, 2019

Record last verified: 2021-01

Locations

CA (1); FR (5); DE (7); ES (1); GR (3); BR (4); SE (2); SL (2); IT (4); AR (2); RU (6); PT (3)