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)

Non-Small Cell Lung Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02289833
• Other study ID #: BO29389
• Secondary ID: 2014-001237-83
• Status: Completed
• Phase: Phase 2
• Start date: December 15, 2014
• Est. completion date: August 20, 2018

Study information

• Verified date: July 2019
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 49
• Est. completion date: August 20, 2018
• Est. primary completion date: October 25, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-Small Cell Lung Cancer

Intervention

Drug:
• Trastuzumab Emtansine
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.

Locations

Country	Name	City	State
Germany	HELIOS Klinikum Emil von Behring Klinik f.Pneumologie Onkologie u.Infektiologie	Berlin
Germany	Kaiserswerther Diakonie Florence Nightingale-Krankenh. Tagesklinik f.Onkologie	Düsseldorf
Germany	Asklepios-Fachkliniken Muenchen-Gauting; Onkologie	Gauting
Germany	Krankenhaus Martha-Maria Halle-Doelau gGmbH; Klinik fuer Innere Medizin II	Halle
Germany	Fachklinik für Lungenerkrankungen	Immenhausen
Italy	Istituto Europeo Di Oncologia	Milano	Lombardia
Italy	Azienda Ospedaliera Univ Parma; Dept Oncologia Medica	Parma	Emilia-Romagna
Korea, Republic of	Asan Medical Center - Oncology	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Poland	Medical University of Gdansk	Gdansk
Poland	Mazowieckie Centrum Leczenia Chorob Pluc I Gruzlicy; Oddzial Iii	Otwock
Poland	Centrum Onkologii - Instytut im. Marii Sklodowskiej-Curie Klinika Nowotworów Piersi i Chirurgii	Warszawa
Spain	Hospital Univ Vall d'Hebron; Servicio de Oncologia	Barcelona
Spain	Hospital Ramon y Cajal; Servicio de Oncologia	Madrid
Spain	Hospital Universitario La Paz; Servicio de Oncologia	Madrid
Spain	Hospital Clinico Universitario Lozano Blesa; Servicio de Oncologia	Zaragoza
Switzerland	CHUV; Departement d'Oncologie	Lausanne
Switzerland	UniversitätsSpital Zürich; Zentrum für Hämatologie und Onkologie, Klinik für Onkologie	Zürich
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Rush University Medical Center	Chicago	Illinois
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	Cancer Specialists; North Florida ;Jacksonville (AC Skinner Pkwy)	Jacksonville	Florida
United States	Seattle Cancer Care Alliance	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Germany,  Italy,  Korea, Republic of,  Poland,  Spain,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Percentage of Participants Who Died		From Day 1 to death from any cause, up to the study completion date (approximately 43 months)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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