E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heregulin Positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059515 |
E.1.2 | Term | Non-small cell lung cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to determine whether the combination of MM-121 plus docetaxel or MM-121 plus pemetrexed is more effective than docetaxel or pemetrexed alone based on Overall Survival (OS) in HRG positive patients (defined as HRG ISH score of > 1+). |
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E.2.2 | Secondary objectives of the trial |
• To determine whether the combination of MM-121 plus docetaxel or MM-121 plus pemetrexed is more effective than docetaxel or pemetrexed alone in HRG positive patients (defined as HRG ISH score of > 1+) for the following clinical outcome parameters:
- Investigator Assessed Progression Free Survival (PFS)
- Independent Central Review - PFS
- Objective Response Rate (ORR) based on RECIST v 1.1
- Time to Progression (TTP)
• To describe the safety profile of MM-121 in combination with docetaxel or oemetrexed
• To assess health-related quality of life (HRQOL) in NSCL
• To characterize the pharmacokinetic (PK) profile of MM-121 when given in combination with docetaxel or pemetrexed and of docetaxel or pemetrexed when given in combination with MM-121 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
To be eligible for participation in the study, patients must meet the following criteria. Patients who are assessed to be HRG negative do not complete any screening procedures beyond HRG assessment.
• Patients with cytologically or histologically documented NSCLC that is presenting as
either:
o Stage IV (metastatic disease) or
o Stage IIIB disease not amenable to surgery with curative intent or
o Recurrent or progressive disease following multimodal therapy (chemotherapy, radiation therapy, surgical resection or definitive chemoradiation therapy for locally advanced or metastatic disease)
• Disease progression or evidence of recurrent disease during or after the last systemic therapy as documented by radiographic assessment
• Received nivolumab, pembrolizumab, or other anti-PD-1 or anti-PD-L1 therapy
• Clinically eligible for intended chemotherapy, docetaxel or pemetrexed, once every three weeks per the investigator’s judgment
• Must have:
o Available recent tumor specimen, collected following completion of most recent systemic therapy OR
o A lesion amenable to either core needle biopsy or fine needle aspiration
• A positive in-situ hybridization (ISH) test for heregulin with a score of >1+, as determined by centralized testing
• ECOG performance status (PS) of 0 or 1
• Screening ECG without clinically significant abnormalities
• Women of childbearing potential, as well as fertile men and their partners, must be willing to abstain from sexual intercourse or to use an effective form of contraception (an effective form of contraception is an oral contraceptive or a double barrier method or as defined by country-specific guidelines) during the study and for 6 months, in males and females, following the last dose of study drug(s), or greater, as in accordance with the label requirements or institutional guidelines for docetaxel/pemetrexed
• ≥ 18 years of age
• Able to provide informed consent, or have a legal representative able and willing to do so |
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E.4 | Principal exclusion criteria |
• Known Anaplastic Lymphoma Kinase (ALK) gene rearrangement
• For adenocarcinoma patients only: Presence of exon 19 deletion or exon 21 (L858R) substitution of the EGFR gene
• Pregnant or lactating
• Prior radiation therapy to >25% of bone marrow-bearing areas
• Received >3 prior systemic anti-cancer drug regimens for locally advanced and/or metastatic disease
o Any type of maintenance therapy, e.g. pemetrexed maintenance following first line treatment with cisplatin and pemetrexed, is not considered a separate line of therapy
• Prior treatment with an anti-ErbB3 antibody
• Patients who have received prior docetaxel for advanced/ metastatic disease are not eligible for the docetaxel-containing chemotherapy backbone
• Patients who have received prior pemetrexed for advanced/metastatic disease and/or maintenance therapy are not eligible for the pemetrexed-containing chemotherapy backbone
• Received other recent antitumor therapy including:
o Investigational therapy administered within the 28 days or 5 half-lives, whichever is shorter, prior to the first scheduled day of dosing in this study
o Radiation or other standard systemic therapy within 14 days prior to the first scheduled dose in this study, including, in addition (if necessary), the timeframe for resolution of any actual or anticipated toxicities from such radiation
• CTCAE grade 3 or higher peripheral neuropathy for patients considered for the docetaxel backbone
• Presence of an unexplained fever > 38.5°C during screening visits that does not resolve prior to the first day of dosing. If the fever and active infection have resolved prior to randomization, the patient will be eligible. At the discretion of the
investigator, patients with tumor fever may be enrolled.
• Clinically active CNS metastasis
• Use of strong CYP3A4 inhibitors for patients considered for the docetaxel backbone
• Any other active malignancy requiring systemic therapy
• Known hypersensitivity to any of the components of MM-121 or previous CTCAE grade 3 or higher hypersensitivity reactions to fully human monoclonal antibodies
• History of severe hypersensitivity reactions to docetaxel or pemetrexed
• Known hypersensitivity to polysorbate (Tween) 80 or arginine
• Inadequate bone marrow reserve as evidenced by:
o ANC < 1,500/μl or
o Platelet count < 100,000/μl or
o Hemoglobin < 9 g/dL (5.59 mmol/L)
• Serum/plasma creatinine > 1.5 x ULN for patients receiving docetaxel or a creatinine clearance < 45 mL/min (0.75 ml/s) for patients receiving pemetrexed
• For patients receiving pemetrexed: Total bilirubin > 1.5 x ULN, alkaline phosphatase (AP), aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x ULN (> 5 x ULN if liver metastases are present)
• For patients receiving docetaxel:
o Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 x ULN concomitant with Alkaline phosphatase (AP) > 2.5 x ULN
o Serum/plasma total bilirubin > ULN
• Clinically significant cardiac disease, including: symptomatic congestive heart failure, unstable angina, acute myocardial infarction within 12 months of planned first dose, or unstable cardiac arrhythmia requiring therapy (including torsades de pointes)
• Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; or active human immunodeficiency virus (HIV) infection, active hepatitis B infection or active hepatitis C infection
• Patients who are not appropriate candidates for participation in this clinical study for any other reason as deemed by the investigator |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the study is Overall Survival (OS). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Overall Survival (OS) is the primary endpoint, and is defined as the time from the date of randomization to the date of death from any cause.
Assuming a 27 month enrollment period, the required number of OS events is estimated to be achieved at approximately 35 months.
An interim analysis will be conducted when reporting approximately 50% of final OS events (i.e., 114 of 227 OS events) has been observed in the primary efficacy population. The purpose of the interim analysis is to assess the potential for early stopping due to futility or efficacy. |
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E.5.2 | Secondary end point(s) |
PFS, based on investigator assessment and independent central review, are secondary endpoints of this study. PFS is defined as the time from randomization to the first documented radiographical progression of disease using RECIST 1.1, or death from any cause, whichever comes first. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The time from randomization to the first documented radiographical progression of disease using RECIST 1.1, or death from any cause, whichever comes first. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Biomarker analysis and MM-121 Anti-Immunogenicity |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 29 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
France |
Germany |
Hungary |
Korea, Republic of |
Poland |
Spain |
Taiwan |
Thailand |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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It is intended that patients will be treated until radiographic disease progression per RECIST 1.1, death or intolerable toxicity, as assessed by the investigator. The primary analysis will be event driven. It is estimated that the accrual will be approximately 20 patients per month over an approximately 27 month period after a 6-month ramp-up period. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |