Clinical trial NCT00800436: A Dose-Finding Study of Subcutaneous Herceptin (Trastuzumab) in Healthy Male Volunteers and Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Females
Official title: An Open-Label, Two-Part, Multi-Centre, Trastuzumab Dose-Finding Study in Healthy Male Volunteers and HER2 Positive Female Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Breast Cancer
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2008-12-02
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This two-part study is designed to select the subcutaneous (SC) dose of Herceptin that results in comparable exposure to intravenous (IV) Herceptin in healthy male participants and in HER2-positive female participants. The study will also assess the safety and tolerability of the SC and IV formulations. In Part 1 of the study, four cohorts will be treated with a single dose of Herceptin as follows: Cohort 1 (6 milligrams per kilogram \[mg/kg\] IV in healthy male participants); Cohort 2 (6 mg/kg IV in HER2-positive female participants); Cohort 3 (6 mg/kg SC in healthy male participants); Cohort 4 (10 mg/kg SC in healthy male participants). An additional cohort of healthy volunteers (Cohort 5) will be opened if both SC dose levels from Cohorts 3 and 4 result in Herceptin exposures different from the target concentration produced by a single IV dose, or if the variability in pharmacokinetic (PK) parameter values cannot be used to define the target SC dose level. In Part 2 of the study, HER2-positive female participants will receive a single dose of SC Herceptin at the dose level defined in Part 1. Participants from Part 1 are eligible to enter Part 2 provided they receive the second (Part 2) study dose of Herceptin a minimum of 22 days after their first (Part 1) dose.


Eligibility criteria: Inclusion Criteria:

* Healthy Participants (Part 1 only)

  * Males 18 to 45 to years of age
  * Baseline left ventricular ejection fraction (LVEF) greater than (\>) 60 percent (%)
* HER2-Positive Females (Parts 1 and 2)

  * Females greater than or equal to (≥) 18 years of age
  * Eastern Cooperative Oncology Group (ECOG) performance status of 0
  * Previous non-metastatic operable primary invasive HER2-positive breast cancer
  * Baseline LVEF \>55%

Exclusion Criteria:

* Healthy Participants (Part 1 only)

  * Clinically significant abnormalities in laboratory test results or electrocardiogram
  * History of significant allergies, gastrointestinal, renal, hepatic, cardiovascular, or pulmonary disease
  * History of hypersensitivity or allergic reaction, spontaneous or following drug administration
  * History of cardiac conditions
* HER2-Positive Females (Parts 1 and 2)

  * Metastatic disease
  * Concurrent other malignancy requiring therapy of any modality which may interfere with PK investigations or result in unexpected toxicity
  * Use of Herceptin in previous 5 months
  * Serious cardiac illness

Primary outcomes:
measure: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUCinf) of Trastuzumab
timeFrame: Predose (0 hours) and postdose from start of 1.5-hour infusion (1.5 and 3 hours for IV) (6, 8, 12 hours for SC) on Day 1; on Days 2, 3, 5, 8, 15, 22, 43, 85; additionally on Day 10 for SC and Day 35 for IV; and 5 months postdose (up to 5 months overall)
Secondary outcomes:
measure: Trough Serum Concentration on Day 22 (CDay22) of Trastuzumab
timeFrame: Day 22
measure: Maximum Observed Serum Concentration of Trastuzumab (Cmax)
timeFrame: Postdose from start of 1.5-hour infusion (1.5 and 3 hours for IV) (6, 8, 12 hours for SC) on Day 1; on Days 2, 3, 5, 8, 15, 22, 43, 85; additionally on Day 10 for SC and Day 35 for IV; and 5 months postdose (up to 5 months overall)
measure: Time to Maximum Serum Concentration (Tmax) of Trastuzumab
timeFrame: Postdose from start of 1.5-hour infusion (1.5 and 3 hours for IV) (6, 8, 12 hours for SC) on Day 1; on Days 2, 3, 5, 8, 15, 22, 43, 85; additionally on Day 10 for SC and Day 35 for IV; and 5 months postdose (up to 5 months overall)
measure: Terminal Elimination Half-Life (T1/2) of Trastuzumab
timeFrame: Postdose from start of 1.5-hour infusion (1.5 and 3 hours for IV) (6, 8, 12 hours for SC) on Day 1; on Days 2, 3, 5, 8, 15, 22, 43, 85; additionally on Day 10 for SC and Day 35 for IV; and 5 months postdose (up to 5 months overall)
Other outcomes:
Locations:
city: East Bentleigh
country: Australia
city: Christchurch
country: New Zealand
city: Grafton
country: New Zealand
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Wynne C, Harvey V, Schwabe C, Waaka D, McIntyre C, Bittner B. Comparison of subcutaneous and intravenous administration of trastuzumab: a phase I/Ib trial in healthy male volunteers and patients with HER2-positive breast cancer. J Clin Pharmacol. 2013 Feb;53(2):192-201. doi: 10.1177/0091270012436560.