A Study of IMGN901 for Patients With Advanced Solid Tumors and Extensive Stage Small Cell Lung Cancer
- Conditions
- Small Cell Lung Cancer
- Interventions
- Registration Number
- NCT01237678
- Lead Sponsor
- ImmunoGen, Inc.
- Brief 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.
- Detailed 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 & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 181
- 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
- Pregnant or lactating females
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Carboplatin and Etoposide Carboplatin and Etoposide Patients will receive Carboplatin and etoposide for up to 6 cycles. IMGN901 with carboplatin and etoposide IMGN901 Patients will receive IMGN901 along with carboplatin and etoposide for up to 6 cycles and then be able to continue on IMGN901 alone until no further benefit or toxicity.
- Primary Outcome Measures
Name Time Method Occurrence of Dose Limiting Toxicities (DLT) 21 days (Cycle 1) 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)
Maximum Tolerated Dose (MTD) of IMGN901 21 days (Cycle 1) 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.
Progression Free Survival (PFS) in Phase II From randomization to objective tumor progression or death (up to post-treatment follow-up 28 days after last dose, up to 22 months) 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.
- Secondary Outcome Measures
Name Time Method Overview of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) From the first dose of study drug on Cycle 1, Day 1 until 28 days after the last study treatment (up to 22 months) 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.
Median Overall Survival (OS) in Phase II 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) 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.
Progression Free Survival (PFS) Rate at 6 Months 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.
Overall Survival (OS) Rate at 12 Months 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.
Trial Locations
- Locations (47)
Johns Hopkins University
🇺🇸Baltimore, Maryland, United States
Hospital Universitario Virgen del Rocio
🇪🇸Sevilla, Spain
Royal Marsden, London
🇬🇧London, United Kingdom
Univeristy of Pittsburg Medical Center
🇺🇸Pittsburgh, Pennsylvania, United States
Hospital Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital de la Santa Creu y Sand Pau
🇪🇸Barcelona, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Hospital Universitario
🇪🇸Madrid, Spain
UCLA Oncology Center
🇺🇸Westlake Village, California, United States
UCLA Oncology Clinic
🇺🇸Santa Monica, California, United States
UCLA Santa Clarita Valley Cancer Center
🇺🇸Valencia, California, United States
University Hospitals of Cleveland
🇺🇸Cleveland, Ohio, United States
UPMC Cancer Centers East, Oxford Drive
🇺🇸Monroeville, Pennsylvania, United States
The Christie Hospital
🇬🇧Withington, Manchester, United Kingdom
St. Joseph's Hospital
🇺🇸Orange, California, United States
Johnson Therurer Cancer Center at Hackensack
🇺🇸Hackensack, New Jersey, United States
UPMC Cancer Center St. Margaret
🇺🇸Pittsburgh, Pennsylvania, United States
South Carolina Oncology Associates
🇺🇸Columbia, South Carolina, United States
UPMC Cancer Center at UPMC Passavant (HOA)
🇺🇸Pittsburgh, Pennsylvania, United States
University of Tennessee Medical Center Cancer Institute
🇺🇸Knoxville, Tennessee, United States
Northwest Medical Specialties
🇺🇸Tacoma, Washington, United States
Barbara Ann Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Oklahoma University
🇺🇸Oklahoma City, Oklahoma, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Sarah Cannon Research Institute
🇺🇸Nashville, Tennessee, United States
UTHSC at San Antonio
🇺🇸San Antonio, Texas, United States
Greater Baltimore Medical Center
🇺🇸Baltimore, Maryland, United States
Royal Victoria
🇨🇦Montreal, Quebec, Canada
Sibley Memorial Hospital
🇺🇸Washington, District of Columbia, United States
Holy Cross Hospital Bienes Comprehensive Cancer Center
🇺🇸Fort Lauderdale, Florida, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Arizona Cancer Center @ UMC North
🇺🇸Tucson, Arizona, United States
University College of London
🇬🇧London, England, United Kingdom
Bayview Medical Center
🇺🇸Baltimore, Maryland, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
Royal Sussex Hospital
🇬🇧Brighton, East Sussex, United Kingdom
Yale Medical Center
🇺🇸New Haven, Connecticut, United States
University of Florida
🇺🇸Gainesville, Florida, United States
Anne Arundel Medical Center
🇺🇸Annapolis, Maryland, United States
Juravinski Cancer Center
🇨🇦Hamilton, Ontario, Canada
Montreal General Hospital
🇨🇦Montreal, Quebec, Canada
Royal Marsden
🇬🇧Sutton, Surrey, United Kingdom
Corporacio Sanitaria Parc Tauli
🇪🇸Sabadell, Barcelona, Spain
St. Mary's Hospital
🇨🇦Montreal, Quebec, Canada
UCLA Hematology
🇺🇸Pasadena, California, United States