Clinical trial NCT00951665: A Study of Trastuzumab Emtansine, Paclitaxel, and Pertuzumab in Patients With HER2-Positive, Locally Advanced or Metastatic Breast Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Metastatic Breast Cancer
Keywords: Trastuzumab DM1 (T-DM1)
Trastuzumab emtansine
Armed Herceptin
HER2
HER2+
HER2 Positive Breast Cancer
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2009-08-04
Enrollment: 107
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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

Primary outcomes:
measure: Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death
timeFrame: Up to 30 days after the last dose of study treatment or study discontinuation/termination, whichever is later
measure: 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
timeFrame: Up to 23 days
measure: Maximum Tolerated Dose of T-DM1 When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab
timeFrame: Days 1 to 21
measure: Maximum Tolerated Dose of Paclitaxel When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab
timeFrame: Days 1 to 21
measure: Number of Participants in Phase IIa of the Study Who Received 12 or More Paclitaxel Doses in Combination With T-DM1 and/or Pertuzumab
timeFrame: From Day 1 to 15 weeks
measure: Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel
timeFrame: Up to 30 days after the last dose of study treatment or study discontinuation/termination, whichever is later
measure: Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen
timeFrame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion)
measure: Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After Q3W Dose Regimen
timeFrame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion)
measure: 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
timeFrame: 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)
measure: Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen
timeFrame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before paclitaxel infusion)
measure: Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After QW Dose Regimen
timeFrame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1, and Day 8 (before T-DM1 dose)
measure: Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen
timeFrame: Pre-dose, and 0.25 and 4 hours post-dose on Day 1; Day 8 (before T-DM1 dose)
measure: Maximum Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence T-DM1) and Cycle 2 (in the Presence T-DM1)
timeFrame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2
measure: 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)
timeFrame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2
measure: 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)
timeFrame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2
measure: 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)
timeFrame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2
measure: 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)
timeFrame: Pre-dose, and 0.25, 1, 2, 4, 6, and 24 hours post-dose for Cycle 1 and Cycle 2
measure: Number of Participants With Change From Baseline in Cardiac Function
timeFrame: 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
Secondary outcomes:
measure: Percentage of Participants With Objective Response Rate (ORR)
timeFrame: 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
measure: Duration of Objective Response
timeFrame: 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
measure: Percentage of Participants With Clinical Benefit
timeFrame: 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
measure: Progression-free Survival (PFS)
timeFrame: 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
Other outcomes:
Locations:
city: Stanford
country: United States
state: California
city: Aurora
country: United States
state: Colorado
city: Boston
country: United States
state: Massachusetts
city: Detroit
country: United States
state: Michigan
city: New York
country: United States
state: New York
Study officials:
affiliation: Genentech, Inc.
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Krop IE, Modi S, LoRusso PM, Pegram M, Guardino E, Althaus B, Lu D, Strasak A, Elias A. Phase 1b/2a study of trastuzumab emtansine (T-DM1), paclitaxel, and pertuzumab in HER2-positive metastatic breast cancer. Breast Cancer Res. 2016 Mar 15;18(1):34. doi: 10.1186/s13058-016-0691-7.