Early Breast Cancer
Conditions
Keywords
Biosimilars, Non-inferiority, Neoadjuvant Setting, Early Breast Cancer, PK, Phase 3, Trastuzumab, Herceptin, HER2 Positive
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%.
Interventions
BIOLOGICALPF-05280014
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.
DRUGTaxotere®
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.
DRUGParaplatin®
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.
BIOLOGICALTrastuzumab-EU
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.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Steady State Drug Concentration Ctrough (Cycle 6 Pre-dose) >20 µg/mL at Cycle 5. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6. | 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. |
| Pathologic Complete Response (pCR) Defined as the Absence of Invasive Neoplastic Cells in the Breast and Lymph Nodes. | Cycle 6/End of treatment | Following surgery after treatment completion, tumors were assessed as Complete Pathological Response, Partial Pathological Response, or No Pathological Response. |
| 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. | Cycle 6/End of treatment | 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. |
| Incidence of Anti-trastuzumab Antibodies (ADAs) at Cycles 1 Through 6. | 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. |
| Incidence of Neutralizing Antibodies (NAb) at Cycles 1 Through 6. | 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. |
Countries
Belarus, Czechia, Hungary, Italy, Poland, Russia, Serbia, Slovakia, Ukraine, United States
Participant flow
Pre-assignment details
A single participant was randomized but not treated; this participant was included in the ITT population, but not in the Participant Flow, Per Protocol, or Safety populations.
Participants by arm
| Arm | Count |
|---|---|
| PF-05280014 Participants received a loading dose of 8 mg/kg of PF-05280014 on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle. | 114 |
| Trastuzumab-EU Participants received a loading dose of 8 mg/kg of trastuzumab-EU on Cycle 1 Day 1. Subsequent infusions followed every 3 weeks with a dose of 6 mg/kg. Taxotere 75 mg/m2 and carboplatin AUC 6 were administered on Day 1 of each cycle. | 112 |
| Total | 226 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Study | Death | 1 | 0 |
| Study | Lost to Follow-up | 0 | 2 |
| Study | Other | 2 | 1 |
| Study | Participant refused further follow-up | 1 | 0 |
| Study | Related adverse event, not serious | 0 | 2 |
| Study | Related adverse event, serious non-fatal | 0 | 1 |
| Treatment | Death | 1 | 0 |
| Treatment | Lost to Follow-up | 0 | 1 |
| Treatment | Other | 2 | 0 |
| Treatment | Participant refused continued treatment | 1 | 1 |
| Treatment | Related adverse event, not serious | 0 | 2 |
| Treatment | Related adverse event, serious non-fatal | 0 | 1 |
Baseline characteristics
| Characteristic | PF-05280014 | Trastuzumab-EU | Total |
|---|---|---|---|
| Age, Continuous | 54.0 Years STANDARD_DEVIATION 11.9 | 51.2 Years STANDARD_DEVIATION 12.7 | 52.6 Years STANDARD_DEVIATION 12.3 |
| Sex/Gender, Customized Female | 114 Participants | 112 Participants | 226 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 106 / 113 | 106 / 112 |
| serious Total, serious adverse events | 7 / 113 | 6 / 112 |
Outcome results
Primary
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.
Time frame: Cycle 5
Population: All participants who were HER2+ and randomized into the study; and who had received 6 cycles of PF-05280014 or trastuzumab-EU treatment; and had no temporary delays of PF-05280014 or trastuzumab-EU treatment lasting more than 1 week; and had no other significant protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-05280014 | Percentage of Participants With Steady State Drug Concentration Ctrough (Cycle 6 Pre-dose) >20 µg/mL at Cycle 5. | 92.1 Percentage of participants |
| Trastuzumab-EU | Percentage of Participants With Steady State Drug Concentration Ctrough (Cycle 6 Pre-dose) >20 µg/mL at Cycle 5. | 93.3 Percentage of participants |
95% CI: [-8.02, 6.49]
95% CI: [-8.59, 6.23]
Secondary
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.
Time frame: Cycles 1 through 6
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-05280014 | Incidence of Anti-trastuzumab Antibodies (ADAs) at Cycles 1 Through 6. | Cycle 1 (n=113,112) | 0 Number of participants |
| PF-05280014 | Incidence of Anti-trastuzumab Antibodies (ADAs) at Cycles 1 Through 6. | Cycle 2 (n=111,112) | 0 Number of participants |
| PF-05280014 | Incidence of Anti-trastuzumab Antibodies (ADAs) at Cycles 1 Through 6. | Cycle 4 (n=108,109) | 0 Number of participants |
| PF-05280014 | Incidence of Anti-trastuzumab Antibodies (ADAs) at Cycles 1 Through 6. | Cycle 6 (n=108,108) | 0 Number of participants |
| Trastuzumab-EU | Incidence of Anti-trastuzumab Antibodies (ADAs) at Cycles 1 Through 6. | Cycle 6 (n=108,108) | 0 Number of participants |
| Trastuzumab-EU | Incidence of Anti-trastuzumab Antibodies (ADAs) at Cycles 1 Through 6. | Cycle 1 (n=113,112) | 1 Number of participants |
| Trastuzumab-EU | Incidence of Anti-trastuzumab Antibodies (ADAs) at Cycles 1 Through 6. | Cycle 4 (n=108,109) | 0 Number of participants |
| Trastuzumab-EU | Incidence of Anti-trastuzumab Antibodies (ADAs) at Cycles 1 Through 6. | Cycle 2 (n=111,112) | 0 Number of participants |
Secondary
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.
Time frame: Cycles 1 through 6
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-05280014 | Incidence of Neutralizing Antibodies (NAb) at Cycles 1 Through 6. | Cycle 1 (n=113,112) | 0 Number of participants |
| PF-05280014 | Incidence of Neutralizing Antibodies (NAb) at Cycles 1 Through 6. | Cycle 2 (n=110,112) | 0 Number of participants |
| PF-05280014 | Incidence of Neutralizing Antibodies (NAb) at Cycles 1 Through 6. | Cycle 4 (n=108,110) | 0 Number of participants |
| PF-05280014 | Incidence of Neutralizing Antibodies (NAb) at Cycles 1 Through 6. | Cycle 6 (n=108,108) | 0 Number of participants |
| Trastuzumab-EU | Incidence of Neutralizing Antibodies (NAb) at Cycles 1 Through 6. | Cycle 6 (n=108,108) | 0 Number of participants |
| Trastuzumab-EU | Incidence of Neutralizing Antibodies (NAb) at Cycles 1 Through 6. | Cycle 1 (n=113,112) | 0 Number of participants |
| Trastuzumab-EU | Incidence of Neutralizing Antibodies (NAb) at Cycles 1 Through 6. | Cycle 4 (n=108,110) | 0 Number of participants |
| Trastuzumab-EU | Incidence of Neutralizing Antibodies (NAb) at Cycles 1 Through 6. | Cycle 2 (n=110,112) | 0 Number of participants |
Secondary
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.
Time frame: Cycles 1 through 6
Population: All participants who were HER2+ and randomized into the study; and who have received 6 cycles of PF-05280014 or trastuzumab-EU treatment; and had no temporary delays of PF-05280014 or trastuzumab-EU treatment lasting more than 1 week; and had no other significant protocol deviations.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-05280014 | Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6. | Cycle 2/Day 21 0 hours N= 99, 88 | 24.29 μg/mL | Standard Deviation 13.796 |
| PF-05280014 | Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6. | Cycle 5/Day 84 0 hours N= 101, 87 | 35.01 μg/mL | Standard Deviation 15.571 |
| PF-05280014 | Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6. | Cycle 1/Day 1 1 hour N= 97, 80 | 160.4 μg/mL | Standard Deviation 57.329 |
| PF-05280014 | Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6. | Cycle 5/Day 84 1 hour N= 90, 80 | 137.0 μg/mL | Standard Deviation 37.748 |
| PF-05280014 | Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6. | Cycle 4/Day 63 0 hours N= 98, 89 | 33.43 μg/mL | Standard Deviation 14.488 |
| PF-05280014 | Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6. | Cycle 6/Day 105 0 hours N= 101, 89 | 37.77 μg/mL | Standard Deviation 17.523 |
| PF-05280014 | Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6. | Cycle 1/Day 1 0 hours N= 101, 88 | 2.313 μg/mL | Standard Deviation 17.949 |
| Trastuzumab-EU | Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6. | Cycle 6/Day 105 0 hours N= 101, 89 | 40.10 μg/mL | Standard Deviation 16.67 |
| Trastuzumab-EU | Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6. | Cycle 1/Day 1 0 hours N= 101, 88 | 1.318 μg/mL | Standard Deviation 12.366 |
| Trastuzumab-EU | Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6. | Cycle 1/Day 1 1 hour N= 97, 80 | 164.8 μg/mL | Standard Deviation 47.033 |
| Trastuzumab-EU | Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6. | Cycle 2/Day 21 0 hours N= 99, 88 | 27.20 μg/mL | Standard Deviation 10.65 |
| Trastuzumab-EU | Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6. | Cycle 4/Day 63 0 hours N= 98, 89 | 37.33 μg/mL | Standard Deviation 15.629 |
| Trastuzumab-EU | Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6. | Cycle 5/Day 84 0 hours N= 101, 87 | 40.44 μg/mL | Standard Deviation 26.765 |
| Trastuzumab-EU | Mean Predose Trastuzumab-Pfizer and Trastuzumab-EU Concentrations at Cycles 1 Through 6. | Cycle 5/Day 84 1 hour N= 90, 80 | 138.8 μg/mL | Standard Deviation 37.417 |
Secondary
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.
Time frame: Cycle 6/End of treatment
Population: All participants who were HER2+ and randomized into the study; and who have received 6 cycles of PF-05280014 or trastuzumab-EU treatment; and had no temporary delays of PF-05280014 or trastuzumab-EU treatment lasting more than 1 week; and had no other significant protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-05280014 | 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. | 88.1 Percentage of participants |
| Trastuzumab-EU | 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. | 82.0 Percentage of participants |
95% CI: [-4.01, 15.94]
95% CI: [-4.08, 16.27]
Secondary
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.
Time frame: Cycle 6/End of treatment
Population: All participants who were HER2+ and randomized into the study; and who have received 6 cycles of PF-05280014 or trastuzumab-EU treatment; and had no temporary delays of PF-05280014 or trastuzumab-EU treatment lasting more than 1 week; and had no other significant protocol deviations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-05280014 | Pathologic Complete Response (pCR) Defined as the Absence of Invasive Neoplastic Cells in the Breast and Lymph Nodes. | 47.0 Percentage of participants |
| Trastuzumab-EU | Pathologic Complete Response (pCR) Defined as the Absence of Invasive Neoplastic Cells in the Breast and Lymph Nodes. | 50.0 Percentage of participants |
95% CI: [-16.58, 10.96]
95% CI: [-17.4, 11.4]