Study of Efficacy and Safety of Myl1401O + Taxane vs Herceptin©+ Taxane for 1st Line, Met. Br. Ca.

NCT ID: NCT02472964

Last Updated: 2022-02-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 500 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-07-31
• Study Completion Date: 2018-08-31

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

Conditions

Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Herceptin© + Taxane

Part 1: Herceptin© (trastuzumab) intravenously+ paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint.

Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to Herceptin© (trastuzumab) alone once every 3 weeks until DP or subject withdrawal .

Group Type: ACTIVE_COMPARATOR

Trastuzumab

Intervention Type: BIOLOGICAL

Trastuzumab 8mg/kg Iv over 90 minutes x 1 then Trastuzumab 6 mg/kg IV over 30 minutes every 3 weeks

Paclitaxel

Intervention Type: DRUG

Paclitaxel 80mg/m2 IV over 60 minutes weekly.

Docetaxel

Intervention Type: DRUG

Docetaxel 75mg/m2 IV over 60 minutes on day 1 of a 3 week cycle

MYL- 1401O + Taxane

Part 1:MYL-1401O Intravenously + paclitaxel 80 mg/m2 weekly intravenously or docetaxel 75 mg/m2 intravenously once every three weeks (investigators choice) for 8 cycles then evaluate for primary endpoint.

Part 2: If SD or PR, CR at cycle 9 (week 24) proceed to MYL-1401O alone once every 3 weeks until DP or subject withdrawal.

Group Type: EXPERIMENTAL

MYL- 1401O

Intervention Type: BIOLOGICAL

MYL-1401O 8mg/kg Iv over 90 minutes x 1 then HERMyl 1401O Trastuzumab 6 mg/kg IV over 30 minutes every 3 weeks

Paclitaxel

Intervention Type: DRUG

Paclitaxel 80mg/m2 IV over 60 minutes weekly.

Docetaxel

Intervention Type: DRUG

Docetaxel 75mg/m2 IV over 60 minutes on day 1 of a 3 week cycle

Interventions

Trastuzumab

Trastuzumab 8mg/kg Iv over 90 minutes x 1 then Trastuzumab 6 mg/kg IV over 30 minutes every 3 weeks

Intervention Type: BIOLOGICAL

MYL- 1401O

MYL-1401O 8mg/kg Iv over 90 minutes x 1 then HERMyl 1401O Trastuzumab 6 mg/kg IV over 30 minutes every 3 weeks

Intervention Type: BIOLOGICAL

Paclitaxel

Paclitaxel 80mg/m2 IV over 60 minutes weekly.

Intervention Type: DRUG

Docetaxel

Docetaxel 75mg/m2 IV over 60 minutes on day 1 of a 3 week cycle

Intervention Type: DRUG

Other Intervention Names

Herceptin©; Hercules

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Mylan GmbH

INDUSTRY

Sponsor Role: collaborator

Mylan Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Eduardo Pennella, MD

Role: STUDY_DIRECTOR

Mylan Inc.

Locations

Mylan Investigational Site

Barretos, , Brazil

Mylan Investigational Site

Brasília, , Brazil

Mylan Investigational Site

Goiânia, , Brazil

Mylan Investigational Site

Ijuí, , Brazil

Mylan Investigational Site

Jaú, , Brazil

Mylan Investigational Site

Joinville, , Brazil

Mylan Investigational Site

Morumbi, , Brazil

Mylan Investigational Site

Porto Alegre, , Brazil

Mylan Investigational Site

Salvador, , Brazil

Mylan Investigational Site

Santo André, , Brazil

Mylan Investigational Site

São Paulo, , Brazil

Mylan Investigational Site

Sorocaba, , Brazil

Mylan Investigational Site

Santiago, , Chile

Mylan Investigational Site

Temuco, , Chile

Mylan Investigational Site

Batumi, , Georgia

Mylan Investigational Site

Tbilisi, , Georgia

Mylan Investigational Site

Budapest, , Hungary

Mylan Investigational Site

Debrecen, , Hungary

Mylan Investigational Site

Gyód, , Hungary

Mylan Investigational Site

Gyula, , Hungary

Mylan Investigational Site

Miskolc, , Hungary

Mylan Investigational Site

Nyíregyháza, , Hungary

Mylan Investigational Site

Szekszárd, , Hungary

Mylan Investigational Site

Szolnok, , Hungary

Mylan Investigational Site

Ahmedabad, , India

Mylan Investigational Site

Bangalore, , India

Mylan Investigational Site

Chennai, , India

Mylan Investigational Site

Gurgaon, , India

Mylan Investigational Site

Hyderabad, , India

Mylan Investigational Site

Jaipur, , India

Mylan Investigational Site

Karamsad, , India

Mylan Investigational Site

Madurai, , India

Mylan Investigational Site

Mumbai, , India

Mylan Investigational Site

Nashik, , India

Mylan Investigational Site

Pune, , India

Mylan Investigational Site

Surat, , India

Mylan Investigational Site

Vijaywada, , India

Mylan Investigational Site

Daugavpils, , Latvia

Mylan Investigational Site

Leipaja, , Latvia

Mylan Investigational Site

Riga, , Latvia

Mylan Investigational Site

Arequipa, , Peru

Mylan Investigational Site

Lima, , Peru

Mylan Investigational Site

Surquillo, , Peru

Mylan Investigational Site

Brasov, , Romania

Mylan Investigational Site

Bucharest, , Romania

Mylan Investigational Site

Cluj-Napoca, , Romania

Mylan Investigational Site

Constanța, , Romania

Mylan Investigational Site

Craiva, , Romania

Mylan Investigational Site

Făurei, , Romania

Mylan Investigational Site

Iași, , Romania

Mylan Investigational Site

Oradea, , Romania

Mylan Investigational Site

Timișoara, , Romania

Mylan Investigational Site

Arkhangelsk, , Russia

Mylan Investigational Site

Ivanovo, , Russia

Mylan Investigational Site

Kazan', , Russia

Mylan Investigational Site

Kursk, , Russia

Mylan Investigational Site

Moscow, , Russia

Mylan Investigational Site

Rostov-on-Don, , Russia

Mylan Investigational Site

Ryazan, , Russia

Mylan Investigational Site

Saint Petersburg, , Russia

Mylan Investigational Site

Samara, , Russia

Mylan Investigational Site

Belgrade, , Serbia

Mylan Investigational Site

Kamenica, , Serbia

Mylan Investigational Site

Sremska, , Serbia

Mylan Investigational Site

Bardejov, , Slovakia

Mylan Investigational Site

Košice, , Slovakia

Mylan Investigational Site

Nové Zámky, , Slovakia

Mylan Investigational Site

Trnava, , Slovakia

Mylan Investigator Site

Bloemfontein, , South Africa

Mylan Investigator Site

Durban, , South Africa

Mylan Investigational Site

George, , South Africa

Mylan Investigational Site

Johannesburg, , South Africa

Mylan Investigator Site

Kraaifontein, , South Africa

Mylan Investigational Site

Port Elizabeth, , South Africa

Mylan Investigational Site

Pretoria, , South Africa

Mylan Investigational Site

Vereeniging, , South Africa

Mylan Investigator Site

Bangkok, , Thailand

Mylan Investigator Site

Chiang Mai, , Thailand

Mylan Investigator Site

Phitsanulok, , Thailand

Mylan Investigator Site

Rajthavee, , Thailand

Mylan Investigator Site

Songkhla, , Thailand

Mylan Investigator Site

Ankara, , Turkey (Türkiye)

Mylan Investigator Site

Istanbul, , Turkey (Türkiye)

Mylan Investigator Site

Izmir, , Turkey (Türkiye)

Mylan Investigator Site

Kocaeli, , Turkey (Türkiye)

Mylan Investigator Site

Cherkassy, , Ukraine

Mylan Investigator Site

Chernivtsi, , Ukraine

Mylan Investigator Site

Dnipropetrovsk, , Ukraine

Mylan Investigator Site

Lutsk, , Ukraine

Mylan Investigator Site

Lviv, , Ukraine

Mylan Investigator Site

Sumy, , Ukraine

Mylan Investigator Site

Uzhhorod, , Ukraine

Countries

Brazil; Chile; Georgia; Hungary; India; Latvia; Peru; Romania; Russia; Serbia; Slovakia; South Africa; Thailand; Turkey (Türkiye); Ukraine

References

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.

Reference Type: DERIVED

PMID: 34125340 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27918780 (View on PubMed)

Other Identifiers

2011-001965-42

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MYL-Her 3001

Identifier Type: -

Identifier Source: org_study_id