A Study of Trastuzumab Emtansine in Participants With Human Epidermal Growth Factor Receptor (HER)2 Immunohistochemistry (IHC)-Positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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This is a Phase 2, multicenter study designed to evaluate the efficacy and safety of trastuzumab emtansine administered as a single-agent in participants with HER2-positive (HER2 IHC 2+ or HER2 IHC 3+) advanced or metastatic NSCLC. Participants will be treated with trastuzumab emtansine administered intravenously at a dose of 3.6 milligrams per kilogram (mg/kg) on Day 1 of 21-day cycles until disease progression (as assessed by the investigator), unmanageable toxicity, or study termination by the Sponsor, whichever occurs first.

Official Title
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A Phase 2, Multicenter, Single-Arm Study of Trastuzumab Emtansine in Patients With HER2 IHC-Positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Received At Least One Prior Chemotherapy Regimen

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Trastuzumab Emtansine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically documented diagnosis of Stage IIIB not amenable to radical treatment or Stage IV NSCLC (pathological characterization must determine the non-squamous or squamous histological subtype as well as adenocarcinoma subtype classification) HER2 status of IHC 2+ or 3+ as determined by a Sponsor-designated central laboratory Prior treatment with at least one regimen of platinum-based (cisplatin or carboplatin) chemotherapy in the locally advanced or metastatic setting/recurrent NSCLC with documented disease progression by investigator assessment Participants with a known anaplastic lymphoma kinase (ALK) fusion oncogene (must be documented in the participant's chart) must have also experienced disease progression or intolerance with a first-line ALK Tyrosine Kinase Inhibitor (TKI) approved for the treatment of ALK fusion oncogene NSCLC (for example, crizotinib). Disease progression or intolerance must be documented Participants with a known mutation in the epidermal growth factor receptor (EGFR) gene (must be documented in the participant's chart) must have also experienced disease progression or intolerance with an EGFR TKI approved for the treatment of EGFR-mutant NSCLC (for example, gefitinib, erlotinib, afatinib). Disease progression or intolerance must be documented Measurable disease determined as per the RECIST v1.1 Life expectancy of at least (>/=) 12 weeks Adequate organ function Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Left ventricular ejection fraction (LVEF) >/= 50 percent (%) by either echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan Use of highly effective contraception Exclusion Criteria: Cancer-Related Criteria: Any approved anti-cancer therapy less than or equal to (</=) 21 days (including chemotherapy or hormonal therapy) before the first study treatment; the following exceptions are allowed: (1) TKIs approved for the treatment of NSCLC must be discontinued greater than (>) 7 days prior to the first study treatment on D1C1 (The baseline computed tomography [CT] scan must be completed after discontinuation of TKIs); (2) Hormone-replacement therapy or oral contraceptives; (3) Anti-emetics, Granulocyte-colony stimulating factor (GCS-F), and prophylactic antibiotics according to local standards Investigational therapy participation in another clinical study with therapeutic intent </= 21 days before first study treatment Previous irradiation is permitted if >/=14 days since the last fraction of radiotherapy have elapsed before the first study treatment on Day 1 as long as a sufficient number of target lesions remain to allow for measurable disease as per RECIST v1.1 Participants who have untreated brain metastases or are symptomatic; participants with treated brain metastases must have discontinued corticosteroid therapy and not have any neurological symptoms History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity to trastuzumab or murine proteins or any excipient of the product History of exposure to the following cumulative doses of anthracyclines: Doxorubicin or liposomal doxorubicin > 500 milligram per meter-square (mg/m^2); Epirubicin > 900 mg/m^2; Mitoxantrone > 120 mg/m^2. If another anthracycline, or more than one anthracycline, has been used, the cumulative dose must not exceed the equivalent of 500 mg/m^2 doxorubicin Peripheral neuropathy of Grade >/= 3 per the National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.0 (NCI CTCAE v. 4.0) History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other cancers with a similar outcome as those mentioned above Cardiopulmonary Function Criteria: Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures Severe dyspnea at rest due to complications of advanced malignancy or requiring current continuous oxygen therapy Clinical history of active hemoptysis Evidence of active pneumonitis during screening Current unstable ventricular arrhythmia requiring treatment History of symptomatic congestive heart failure (CHF) New York Heart Association (NYHA) classes II-IV History of myocardial infarction or unstable angina within 6 months of enrollment History of a decrease in LVEF to <50% General Criteria: Current severe, uncontrolled systemic disease (for example, clinically significant cardiovascular, pulmonary, or metabolic disease) Major surgical procedure or significant traumatic injury within 28 days before enrollment or anticipation of the need for major surgery during the course of study treatment Current pregnancy or lactation Current known active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort IHC2+<br>Participants with HER2 IHC2-positive (IHC 2+) locally advanced or metastatic NSCLC, who had received at least one prior platinum-based chemotherapy regimen, will receive trastuzumab emtansine. | Drug: Trastuzumab Emtansine<br>* Trastuzumab emtansine will be administered intravenously (IV) at a dose of 3.6 mg/kg on Day 1 of every 21-day cycle until disease progression (as assessed by the investigator), unmanageable toxicity, or study termination by the sponsor, whichever occurs first.<br>* Other names: Kadcyla, T-DM1;|
| Experimental: Cohort IHC3+<br>Participants with HER2 IHC3-positive (IHC 3+) locally advanced or metastatic NSCLC, who had received at least one prior platinum-based chemotherapy regimen, will receive trastuzumab emtansine. | Drug: Trastuzumab Emtansine<br>* Trastuzumab emtansine will be administered intravenously (IV) at a dose of 3.6 mg/kg on Day 1 of every 21-day cycle until disease progression (as assessed by the investigator), unmanageable toxicity, or study termination by the sponsor, whichever occurs first.<br>* Other names: Kadcyla, T-DM1;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Objective Response as Per Investigator Assessment According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v. 1.1) | Objective response is defined as a complete response (CR) or partial response (PR) determined on two consecutive assessments ≥ 4 weeks apart, based on investigator assessment according to RECIST, Version 1.1. CR: disappearance of all target lesions; and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 millimeters (mm). PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. | From Day 1 to disease progression (PD) or death from any cause, up to the clinical cutoff date (approximately 22 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Died |  | From Day 1 to death from any cause, up to the study completion date (approximately 43 months) | 
| Overall Survival (OS) | OS is defined as the time from first study drug administration to death from any cause. | From Day 1 to death from any cause, up to the study completion date (approximately 43 months) | 
| Percentage of Participants With PFS Event of Disease Progression, as Per Investigator Assessment According to RECIST v. 1.1, or Death | PFS is defined as the time from first study drug administration to first documented disease progression, based on investigator assessment using RECIST, v1.1, or death from any cause during the study, whichever occurs first. Disease progression is defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. | From Day 1 to PD or death from any cause, up to the study completion date (approximately 43 months) | 
| Progression-Free Survival (PFS) as Per Investigator Assessment According to RECIST v. 1.1 | PFS is defined as the time from first study drug administration to first documented disease progression, based on investigator assessment using RECIST, v1.1, or death from any cause during the study, whichever occurs first. Disease progression is defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. | From Day 1 to PD or death from any cause, up to the study completion date (approximately 43 months) | 
| Percentage of Participants With DOR Event of Disease Progression, Assessed According to RECIST v1.1 | DOR is defined as the time from the initial documentation of response (CR or PR using RECIST, v1.1) to documented disease progression using RECIST v1.1 or death from any cause during the study. CR: disappearance of all target lesions; and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Disease progression: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. | From first documented objective response to PD or death from any cause, up to the study completion date (approximately 43 months) | 
| Duration of Objective Response (DOR) Assessed According to RECIST v1.1 | DoR is defined as the time from the initial documentation of response (CR or PR using RECIST, v1.1) to documented disease progression using RECIST v1.1 or death from any cause during the study. CR: disappearance of all target lesions; and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Disease progression: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. | From first documented objective response to PD or death from any cause, up to the study completion date (approximately 43 months) | 
| Percentage of Participants With Clinical Benefit as Per Investigator Assessment According to RECIST, v1.1 | Clinical benefit is defined as having a CR or PR or stable disease (using RECIST, v1.1) at 6 months. Participants with no post-baseline response assessment are considered as experiencing no clinical benefit. CR: disappearance of all target lesions; and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Stable disease: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum while in the study. Disease progression: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; the appearance of one or more new lesions. | From Day 1 to PD or death from any cause, up to the study completion date (approximately 43 months) | 
| Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) | An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, whether or not considered related to the study drug. A SAE is any experience that: results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is medically significant. | From Day 1 to 30 days after last dose of study drug, up to the study completion date (approximately 43 months) | 
| Maximum Observed Concentration (Cmax) for Trastuzumab Emtansine and Total Trastuzumab | Cmax is the 0-21 day maximum observed concentration of a drug and was measured in blood serum. | Pre-dose (within 2 days) and 30 minutes (min) after end of infusion (infusion length= 100 min or less) on Day 1 of Cycles 1 and 3 (one cycle=21 days); at treatment discontinuation/early termination, up to primary analysis, approx. 22 months | 
| AUCinf for Trastuzumab Emtansine and Total Trastuzumab | AUC (from zero to infinity) represents the total drug exposure over time in blood serum. | Pre-dose & 30 minutes (min) post-infusion (inf.) on Day (D) 1 of Cycles (C) 1 & 3; post- inf. on D 2, 3, 4 or 5, 8, & 15 of C 1, & pre- inf. on D1 of C2 & D1 of C 4 (C=21 D); at discontin./termination, up to primary analysis, approx. 22 months | 
| Elimination Half-Life (t1/2) for Trastuzumab Emtansine and Total Trastuzumab | t1/2 is the time required for the drug serum concentration to be reduced to half. | Pre-dose & 30 minutes (min) post-infusion (inf.) on D 1 of C 1 & 3; post- inf. on D 2, 3, 4 or 5, 8, & 15 of C 1, & pre- inf. on D 1 of C 2 & D 1 of C 4 (C=21 days); at treatment discontin./early termination, up to primary analysis, approx. 22 months | 
| Volume of Distribution (Vss) for Trastuzumab Emtansine and Total Trastuzumab | Vss is the volume of distribution of study drug at steady state. | Pre-dose & 30 minutes (min) post-infusion (inf.) on D1 of C1 & 3; post- inf. on D2, 3, 4 or 5, 8, & 15 of C 1, & pre- inf. on D 1 of C 2 & D1 of C 4 (C=21 days); at treatment discontin/early termination, up to primary analysis, approx. 22 months | 
| Clearance (CL) for Trastuzumab Emtansine and Total Trastuzumab | CL is a measure of the body's elimination of a drug from blood serum over time. | Pre-dose & 30 minutes (min) post-infusion (inf.) on D 1 of C 1 & 3; post- inf. on D 2, 3, 4 or 5, 8, & 15 of C 1, & pre- inf. on D 1 of C 2 & D 1 of C 4 (C=21 days); at treatment discontin/early termination, up to primary analysis, approx. 22 months | 
| Maximum Observed Concentration (Cmax) for N2'- Deacetyl-N2'-(3-mercapto-1-oxopropyl)-Maytansine (DM1) | Cmax is the maximum observed concentration of a drug and was measured in blood plasma. | Pre-dose (within 2 days) and 30 minutes (min) after end of infusion (infusion length= 100 min or less) on Day 1 of Cycle 1 (one cycle=21 days); at treatment discontinuation/early termination,up to primary analysis, approx. 22 months | 
| Percentage of Participants With Treatment-Emergent Anti-Drug Antibodies (ADAs) | The presence of ADAs in blood serum is an indication of the body's immune response to a drug. | Pre-dose (within 2 days) on Day 1 of Cycles 1 and 3; at treatment discontinuation/early termination,up to primary analysis, approx. 22 months |