A Study of Trastuzumab Emtansine, Paclitaxel, and Pertuzumab in Patients With HER2-Positive, Locally Advanced or Metastatic Breast Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT00951665
First received: August 3, 2009
Last updated: May 17, 2016
Last verified: May 2016
  Purpose
This Phase Ib-IIa, multi-institutional, open-label, dose-escalation study is designed to evaluate the safety, tolerability, pharmacokinetics and feasibility of trastuzumab emtansine (T-DM1) administered by intravenous (IV) infusion in combination with paclitaxel (and pertuzumab, if applicable) in patients with human epidermal growth factor receptor 2-positive (HER2-positive), locally advanced or metastatic breast cancer.

Condition Intervention Phase
Metastatic Breast Cancer
Drug: paclitaxel
Drug: pertuzumab [Perjeta]
Drug: trastuzumab emtansine [Kadcyla]
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase Ib-IIa, Open-label, Dose-Escalation Study of the Safety, Tolerability and Pharmacokinetics of Trastuzumab Emtansine, Paclitaxel and Pertuzumab Administered Intravenously to Patients With Her2-positive, Locally Advanced or Metastatic Breast Cancer

Resource links provided by NLM:


Further study details as provided by Genentech, Inc.:

Primary Outcome Measures:
  • Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death [ Time Frame: Up to 30 days after the last dose of study treatment or study discontinuation/termination, whichever is later ] [ Designated as safety issue: No ]
    An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect.

  • Number of Participants With Dose Limiting Toxicity (DLT) of the Combination of T-DM1 and Paclitaxel When T-DM1 Was Administered on Either an Q3W or QW Schedule for Both With and Without Pertuzumab Treatment [ Time Frame: Up to 23 days ] [ Designated as safety issue: No ]
    DLT is defined as one of the following toxicities related to study drug during Cycle 1, according to the NCI CTCAE, Version 3: Grade 3 or higher non-hematologic AEs; Grade 3 or higher elevation of serum bilirubin, hepatic transaminases, or alkaline phosphatase; Grade 4 or higher thrombocytopenia; Grade 4 or higher neutropenia; any subjectively intolerable toxicity related to T-DM1, paclitaxel, or pertuzumab; any treatment-related toxicity prohibiting the start of the second cycle of treatment and/or prompting to a dose delay or modification during the DLT observation period, such as prompting a dose reduction at Cycle 2 Day1.

  • Maximum Tolerated Dose of T-DM1 When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab [ Time Frame: Days 1 to 21 ] [ Designated as safety issue: No ]
    The MTD was defined as the highest dose of T-DM1 and paclitaxel at which 0 of 3 participants or 1 of 6 experienced a DLT, when T-DM1 (Q3W or QW) and paclitaxel (QW) was administered with and without pertuzumab treatment.

  • Maximum Tolerated Dose of Paclitaxel When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab [ Time Frame: Days 1 to 21 ] [ Designated as safety issue: No ]
    The MTD was defined as the highest dose of paclitaxel at which 0 of 3 participants or 1 of 6 experienced a DLT, when paclitaxel (QW) and T-DM1 (Q3W or QW) was administered with and without pertuzumab treatment.

  • Number of Participants in Phase IIa of the Study Who Received 12 or More Paclitaxel Doses in Combination With T-DM1 and/or Pertuzumab [ Time Frame: From Day 1 to 15 weeks ] [ Designated as safety issue: No ]
    Participants in Phase IIa received T-DM1 Q3W and paclitaxel in Group A and T-DM1, paclitaxel, and pertuzumab in Group B.

  • Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel [ Time Frame: Up to 30 days after the last dose of study treatment or study discontinuation/termination, whichever is later ] [ Designated as safety issue: No ]
    Participants were assessed for toxicity prior to each dose of T-DM1 and paclitaxel; dosing occurred only if the clinical assessment and laboratory test values were acceptable. Dose modifications included dose delayed or any dose reduction. Participants in whom significant toxicities had not recovered to the treatment range defined by the dose modification guidelines at the time of their next scheduled dose, had their dose of T-DM1 and/or paclitaxel delayed or reduced for up to 21 days.

  • Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen [ Time Frame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion) ] [ Designated as safety issue: No ]
    Cmax of serum T-DM1 and total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered Q3W.

  • Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After Q3W Dose Regimen [ Time Frame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion) ] [ Designated as safety issue: No ]
    Cmax of plasma DM1 in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered Q3W.

  • Area Under the Serum Concentration-time Curve of Total Exposure (AUC0-Day 21) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen [ Time Frame: Pre- and post-dose (0.25 and 4 hours and Day 8 [before paclitaxel infusion) for Cycle 1 and pre- and post-dose (0.25 and 4 hours) for Cycle 2 (each cycle of 21 days) ] [ Designated as safety issue: No ]
    AUC0-21 for serum T-DM1 and total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered Q3W.

  • Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen [ Time Frame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion) ] [ Designated as safety issue: No ]
    Cmax for serum T-DM1 and total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis when T-DM1 was administered QW.

  • Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After QW Dose Regimen [ Time Frame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1, and Day 8 (before T-DM1 dose) ] [ Designated as safety issue: No ]
    Cmax for plasma DM1 in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered QW

  • Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen [ Time Frame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before T-DM1 dose) ] [ Designated as safety issue: No ]
    AUClast for serum T-DM1 and serum total trastuzumab (sum of conjugated and unconjugated trastuzumab) in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered QW

  • Maximum Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence T-DM1) and Cycle 2 (in the Presence T-DM1) [ Time Frame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 ] [ Designated as safety issue: No ]
    Plasma Cmax of paclitaxel (65 mg/m^2 and 80 mg/m^2) for Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1) was estimated by non-compartmental analysis.

  • Area Under Plasma Concentration - Time Curve of Paclitaxel From Time 0 to Infinity (AUC0-inf) in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) [ Time Frame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 ] [ Designated as safety issue: No ]
    Plasma AUC0-inf of paclitaxel (65 mg/m^2 and 80 mg/m^2) was estimated by non-compartmental analysis in Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1).

  • An Elimination Half-life (t1/2) of Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) [ Time Frame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 ] [ Designated as safety issue: No ]
    Plasma t1/2 of paclitaxel (65 mg/m^2 and 80 mg/m^2) was estimated by non-compartmental analysis in Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1).

  • Plasma Clearance (CL) of Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) [ Time Frame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 ] [ Designated as safety issue: No ]
    Plasma CL of paclitaxel (65 mg/m^2 and 80 mg/m^2) was estimated by non-compartmental analysis for in Cycle 1 (in the absence T-DM1) and Cycle 2 (in the presence T-DM1).

  • An Apparent Volume of Distribution at Steady-state (Vss) of Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence of T-DM1) and Cycle 2 (in the Presence of T-DM1) [ Time Frame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2 ] [ Designated as safety issue: No ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state which is estimated by (D/AUC[0-inf]) X (AUMC[0-inf])/AUC[0-inf]) where D is the dose of study drug, AUMC(0-inf) is the area under the first moment curve extrapolated to infinity and AUC(0-inf) is the area under the plasma concentration-time curve from time zero to infinite time. The Vss of paclitaxel (65 mg/m2 and 80 mg/m2) is observed in Cycle 1 (in the absence of T-DM1) and Cycle 2 (in the presence of T-DM1).

  • Number of Participants With Change From Baseline in Cardiac Function [ Time Frame: Baseline (30 days prior to study dose), end of Cycle 2, and then every three cycles in Phase Ib and every four cycles in Phase IIa throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first ] [ Designated as safety issue: No ]
    Change in cardiac functions i.e., left ventricular ejection fraction (LVEF) and segmental wall abnormalities were assessed by echocardiogram or multigated acquisition scans. LVEF was assessed as change from baseline as 0 to <15%, >=15 to <25%, >=25%, and missing values.


Secondary Outcome Measures:
  • Percentage of Participants With Objective Response Rate (ORR) [ Time Frame: Tumor assessments performed at the end of Cycle 2 and then every 2 cycles (i.e., Cycles 4, 6, 8, 10, etc. [each cycle of 21 days]) throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first ] [ Designated as safety issue: No ]
    Participants with measurable disease (at least one lesion 2 centimeters [cm] or more on computed tomography (CT) scan or 1 cm or more on spiral CT scan) were considered for OR. ORR is defined as the percentage of patients with a complete response (CR)/partial response (PR) determined on two consecutive tumor assessments at least 4 weeks apart based on modified Response Evaluation Criteria in Solid Tumors, Version 1.0 (RECIST). CR defined as disappearance of all target and non-target lesions and normalization of tumor marker level. PR defined as at least 30 percent decrease in sum of the longest diameters of the target lesions taking as reference the baseline sum longest diameters.

  • Duration of Objective Response [ Time Frame: Tumor assessments performed at the end of Cycle 2 and then every 2 cycles (i.e., Cycles 4, 6, 8, 10, etc. [each cycle of 21 days]) throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first ] [ Designated as safety issue: No ]
    Duration of OR is only calculated for participants with OR and is defined as the time from the first tumor assessment that supports the participant`s OR to disease progression or death.

  • Percentage of Participants With Clinical Benefit [ Time Frame: Tumor assessments performed at the end of Cycle 2 and then every 2 cycles (i.e., Cycles 4, 6, 8, 10, etc. [each cycle of 21 days]) throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first ] [ Designated as safety issue: No ]
    Clinical benefit is defined as CR, PR, or stable disease (SD) of 6 months or more duration as assessed by the investigator. CR and PR are identified in previous outcome measure. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter since the treatment started. PD is defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions.

  • Progression-free Survival (PFS) [ Time Frame: Tumor assessments performed at the end of Cycle 2 and then every 2 cycles (i.e., Cycles 4, 6, 8, 10, etc. [each cycle of 21 days]) throughout the duration of the study (12 months) until disease progression or study discontinuation, whichever occurs first ] [ Designated as safety issue: No ]
    PFS is defined as the time from the first day of study treatment to documented disease progression or death on study i.e., death due to any cause within 30-days of last dose of study treatment, whichever occurs first.


Enrollment: 107
Study Start Date: August 2009
Study Completion Date: June 2013
Primary Completion Date: February 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase lb Regimen 1
Participants received trastuzumab emtansine (T-DM1) every three weeks (Q3W) + paclitaxel weekly (QW) intravenously.
Drug: trastuzumab emtansine [Kadcyla]
Intravenous escalating dose
Drug: paclitaxel
Intravenous escalating dose
Experimental: Phase Ib Regimen 2
Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously.
Drug: pertuzumab [Perjeta]
Intravenous repeating dose
Drug: trastuzumab emtansine [Kadcyla]
Intravenous escalating dose
Drug: paclitaxel
Intravenous escalating dose
Experimental: Phase Ib Regimen 3
Participants received T-DM1 QW + paclitaxel QW intravenously.
Drug: trastuzumab emtansine [Kadcyla]
Intravenous escalating dose
Drug: paclitaxel
Intravenous escalating dose
Experimental: Phase Ib Regimen 4
Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously.
Drug: pertuzumab [Perjeta]
Intravenous repeating dose
Drug: trastuzumab emtansine [Kadcyla]
Intravenous escalating dose
Drug: paclitaxel
Intravenous escalating dose
Experimental: Phase IIa Group A
Participants received maximum tolerated dose (MTD) from Phase 1b i.e. T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m^2 QW intravenously.
Drug: paclitaxel
Intravenous repeating dose
Drug: trastuzumab emtansine [Kadcyla]
Intravenous repeating dose
Experimental: Phase IIa Group B
Participants received MTD from Phase 1b i.e. T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m^2 QW + pertuzumab Q3W intravenously.
Drug: paclitaxel
Intravenous repeating dose
Drug: pertuzumab [Perjeta]
Intravenous repeating dose
Drug: trastuzumab emtansine [Kadcyla]
Intravenous repeating dose

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically documented 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 (Phase Ib patients only)
  • No prior T-DM1 or pertuzumab therapy
  • Measurable or evaluable disease
  • Cardiac ejection fraction >=50% by either echocardiogram or multigated acquisition scan
  • Life expectancy >= 90 days as assessed by the investigator

Exclusion Criteria:

  • Fewer 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 are allowed; palliative radiation therapy involving <=25% of marrow-bearing bone is allowed if completed within >= 14 days prior to first study treatment
  • History of intolerance or hypersensitivity to trastuzumab and/or adverse events related to trastuzumab, murine proteins, or any of the excipients that resulted in trastuzumab being permanently discontinued
  • Peripheral neuropathy of Grade >= 2 per NCI CTCAE, Version 3.0, at the time of, or within 3 weeks prior to, the first study therapy (Phase Ib patients)
  • Peripheral neuropathy of Grade >/=1 per NCI CTCAE, Version 3.0, at the time of, or within 3 weeks prior to, the first study therapy (Phase IIa patients)
  • History of exposure to the following cumulative doses of anthracyclines: Doxorubicin > 500 mg/m^2; Liposomal doxorubicin > 900 mg/m^2; Epirubicin > 720 mg/m^2
  • History of clinically significant cardiac dysfunction
  • Brain metastases that are untreated, or progressive, or have required any type of therapy (including radiation, surgery, or steroids) to control symptoms from brain metastases within 60 days prior to the first study treatment.
  • History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, basal cell carcinoma, or synchronous or subsequent HER2-positive breast cancer or other malignancy with a similar expected curative outcome
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00951665

Locations
United States, California
Stanford, California, United States, 94305-5456
United States, Colorado
Aurora, Colorado, United States, 80045
United States, Massachusetts
Boston, Massachusetts, United States, 02115
United States, Michigan
Detroit, Michigan, United States, 48201
United States, New York
New York, New York, United States, 10065
Sponsors and Collaborators
Genentech, Inc.
Investigators
Study Director: Clinical Trials Genentech, Inc.
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT00951665     History of Changes
Other Study ID Numbers: TDM4652g  GO01355 
Study First Received: August 3, 2009
Results First Received: January 4, 2016
Last Updated: May 17, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Genentech, Inc.:
Trastuzumab DM1 (T-DM1)
Trastuzumab emtansine
Armed Herceptin
HER2
HER2+
HER2 Positive Breast Cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Maytansine
Ado-trastuzumab emtansine
Pertuzumab
Albumin-Bound Paclitaxel
Trastuzumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 21, 2016