A Study Of PF-05280014 Or Trastuzumab Plus Taxotere® And Carboplatin In HER2 Positive Breast Cancer In The Neoadjuvant Setting (REFLECTIONS B327-04)

Study Overview
=================
Brief Summary
-----------------
The current study will compare PK, efficacy, safety, and immunogenicity of PF-05280014 (Trastuzumab-Pfizer) in combination with Taxotere® and Carboplatin (Paraplatin) versus Herceptin® (Trastuzumab-EU) approved in the EU in combination with Taxotere® and Carboplatin (Paraplatin) in patients with operable HER2 positive, breast cancer in the neoadjuvant setting. The hypothesis to be tested in this study is the percentage of patients with steady state Cycle 5 Ctrough (Cycle 6 pre-dose) >20 µg/mL of trastuzumab-Pfizer is similar to EU-approved trastuzumab, using a margin of -12.5%.

Official Title
-----------------
A RANDOMIZED, DOUBLE-BLIND PHARMACOKINETIC STUDY OF PF-05280014 PLUS TAXOTERE (REGISTERED) AND CARBOPLATIN VERSUS HERCEPTIN (REGISTERED) PLUS TAXOTERE (REGISTERED) AND CARBOPLATIN FOR THE NEOADJUVANT TREATMENT OF PATIENTS WITH OPERABLE HER2-POSITIVE BREAST CANCER

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

Intervention / Treatment
-----------------
* Biological: PF-05280014
* Drug: Taxotere®
* Drug: Paraplatin®
* Biological: Trastuzumab-EU
* Drug: Taxotere®
* Drug: Paraplatin®


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed HER2 overexpressing invasive breast cancer. Plan for definitive surgical resection of breast tumor (i.e., lumpectomy or mastectomy, and sentinel node (SN) biopsy or axillary lymph node dissection (ALND). Plan for neoadjuvant chemotherapy. Measurable disease in the breast after diagnostic biopsy, defined as longest diameter ≥ 2.0 cm. Exclusion Criteria: Bilateral breast cancer. Inflammatory breast cancer. Presence of known distant metastases. Received prior treatment, including chemotherapy, endocrine therapy, biologic therapy, radiation or surgery with the exception of diagnostic biopsy for primary breast cancer.

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

Sexes Eligible for Study
-----------------
Female

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-05280014<br> | Biological: PF-05280014<br>* Concentrate for solution for infusion, sterile vial 150 mg, Day 1 Cycle 1 will be a loading dose of 8 mg/kg infused over 90 minutes. Subsequent infusions will follow every 3 weeks (i.e., cycled every 21 days) with a dose of 6 mg/kg administered over 30 to 90 minutes depending on tolerability, maximum of 6 cycles.<br>Drug: Taxotere®<br>* Injection concentrate single-dose vials containing 20 mg (0.5 mL) or 80 mg (2 mL), each mL contains 40 mg docetaxel (anhydrous) and 1040 mg polysorbate 80, The starting dose of Taxotere® (docetaxel) will be 75 mg/m2 administered intravenously over 60 minutes every three weeks on Day 1 of each cycle (i.e., every 21 days), maximum 6 cycles.<br>* Other names: docetaxel;Drug: Paraplatin®<br>* Lyophilized powder, single-dose vials containing 50 mg, 150 mg, and 450 mg of Carboplatin for administration by intravenous infusion (each vial contains equal parts by weight of Carboplatin and mannitol), starting dose 6 AUC, over 15 minutes or longer every three weeks on Day 1 of each cycle (i.e., every 21 days), maximum 6 cycles.<br>* Other names: carboplatin;|
| Active Comparator: Herceptin®<br> | Biological: Trastuzumab-EU<br>* Concentrate for solution for infusion, sterile vial 150 mg, Day 1 Cycle 1 will be a loading dose of 8 mg/kg infused over 90 minutes. Subsequent infusions will follow every 3 weeks (i.e., cycled every 21 days) with a dose of 6 mg/kg administered over 30 to 90 minutes depending on tolerability, maximum 6 cycles.<br>Drug: Taxotere®<br>* Injection concentrate single-dose vials containing 20 mg (0.5 mL) or 80 mg (2 mL), each mL contains 40 mg docetaxel (anhydrous) and 1040 mg polysorbate 80, The starting dose of Taxotere® (docetaxel) will be 75 mg/m2 administered intravenously over 60 minutes every three weeks on Day 1 of each cycle (i.e., every 21 days), maximum 6 cycles.<br>* Other names: docetaxel;Drug: Paraplatin®<br>* Lyophilized powder, single-dose vials containing 50 mg, 150 mg, and 450 mg of Carboplatin for administration by intravenous infusion (each vial contains equal parts by weight of Carboplatin and mannitol), starting dose 6 AUC, over 15 minutes or longer every three weeks on Day 1 of each cycle (i.e., every 21 days), maximum 6 cycles.<br>* Other names: carboplatin;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Steady State Drug Concentration Ctrough (Cycle 6 Pre-dose) >20 µg/mL at Cycle 5. | The percentage of participants with Cycle 5 Ctrough (Cycle 6 pre-dose) >20 μg/mL in each treatment group, the denominator being the number of participants in the per protocol population for each treatment group. | Cycle 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6. | Samples of blood were taken pre-dose on Cycles 1, 2, 4, 5, and 6, and at 1 hour post dose on Cycles 1 and 5 for pharmacokinetic evaluation. | Cycles 1 through 6 | 
| Pathologic Complete Response (pCR) Defined as the Absence of Invasive Neoplastic Cells in the Breast and Lymph Nodes. | Following surgery after treatment completion, tumors were assessed as Complete Pathological Response, Partial Pathological Response, or No Pathological Response. | Cycle 6/End of treatment | 
| Objective Response Rate (ORR) Defined as the Percentage of Participants Having Complete or Partial Response at End of Treatment, Based on Radiographic Assessments of the Tumor. | ORR was defined as Complete Response (CR), Partial Response (PR), Stable (SD), Progressive Disease (PD) or Indeterminate (IND). ORR was the percentage of participants who had CR or PR at Cycle 6/End of treatment. | Cycle 6/End of treatment | 
| Incidence of Anti-trastuzumab Antibodies (ADAs) at Cycles 1 Through 6. | The number of participants with positive (titer >=1.00) pre-dose ADA samples, participants counted towards the total if for at least one sample, the ADA was positive. | Cycles 1 through 6 | 
| Incidence of Neutralizing Antibodies (NAb) at Cycles 1 Through 6. | The number of participants with positive (NAb response >=1.48) pre-dose NAb samples, participants counted towards the total if for at least one sample, the NAb was positive. | Cycles 1 through 6 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Biosimilars, Non-inferiority, Neoadjuvant Setting, Early Breast Cancer, PK, Phase 3, Trastuzumab, Herceptin, HER2 Positive