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)

Phase 2TerminatedNCT01702558

Hoffmann-La Roche182 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

182

Conditions

Breast Cancer Gastric Cancer

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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)

Locations (40)

Fundacion Investigar

CABA, Argentina

Centro Oncologico Riojano Integral (CORI)

La Rioja, Argentina

Hospital Erasto Gaertner

Curitiba, Paraná, Brazil

Instituto Oncologico de Ribeirao Preto - INORP

Ribeirão Preto, São Paulo, Brazil

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

São José do Rio Preto, São Paulo, Brazil

Outcomes

Primary Outcomes

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 (%).

Time frame: 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%.

Time frame: 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.

Time frame: 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%.

Time frame: 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%.

Time frame: Continuously during 3 weeks

Secondary Outcomes

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.

Time frame: 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

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)

Phase 1 (mBC): Serum Concentration of Trastuzumab

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)

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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)

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.

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

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.

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

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.

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

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.

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

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

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

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.

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

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.

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

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.

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

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

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

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.

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

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

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

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

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

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

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

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

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

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

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