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

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.