SPI-2012 vs Pegfilgrastim in Management of Neutropenia in Breast Cancer Participants With Docetaxel and Cyclophosphamide

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy of SPI-2012 versus pegfilgrastim in participants with early-stage breast cancer receiving docetaxel and cyclophosphamide (TC) as measured by the duration of severe neutropenia (DSN).

Detailed Description
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This is a Phase 3, randomized, open-label, active-controlled, multicenter study to compare the efficacy and safety of SPI-2012 versus pegfilgrastim in participants with early-stage breast cancer treated with TC chemotherapy as measured by the duration of severe neutropenia (DSN). Each cycle was 21 days. Four cycles were evaluated for this study. On Day 1 of each cycle, participants received TC chemotherapy. On Day 2 of each cycle, participants received study drug (SPI-2012 or pegfilgrastim). After cycle 1, as applicable, participants who received at least one dose of study drug will be followed for safety for 12 months after the last dose of study treatment.

Official Title
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Randomized, OpEn-Label, Active-ContrOl Trial of SPI-2012 (Eflapegrastim) Versus Pegfilgrastim in the Management of Chemotherapy-Induced Neutropenia in Early-Stage BReast Cancer Patients Receiving Docetaxel and Cyclophosphamide (TC) (RECOVER)

Conditions
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Neutropenia, Breast Cancer

Intervention / Treatment
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* Drug: SPI-2012
* Drug: Pegfilgrastim
* Drug: Docetaxel
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: New diagnosis of histologically confirmed early-stage breast cancer (ESBC), defined as operable Stage I to Stage IIIA breast cancer Candidate for adjuvant or neo-adjuvant TC chemotherapy Eastern Cooperative Oncology Group (ECOG) performance status <= 2 Absolute neutrophil count (ANC) >=1.5×10^9/L Platelet count >=100×10^9/L Hemoglobin >9 g/dL Calculated creatinine clearance > 50 mL/min Total bilirubin <=1.5 mg/dL Aspartate aminotransferase (AST) / Serum glutamic oxaloacetic transaminase (SGOT) and Alanine aminotransferase (ALT)/Serum glutamic pyruvic transaminase (SGPT) <=2.5×ULN (upper limit of normal) Alkaline phosphatase <=2.0×ULN Key Exclusion Criteria: Active concurrent malignancy (except non melanoma skin cancer or carcinoma in situ of the cervix) or life-threatening disease Locally recurrent/metastatic breast cancer Known sensitivity to E. coli-derived products Concurrent adjuvant cancer therapy Previous exposure to filgrastim, pegfilgrastim, or other G-CSF products in clinical development within 12 months prior to the administration of study drug Active infection, receiving anti-infectives, or any underlying medical condition that would impair ability to receive protocol treatment Prior bone marrow or stem cell transplant Used any investigational drugs, biologics, or devices within 30 days prior to study treatment or plans to use any of these during the course of the study• Radiation therapy within 30 days prior to enrollment Major surgery within 30 days prior to enrollment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: (Arm 1): SPI-2012 and TC<br>At each cycle for 4 cycles, participants received SPI-2012 at a fixed dose of 13.2 milligrams (mg)/0.6 milliliter (mL), [3.6 mg granulocyte colony-stimulating factor {G-CSF}] subcutaneously (SC) approximately 24-26 hours after receiving intravenous (IV) infusion of docetaxel 75 mg/m^2 and cyclophosphamide 600 mg/m^2 IV infusion per institute's standard of care. All participants were followed for 35 (±5) days after last study treatment or patient discontinuation and long-term safety follow-up continued for 12 months after last dose of study treatment. | Drug: SPI-2012<br>* Supplied in prefilled single-use syringes for subcutaneous injection, administered on Day 2 of each cycle<br>* Other names: Eflapegrastim;Drug: Docetaxel<br>* 75mg/m^2 IV infusion administered on Day 1 of each cycle<br>* Other names: Taxotere;Drug: Cyclophosphamide<br>* 600mg/m^2 IV infusion administered on Day 1 of each cycle<br>* Other names: Cytoxan;|
| Experimental: (Arm 2): Pegfilgrastim and TC<br>At each cycle for 4 cycles, participants received pegfilgrastim 6 mg (6 mg/0.6 mL GCSF) SC approximately 24-26 hours after receiving IV infusion of docetaxel 75 mg/m^2 and cyclophosphamide 600 mg/m^2 IV infusion per institute's standard of care. All participants were followed for 35 (±5) days after last study treatment or patient discontinuation and long-term safety follow-up continued for 12 months after last dose of study treatment. | Drug: Pegfilgrastim<br>* Subcutaneous injection administered on Day 2 of each cycle.<br>* Other names: Neulasta®;Drug: Docetaxel<br>* 75mg/m^2 IV infusion administered on Day 1 of each cycle<br>* Other names: Taxotere;Drug: Cyclophosphamide<br>* 600mg/m^2 IV infusion administered on Day 1 of each cycle<br>* Other names: Cytoxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Severe Neutropenia (DSN) in Cycle 1 | DSN was defined as the number of days of severe neutropenia (absolute neutrophil count [ANC] <0.5×10^9 per liter [L]) from the first occurrence of ANC below the threshold. | Day 1 and daily on Days 4-15 in Cycle 1 (each cycle = 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Absolute Neutrophil Count (ANC) Recovery in Cycle 1 | Time to ANC recovery was defined as the time from chemotherapy administration until the participants ANC increased to >=1.5×10^9/L after the expected nadir. For participants with ANC value >=1.5×10^9/L at all times, time to ANC Recovery was assigned a value of 0. | Day 1 and daily on Days 4-15 in Cycle 1 (each cycle = 21 days) | 
| Depth of ANC Nadir in Cycle 1 | The depth of ANC Nadir was defined as the lowest ANC value after administration of study drug (SPI-2012 or pegfilgrastim) in Cycle 1. | Day 1 and daily on Days 4-15 in Cycle 1 (each cycle = 21 days) | 
| Number of Participants With Febrile Neutropenia (FN) in Cycle 1 | FN was defined as an oral temperature >38.3 degree Celsius (°C) (101.0 degrees Fahrenheit [°F]) or two consecutive readings of >38.0°C (100.4°F) for 2 hours and ANC <1.0×10^9/L. | Day 1 and daily on Days 4-15 in Cycle 1 (each cycle = 21 days) | 
| Duration of Severe Neutropenia (DSN) in Cycles 2, 3 and 4 | DSN was defined as the number of days of severe neutropenia (ANC <0.5×10^9/L) from the first occurrence of ANC below the threshold. | Days 1, 4, 7, 10, and 15 of Cycles 2, 3, and 4 (each cycle = 21 days) | 
| Number of Participants With Neutropenic Complications in Cycle 1 | Neutropenic complications refer to hospitalizations due to neutropenic events and/or the use of anti-infectives due to neutropenia. | Day 1 and daily on Days 4-15 in Cycle 1 (each cycle = 21 days) | 
| Number of Participants With Febrile Neutropenia in Cycles 2, 3 and 4 | FN was defined as an oral temperature >38.3°C (101.0°F) or two consecutive readings of >38.0°C (100.4°F) for 2 hours and ANC <1.0×10^9/L. | Days 1, 4, 7, 10, and 15 of Cycles 2, 3, and 4 (each cycle = 21 days) | 
| Relative Dose Intensity (RDI) of TC Chemotherapy | RDI was defined as the percentage of the planned dose of TC chemotherapy that each participant actually received during the study, and is expressed as the total dose received, divided by total dose planned multiplied by 100. The planned dose was defined as the dose that would be given if no doses were missed and/or no dose reductions were made for the number of cycles started. The total planned dose was the sum of planned doses over all cycles. | Cycles 1, 2, 3 and 4 (each cycle = 21 days) | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs), and Death | An adverse event (AE) is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product or study procedure, whether or not considered related to the medicinal product. A TEAE is any AE that occurred from the first dose of study treatment through 12 months after the last dose of study treatment or 35 (±5) days after date of participant early discontinuation. SAE is defined as any AE which meets any of the following criteria: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in a persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, includes important medical events. | Up to 4 cycles (each cycle = 21 days) plus a 12-month follow-up from the last dose (up to 15 months) | 
| Number of Participants With Clinically Significant Laboratory Abnormalities | The number of participants with clinically significant hematology (including basophils, basophils/leukocytes, eosinophils, eosinophils/leukocytes, hematocrit, hemoglobin, lymphocytes, lymphocytes/leukocytes, monocytes, monocytes/leukocytes, neutrophils, neutrophils/leukocytes, platelets, and white blood cells) and serum chemistry (including alanine aminotransferase [ALT], alkaline phosphatase [ALP], aspartate aminotransferase [AST], bilirubin, calcium, cholesterol, creatinine, potassium, sodium, and triglycerides) laboratory abnormalities were reported. Clinically significant findings in laboratory parameters were based on investigator's discretion according to Common Technical Criteria for Adverse Events (CTCAE) Version 4.03. | Up to 4 cycles (each cycle = 21 days) plus a 12-month follow-up from the last dose (up to 15 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neutropenia, Breast Cancer, Long-acting Granulocyte Colony Stimulating Factor, Early Stage Breast Cancer, Docetaxel + Cyclophosphamide (TC) chemotherapy