A Study of Subcutaneously Administered Herceptin (Trastuzumab) in Patients With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Early Breast Cancer

Study Overview
=================
Brief Summary
-----------------
This open-label, randomized crossover study evaluated the quality of life, efficacy, and safety of subcutaneous Herceptin (trastuzumab) injected either into the thigh or the upper arm of participants with early HER2-positive breast cancer.

Detailed Description
-----------------
In the run-in phase, participants received trastuzumab intravenously every 3 weeks for 18 weeks (Cycles 1-6). They first received trastuzumab 8 mg/kg once (Cycle 1) followed by trastuzumab 6 mg/kg 5 times for 15 weeks (Cycles 2-6). Participants could also receive a maximum of 6 cycles of standard chemotherapy for early breast cancer (neo-adjuvant or adjuvant) in the run-in phase. Following the run-in phase, participants were randomized to receive trastuzumab 600 mg subcutaneously every 3 weeks in the thigh and upper arm in a cross-over design for a total of 24 weeks (Cycles 7-14). They received trastuzumab either in the thigh first for 4 cycles (Cycles 7-10) followed by trastuzumab in the upper arm for 4 cycles (Cycles 11-14) or the upper arm first (Cycles 7-10) followed by the thigh (Cycles 11-14). For Cycles 15-18, participants could choose the injection site for trastuzumab 600 mg subcutaneously every 3 weeks.

Official Title
-----------------
LISAH: An Open-label, Randomised Phase II Study Assessing Quality of Life Associated With Subcutaneous Trastuzumab Injected Into the Thigh or Upper Arm in Patients With HER2-positive Early Breast Cancer

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Trastuzumab - intravenous solution
* Drug: Trastuzumab - subcutaneous solution
* Drug: Chemotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Female and male patients ≥ years of age. HER2-positive early breast cancer. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Hormonal therapy will be allowed as per institutional guidelines. Patients must be Herceptin (trastuzumab) naïve. Left ventricular ejection fraction (LVEF) of ≥ 55%. Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast. No evidence of residual, locally recurrent, or metastatic disease after completion of surgery and chemotherapy, or during concurrent chemotherapy (neo-adjuvant or adjuvant). Use of concurrent curative radiotherapy will be permitted. Exclusion Criteria: History of other malignancy which could affect compliance with the protocol or interpretation of results. Patients with curatively treated carcinoma in situ of the cervix or basal cell carcinoma, and patients with other curatively treated malignancies who have been disease-free for at least 5 years, are eligible. Patients with severe dyspnea at rest or requiring supplementary oxygen therapy. Patients with other concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions/illness. Serious cardiac illness or medical conditions that would preclude the use of Herceptin, specifically, a history of documented congestive heart failure (CHF), high-risk uncontrolled arrhythmias, angina pectoris requiring medication, clinically significant valvular disease, evidence of transmural infarction on electrocardiogram (ECG), or diagnosed poorly controlled hypertension. Pregnant or lactating women. Women of childbearing potential and male patients with partners of childbearing potential who are unable or unwilling to use adequate contraceptive measures during study treatment. Concurrent enrollment in another clinical trial using an investigational anti-cancer treatment, including hormonal therapy, bisphosphonate therapy, and immunotherapy, within 28 days prior to the first dose of study treatment. Known hypersensitivity to trastuzumab, murine proteins, to any of the excipients of Herceptin including hyaluronidase, or a history of severe allergic or immunological reactions, eg, difficult to control asthma. Inadequate bone marrow, hepatic, or renal function.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trastuzumab - Thigh first, then upper arm<br>In the run-in phase, participants received trastuzumab intravenously every 3 weeks for 18 weeks (Cycles 1-6). They first received trastuzumab 8 mg/kg once (Cycle 1) followed by trastuzumab 6 mg/kg 5 times for 15 weeks (Cycles 2-6). Participants could also receive a maximum of 6 cycles of standard chemotherapy for early breast cancer (neo-adjuvant or adjuvant) in the run-in phase. Following the run-in phase, participants received trastuzumab 600 mg subcutaneously (SC) every 3 weeks into the thigh for 12 weeks (Cycles 7-10) followed by trastuzumab 600 mg SC every 3 weeks into the upper arm for 12 weeks (Cycles 11-14). In Cycles 15-18, participants received trastuzumab 600 mg SC every 3 weeks into either the thigh or the upper arm (participant's choice) for 12 weeks (Cycles 15-18). | Drug: Trastuzumab - intravenous solution<br>* Trastuzumab was supplied as a powder to be reconstituted as a solution for intravenous infusion.<br>* Other names: Ro 45-2317;Drug: Trastuzumab - subcutaneous solution<br>* Trastuzumab was supplied as a solution for subcutaneous injection.<br>* Other names: Ro 45-2317;Drug: Chemotherapy<br>* Standard chemotherapy for early breast cancer.<br>|
| Experimental: Trastuzumab - Upper arm first, then thigh<br>In the run-in phase, participants received trastuzumab intravenously every 3 weeks for 18 weeks (Cycles 1-6). They first received trastuzumab 8 mg/kg once (Cycle 1) followed by trastuzumab 6 mg/kg 5 times for 15 weeks (Cycles 2-6). Participants could also receive a maximum of 6 cycles of standard chemotherapy for early breast cancer (neo-adjuvant or adjuvant) in the run-in phase. Following the run-in phase, participants received trastuzumab 600 mg subcutaneously (SC) every 3 weeks into the upper arm for 12 weeks (Cycles 7-10) followed by trastuzumab 600 mg SC every 3 weeks into the thigh for 12 weeks (Cycles 11-14). In Cycles 15-18, participants received trastuzumab 600 mg SC every 3 weeks into either the thigh or the upper arm (participant's choice) for 12 weeks (Cycles 15-18). | Drug: Trastuzumab - intravenous solution<br>* Trastuzumab was supplied as a powder to be reconstituted as a solution for intravenous infusion.<br>* Other names: Ro 45-2317;Drug: Trastuzumab - subcutaneous solution<br>* Trastuzumab was supplied as a solution for subcutaneous injection.<br>* Other names: Ro 45-2317;Drug: Chemotherapy<br>* Standard chemotherapy for early breast cancer.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of Life Score | Participants rated their quality of life on a visual analog scale (VAS) at the end of each cycle for Cycles 7-14. The left-end of the VAS represented the lowest-rated quality of life and the right-end of the VAS represented the highest-rated quality of life. Both the mean ratings for injections into the thigh and the upper arm and the minimum ratings for during injections into the thigh and the upper arm are reported. Quality of life scores ranged from 1 to 100 with a higher score indicating a better rated quality of life. | Cycles 7-14 (Weeks 19-42, 24 weeks total) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival was defined as the time in months from Baseline to death from any cause. | Baseline to the end of the study (up to 54 weeks) | 
| Disease-free Survival | Disease-free survival was defined as the time in months from Baseline to disease recurrence or death, whichever occurred first. | Baseline to the end of the study (up to 54 weeks) | 
| Health Care Provider's Satisfaction With the Injection Site | The health care provider for each participant was asked to rate their satisfaction with the 2 injection sites, thigh and upper arm, on a scale of 1 to 10, where 10 represents greater satisfaction. Ratings were made at the end of Cycles 10 and 14. | End of Cycles 10 and 14 (Weeks 30 and 42) | 
| Participant's Satisfaction With the Injection Site | Each participant was asked to rate their satisfaction with the 2 injection sites, thigh and upper arm, on a scale of 1 to 10, where 10 represents greater satisfaction. Ratings were made at the end of Cycles 10 and 14. | End of Cycles 10 and 14 (Weeks 30 and 42) | 
| Percentage of Participants Preferring Each Injection Site | Participants were asked which of the 2 injection sites was their preferred site at the end of Cycle 14. | End of Cycle 14 (Week 42) |