Clinical trial NCT02472964: Study of Efficacy and Safety of Myl1401O + Taxane vs Herceptin©+ Taxane for 1st Line, Met. Br. Ca.
Official title: A Multicenter, Double-Blind, Randomized, Parallel-Group, Phase III Study of the Efficacy and Safety of Hercules Plus Taxane Versus Herceptin® Plus Taxane as First Line Therapy in Patients With HER2-Positive Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Lead sponsor: Viatris Inc.
Sponsor class: INDUSTRY
Collaborators: name: Mylan GmbH
First posted: 2015-06-16
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A multicenter, double-blind, randomized, parallel-group, Phase III study of the efficacy and safety of Hercules( Myl 1401O, Mylan Trastuzumab) plus taxane versus Herceptin® plus taxane as first line therapy in patients with HER2-positive metastatic breast cancer.

Detailed description: Part 1: A multicenter, double-blind, randomized, parallel-group, Phase III study to compare the efficacy and safety of MYL-1401O (Mylan Trastuzumab biosimiliar) plus taxane versus Herceptin® plus taxane in patients with HER2+ MBC. Either docetaxel or paclitaxel (Investigator site level choice) is planned for at least 24 weeks until documented response to therapy, disease progression, or discontinuation. Disease response and progression will be assessed locally by the Investigator on the basis of clinical and radiographic evidence using RECIST 1.1 criteria. The primary and secondary efficacy analyses will be performed using independently assessed radiographic evidence for the Intent-to-Treat (ITT) population. The primary analysis population for best ORR will be those patients who had measureable disease at baseline and for the secondary endpoint, DR, only those who are responders will be included in the analysis.

Part 2: A multicenter, double-blind, parallel-group study to continue to compare the safety and immunogenicity and efficacy of MYL-1401O versus Herceptin® in patients with HER2+ MBC who have clinical benefit to first-line combination therapy with a taxane. All patients who have at least stable disease (SD), will continue with either single agent MYL-1401O or Herceptin® alone until death, unacceptable toxicity or disease progression.

Population pharmacokinetics: During Part 1 of the study, for both MYL-1401O, and Herceptin® treatment arms, PK sampling for Cmin and Cmax (end of infusion) will be collected for all patients. A PopPK subset, with sufficient samples available to perform the necessary analysis of PopPK modeling will be used to assess AUC, Cmax, Cmin, clearance, Vd, and T1/2 at various time points in the PopPK. Patients randomized into the main study will sign an additional consent form for the PopPK subset. We anticipate that approximately 80 patients will need to be enrolled in this subset collection in order to obtain sufficient samples for analysis.

Long term survival follow-up: OS for this treated population will be determined with every 3 month follow-up until either 240 deaths or 36 months, whichever occurs first, as observed from the time of randomization. The results for OS are expected to be reported March 2019. Exploratory evaluations: In addition, during Part 1 of the study, blood samples will be collected in all patients to assess the impact of soluble shed HER2/ECD on PK and efficacy at pre-dose on Cycles 1, 3, 5, 7, and end of treatment (EOT). Additional samples (ECD) will be obtained on Cycles 9, 13 and every 4 cycles thereafter, EOT and end of study (EOS) for continued evaluation of immunogenicity in patients continuing to receive therapy. A blood sample will be obtained on Cycle 1, Day 1, to be used for assay development and validation

Eligibility criteria: Inclusion Criteria:

Locally recurrent or MBC that is not amenable to curative surgery and/or radiation.

Documentation of HER2 gene amplification by fluorescent in situ hybridization (FISH) (as defined by a ratio \>2.0) or documentation of HER2-overexpression by immunohistochemistry (IHC) (defined as IHC3+, or IHC2+ with FISH confirmation) based on the sponsor-identified central laboratory prior to randomization. Archival tumor tissue samples can be used.

Pathologically confirmed breast cancer with at least one measurable metastatic target lesion (based on RECIST criteria, version 1.1). Bone, central nervous system (CNS), and skin lesions, as well as lesions that were irradiated, biopsied or had any form of local intervention or surgical manipulation are only to be assessed as non-target lesions.

Patients previously treated with trastuzumab or lapatinib in the adjuvant setting are allowed if metastatic disease was diagnosed at least one year after the last dose of treatment.

Prior treatment with hormonal agents or bisphosphonates/denosumab is allowed. Bisphosphonates/denosumab can be given simultaneously with study treatment but cannot start after randomization and is considered an indication of progressive disease (PD). Hormonal agents must be discontinued prior to beginning study therapy.

Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 - 2

* Serum creatinine ≤1.5 x ULN (upper limit of normal),
* Total bilirubin ≤1.0 x ULN (\>1.0 x ULN if documented Gilbert's disease),
* Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤2.5 x ULN,
* AST and/or ALT \<1.5 x ULN if alkaline phosphatase \>2.5 x ULN,
* Alkaline phosphatase \>2.5 x ULN;if bone metastases present and no liver dysfunction present.

Left ventricular ejection fraction (LVEF) within institutional range of normal as measured by multiple gated acquisition scan or echocardiogram.

Exclusion Criteria:

Prior systemic therapy in the metastatic disease setting. This includes: chemotherapy, signal transduction inhibitors (e.g., lapatinib), HER2 targeted therapy (e.g., trastuzumab), or other investigational anticancer therapy.

Prior treatment with neoadjuvant or adjuvant anthracyclines with a cumulative dose of doxorubicin of \>400 mg/m2, epirubicin dose \>800 mg/m2.

Patients with bone or skin as the only site of disease. Patients with skin lesions measurable by CT scans or MRI as only site of measurable disease are allowed.

Surgery or radiotherapy ≤2 weeks preceding Day 1. Target lesions have to be outside the irradiated fields and the patient has fully recovered from surgery or radiotherapy.

Presence of unstable angina or a history of congestive heart failure according to the New York Heart Association criteria, history of myocardial infarction \<1 year from randomization, clinically significant valvular disease, serious cardiac arrhythmia requiring treatment, uncontrolled hypertension or known pulmonary hypertension.

Peripheral sensory or motor neuropathy Grade 2 or higher according to the National Cancer Institute-Common Terminology Criteria (NCI-CTC) Version 4.03 \[19\].

Any other cancer, including contralateral breast cancer, within 5 years prior to screening with the exception of adequately treated ductal carcinoma in situ, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin.

Immunocompromized patients, including known seropositivity for human immunodeficiency virus, or current or chronic hepatitis B and/or hepatitis C infection (as detected by positive testing for hepatitis B surface antigen or antibody to hepatitis C virus with confirmatory testing).

Complete listing of Inc/Excl. within protocol

Primary outcomes:
measure: Primary Endpoint : Compare Best Overall Response Rate (ORR) (According to Response Evaluation Criteria in Solid Tumor [RECIST] 1.1 Criteria) at Week 24 of MYL-1401O Plus Taxane Versus Herceptin® Plus Taxane in the ITT1 Population
timeFrame: from time of First treatment to week 24
Secondary outcomes:
Other outcomes:
Locations:
city: Barretos
country: Brazil
facility: Mylan Investigational Site
city: Brasilia
country: Brazil
facility: Mylan Investigational Site
city: Goiania
country: Brazil
facility: Mylan Investigational Site
city: Ijui
country: Brazil
facility: Mylan Investigational Site
city: Jau
country: Brazil
facility: Mylan Investigational Site
city: Joinville
country: Brazil
facility: Mylan Investigational Site
city: Morumbi
country: Brazil
facility: Mylan Investigational Site
city: Porto Alegre
country: Brazil
facility: Mylan Investigational Site
city: Salvador,
country: Brazil
facility: Mylan Investigational Site
city: Santo Andre
country: Brazil
facility: Mylan Investigational Site
city: Sao Paulo
country: Brazil
facility: Mylan Investigational Site
city: Sorocaba
country: Brazil
facility: Mylan Investigational Site
city: Santiago
country: Chile
facility: Mylan Investigational Site
city: Temuco
country: Chile
facility: Mylan Investigational Site
city: Batumi
country: Georgia
facility: Mylan Investigational Site
city: Tblisi
country: Georgia
facility: Mylan Investigational Site
city: Budapest
country: Hungary
facility: Mylan Investigational Site
city: Debrecen
country: Hungary
facility: Mylan Investigational Site
city: Gyod
country: Hungary
facility: Mylan Investigational Site
city: Gyula
country: Hungary
facility: Mylan Investigational Site
city: Miskolc
country: Hungary
facility: Mylan Investigational Site
city: Nyiregyhaza
country: Hungary
facility: Mylan Investigational Site
city: Szekszard
country: Hungary
facility: Mylan Investigational Site
city: Szolnok
country: Hungary
facility: Mylan Investigational Site
city: Ahmedabad
country: India
facility: Mylan Investigational Site
city: Bangalore
country: India
facility: Mylan Investigational Site
city: Chennai
country: India
facility: Mylan Investigational Site
city: Gurgaon
country: India
facility: Mylan Investigational Site
city: Hyderabad
country: India
facility: Mylan Investigational Site
city: Jaipur
country: India
facility: Mylan Investigational Site
city: Karamsad
country: India
facility: Mylan Investigational Site
city: Madurai
country: India
facility: Mylan Investigational Site
city: Mumbai
country: India
facility: Mylan Investigational Site
city: Nashik
country: India
facility: Mylan Investigational Site
city: Pune
country: India
facility: Mylan Investigational Site
city: Surat
country: India
facility: Mylan Investigational Site
city: Vijaywada
country: India
facility: Mylan Investigational Site
city: Daugavpils
country: Latvia
facility: Mylan Investigational Site
city: Leipaja
country: Latvia
facility: Mylan Investigational Site
city: Riga
country: Latvia
facility: Mylan Investigational Site
city: Arequipa
country: Peru
facility: Mylan Investigational Site
city: Lima
country: Peru
facility: Mylan Investigational Site
city: Surquillo
country: Peru
facility: Mylan Investigational Site
city: Brasov
country: Romania
facility: Mylan Investigational Site
city: Bucharest
country: Romania
facility: Mylan Investigational Site
city: Bucuresti
country: Romania
facility: Mylan Investigational Site
city: Cluj- Napoca
country: Romania
facility: Mylan Investigational Site
city: Constanta
country: Romania
facility: Mylan Investigational Site
city: Craiva
country: Romania
facility: Mylan Investigational Site
city: Filimon Sirbu
country: Romania
facility: Mylan Investigational Site
city: Iasi
country: Romania
facility: Mylan Investigational Site
city: Oradea
country: Romania
facility: Mylan Investigational Site
city: Timisoara
country: Romania
facility: Mylan Investigational Site
city: Arkhangelsk
country: Russian Federation
facility: Mylan Investigational Site
city: Ivanovo
country: Russian Federation
facility: Mylan Investigational Site
city: Kazan
country: Russian Federation
facility: Mylan Investigational Site
city: Kursk
country: Russian Federation
facility: Mylan Investigational Site
city: Moscow
country: Russian Federation
facility: Mylan Investigational Site
city: Rostov-On-Don
country: Russian Federation
facility: Mylan Investigational Site
city: Ryazan
country: Russian Federation
facility: Mylan Investigational Site
city: Samara
country: Russian Federation
facility: Mylan Investigational Site
city: St. Petersburg
country: Russian Federation
facility: Mylan Investigational Site
city: Belgrade
country: Serbia
facility: Mylan Investigational Site
city: Kamenica
country: Serbia
facility: Mylan Investigational Site
city: Sremska
country: Serbia
facility: Mylan Investigational Site
city: Bardejov
country: Slovakia
facility: Mylan Investigational Site
city: Kosice
country: Slovakia
facility: Mylan Investigational Site
city: Nove Zamky
country: Slovakia
facility: Mylan Investigational Site
city: Trnava
country: Slovakia
facility: Mylan Investigational Site
city: Bloemfontein
country: South Africa
facility: Mylan Investigator Site
city: Durban
country: South Africa
facility: Mylan Investigator Site
city: George
country: South Africa
facility: Mylan Investigational Site
city: Johannesburg
country: South Africa
facility: Mylan Investigational Site
city: Kraaifontein
country: South Africa
facility: Mylan Investigator Site
city: Port Elizabeth
country: South Africa
facility: Mylan Investigational Site
city: Pretoria
country: South Africa
facility: Mylan Investigational Site
city: Vereeniging
country: South Africa
facility: Mylan Investigational Site
city: Bangkok
country: Thailand
facility: Mylan Investigator Site
city: Chiang mai
country: Thailand
facility: Mylan Investigator Site
city: Phitsanulok
country: Thailand
facility: Mylan Investigator Site
city: Rajthavee
country: Thailand
facility: Mylan Investigator Site
city: Songkla
country: Thailand
facility: Mylan Investigator Site
city: Ankara
country: Turkey
facility: Mylan Investigator Site
city: Istanbul
country: Turkey
facility: Mylan Investigator Site
city: Izmir
country: Turkey
facility: Mylan Investigator Site
city: Kocaeli
country: Turkey
facility: Mylan Investigator Site
city: Cherkassy
country: Ukraine
facility: Mylan Investigator Site
city: Chernivtsi
country: Ukraine
facility: Mylan Investigator Site
city: Dnipropetrovsk
country: Ukraine
facility: Mylan Investigator Site
city: Lutsk
country: Ukraine
facility: Mylan Investigator Site
city: Lviv
country: Ukraine
facility: Mylan Investigator Site
city: Sumy
country: Ukraine
facility: Mylan Investigator Site
city: Uzhgorod
country: Ukraine
facility: Mylan Investigator Site
Study officials:
affiliation: Mylan Inc.
name: Eduardo Pennella, MD
role: STUDY_DIRECTOR
References:
citation: Rugo HS, Pennella EJ, Gopalakrishnan U, Hernandez-Bronchud M, Herson J, Koch HF, Loganathan S, Deodhar S, Marwah A, Manikhas A, Bondarenko I, Mukhametshina G, Nemsadze G, Parra JD, Abesamis-Tiambeng MLT, Baramidze K, Akewanlop C, Vynnychenko I, Sriuranpong V, Mamillapalli G, Roy S, Yanez Ruiz EP, Barve A, Fuentes-Alburo A, Waller CF. Final overall survival analysis of the phase 3 HERITAGE study demonstrates equivalence of trastuzumab-dkst to trastuzumab in HER2-positive metastatic breast cancer. Breast Cancer Res Treat. 2021 Jul;188(2):369-377. doi: 10.1007/s10549-021-06197-5. Epub 2021 Jun 14.
citation: Rugo HS, Barve A, Waller CF, Hernandez-Bronchud M, Herson J, Yuan J, Sharma R, Baczkowski M, Kothekar M, Loganathan S, Manikhas A, Bondarenko I, Mukhametshina G, Nemsadze G, Parra JD, Abesamis-Tiambeng ML, Baramidze K, Akewanlop C, Vynnychenko I, Sriuranpong V, Mamillapalli G, Ray S, Yanez Ruiz EP, Pennella E; Heritage Study Investigators. Effect of a Proposed Trastuzumab Biosimilar Compared With Trastuzumab on Overall Response Rate in Patients With ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Randomized Clinical Trial. JAMA. 2017 Jan 3;317(1):37-47. doi: 10.1001/jama.2016.18305.