Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Rare Diseases

Small Cell Lung Carcinoma

Lung Neoplasms

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Small Cell Lung Cancer

Antineoplastic Agents

All Drugs and Chemicals

Carboplatin

Etoposide

Etoposide phosphate

Lorvotuzumab mertansine

Enzyme Inhibitors

Antineoplastic Agents, Immunological

Immunotoxins

Immunoconjugates

Immunologic Factors

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.

Patients will receive Carboplatin and etoposide for up to 6 cycles.

Phase 2 regimen is IMGN901, Carboplatin, and Etoposide. IMGN901 to be given on days 1 and 8 every 21 days.

IMGN901

Patients assigned to Arm 2 were to receive carboplatin at the same AUC as utilized in Arm 1

Carboplatin and Etoposide

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.

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.

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

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

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)

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.

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.

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.

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.

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.

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.

ImmunoGen, Inc.

AEs and laboratory results were graded using the NCI CTCAE, version 4.0.

Participants received IMGN901 on Days 1 and 8 of a 21-day cycle. All patients also received carboplatin on Day 1 and etoposide (100 mg/m2) on Days 1, 2, and 3 of each 21-day cycle. The starting dose of IMGN901 was 60 mg/m2; dose escalation proceeded, as tolerated, through 75, 90, and 112 mg/m2. Carboplatin was originally dosed at an AUC 6 however due to poor tolerability this was reduced to an AUC of 5. Study drug combinations were administered for four cycles, with up to 6 cycles allowed. IMGN901 was continued as monotherapy for patients who achieved a response or stable disease.

Phase I - IMGN901 + Carboplatin + Etoposide

IMGN901 was administered at the RP2D determined in Phase I (112 mg/m2; later reduced to 90 mg/m2) on Days 1 and 8 of each 21-day cycle. Patients also received carboplatin (AUC 5) on Day 1 and etoposide (100 mg/m2) on Days 1, 2, and 3 of each 21-day cycle. Study drug combinations were administered for four cycles, with up to 6 cycles allowed. IMGN901 was continued as monotherapy for patients who achieved a response or stable disease.

Phase II - IMGN901 + Carboplatin + Etoposide

Carboplatin (AUC 5) was administered on Day 1 and etoposide (100 mg/m2) on Days 1, 2, and 3 of each 21-day cycle. Drugs were administered for 6 cycles as tolerated.

Phase II - Carboplatin + Etoposide

Participants received IMGN901 on Days 1 and 8 of a 21-day cycle. All patients also received carboplatin on Day 1 and etoposide on Days 1, 2, and 3 of each 21-day cycle.The starting dose of IMGN901 was 60 mg/m2; dose escalation proceeded, as tolerated, through 75, 90, and 112 mg/m2. Carboplatin was originally dosed at an AUC 6 however due to poor tolerability this was reduced to an AUC of 5. Study drug combinations were administered for four cycles, with up to 6 cycles allowed. IMGN901 was continued as monotherapy for patients who achieved a response or stable disease.

Total

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

0 = Fully active, able to carry out all pre-disease performance without restriction.

1. = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.
2. = Ambulatory and capable of all self-care but unable to carry out work activities. Up and about more than 50% of waking hours.

Eastern Cooperative Oncology Group (ECOG) Performance Status

History of Smoking

Dr. Richard Bates, Sr. Manager, Publications

Grade 3 febrile neutropenia

Grade 4 febrile neutropenia

Grade 4 thrombocytopenia

Grade 4 granulocytopenia

Grade 3 lobar pneumonia

IMGN901 60 mg/m2 + Carboplatin AUC 6 + Etoposide 100 mg/m2

IMGN901 75 mg/m2 + Carboplatin AUC 6 + Etoposide 100 mg/m2

IMGN901 75 mg/m2 + Carboplatin AUC 5 + Etoposide 100 mg/m2

IMGN901 90 mg/m2 + Carboplatin AUC 5 + Etoposide 100 mg/m2

IMGN901 112 mg/m2 + Carboplatin AUC 5 + Etoposide 100 mg/m2

A total of 33 patients were analyzed as part of the Dose escalation phase.

Occurrence of Dose Limiting Toxicities (DLT)

A total of 82 patients from the IMGN901 + carboplatin + etoposide safety population (N=94) were included in the efficacy analyses, due to the lack of post-baseline evaluations for 12 participants.

Progression Free Survival (PFS) in Phase II

During escalation, carboplatin dosing was reduced from AUC 6 to AUC 5 due to poor tolerability; therefore the MTD for IMGN901 was determined in combination with carboplatin AUC5 and 100 mg/m\^2 etoposide

Maximum Tolerated Dose (MTD) of IMGN901

Any TEAE

Related TEAE

Any SAE

Related SAE

TEAEs leading to discontinuation

Any Grade ≥ 3 TEAE

Related Grade ≥ 3 TEAE

Deaths within 28 days of last dose

Overview of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Progression Free Survival (PFS) Rate at 6 Months

A total of 121 patents were included in the analyses (82 in Arm1 and 39 in Arm 2) due to due to the lack of post-baseline evaluations for 20 participants.

Median Overall Survival (OS) in Phase II

Overall Survival (OS) Rate at 12 Months

IMGN901 was administered at the RP2D (recommended phase II dose) determined in Phase I (112 mg/m2; later reduced to 90 mg/m2) on Days 1 and 8 of each 21-day cycle. Patients also received carboplatin (AUC 5) on Day 1 and etoposide (100 mg/m2) on Days 1, 2, and 3 of each 21-day cycle. Study drug combinations were administered for four cycles, with up to 6 cycles allowed. IMGN901 was continued as monotherapy for patients who achieved a response or stable disease.

Phase I - IMGN901+Carboplatin+Etoposide

Phase II

Antibodies

Antibodies, Monoclonal

Immunoglobulins

HLX07+HLX 10+Chemotherapy (Carboplatin-Etoposide)

HLX07 is a recombinant humanized anti-EGFR monoclonal antibody injection, developed by Shanghai Henlius Biotech, Inc.

HLX07

HLX10 is a recombinant humanized anti-PD-1 monoclonal antibody injection, developed by Shanghai Henlius Biotech, Inc.

HLX10

carboplatin and etoposide

Xuhui Hu, MD

Ying Cheng, MD

This study is conducted in patients with advanced metastatic small cell lung cancer (SCLC). This study includes a single arm: the patients will receive HLX07 combination therapy with HLX10 and chemotherapy (carboplatin+etoposide) as first-line treatment. All of eligible patients will receive study drug treatment until loss of clinical benefit, unacceptable toxicity, death, withdrawal of informed consent (whichever occurs first, HLX10 treatment up to 2 years).

A Clinical Study to Evaluate the Efficacy and Safety of HLX07 Combination Therapy in Patients With Extensive Small Cell Lung Cancer

An Open-label, Multicenter, Phase II Clinical Study to Evaluate the Efficacy and Safety of HLX07 (Recombinant Humanized Anti-EGFR Monoclonal Antibody Injection) + HLX10 (Recombinant Humanized Anti-PD-1 Monoclonal Antibody Injection) + Chemotherapy in Patients With Extensive Small Cell Lung Cancer (ES-SCLC)

Objective response rate by investigator assessment per RECIST 1.1

Progression-free survival by investigator assessment per RECIST v1.1

Shanghai Henlius Biotech

Obatoclax

Obatoclax Mesylate:

30 mg fixed dose;administered IV on days 1-3 every 21 days for 6 cycles. Maintenance therapy (optional and only if documented CR or PR) with obatoclax mesylate is administered at the same IV dose on days 1-3 every 21 days until disease progression or death.

Carboplatin:

Dose targeted at AUC of 5; administered IV on Day 1 only every 21 days for 6 cycles

Etoposide:

100mg/m2 administered IV on Days 1-3 every 21days for 6 cycles

Obatoclax Mesylate, Carboplatine and Etoposide

Carboplatin:

Dose targeted at AUC of 5 administered IV on Day 1 only every 21 days for 6 cycles.

Etoposide:

100mg/m2 administered IV on Days 1-3 every 21 days for 6 cycles

This is a randomized, multi-center, open-label study of approximately 24 months duration (including follow up survival) to evaluate the safety and efficacy of obatoclax mesylate in combination with carboplatin and etoposide versus carboplatin and etoposide alone in chemotherapy-naive patients with extensive-stage small cell lung cancer.

Efficacy and Safety of Obatoclax Mesylate in Combination With Carboplatin and Etoposide Compared With Carboplatin and Etoposide Alone in Chemotherapy-Naive Patients With Extensive-Stage Small Cell Lung Cancer

A Randomized, Open-Label Study to Evaluate the Efficacy and Safety of Obatoclax Mesylate in Combination With Carboplatin and Etoposide Compared With Carboplatin and Etoposide Alone in Chemotherapy-Naive Patients With Extensive-Stage Small Cell Lung Cancer

After 570 death events have been observed (Interim Analysis after 171 death events)or 24 months from last patient enrolled

Randomization to Date of First Documented Disease Progression or Death for up to 24 months from last patient enrolled

First Response to Disease Progression or Death up to 24 months from last patient enrolled

This is assessed with the European Organization for Research and Treatment of Cancer(EORTC)QLQ-C30 and EORTC QLQ-LC13 questionnaires

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of IMGN901 for Patients With Advanced Solid Tumors and Extensive Stage Small Cell Lung Cancer	NCT01237678	Small Cell Lung...	IMGN901 Carboplatin and...	18 Years -	ImmunoGen, Inc.
A Clinical Study to Evaluate the Efficacy and Safety of HLX07 Combination Therapy in Patients With Extensive Small Cell Lung Cancer	NCT05354700	Small-cell Lung...	HLX07 HLX10 carboplatin and...	18 Years -	Shanghai Henlius Biotech
Efficacy and Safety of Obatoclax Mesylate in Combination With Carboplatin and Etoposide Compared With Carboplatin and Etoposide Alone in Chemotherapy-Naive Patients With Extensive-Stage Small Cell Lung Cancer	NCT01563601	Extensive-stage...	Obatoclax Mesyl... Carboplatin and...	18 Years -	Teva Branded Pharmaceutical Products R&D, Inc.
Efficacy and Safety of Obatoclax Mesylate in Combination With Carboplatin and Etoposide Compared With Carboplatin and Etoposide Alone in Chemotherapy-Naive Patients With Extensive-Stage Small Cell Lung Cancer	NCT01563601	Extensive-stage...	Obatoclax Mesyl... Carboplatin and...	18 Years -	Teva Branded Pharmaceutical Products R&D, Inc.

Spots Global Cancer Trial Database for carboplatin and etoposide