Breast Cancer
Conditions
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
Interventions
BIOLOGICALTrastuzumab
Trastuzumab 8mg/kg Iv over 90 minutes x 1 then Trastuzumab 6 mg/kg IV over 30 minutes every 3 weeks
BIOLOGICALMYL- 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
DRUGPaclitaxel
Paclitaxel 80mg/m2 IV over 60 minutes weekly.
DRUGDocetaxel
Docetaxel 75mg/m2 IV over 60 minutes on day 1 of a 3 week cycle
Sponsors
Mylan GmbH
Mylan Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | from time of First treatment to week 24 | Tumor measurements were perform by centralized blinded reviewers using RECIST 1.1 criteria. Per RECIST 1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph node must have reduction in short axis to \<10 mm.Partial Response (PR): \>/= 30% decrease sum of the diameters of target lesions from baseline sum diameters. Progressive Disease (PD): \</= 20% increase in the sum of the diameters of target lesions, from the smallest sum on study with at least a 5 mm absolute increase in the sum of all lesions. The appearance of one or more new lesions\* denotes disease progression. Stable Disease (SD): Neither sufficient decrease or increase. Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions. Non-complete Response/Non-Progressive Disease: Persistence of one or more non-target lesions. Progressive Disease (PD): Substantial, unequivocal progression of existing non-target lesions. |
Countries
Brazil, Chile, Georgia, Hungary, India, Latvia, Peru, Romania, Russia, Serbia, Slovakia, South Africa, Thailand, Turkey (Türkiye), Ukraine
Participant flow
Recruitment details
500 subjects enrolled at 95 sites across Eastern Europe, Russia, Asia Pacific, Africa and South America. The intent to treat1(ITT1) population of 458 was used to determine Primary Outcome of Overall Response Rate.
Pre-assignment details
The primary efficacy analysis was derived fromITT1 population 230 (MYL-1401O) + 228 (Herceptin)= 458. Safety analysis was derived from the Safety Population 247(MYL-1401O)+246(Herceptin)= 493. Total Randomized population 249(MYL-1401O) +251(Herceptin)= 500.
Participants by arm
| Arm | Count |
|---|---|
| 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 .
Herceptin© 8mg/kg Iv over 90 minutes x 1 then Herceptin© 6 mg/kg IV over 30 minutes every 3 weeks
Paclitaxel 80mg/m2 IV over 60 minutes weekly.
Docetaxel 75mg/m2 IV over 60 minutes on day 1 of a 3 week cycle | 228 |
| 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.
MYL-1401O 8mg/kg Iv over 90 minutes x 1 then MYL-1401O 6 mg/kg IV over 30 minutes every 3 weeks
Paclitaxel 80mg/m2 IV over 60 minutes weekly.
Docetaxel 75mg/m2 IV over 60 minutes on day 1 of a 3 week cycle | 230 |
| Total | 458 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Part 1 (up to Week 24) | Adverse Event | 2 | 4 |
| Part 1 (up to Week 24) | Death | 3 | 6 |
| Part 1 (up to Week 24) | disease progression | 58 | 47 |
| Part 1 (up to Week 24) | Lost to Follow-up | 0 | 1 |
| Part 1 (up to Week 24) | Other | 2 | 1 |
| Part 1 (up to Week 24) | Physician Decision | 3 | 1 |
| Part 1 (up to Week 24) | Withdrawal by Subject | 7 | 2 |
| Part 2 (Week 24-week 48) | Adverse Event | 4 | 2 |
| Part 2 (Week 24-week 48) | Death | 0 | 1 |
| Part 2 (Week 24-week 48) | Disease Progression | 52 | 56 |
| Part 2 (Week 24-week 48) | Lost to Follow-up | 2 | 1 |
| Part 2 (Week 24-week 48) | Physician Decision | 1 | 1 |
| Part 2 (Week 24-week 48) | Protocol Violation | 3 | 1 |
| Part 2 (Week 24-week 48) | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Total | Herceptin© + Taxane | MYL-1401O + Taxane |
|---|---|---|---|
| Age, Customized < 50years of age | 160 Participants | 86 Participants | 74 Participants |
| Age, Customized >/= 50years of age | 298 Participants | 142 Participants | 156 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 142 Participants | 72 Participants | 70 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 313 Participants | 154 Participants | 159 Participants |
| Region of Enrollment Chile | 5 participants | 4 participants | 1 participants |
| Region of Enrollment Czechia | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Georgia | 49 participants | 23 participants | 26 participants |
| Region of Enrollment Hungary | 13 participants | 8 participants | 5 participants |
| Region of Enrollment India | 55 participants | 31 participants | 24 participants |
| Region of Enrollment Latvia | 6 participants | 2 participants | 4 participants |
| Region of Enrollment Philippines | 48 participants | 18 participants | 30 participants |
| Region of Enrollment Poland | 19 participants | 6 participants | 13 participants |
| Region of Enrollment Romania | 8 participants | 5 participants | 3 participants |
| Region of Enrollment Russia | 144 participants | 73 participants | 71 participants |
| Region of Enrollment Serbia | 5 participants | 2 participants | 3 participants |
| Region of Enrollment Slovakia | 3 participants | 1 participants | 2 participants |
| Region of Enrollment South Africa | 11 participants | 3 participants | 8 participants |
| Region of Enrollment Thailand | 39 participants | 23 participants | 16 participants |
| Region of Enrollment Ukraine | 52 participants | 28 participants | 24 participants |
| Sex: Female, Male Female | 458 Participants | 228 Participants | 230 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 232 / 246 | 229 / 247 |
| serious Total, serious adverse events | 91 / 246 | 97 / 247 |
Outcome results
Primary
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
Tumor measurements were perform by centralized blinded reviewers using RECIST 1.1 criteria. Per RECIST 1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph node must have reduction in short axis to \<10 mm.Partial Response (PR): \>/= 30% decrease sum of the diameters of target lesions from baseline sum diameters. Progressive Disease (PD): \</= 20% increase in the sum of the diameters of target lesions, from the smallest sum on study with at least a 5 mm absolute increase in the sum of all lesions. The appearance of one or more new lesions\* denotes disease progression. Stable Disease (SD): Neither sufficient decrease or increase. Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions. Non-complete Response/Non-Progressive Disease: Persistence of one or more non-target lesions. Progressive Disease (PD): Substantial, unequivocal progression of existing non-target lesions.
Time frame: from time of First treatment to week 24
Population: The primary efficacy analysis was conducted in the Intent To Treat population 1 (ITT1) ( all patients randomized after Amendment 2 of the protocol)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Herceptin© + Taxane | 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 | Partial Response | 146 Participants |
| Herceptin© + Taxane | 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 | Progressive Disease | 20 Participants |
| Herceptin© + Taxane | 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 | Stable Disease | 49 Participants |
| Herceptin© + Taxane | 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 | Not Evaluable | 13 Participants |
| Herceptin© + Taxane | 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 | Complete Response | 0 Participants |
| MYL-1401O Trastuzumab + Taxane | 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 | Not Evaluable | 13 Participants |
| MYL-1401O Trastuzumab + Taxane | 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 | Complete Response | 3 Participants |
| MYL-1401O Trastuzumab + Taxane | 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 | Partial Response | 157 Participants |
| MYL-1401O Trastuzumab + Taxane | 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 | Stable Disease | 48 Participants |
| MYL-1401O Trastuzumab + Taxane | 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 | Progressive Disease | 9 Participants |