Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Myotonic Dystrophy Type 1

Antineoplastic Agents

All Drugs and Chemicals

Anti-Arrhythmia Agents

Vasodilator Agents

Analgesics

Trastuzumab

Paclitaxel

Albumin-Bound Paclitaxel

Pertuzumab

Ado-Trastuzumab Emtansine

Maytansine

Adenosine

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Immunological

Immunotoxins

Immunoconjugates

Immunologic Factors

Participants received trastuzumab emtansine (T-DM1) every three weeks (Q3W) + paclitaxel weekly (QW) intravenously.

Participants received T-DM1 Q3W + paclitaxel QW + pertuzumab Q3W intravenously.

Participants received T-DM1 QW + paclitaxel QW intravenously.

Participants received T-DM1 QW + paclitaxel QW + pertuzumab Q3W intravenously.

Participants received maximum tolerated dose (MTD) from Phase 1b i.e. T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m\^2 QW intravenously.

Participants received MTD from Phase 1b i.e. T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m\^2 QW + pertuzumab Q3W intravenously.

paclitaxel

pertuzumab [Perjeta]

trastuzumab emtansine [Kadcyla]

Clinical Trials

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.

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

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

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.

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.

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.

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.

Participants in Phase IIa received T-DM1 Q3W and paclitaxel in Group A and T-DM1, paclitaxel, and pertuzumab in Group B.

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.

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.

Cmax of plasma DM1 in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered Q3W.

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.

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.

Cmax for plasma DM1 in Cycle 1 was estimated by non-compartmental analysis for Phase Ib when T-DM1 was administered QW

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

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.

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).

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 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).

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).

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.

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 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.

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.

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.

Genentech, Inc.

SAEs and other AEs were collected in the safety population, which was defined as all participants who received at least a single dose of study medication. There was one SAE that lead to death and the preferred term was not captured for it. The same SAE was captured as 'Death - unknown cause' in the below SAE table.

Participants received T-DM1 Q3W + paclitaxel QW intravenously.

Phase Ib Regimen 1

Phase Ib Regimen 2

Phase Ib Regimen 3

Phase Ib Regimen 4

Participants received MTD from Phase 1b i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m\^2 QW intravenously.

Phase IIa Group A

Participants received MTD from Phase 1b , i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m\^2 QW, plus pertuzumab Q3W intravenously.

Phase IIa Group B

Participants received MTD from Phase 1b i.e. T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m\^2 QW intravenously.

Participants received T-DM1 3.6mg/kg Q3W + paclitaxel 80mg/m\^2 QW + pertuzumab Q3W intravenously.

Total

Age, Continuous

Sex: Female, Male

Given the small sample size in the different patient subsets, no formal hypothesis testing was performed, and all statistical analyses should be considered descriptive and hypothesis-generating only.

Roche Trial Information Hotline

Any AEs

Any SAEs

Death

Any AEs Grade 3

Any AEs Grade 4

AEs leading to T-DM1 discontinuation

AEs leading to paclitaxel discontinuation

AEs leading to pertuzumab discontinuation

Safety Population: All participants who received at least a single dose of study medication were included.

Number of Participants With Any Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Grades 3/4, and Death

Safety Population: All participants of the dose finding part of the study (phase 1b) who received at least a single dose of study medication were included. Participants in Phase 1b (Regimen 1, Regimen 2, Regimen 3 and Regimen 4 \[60 participants\]) were considered for this analysis.

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

Safety Population: All participants of the dose finding part of the study (phase 1b) who received at least a single dose of study medication were included.

Maximum Tolerated Dose of T-DM1 When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab

Maximum Tolerated Dose of Paclitaxel When T-DM1 (Q3W or QW) and Paclitaxel (QW) Was Administered With and Without Pertuzumab

Participants received MTD from Phase Ib i.e. T-DM1 3.6mg/kg Q3W and paclitaxel 80mg/m\^2 QW intravenously.

Participants received T-DM1 3.6mg/kg Q3W, paclitaxel 80mg/m\^2 QW, and pertuzumab 420 mg Q3W intravenously.

Safety Population: All participants of the phase IIa part of the study who received at least a single dose of study medication and did not have disease progression in the first 12 weeks of study treatment were included.

Number of Participants in Phase IIa of the Study Who Received 12 or More Paclitaxel Doses in Combination With T-DM1 and/or Pertuzumab

T-DM1

Participants received of T-DM1 3.6mg/kg Q3W, paclitaxel 80mg/m\^2 QW, and pertuzumab Q3W intravenously.

Number of Participants Who Had Adverse Events That Required Dose Modification of T-DM1 or Paclitaxel

Total trastuzumab

Participants received 2 mg/kg T-DM1 Q3W and 65 mg/m\^2 paclitaxel QW intravenously.

Phase Ib Cohort A

Participants received 2 mg/kg T-DM1 Q3W and 80 mg/m\^2 paclitaxel QW intravenously.

Phase Ib Cohort B

Participants received 2.4 mg/kg T-DM1 Q3W and 65 mg/m\^2 paclitaxel QW intravenously.

Phase Ib Cohort 1

Participants received 2.4 mg/kg T-DM1 Q3W and 80 mg/m\^2 paclitaxel QW intravenously.

Phase Ib Cohort J

Participants received 3.0 mg/kg T-DM1 Q3W and 80 mg/m\^2 paclitaxel QW intravenously.

Phase Ib Cohort D

Participants received 3.6 mg/kg T-DM1 Q3W and 80 mg/m\^2 paclitaxel QW intravenously.

Phase Ib Cohort 3B

Pharmacokinetics (PK) population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. Only participants with data available for this parameter were analyzed.

Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After Q3W Dose Regimen

PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. Only participants with data available for this parameter were analyzed.

Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After Q3W Dose Regimen

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

Participants received 1.2 mg/kg T-DM1 QW and 65 mg/m\^2 paclitaxel QW intravenously.

Phase Ib Cohort 6

Participants received 1.6 mg/kg T-DM1 QW and 65 mg/m\^2 paclitaxel QW intravenously.

Phase Ib Cohort 7

Participants received 2.0 mg/kg T-DM1 QW and 65 mg/m\^2 paclitaxel QW intravenously.

Phase Ib Cohort 8

Participants received 2.4 mg/kg T-DM1 QW and 65 mg/m\^2 paclitaxel QW intravenously.

Phase Ib Cohort F

Participants received 2.4 mg/kg T-DM1 QW and 80 mg/m\^2 paclitaxel QW intravenously.

Phase Ib Cohort 4

Maximum Serum Concentration (Cmax) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen

Maximum Plasma Concentration (Cmax) of DM1 in Cycle 1 After QW Dose Regimen

Area Under the Serum Concentration-time Curve of Total Exposure (AUClast) of T-DM1 and Total Trastuzumab in Cycle 1 After QW Dose Regimen

65 mg, Cycle 1 (n = 29)

65 mg, Cycle 2 (n = 24)

80 mg, Cycle 1 (n = 18)

80 mg, Cycle 2 (n = 17)

For paclitaxel, plasma concentration-time data were available from 47 patients receiving administration of paclitaxel at QW doses of 65 and 80 mg/m\^2.

Phase Ib

PK population included all participants from Phase Ib who received at least one dose of T-DM1 or paclitaxel with at least one post-dose concentration data point. "n" denotes number of participants who received the indicated study drug.

Maximum Plasma Concentration of Paclitaxel in Cycle 1 (in the Absence T-DM1) and Cycle 2 (in the Presence T-DM1)

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)

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)

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)

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)

LVEF, increase

LVEF, 0 to <15%

LVEF, >=15 to <25%

LVEF, missing

New segmental wall abnormality

Number of Participants With Change From Baseline in Cardiac Function

An efficacy population: All participants who received at least a single dose of study medication were included. Participants with measurable disease were considered for OR.

Percentage of Participants With Objective Response Rate (ORR)

An efficacy population: All participants who received at least a single dose of study medication were included. Participants with OR were considered for this outcome measure.

Duration of Objective Response

An efficacy population: All participants who received at least a single dose of study medication were included.

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

Trial Identification

Conditions

Interventions

Study Description

Keywords

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