Clinical trial NCT00934856: A Study of Trastuzumab Emtansine (T-DM1) in Combination With Docetaxel, and Potentially Pertuzumab, in Participants With Advanced Breast Cancer
Official title: An Open-Label, Multi-Center Phase I/II Study of the Safety and Tolerability of the Combination of Trastuzumab-MCC-DM1 (T-DM1) With Docetaxel, and Potentially Pertuzumab, for Treatment for Patients With Advanced Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Breast Cancer
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2009-07-08
Enrollment: 98
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is an open-label, multi-center, non-randomized study of the safety and tolerability of the combination of T-DM1 plus docetaxel for the treatment of participants with metastatic breast cancer (MBC) and of T-DM1 plus docetaxel with or without pertuzumab, for the treatment of participants with locally advanced breast cancer (LABC). The study comprises an initial dose finding (feasibility) part to determine the maximum tolerated dose (MTD) of T-DM1 and docetaxel, followed by an extension part aiming to consolidate the safety and efficacy of the recommended docetaxel/T-DM1 combination regimen.


Eligibility criteria: Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (ECOG performance status of 2 will be allowed if only due to debilitating bone disease)
* HER2-positive metastatic or locally advanced breast cancer

For MBC participants:

* Documented metastatic or inoperable locally advanced (without meeting LABC criteria) disease, amenable for treatment with docetaxel
* History of disease progression within 3 months prior to study entry

For LABC participants:

* Newly diagnosed locally advanced breast cancer, Stage IIA-IIIC (American Joint Committee on Cancer \[AJCC\] staging system)

Exclusion Criteria:

* Significant cardiac disease
* Inadequate bone marrow, liver or renal function

For MBC participants:

* Participants must not have received radiotherapy for the treatment of metastatic or locally recurrent/advanced disease other than for the relief of pain in progressing metastatic bone lesions and/or brain metastases
* Brain metastases that are untreated, symptomatic or require therapy to control symptoms; or any radiation, surgery, or other therapy to control symptoms from brain metastasis within 2 months of the first study treatment.

For LABC participants:

* Clinically or radiologically detectable metastasis (M1 disease)
* Participants for whom surgery as primary intent procedure is the best option to treat their disease
* Participants must not have received any systemic or loco-regional anti-cancer therapy for the treatment of locally advanced disease

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicity (DLT) - MBC and LABC Feasibility Population
timeFrame: Cycle 1 (up to 21 days)
measure: Percentage of Participants With Adverse Events (AEs) or Serious AEs (SAEs) - MBC and LABC Population
timeFrame: Baseline up to 28 days after last dose for MBC participants and for LABC participants who could not undergo surgery, and up to 6 weeks post-surgery for LABC participants who underwent surgery (maximum up to approximately 3 years)
Secondary outcomes:
measure: Percentage of Participants With Progression-Free Survival (PFS) Event - MBC Population
timeFrame: Baseline until disease progression or death (up to approximately 3 years)
measure: PFS - MBC Population
timeFrame: Baseline until disease progression or death (up to approximately 3 years)
measure: Percentage of Participants With a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) - MBC Population
timeFrame: Baseline until disease progression or recurrence (up to approximately 3 years)
measure: Percentage of Participants With Treatment Failure - MBC Population
timeFrame: Baseline until end of treatment (up to 39.8 months)
measure: Time to Treatment Failure (TTF) - MBC Population
timeFrame: Baseline until end of treatment (up to 39.8 months)
measure: Percentage of Participants With CR or PR or Stable Disease (SD) for at Least 6 Months [Clinical Benefit Rate (CBR)] - MBC Population
timeFrame: Baseline until disease progression, recurrence or death (up to approximately 3 years)
measure: Duration of Response - MBC Population
timeFrame: Baseline until disease progression, recurrence or death (up to approximately 3 years)
measure: Percentage of Participants With Pathological CR (pCR) - LABC Population
timeFrame: Within 6 weeks of post-surgery (up to approximately 3 years)
measure: Percentage of Participants With a BOR of CR or PR - LABC Population
timeFrame: Baseline until disease progression, recurrence or death (up to approximately 3 years)
measure: Number of Participants With Anti-Therapeutic Antibody (ATA) Response to Trastuzumab - MBC and LABC Population
timeFrame: Baseline (Day 1 of Cycle 1), Post baseline (at first follow-up visit [28 days after last dose of study drug][up to approximately 145 weeks])
measure: Maximum Observed Concentration (Cmax) of Serum Trastuzumab Emtansine
timeFrame: Cycle 1: pre-dose (Hour [Hr] 0), 0.25, 4 hrs post end of infusion (EOI) of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
measure: Apparent Terminal Half-Life (t1/2) of Serum Trastuzumab Emtansine
timeFrame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
measure: Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Serum Trastuzumab Emtansine
timeFrame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
measure: Clearance (CL) of Serum Trastuzumab Emtansine
timeFrame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
measure: Volume of Distribution at Steady State (Vss) of Serum Trastuzumab Emtansine
timeFrame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
measure: Cmax of Total Serum Trastuzumab
timeFrame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
measure: t1/2 of Total Serum Trastuzumab
timeFrame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
measure: AUCinf of Total Serum Trastuzumab
timeFrame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
measure: CL of Total Serum Trastuzumab
timeFrame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
measure: Vss of Total Serum Trastuzumab
timeFrame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
measure: Cmax of Plasma N2'-Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1)
timeFrame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
measure: t1/2 of Plasma DM1
timeFrame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
measure: AUCinf of Plasma DM1
timeFrame: Cycle 1: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 2; on Days 3 and 8. Cycle 2: pre-dose (Hr 0), 0.25, 4 hrs post EOI of T-DM1 on Day 1; on Day 8 (1 cycle = 21 days) (T-DM1 infusion duration = 1.5 hrs)
measure: Cmax of Plasma Docetaxel
timeFrame: Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days)
measure: t1/2 of Plasma Docetaxel
timeFrame: Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days)
measure: AUCinf of Plasma Docetaxel
timeFrame: Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days)
measure: CL of Plasma Docetaxel
timeFrame: Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days)
measure: Vss of Plasma Docetaxel
timeFrame: Cycle 1: pre-dose (Hr 0), 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1. Cycle 2: pre-dose (Hr 0), 0.5 hr and 59 min after start of infusion, 0.25, 0.5, 1, 2, 4, 8, 23 hrs post EOI of docetaxel on Day 1 (1 cycle = 21 days)
Other outcomes:
Locations:
city: Charlotte
country: United States
state: North Carolina
city: Houston
country: United States
state: Texas
city: Dijon
country: France
city: Saint Herblain
country: France
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Madrid
country: Spain
city: Dundee
country: United Kingdom
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Martin M, Fumoleau P, Dewar JA, Albanell J, Limentani SA, Campone M, Chang JC, Patre M, Strasak A, de Haas SL, Xu J, Garcia-Saenz JA. Trastuzumab emtansine (T-DM1) plus docetaxel with or without pertuzumab in patients with HER2-positive locally advanced or metastatic breast cancer: results from a phase Ib/IIa study. Ann Oncol. 2016 Jul;27(7):1249-56. doi: 10.1093/annonc/mdw157. Epub 2016 Apr 6.