A Study of IMGN901 for Patients With Advanced Solid Tumors and Extensive Stage Small Cell Lung Cancer

Small Cell Lung Cancer Clinical Trial

Official title:

A Phase 1/2 Study to Assess the Safety and Efficacy of Lorvotuzumab Mertansine in Combination With Carboplatin/Etoposide in Patients With Advanced Solid Tumors Including Extensive Stage Small Cell Lung Cancer

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01237678
• Other study ID #: Immunogen 0007
• Status: Terminated
• Phase: Phase 1/Phase 2
• First received: November 8, 2010
• Last updated: December 19, 2017
• Start date: November 2010
• Est. completion date: May 2015

Study information

• Verified date: December 2017
• Source: ImmunoGen, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to test safety and efficacy of this combination treatment (IMGN901, carboplatin and etoposide) in patients with solid tumors and extensive stage small cell lung cancer.

Description:

Small-Cell Lung Cancer (SCLC) is a neuroendocrine cancer of the lung that is typically caused by smoking. Patients generally present with symptoms of cough, dyspnea, pain and weakness, and often have extensive disease at that time. It is estimated that 13% of lung cancers are SCLC in origin1. Approximately 28,530 new cases of SCLC were expected in 2009 based on an estimate of 219,440 new cases of any cancer of the lung in the US in 20092.

There are 2 stages of the disease: limited-stage disease (LD) and extensive-stage disease (ED). SCLC-LD is confined to a region of the chest (the hemithorax and mediastinum) that is more amenable to radiation therapy. Thirty percent (30%) of patients present with SCLC-LD. The remaining patients (70%) present with SCLC-ED, in which the disease has progressed outside this region of the chest. Common sites of metastatic disease include the contralateral lung, liver, adrenal glands, brain, bones and/or bone marrow3. Recurrence after therapy is typical. In the rare patient who has longer-term survival, secondary malignancies (new SCLC tumors and other malignancies) are common because of long-term exposure to carcinogens.

SCLC is very responsive to chemotherapy and radiation therapy, having response rates of up to 80%4-7. In limited stage disease, the standard treatment is 'combined-modality therapy' consisting of combination chemotherapy such as cisplatin plus etoposide followed by thoracic radiation therapy. Surgery is rarely used.

Despite high response rates, therapy is rarely curative due to high rates of recurrence and metastasis. Overall 5-year survival for SCLC patients is 4%5. SCLC-LD patients typically achieve median survival of 14 to 24 months after therapy, with a 2-year survival rate of 40% to 50%. This survival rate drops to about 20% at 5 years4-7. SCLC-ED patients achieve a median survival of 8 to 12 months on therapy8.

Patients will typically have recurrent disease after therapy. While many of these patients may be eligible for further chemotherapy, survival at this stage is usually less than 6 months.

No treatment modality has a significant impact on overall survival. Studies utilizing regimens with greater numbers of chemotherapeutic agents or longer therapy duration have not improved survival. Thus, a new therapy that can improve survival is needed.

IMGN901 is an antibody drug conjugate which is anticipated to result in lower systemic toxicity and greater efficacy than currently available therapies based on its specific and high affinity binding to its target antigen, CD56. This antigen has been shown to be present in almost all cases of SCLC (~ 95% based on in-house data). In in vivo studies, IMGN901 has demonstrated potent anti-tumor activity against CD56-positive carcinomas including xenograft models of SCLC as well as complete regressions when combined with cisplatin/etoposide. Preliminary clinical activity of single agent IMGN901 based on data from two Phase 1 studies shows a disease control rate (PR and SD, defined as non-progression for at least 75 days) estimated to be 24% in a heterogeneous population of patients with pretreated and drug resistant SCLC. Additional data supportive of the potential activity of IMGN901 includes complete responses and clinically relevant stable disease in patients with MCC (clinical benefit rate = 39%). Further, the tolerability profile demonstrating minimal myelosuppression with administration of IMGN901 is supportive of exploring its use in combination with established chemotherapy regimens.

IMGN901 is supportive of exploring its use in combination with established chemotherapy regimens.

Therefore, the Phase 1 portion of this study is designed to first determine the MTD, presumably the recommended Phase 2 dose, of IMGN901 when administered in combination with carboplatin/etoposide treatment and to characterize the safety, tolerability, PK, pharmacodynamics, immunogenicity, and preliminary anti-tumor activity of this triplet combination.

Improvement in disease control and survival of patients with SCLC-ED remains a major therapeutic challenge. New agents with better activity and tolerability are needed for this population. However, because large-scale clinical studies often are necessary to demonstrate the safety and effectiveness of these new agents, it is desirable to first evaluate some measure of relative effectiveness in a Phase 2 study.

Therefore the Phase 2 portion of the study will utilize a Simon two-stage design in which the activity of IMGN901 will be assessed by comparing the PFS rate at six months in the IMGN901 experimental arm (triplet combination) against the historical 6 month PFS rate of 0.44 (equivalently a median PFS = 5 months). In this study, an improvement of 2.5 months in median PFS will be deemed clinically relevant and correlates to a PFS rate of 0.58 (HR = 0.667). The control arm will be used primarily to reliably assess the safety of IMGN901 and will further serve as an informal validation of the historical data.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 181
• Est. completion date: May 2015
• Est. primary completion date: May 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients must be 18 years old

• Patients must have been diagnosed with small-cell lung cancer (SCLC) and extensive disease

• ECOG performance status of 0, 1, or 2

• No prior systemic chemotherapy for the treatment of SCLC

Exclusion Criteria:

• Pregnant or lactating females

Related Conditions & MeSH terms

• Lung Neoplasms
• Small Cell Lung Cancer
• Small Cell Lung Carcinoma

Intervention

Drug:
• IMGN901
Phase 2 regimen is IMGN901, Carboplatin, and Etoposide. IMGN901 to be given on days 1 and 8 every 21 days.
• Carboplatin and Etoposide
Patients assigned to Arm 2 were to receive carboplatin at the same AUC as utilized in Arm 1

Locations

Country	Name	City	State
Canada	Juravinski Cancer Center	Hamilton	Ontario
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Montreal General Hospital	Montreal	Quebec
Canada	Royal Victoria	Montreal	Quebec
Canada	St. Mary's Hospital	Montreal	Quebec
Spain	Hospital de la Santa Creu y Sand Pau	Barcelona
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital Universitario	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Corporacio Sanitaria Parc Tauli	Sabadell	Barcelona
Spain	Hospital Universitario Virgen del Rocio	Sevilla
United Kingdom	Royal Sussex Hospital	Brighton	East Sussex
United Kingdom	Royal Marsden, London	London
United Kingdom	University College of London	London	England
United Kingdom	Royal Marsden	Sutton	Surrey
United Kingdom	The Christie Hospital	Withington	Manchester
United States	Anne Arundel Medical Center	Annapolis	Maryland
United States	Bayview Medical Center	Baltimore	Maryland
United States	Greater Baltimore Medical Center	Baltimore	Maryland
United States	Johns Hopkins University	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University Hospitals of Cleveland	Cleveland	Ohio
United States	South Carolina Oncology Associates	Columbia	South Carolina
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Holy Cross Hospital Bienes Comprehensive Cancer Center	Fort Lauderdale	Florida
United States	University of Florida	Gainesville	Florida
United States	Johnson Therurer Cancer Center at Hackensack	Hackensack	New Jersey
United States	University of Tennessee Medical Center Cancer Institute	Knoxville	Tennessee
United States	UCLA Oncology Center	Los Angeles	California
United States	UPMC Cancer Centers East, Oxford Drive	Monroeville	Pennsylvania
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Yale Medical Center	New Haven	Connecticut
United States	Oklahoma University	Oklahoma City	Oklahoma
United States	St. Joseph's Hospital	Orange	California
United States	UCLA Hematology	Pasadena	California
United States	Univeristy of Pittsburg Medical Center	Pittsburgh	Pennsylvania
United States	UPMC Cancer Center at UPMC Passavant (HOA)	Pittsburgh	Pennsylvania
United States	UPMC Cancer Center St. Margaret	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	UTHSC at San Antonio	San Antonio	Texas
United States	UCLA Oncology Clinic	Santa Monica	California
United States	Northwest Medical Specialties	Tacoma	Washington
United States	Arizona Cancer Center @ UMC North	Tucson	Arizona
United States	UCLA Santa Clarita Valley Cancer Center	Valencia	California
United States	Sibley Memorial Hospital	Washington	District of Columbia
United States	UCLA Oncology Center	Westlake Village	California

Sponsors (1)

Lead Sponsor	Collaborator
ImmunoGen, Inc.

Countries where clinical trial is conducted

United States,  Canada,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Occurrence of Dose Limiting Toxicities (DLT)	The primary outcome measure for Phase I was to determine the maximum tolerated dose (MTD) and characterize the dose limiting toxicities (DLT) of IMGN901 when administered in combination with carboplatin/etoposide chemotherapy followed by IMGN901 alone in patients with solid tumors. For the purposes of dose escalation and determination of MTD, DLTs were defined as AEs or abnormal laboratory values related to study treatment which occurred in Cycle 1 of the Dose Escalation phase, including any AEs that resulted in failure to meet the criteria for re-treatment. The following events were considered DLTs (using the most current version of CTCAE): febrile neutropenia; Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding; = Grade 3 peripheral neuropathy; = Grade 3 vomiting, nausea, or diarrhea that persisted despite the use of optimal therapy; other = grade 3 non-hematologic toxicity (with the exception of brief fatigue i.e. = 72 hours and alopecia)	21 days (Cycle 1)
Primary	Progression Free Survival (PFS) in Phase II	The primary outcome measure for Phase II was to determine the efficacy of IMGN901 in combination with carboplatin/etoposide chemotherapy as first-line treatment for patients with extensive stage small cell lung cancer. PFS was defined as the time from enrollment until objective tumor progression according to RECIST 1.1 or death on study due to any cause, whichever occurred first. Only the results from the experimental arm (IMGN901 + carboplatin + etoposide) are presented as the primary objective of this phase of the study was to compare PFS in the experimental arm (triplet combination) against historical PFS rates for carboplatin and etoposide. The control arm was planned primarily to reliably assess the safety of IMGN901 and to demonstrate whether the or not the historical assumptions regarding efficacy were confirmed.	From randomization to objective tumor progression or death (up to post-treatment follow-up 28 days after last dose, up to 22 months)
Primary	Maximum Tolerated Dose (MTD) of IMGN901	A primary outcome measure for Phase I was to determine the maximum tolerated dose (MTD) of IMGN901 when administered in combination with carboplatin/etoposide chemotherapy followed by IMGN901 alone in patients with solid tumors. The MTD was determined based on DLTs that occurred during Cycle 1.	21 days (Cycle 1)
Secondary	Overview of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	To assess the type and frequency of Adverse Events (AEs) and Serious Adverse Events (SAEs). An AE was defined as any noxious, pathologic, or unintended change un anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of the study, whether or not deemed study drug-related. An SAE was any AE resulting in death, life-threatening experience, initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, or congenital defect. All AEs were reported from the time of the first dose of study treatment until 28 days after the final dose of study drug. the severity of AEs were graded by the Investigator using National cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE) version 4.0.	From the first dose of study drug on Cycle 1, Day 1 until 28 days after the last study treatment (up to 22 months)
Secondary	Progression Free Survival (PFS) Rate at 6 Months	The trial was not empowered to permit a statistically informative comparison of the randomized treatment groups with respect to PFS. The activity of IMGN901 was assessed by comparing the PFS rate at 6 months in the IMGN901 experimental arm against the historical 6-month PFS rate of 0.44 (equivalently a median PFS = 5 months). Only the results from the experimental arm (IMGN901 + carboplatin + etoposide) are presented as the objective was to compare PFS at 6 months in the experimental arm (triplet combination) against the historical PFS rate of 0.44 (equivalently a median PFS = 5 months) for carboplatin and etoposide. The control arm was planned primarily to reliably assess the safety of IMGN901 and to demonstrate whether the or not the historical assumptions regarding efficacy were confirmed.	6 months
Secondary	Median Overall Survival (OS) in Phase II	A secondary outcome measure for Phase II was to determine the overall survival of patients treated with IMGN901 in combination with carboplatin/etoposide chemotherapy versus carboplatin/etoposide chemotherapy alone as first-line treatment for patients with extensive stage small cell lung cancer.	From the time of enrollment until death on study due to any cause (up to post-treatment follow-up 28 days after last dose, up to 22 months)
Secondary	Overall Survival (OS) Rate at 12 Months	OS was analyzed based on a binary definition of the number of patients dead or censored prior to 12 months and the number of patients alive at 12 months. The primary objective of this phase of the study was to compare PFS in the experimental arm (triplet combination) against historical PFS rates. The control arm was primarily planned to demonstrate whether the or not the historical assumptions regarding efficacy were confirmed. Further, the trial was not empowered to permit a statistically informative comparison of the randomized treatment groups with respect to OS and no determination of the OS rate at 12 months for the control arm was performed; therefore only the results from the experimental arm (IMGN901 + carboplatin + etoposide) are presented.	12 months