A Study of Trastuzumab Emtansine (Trastuzumab-MCC-DM1, T-DM1) in Combination With Pertuzumab Administered to Patients With Human Epidermal Growth Factor Receptor-2 (HER2)-Positive Locally Advanced or Metastatic Breast Cancer Who Have Previously Received Trastuzumab

• Sponsor: Hoffmann-La Roche
• Collaborator: Roche Pharma AG
• Information provided by (Responsible Party): Hoffmann-La Roche

Study Description

Brief Summary:

This was a multi-institutional, multinational, open-label, single-arm Phase Ib/II study designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of trastuzumab emtansine (trastuzumab-MCC-DM1) administered by intravenous (IV) infusion in combination with pertuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive locally advanced or metastatic breast cancer who had previously received trastuzumab.

Condition or disease	Intervention/treatment	Phase
Metastatic Breast Cancer	Drug: Trastuzumab emtansine [Kadcyla] 3.0 mg/kg; Drug: Trastuzumab emtansine [Kadcyla] 3.6 mg/kg; Drug: Pertuzumab 420 mg	Phase 1; Phase 2

Detailed Description:

There were 2 phases in the study, a Dose Escalation phase (Phase 1b) and a Dose Expansion phase (Phase 2a). In the Dose Escalation phase, 3 patients were enrolled at the first dose level (3.0 mg/kg trastuzumab emtansine) and and 6 patients were enrolled at the second dose level (3.6 mg/kg trastuzumab emtansine). An additional 58 patients were enrolled at the 3.6 mg/kg trastuzumab emtansine dose level in the Dose Expansion phase (Phase 2a) of the study.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	67 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase Ib/II, Open-label Study of the Safety, Tolerability, and Efficacy of Trastuzumab Emtansine (Trastuzumab-MCC-DM1, T-DM1) in Combination With Pertuzumab Administered Intravenously to Patients With Human Epidermal Growth Factor Receptor-2 (HER2)-Positive Locally Advanced or Metastatic Breast Cancer Who Have Previously Received Trastuzumab
Study Start Date :	May 2009
Actual Primary Completion Date :	August 2011
Actual Study Completion Date :	August 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: Trastuzumab emtansine 3.0 mg/kg + pertuzumab 420 mg; Patients received trastuzumab emtansine 3.0 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.	Drug: Trastuzumab emtansine [Kadcyla] 3.0 mg/kg; Trastuzumab emtansine was provided as a single-use lyophilized formulation.; Other Names: trastuzumab-DM1; trastuzumab-MCC-DM1; T-DM1; Drug: Pertuzumab 420 mg; Pertuzumab was provided as a single-use formulation.; Other Name: Perjeta
Experimental: Trastuzumab emtansine 3.6 mg/kg + pertuzumab 420 mg; Patients received trastuzumab emtansine 3.6 mg/kg intravenously (IV) on Day 1 of every 3 week cycle until progressive disease, intolerable toxicity, initiation of another anti-cancer therapy, or patient discontinuation. Patients also received a loading dose of 840 mg of pertuzumab IV on Day 1 of Cycle 1 followed by pertuzumab 420 mg IV on Day 1 of every subsequent 3 week cycle.	Drug: Trastuzumab emtansine [Kadcyla] 3.6 mg/kg; Trastuzumab emtansine was provided as a single-use lyophilized formulation.; Other Names: trastuzumab-DM1; trastuzumab-MCC-DM1; T-DM1; Drug: Pertuzumab 420 mg; Pertuzumab was provided as a single-use formulation.; Other Name: Perjeta

Outcome Measures

Primary Outcome Measures :

1. Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Baseline through the end of the study (up to 2 years 3 months) ]
   A patient had an objective response if they had a complete response or a partial response on 2 consecutive occasions ≥ 4 weeks apart. For target lesions, a complete response was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. For non-target lesions, a complete response was defined as the disappearance of all non-target lesions; a partial response was defined as the persistence of 1 or more non-target lesions.

Secondary Outcome Measures :

1. Duration of Objective Response Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Baseline through the end of the study (up to 2 years 3 months) ]
   Duration of objective response was defined as the time from initial response to disease progression (PD) or death from any cause. For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions should be selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions.
2. Progression-free Survival Assessed by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Baseline through the end of the study (up to 2 years 3 months) ]
   Progression-free survival was defined as the time from randomization to first documented disease progression (PD) or death due to any cause within 30 days of the last treatment, whichever occurred first. For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions should be selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Histologically documented human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer.
• Tumor tissue blocks or 15-20 unstained tissue slides for confirmatory central laboratory HER2 status testing and other exploratory assessments.
• Prior trastuzumab in any line of therapy.
• No prior trastuzumab emtansine (T-DM1) or pertuzumab therapy.
• Measurable disease.
• For women of childbearing potential, agreement to use an effective form of contraception and to continue its use for the duration of the study.
• Life expectancy ≥ 90 days.

Exclusion Criteria:

• Less than 21 days since the last anti-tumor therapy, including chemotherapy, biologic, experimental, immune, hormonal, or radiotherapy for the treatment of breast cancer, with the following exceptions: Hormone-replacement therapy or oral contraceptives; palliative radiation therapy involving ≤ 25% of marrow-bearing bone if administered ≥ 14 days prior to first study treatment.
• History of intolerance or hypersensitivity to trastuzumab and/or adverse events related to trastuzumab that resulted in trastuzumab being permanently discontinued.
• Peripheral neuropathy of Grade ≥ 2.
• History of clinically significant cardiac dysfunction.
• Current severe, uncontrolled systemic disease, eg, clinically significant cardiovascular, pulmonary, or metabolic disease.
• Brain metastases that are untreated, progressive, or have required any type of therapy to control symptoms from brain metastases within 60 days of the first study treatment.
• History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or other malignancy with a similar expected curative outcome.

Contacts and Locations

Locations

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United States, Florida
Boca Raton, Florida, United States, 33428
Deerfield Beach, Florida, United States, 33442
United States, Illinois
Maywood, Illinois, United States, 60153
United States, Indiana
Indianapolis, Indiana, United States, 46202
United States, Kansas
Wichita, Kansas, United States, 67214
United States, Maryland
Rockville, Maryland, United States, 20850-3348
United States, North Carolina
Chapel Hill, North Carolina, United States, 27514
United States, Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Philadelphia, Pennsylvania, United States, 19111
United States, Tennessee
Nashville, Tennessee, United States, 37203
Belgium
Bruxelles, Belgium, 1000
Canada, British Columbia
Vancouver, British Columbia, Canada, V5Z 1H5
Canada, Quebec
Montreal, Quebec, Canada, H3A 1A1
France
Paris, France, 75248
Villejuif, France, 94805
Germany
Köln, Germany, 50924
Italy
Aviano, Italy, 33081
Milano, Italy, 20133
Spain
Barcelona, Spain, 08035
Valencia, Spain, 46010

Sponsors and Collaborators

Hoffmann-La Roche

Roche Pharma AG

Investigators

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Study Director:	Elaine K. Wong, M.Sc., M.D.	Genentech, Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Miller KD, Diéras V, Harbeck N, Andre F, Mahtani RL, Gianni L, Albain KS, Crivellari D, Fang L, Michelson G, de Haas SL, Burris HA. Phase IIa trial of trastuzumab emtansine with pertuzumab for patients with human epidermal growth factor receptor 2-positive, locally advanced, or metastatic breast cancer. J Clin Oncol. 2014 May 10;32(14):1437-44. doi: 10.1200/JCO.2013.52.6590. Epub 2014 Apr 14.

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Responsible Party:	Hoffmann-La Roche
ClinicalTrials.gov Identifier:	NCT00875979 History of Changes
Other Study ID Numbers:	BO22495; TDM4373g ( Other Identifier: Genentech )
First Posted:	April 6, 2009
Results First Posted:	July 18, 2013
Last Update Posted:	December 24, 2013
Last Verified:	December 2013

Keywords provided by Hoffmann-La Roche:

MBC; Breast Cancer; HER2+; HER2+ breast cancer	HER2 positive breast cancer; herceptin; Trastuzumab emtansine

Additional relevant MeSH terms:

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Pertuzumab; Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Trastuzumab; Ado-trastuzumab emtansine; Maytansine	Mitogens; Antineoplastic Agents, Immunological; Antineoplastic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Phytogenic; Tubulin Modulators; Antimitotic Agents