Phase III Study Comparing the Efficacy and Safety of LA-EP2006 and Neulasta® (PROTECT-1)

• ClinicalTrials.gov Identifier: NCT01735175
• Recruitment Status: Completed
• First Posted: November 28, 2012
• Results First Posted: June 15, 2017
• Last Update Posted: August 7, 2017
• Sponsor: Sandoz
• Collaborator: Sandoz GmbH
• Information provided by (Responsible Party): Sandoz

Study Description

Brief Summary:

The study will assess the efficacy of LA-EP2006 compared to Neulasta® with respect to the mean duration of severe neutropenia during treatment with myelosuppressive chemotherapy in breast cancer patients.

Condition or disease	Intervention/treatment	Phase
Neutropenic Complications; Breast Neoplasms; Chemotherapy-induced Neutropenia; Chemotherapeutic Toxicity	Drug: LA-EP2006; Drug: Neulasta®	Phase 3

Detailed Description:

This randomized, double-blind trial compared the proposed biosimilar LA-EP2006 with the reference Neulasta® in women (≥18 years) receiving chemotherapy for breast cancer. Therefore patients were randomized to receive LA-EP2006 (n = 159) or the reference product (n = 157) for ≤6 cycles of (neo)-adjuvant TAC (docetaxel 75mg/m^2, doxorubicin 50 mg/m^2, and cyclophosphamide 500mg/m^2) chemotherapy. The primary end point was the duration of severe neutropenia (DSN) during Cycle 1 (defined as number of consecutive days with absolute neutrophil count <0.5 × 10^9/l). The equivalence was confirmed if 95% CIs were within a ±1 day margin. LA-EP2006 was equivalent to the reference product in DSN (difference: 0.07 days; 95% CI [-0.12, 0.26]). Further, LA-EP2006 and the reference Neulasta® showed no clinically meaningful differences regarding efficacy and safety.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 316 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: A Randomized, Double-blind, Parallel-group, Multi-center Phase 3 Comparative Study Investigating Efficacy and Safety of LA-EP2006 and Neulasta® in Breast Cancer Patients Treated With Myelosuppressive Chemotherapy
• Study Start Date: June 2012
• Actual Primary Completion Date: May 2013
• Actual Study Completion Date: February 2014

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Neulasta®; During each chemotherapy cycle eligible patients receive Neulasta® s.c. post chemotherapy application.	Drug: Neulasta®; Eligible patients are scheduled to receive six cycles of chemotherapy every three weeks. During each chemotherapy cycle pegfilgrastim is injected s.c. post chemotherapy application.; Other Name: pegfilgrastim
Experimental: LA-EP2006; During each chemotherapy cycle eligible patients receive LA-EP2006 s.c. post chemotherapy application.	Drug: LA-EP2006; Eligible patients are scheduled to receive six cycles of chemotherapy every three weeks. During each chemotherapy cycle pegfilgrastim is injected s.c. post chemotherapy application.; Other Name: pegfilgrastim

Outcome Measures

Primary Outcome Measures :

1. Mean Duration of Severe Neutropenia (DSN) During Cycle 1 of Chemotherapy [ Time Frame: 21 days (Cycle 1 of chemotherapy treatment) ]
   Mean duration of severe neutropenia, defined as number of consecutive days with ANC <0.5 × 10^9 cells/L (grade 4 neutropenia).

Secondary Outcome Measures :

1. Incidence of Febrile Neutropenia (FN) [ Time Frame: across all cycles (18 weeks) ]
   FN was defined as an oral temperature ≥ 38.3°C while having an absolute neutrophil count (ANC) < 0.5 × 10^9 cells/L. Serious treatment-emergent adverse events (TEAEs) were reconciled with the fever and ANC results recorded in the patient diary and CRF and therefore only the serious TEAEs of FN ("febrile neutropenia", "neutropenic sepsis") were taken into account.
2. Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles [ Time Frame: across al cycles (18 weeks) ]
   Fever was defined as an oral temperature ≥ 38.3°C. Fever episodes were characterized by maximum oral temperature and the number of patients who had fever at least once.
3. Depth of ANC Nadir in Cycle 1 [ Time Frame: Cycle 1 (3 weeks) ]
   The depth of ANC nadir was defined as the patient's lowest ANC (10^9 cells/L) in Cycle 1. Only the evaluable patients with a depth of ANC in Cycle 1 are given.
4. Number of Patients With ANC Nadir Per Day in Cycle 1 [ Time Frame: Cycle 1 (3 weeks) ]
   Numbers of patients with ANC nadir based per day during Cycle 1 are given.
5. Time to ANC Recovery in Days in Cycle 1 [ Time Frame: across Cycle 1 (3 weeks) ]
   Time to absolute neutrophil count (ANC) recovery in Cycle 1 was defined as the time in days from ANC nadir until the patient's ANC had increased to ≥ 2 × 10^9 cells/L. Only the evaluable patients with a depth of ANC in Cycle 1 and a later increase of ANC ≥ 2 × 10^9 cells/L are given.
6. Frequency of Infections by Cycle and Across All Cycles [ Time Frame: across all cycles (18 weeks) ]
   The number of patients with infections was recorded for each cycle and across all cycles. Infections were identified by the AE documentation page selecting all events coded with System Organ Class "Infections and Infestations".
7. Mortality Due to Infection [ Time Frame: Study course (41 weeks) ]
   Number of patients with death due to infections

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• histologically proven breast cancer
• eligible for six cycles of neoadjuvant or adjuvant chemotherapy

Exclusion Criteria:

• concurrent or prior chemotherapy for breast cancer
• concurrent or prior anti-cancer treatment for breast cancer such as endocrine therapy, immunotherapy, monoclonal antibodies, and/or biological therapy
• concurrent prophylactic antibiotics
• previous therapy with any G-CSF (granulocyte-colony stimulating factor) product

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

Brazil

Sandoz Investigational Site

Ijui, Brazil, 98700-000

Sandoz Investigational Site

Lajeado, Brazil, 95900-000

Sandoz Investigational Site

Santo Andre, Brazil, 0960-650

India

Sandoz Investigational Site

Andhra Pradesh, India, 530002

Sandoz Investigational Site

Delhi, India, 110095

Sandoz Investigational Site

Madurai, India, 625107

Sandoz Investigational Site

Maharashtra, India, 411001

Sandoz Investigational Site

Maharashtra, India, 416008

Sandoz Investigational Site

Maharashtra, India, 440010

Sandoz Investigational Site

Mumbai, India, 422005

Sandoz Investigational Site

Rajasthan, India, 302013

Mexico

Sandoz Investigational Site

Aguascalientes, Mexico, 20230

Sandoz Investigational Site

Juchitan, Mexico, 70000

Romania

Sandoz Investigational Site

Bucharest, Romania, 11461

Sandoz Investigational Site

Bucharest, Romania, 23423

Sandoz Investigational Site

Iasi, Romania, 700106

Sandoz Investigational Site

Suceava, Romania, 720237

Russian Federation

Sandoz Investigational Site

Barnaul, Russian Federation, 656052

Sandoz Investigational Site

Bashkortostan, Russian Federation, 450054

Sandoz Investigational Site

Berdsk, Russian Federation, 633004

Sandoz Investigational Site

Ivanovo, Russian Federation, 153040

Sandoz Investigational Site

Kabardino, Russian Federation, 361045

Sandoz Investigational Site

Kazan, Russian Federation, 420029

Sandoz Investigational Site

Krasnodar, Russian Federation, 354057

Sandoz Investigational Site

Kursk, Russian Federation, 305035

Sandoz Investigational Site

Leningrad, Russian Federation, 188663

Sandoz Investigational Site

Moscow, Russian Federation, 115478

Sandoz Investigational Site

Novgorod, Russian Federation, 173016

Sandoz Investigational Site

Oktyabrskaya, Russian Federation, 355047

Sandoz Investigational Site

Ryazan, Russian Federation, 390011

Sandoz Investigational Site

St. Petersburg, Russian Federation, 195067

Sandoz Investigational Site

Tula, Russian Federation, 300053

Ukraine

Sandoz Investigational Site

Cherkasy, Ukraine, 18009

Sandoz Investigational Site

Chernivtsi, Ukraine, 58013

Sandoz Investigational Site

Dnipropetrovsk, Ukraine, 49102

Sandoz Investigational Site

Kharkiv, Ukraine, 61176

Sandoz Investigational Site

Kriviy Rig, Ukraine, 50048

Sandoz Investigational Site

Lugansk, Ukraine, 91000

Sandoz Investigational Site

Mariupol, Ukraine, 87500

Sandoz Investigational Site

Vinnytsya, Ukraine, 21029

Sandoz Investigational Site

Zaporizhzhia, Ukraine, 69040

Sponsors and Collaborators

Sandoz

Sandoz GmbH

Investigators

• Study Chair: Sandoz Biopharmaceutical Clinical Development; Sandoz

More Information

Publications of Results:

Harbeck N, Lipatov O, Frolova M, Udovitsa D, Topuzov E, Ganea-Motan DE, Nakov R, Singh P, Rudy A, Blackwell K. Randomized, double-blind study comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Future Oncol. 2016 Jun;12(11):1359-67. doi: 10.2217/fon-2016-0016. Epub 2016 Mar 29.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Blackwell K, Gascon P, Jones CM, Nixon A, Krendyukov A, Nakov R, Li Y, Harbeck N. Pooled analysis of two randomized, double-blind trials comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Ann Oncol. 2017 Sep 1;28(9):2272-2277. doi: 10.1093/annonc/mdx303.

• Responsible Party: Sandoz
• ClinicalTrials.gov Identifier: NCT01735175
• Other Study ID Numbers: LA-EP06-301; 2011-004532-58 ( EudraCT Number )
• First Posted: November 28, 2012
• Results First Posted: June 15, 2017
• Last Update Posted: August 7, 2017
• Last Verified: June 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Sandoz:

biosimilars; Pegfilgrastim,; G-CSF,; neutropenia,; breast cancer,; myelosuppressive chemotherapy,; supportive care; granulocyte-colony-stimulating factor

Additional relevant MeSH terms:

Breast Neoplasms; Neutropenia; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders; Hematologic Diseases