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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) (TRAXHER2)

Primary Purpose

Breast Cancer, Gastric Cancer

Status

Terminated

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Capecitabine

Trastuzumab emtansine (T-DM1)

Capecitabine

About this trial

This is an interventional treatment trial for Breast Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

Fundacion Investigar
Centro Oncologico Riojano Integral (CORI)
Hospital Erasto Gaertner
Instituto Oncologico de Ribeirao Preto - INORP
Faculdade de Medicina de Sao Jose do Rio Preto - FAMERP*X*
Instituto do Cancer do Estado de Sao Paulo - ICESP
British Columbia Cancer Agency (Bcca) - Vancouver Cancer Centre
ICO Paul Papin; Oncologie Medicale.
Centre Leon Berard; Departement Oncologie Medicale
Institut Paoli Calmettes; Oncologie Medicale
Institut Curie; Oncologie Medicale
Ico Rene Gauducheau; Oncologie
Charité-Universitätsm. Berlin; Med. Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunolo.
Onkologische Schwerpunktpraxis Bielefeld; Haemotologie & Internistische onkologie
Heinrich-Heine Universitätsklinik Düsseldorf
Klinik Fulda, Medizinisches Versorgungszentrum Osthessen GmbH
Philipps-Universität Marburg; Klinik für Innere Med.; Schwerpunkt Hämatologie/Onkologie/Immunologie
Klinikum rechts der Isar der TU München; III. Medizinischen Klinik (Hämatologie/Onkologie)
Klinikum rechts der Isar der TU München; Klinik und Poliklinik für Frauenheilkunde
Alexandras General Hospital of Athens; Oncology Department
Univ General Hosp Heraklion; Medical Oncology
University Hospital of Patras Medical Oncology
Istituto Nazionale Tumori Irccs Fondazione g. PASCALE;U.O.C. Oncologia Medica Senologica
Istituto Europeo Di Oncologia
Fondazione Del Piemonte Per L'oncologia Ircc Di Candiolo; Dipartimento Oncologico
Azienda usl 5 Di Pisa-Ospedale Di Pontedera;U.O. Oncologia
Hospital da Luz; Departamento de Oncologia Medica
Hospital de Santa Maria; Servico de Oncologia Medica
IPO do Porto; Servico de Oncologia Medica
Ivanovo Regional Oncology Dispensary
Blokhin Cancer Research Center; Combined Treatment
City Clinical Oncology Hospital
S-Pb clinical scientific practical center of specialized kinds of medical care (oncological)
City Oncology Dispensary
Bashkirian Republican Clinical Oncology Dispensary
Institute for Oncology and Radiology of Serbia; Medical Oncology
Clinical Centre Nis, Clinic for Oncology
Narodny Onkologicky Ustav; Oddelenie klinickej onkologie A
Fakultna nemocnica Trencín; Onkologicke odd.
Hospital Univ Vall d'Hebron; Servicio de Oncologia

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Active Comparator

Experimental

Arm Label

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

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

Phase 2 (mBC): T-DM1 + Capecitabine

Phase 2 (mBC): T-DM1

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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 (%).

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%.

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.

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%.

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%.

Secondary Outcome Measures

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

Tumor response was assessed by the investigator according to RECIST v1.1. BOR in Phase 1 was defined as percentage of participants with a CR or PR. CR was defined as the disappearance of all TLs and non-TLs; SA reduction to <10 mm for nodal TLs/non-TLs; and no new lesions. PR was defined as >/=30% decrease in SoD of TLs, taking as reference the baseline SoD; no progression in non-TLs; and no new lesions.

Phase 1 (mBC): Serum Concentration of Trastuzumab Emtansine

Phase 1 (mBC): Serum Concentration of Trastuzumab

Trastuzumab was derived from trastuzumab emtansine.

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

Cmax for Capecitabine was estimated from plasma concentration versus time data using non-compartmental methods of analysis. Reported dispersion values are for percent coefficient of variation (CV%) and not for standard deviation.

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

AUC(0-inf) is the measure of total drug exposure and is dependent on the total amount of drug absorbed. AUC(0-inf) for capecitabine was estimated from plasma concentration versus time data using non-compartmental methods of analysis. Reported dispersion values are for CV% and not for standard deviation.

Phase 1 (mBC): Plasma Terminal Half-Life (t1/2) of Capecitabine

Plasma terminal half-life is the time measured for the plasma drug concentration to decrease by one half during the elimination phase of the drug. t1/2 for capecitabine was estimated from plasma concentration versus time data using non-compartmental methods of analysis. Reported dispersion values are for CV% and not for standard deviation.

Phase 1 (mBC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)

5-fluorouracil is a metabolite of capecitabine. Cmax for 5-fluorouracil was estimated from plasma concentration versus time data using non-compartmental methods of analysis. Reported dispersion values are for CV% and not for standard deviation.

Phase 1 (mBC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)

5-fluorouracil is a metabolite of capecitabine. AUC(0-inf) is the measure of total drug exposure and is dependent on the total amount of drug absorbed. AUC(0-inf) for 5-fluorouracil was estimated from plasma concentration versus time data using non-compartmental methods of analysis. Reported dispersion values are for CV% and not for standard deviation.

Phase 1 (mBC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)

5-fluorouracil is a metabolite of capecitabine. Plasma terminal half-life is the time measured for the plasma drug concentration to decrease by one half during the elimination phase of the drug. t1/2 for 5-fluorouracil was estimated from plasma concentration versus time data using non-compartmental methods of analysis. Reported dispersion values are for CV% and not for standard deviation.

Phase 2 (mBC): Time to Response (TTR) as Assessed by the Investigator According to RECIST v1.1

Tumor response was assessed by the investigator according to RECIST v1.1. TTR was defined as the time (in months) from randomization to first documentation of confirmed PR or CR (whichever occurred first). CR was defined as the disappearance of all TLs and non-TLs; SA reduction to <10 mm for nodal TLs/non-TLs; and no new lesions. PR was defined as >/=30% decrease in SoD of TLs, taking as reference the baseline SoD; no progression in non-TLs; and no new lesions.

Phase 2 (mBC): Duration of Response (DoR) as Assessed by the Investigator According to RECIST v1.1

Tumor response was assessed by the investigator according to RECIST v1.1. DoR was defined as the time (in months) from the date of first recorded PR/CR until the date of PD or death from any cause. CR: the disappearance of all TLs and non-TLs; SA reduction to <10 mm for nodal TLs/non-TLs; and no new lesions. PR: >/=30% decrease in SoD of TLs, taking as reference the baseline SoD; no progression in non-TLs; and no new lesions. PD: >/=20% relative increase with >/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-TLs. Participants with no documented PD after CR/PR were censored at the time of last tumor assessment. Participants without post-baseline tumor assessment were censored at randomization plus 1 day. The median DOR and 90% CI were estimated using Kaplan-Meier method.

Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1

Tumor response was assessed by the investigator according to RECIST v1.1. PD was defined as >/=20% relative increase with >/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-TLs.

Phase 2 (mBC): Time to Progression (TTP) as Assessed by the Investigator According to RECIST v1.1

Tumor response was assessed by the investigator according to RECIST v1.1. TTP was defined as the time (in months) from randomization to the first occurrence of PD. PD was defined as >/=20% relative increase with >/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-TLs. Participants with no documented PD at the time of study end (including participants who died before PD) or who were lost to follow-up were censored on the date of the last tumor assessment. The median TTP and 90% CI was estimated using Kaplan-Meier method.

Phase 2 (mBC): Percentage of Participants With Treatment Failure as Assessed by the Investigator According to RECIST v1.1

Treatment failure was defined as occurrence of any of the following event while on treatment: PD, death, withdrawal due to adverse event (AE) or laboratory abnormality, or refusal of treatment. PD as assessed by the investigator according to RECIST v1.1 was defined as >/=20% relative increase with >/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-TLs.

Phase 2 (mBC): Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST v1.1

TTF was defined as the time (in months) from randomization until treatment failure (PD, death, withdrawal due to AE or laboratory abnormality, or refusal of treatment). PD as assessed by the investigator according to RECIST v1.1 was defined as >/=20% relative increase with >/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-TLs. Participants who did not experience any of the above events while on study were censored on the date of their last tumor assessment. The median TTF and 90% CI was estimated using Kaplan-Meier method.

Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1 or Death From Any Cause

Phase 2 (mBC): Progression-Free Survival (PFS) as Assessed by the Investigator According to RECIST v1.1

Tumor response was assessed by the investigator according to RECIST v1.1. PFS was defined as the time (in months) from randomization until the first documented PD or death from any cause, whichever occurred first. PD was defined as >/=20% relative increase with >/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-TLs. Participants with no PFS events were censored on the date of the last tumor assessment. Participants without post-baseline tumor assessment were censored at randomization plus 1 day. The median PFS and 90% CI was estimated using Kaplan-Meier method.

Phase 2 (mBC): Percentage of Participants With Clinical Benefit as Assessed by the Investigator According to RECIST v1.1

The clinical benefit was defined as a confirmed response of CR, PR, or stable disease (SD) that lasted for at least 6 months. Tumor response was assessed by the investigator according to RECIST v1.1. CR: the disappearance of all TLs and non-TLs; SA reduction to <10 mm for nodal TLs/non-TLs; and no new lesions. PR: >/=30% decrease in SoD of TLs, taking as reference the baseline SoD; no progression in non-TLs; and no new lesions. PD: >/=20% relative increase with >/=5 mm of absolute increase in the SoD, taking as reference the smallest SoD recorded since treatment started; 1 or more new lesion(s); and/or unequivocal progression of non-TLs. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest SoD on study. The 90% CI was computed using Clopper-Pearson approach.

Phase 2 (mBC): Percentage of Participants Who Died of Any Cause

Phase 2 (mBC): Overall Survival (OS)

OS was defined as the time (in months) from randomization until death from any cause. Participants who were alive at the time of data cut-off were censored on the date of the last follow-up assessment. Participants who were lost to follow-up were censored as having no event (alive) on the date of last contact. The median OS and 90% CI was estimated using Kaplan-Meier method, which use the patients at risk as denominator rather than the whole number of patients.

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

Phase 1 (LA/mGC): Serum Concentration of Trastuzumab Emtansine

Phase 1 (LA/mGC): Serum Concentration of Trastuzumab

Trastuzumab was derived from trastuzumab emtansine.

Phase 1 (LA/mGC): Cmax of Capecitabine

Cmax for capecitabine was estimated from plasma concentration versus time data using non-compartmental methods of analysis. Reported dispersion values are for CV% and not for standard deviation.

Phase 1 (LA/mGC): AUC(0-inf) of Capecitabine

Phase 1 (LA/mGC): t1/2 of Capecitabine

Phase 1 (LA/mGC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)

Phase 1 (LA/mGC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)

Phase 1 (LA/mGC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)

Full Information

NCT ID

NCT01702558

First Posted

October 4, 2012

Last Updated

January 19, 2021

Sponsor

Hoffmann-La Roche

1. Study Identification

Unique Protocol Identification Number

NCT01702558

Brief Title

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)

Acronym

TRAXHER2

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

2. Study Status

Record Verification Date

January 2021

Overall Recruitment Status

Terminated

Why Stopped

The sponsor decided to terminate study after 70% of participants had experienced a progression-free survival event.

Study Start Date

December 3, 2012 (Actual)

Primary Completion Date

May 31, 2017 (Actual)

Study Completion Date

May 31, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hoffmann-La Roche

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Breast Cancer, Gastric Cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

182 (Actual)

8. Arms, Groups, and Interventions

Arm Title

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

Arm Type

Experimental

Arm Description

Arm Title

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

Arm Type

Experimental

Arm Description

Arm Title

Phase 2 (mBC): T-DM1 + Capecitabine

Arm Type

Active Comparator

Arm Description

Arm Title

Phase 2 (mBC): T-DM1

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Capecitabine

Other Intervention Name(s)

Xeloda

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Trastuzumab emtansine (T-DM1)

Other Intervention Name(s)

Kadcyla,, RO5304020

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Trastuzumab emtansine (T-DM1)

Other Intervention Name(s)

Kadcyla,, RO5304020

Intervention Description

Trastuzumab emtansine will be administered at a dose of 2.4 mg/kg via IV infusion every week.

Intervention Type

Drug

Intervention Name(s)

Capecitabine

Other Intervention Name(s)

Xeloda

Intervention Description

Capecitabine will be administered at the MTD determined in Cohort 1.

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Continuously during Cycle 1 (up to 3 weeks)

Title

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

Description

Time Frame

Continuously during Cycle 1 (up to 3 weeks)

Title

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)

Description

Time Frame

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

Title

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

Description

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%.

Time Frame

Continuously during 3 weeks

Title

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

Description

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%.

Time Frame

Continuously during 3 weeks

Secondary Outcome Measure Information:

Title

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

Description

Time Frame

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

Title

Phase 1 (mBC): Serum Concentration of Trastuzumab Emtansine

Time Frame

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)

Title

Phase 1 (mBC): Serum Concentration of Trastuzumab

Description

Trastuzumab was derived from trastuzumab emtansine.

Time Frame

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)

Title

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

Description

Time Frame

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

Title

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

Description

Time Frame

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

Title

Phase 1 (mBC): Plasma Terminal Half-Life (t1/2) of Capecitabine

Description

Time Frame

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

Title

Phase 1 (mBC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)

Description

Time Frame

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

Title

Phase 1 (mBC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)

Description

Time Frame

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

Title

Phase 1 (mBC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)

Description

Time Frame

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

Title

Phase 2 (mBC): Time to Response (TTR) as Assessed by the Investigator According to RECIST v1.1

Description

Time Frame

Baseline until first documentation of confirmed PR or CR, whichever occurred first (up to approximately 2.5 years overall)

Title

Phase 2 (mBC): Duration of Response (DoR) as Assessed by the Investigator According to RECIST v1.1

Description

Time Frame

From the documentation of response until PD, death, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Title

Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1

Description

Time Frame

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

Title

Phase 2 (mBC): Time to Progression (TTP) as Assessed by the Investigator According to RECIST v1.1

Description

Time Frame

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

Title

Phase 2 (mBC): Percentage of Participants With Treatment Failure as Assessed by the Investigator According to RECIST v1.1

Description

Time Frame

Baseline until treatment failure, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Title

Phase 2 (mBC): Time to Treatment Failure (TTF) as Assessed by the Investigator According to RECIST v1.1

Description

Time Frame

Baseline until treatment failure, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Title

Phase 2 (mBC): Percentage of Participants With PD as Assessed by the Investigator According to RECIST v1.1 or Death From Any Cause

Description

Time Frame

Baseline until PD, death from any cause, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Title

Phase 2 (mBC): Progression-Free Survival (PFS) as Assessed by the Investigator According to RECIST v1.1

Description

Time Frame

Baseline until PD, death from any cause, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Title

Phase 2 (mBC): Percentage of Participants With Clinical Benefit as Assessed by the Investigator According to RECIST v1.1

Description

Time Frame

Baseline until clinical benefit response, consent withdrawal, or study end whichever occurred first (up to approximately 2.5 years overall)

Title

Phase 2 (mBC): Percentage of Participants Who Died of Any Cause

Time Frame

Baseline until death or study end whichever occurred first (up to approximately 2.5 years overall)

Title

Phase 2 (mBC): Overall Survival (OS)

Description

Time Frame

Baseline until death or study end whichever occurred first (up to approximately 2.5 years overall)

Title

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

Description

Time Frame

Baseline until CR/PR, consent withdrawal, or study end whichever occurred first (up to approximately 1.5 years overall)

Title

Phase 1 (LA/mGC): Serum Concentration of Trastuzumab Emtansine

Time Frame

Title

Phase 1 (LA/mGC): Serum Concentration of Trastuzumab

Description

Trastuzumab was derived from trastuzumab emtansine.

Time Frame

Title

Phase 1 (LA/mGC): Cmax of Capecitabine

Description

Cmax for capecitabine was estimated from plasma concentration versus time data using non-compartmental methods of analysis. Reported dispersion values are for CV% and not for standard deviation.

Time Frame

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

Title

Phase 1 (LA/mGC): AUC(0-inf) of Capecitabine

Description

Time Frame

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

Title

Phase 1 (LA/mGC): t1/2 of Capecitabine

Description

Time Frame

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

Title

Phase 1 (LA/mGC): Cmax of 5-Fluorouracil (Metabolite of Capecitabine)

Description

Time Frame

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

Title

Phase 1 (LA/mGC): AUC(0-inf) of 5-Fluorouracil (Metabolite of Capecitabine)

Description

Time Frame

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

Title

Phase 1 (LA/mGC): t1/2 of 5-Fluorouracil (Metabolite of Capecitabine)

Description

Time Frame

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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: 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 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)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clinical Trials

Organizational Affiliation

Hoffmann-La Roche

Official's Role

Study Director

Facility Information:

Facility Name

Fundacion Investigar

City

Caba

ZIP/Postal Code

C1025ABI

Country

Argentina

Facility Name

Centro Oncologico Riojano Integral (CORI)

City

La Rioja

ZIP/Postal Code

F5300COE

Country

Argentina

Facility Name

Hospital Erasto Gaertner

City

Curitiba

State/Province

ZIP/Postal Code

81520-060

Country

Brazil

Facility Name

Instituto Oncologico de Ribeirao Preto - INORP

City

Ribeirao Preto

State/Province

ZIP/Postal Code

14025-270

Country

Brazil

Facility Name

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

City

Sao Jose do Rio Preto

State/Province

ZIP/Postal Code

15090-000

Country

Brazil

Facility Name

Instituto do Cancer do Estado de Sao Paulo - ICESP

City

Sao Paulo

State/Province

ZIP/Postal Code

01246-000

Country

Brazil

Facility Name

British Columbia Cancer Agency (Bcca) - Vancouver Cancer Centre

City

Vancouver

State/Province

British Columbia

ZIP/Postal Code

V5Z 4E6

Country

Canada

Facility Name

ICO Paul Papin; Oncologie Medicale.

City

Angers

ZIP/Postal Code

49055

Country

France

Facility Name

Centre Leon Berard; Departement Oncologie Medicale

City

Lyon

ZIP/Postal Code

69373

Country

France

Facility Name

Institut Paoli Calmettes; Oncologie Medicale

City

Marseille

ZIP/Postal Code

13273

Country

France

Facility Name

Institut Curie; Oncologie Medicale

City

Paris

ZIP/Postal Code

75231

Country

France

Facility Name

Ico Rene Gauducheau; Oncologie

City

Saint Herblain

ZIP/Postal Code

44805

Country

France

Facility Name

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

City

Berlin

ZIP/Postal Code

10117

Country

Germany

Facility Name

Onkologische Schwerpunktpraxis Bielefeld; Haemotologie & Internistische onkologie

City

Bielefeld

ZIP/Postal Code

33604

Country

Germany

Facility Name

Heinrich-Heine Universitätsklinik Düsseldorf

City

Düsseldorf

ZIP/Postal Code

40225

Country

Germany

Facility Name

Klinik Fulda, Medizinisches Versorgungszentrum Osthessen GmbH

City

Fulda

ZIP/Postal Code

36043

Country

Germany

Facility Name

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

City

Marburg

ZIP/Postal Code

35043

Country

Germany

Facility Name

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

City

München

ZIP/Postal Code

81675

Country

Germany

Facility Name

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

City

München

ZIP/Postal Code

81675

Country

Germany

Facility Name

Alexandras General Hospital of Athens; Oncology Department

City

Athens

ZIP/Postal Code

115 28

Country

Greece

Facility Name

Univ General Hosp Heraklion; Medical Oncology

City

Heraklion

ZIP/Postal Code

711 10

Country

Greece

Facility Name

University Hospital of Patras Medical Oncology

City

Patras

ZIP/Postal Code

265 04

Country

Greece

Facility Name

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

City

Napoli

State/Province

Campania

ZIP/Postal Code

80131

Country

Italy

Facility Name

Istituto Europeo Di Oncologia

City

Milano

State/Province

Lombardia

ZIP/Postal Code

20141

Country

Italy

Facility Name

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

City

Candiolo

State/Province

Piemonte

ZIP/Postal Code

10060

Country

Italy

Facility Name

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

City

Pontedera

State/Province

Toscana

ZIP/Postal Code

56025

Country

Italy

Facility Name

Hospital da Luz; Departamento de Oncologia Medica

City

Lisboa

ZIP/Postal Code

1500-650

Country

Portugal

Facility Name

Hospital de Santa Maria; Servico de Oncologia Medica

City

Lisboa

ZIP/Postal Code

1649-035

Country

Portugal

Facility Name

IPO do Porto; Servico de Oncologia Medica

City

Porto

ZIP/Postal Code

4200-072

Country

Portugal

Facility Name

Ivanovo Regional Oncology Dispensary

City

Ivanovo

ZIP/Postal Code

153040

Country

Russian Federation

Facility Name

Blokhin Cancer Research Center; Combined Treatment

City

Moscow

ZIP/Postal Code

115478

Country

Russian Federation

Facility Name

City Clinical Oncology Hospital

City

Moscow

ZIP/Postal Code

143423

Country

Russian Federation

Facility Name

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

City

Saint-Petersburg

ZIP/Postal Code

197758

Country

Russian Federation

Facility Name

City Oncology Dispensary

City

St Petersburg

Country

Russian Federation

Facility Name

Bashkirian Republican Clinical Oncology Dispensary

City

UFA

ZIP/Postal Code

450054

Country

Russian Federation

Facility Name

Institute for Oncology and Radiology of Serbia; Medical Oncology

City

Belgrade

ZIP/Postal Code

11000

Country

Serbia

Facility Name

Clinical Centre Nis, Clinic for Oncology

City

Nis

ZIP/Postal Code

18000

Country

Serbia

Facility Name

Narodny Onkologicky Ustav; Oddelenie klinickej onkologie A

City

Bratislava

ZIP/Postal Code

833 10

Country

Slovakia

Facility Name

Fakultna nemocnica Trencín; Onkologicke odd.

City

Trencin

ZIP/Postal Code

911 71

Country

Slovakia

Facility Name

Hospital Univ Vall d'Hebron; Servicio de Oncologia

City

Barcelona

ZIP/Postal Code

08035

Country

Spain

12. IPD Sharing Statement

Citations:

PubMed Identifier

32584367

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.

Results Reference

derived

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