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

• Sponsor: ImmunoGen, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01237678
• Collaborator: (none)
• Enrollment: 181
• Locations: 48
• Arms: 2
• Duration (Months): 53.9
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Small Cell Lung Cancer	Drug: IMGN901; Drug: Carboplatin and Etoposide	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 181 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Study Start Date: Nov 1, 2010
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: May 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IMGN901 with carboplatin and etoposide 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.	Drug: IMGN901; Phase 2 regimen is IMGN901, Carboplatin, and Etoposide. IMGN901 to be given on days 1 and 8 every 21 days.; Other Names: BB-10901, Lorvotuzumab mertansine
Active Comparator: Carboplatin and Etoposide Patients will receive Carboplatin and etoposide for up to 6 cycles.	Drug: Carboplatin and Etoposide; Patients assigned to Arm 2 were to receive carboplatin at the same AUC as utilized in Arm 1; Other Names: Toposar®, VePesid®, Etopophos®

Outcome Measures

Primary Outcome Measures

1. 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)

2. 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.

3. 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.

Secondary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Cancer Center @ UMC North	Tucson	Arizona	United States	85719
2	UCLA Oncology Center	Los Angeles	California	United States	90095
3	St. Joseph's Hospital	Orange	California	United States	92868
4	UCLA Hematology	Pasadena	California	United States	91105
5	UCLA Oncology Clinic	Santa Monica	California	United States	90404
6	UCLA Santa Clarita Valley Cancer Center	Valencia	California	United States	91355
7	UCLA Oncology Center	Westlake Village	California	United States	91361
8	Yale Medical Center	New Haven	Connecticut	United States	06510
9	Sibley Memorial Hospital	Washington	District of Columbia	United States	20016
10	Holy Cross Hospital Bienes Comprehensive Cancer Center	Fort Lauderdale	Florida	United States	33308
11	University of Florida	Gainesville	Florida	United States	32608
12	Anne Arundel Medical Center	Annapolis	Maryland	United States	21401
13	Greater Baltimore Medical Center	Baltimore	Maryland	United States	21204
14	Bayview Medical Center	Baltimore	Maryland	United States	21224
15	Johns Hopkins University	Baltimore	Maryland	United States	21287
16	Massachusetts General Hospital	Boston	Massachusetts	United States	02114-2696
17	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
18	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
19	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201
20	Johnson Therurer Cancer Center at Hackensack	Hackensack	New Jersey	United States	07601
21	University Hospitals of Cleveland	Cleveland	Ohio	United States	44106
22	Oklahoma University	Oklahoma City	Oklahoma	United States	73104-5417
23	Oregon Health and Science University	Portland	Oregon	United States	97239
24	UPMC Cancer Centers East, Oxford Drive	Monroeville	Pennsylvania	United States	15146
25	UPMC Cancer Center St. Margaret	Pittsburgh	Pennsylvania	United States	15215
26	Univeristy of Pittsburg Medical Center	Pittsburgh	Pennsylvania	United States	15232
27	UPMC Cancer Center at UPMC Passavant (HOA)	Pittsburgh	Pennsylvania	United States	15237
28	South Carolina Oncology Associates	Columbia	South Carolina	United States	29210
29	University of Tennessee Medical Center Cancer Institute	Knoxville	Tennessee	United States	37920
30	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
31	UTHSC at San Antonio	San Antonio	Texas	United States	78229
32	Northwest Medical Specialties	Tacoma	Washington	United States	98405
33	Juravinski Cancer Center	Hamilton	Ontario	Canada	L8V 5C2
34	Montreal General Hospital	Montreal	Quebec	Canada	H3G 1A4
35	Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
36	St. Mary's Hospital	Montreal	Quebec	Canada	H3T 1M5
37	Royal Victoria	Montreal	Quebec	Canada	QC H3G
38	Corporacio Sanitaria Parc Tauli	Sabadell	Barcelona	Spain
39	Hospital Vall d'Hebron	Barcelona		Spain	08035
40	Hospital de la Santa Creu y Sand Pau	Barcelona		Spain	08041
41	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
42	Hospital Universitario	Madrid		Spain	28222
43	Hospital Universitario Virgen del Rocio	Sevilla		Spain	41013
44	Royal Sussex Hospital	Brighton	East Sussex	United Kingdom	BN2 5BE
45	University College of London	London	England	United Kingdom	NM12BU
46	The Christie Hospital	Withington	Manchester	United Kingdom	M20 4BX
47	Royal Marsden	Sutton	Surrey	United Kingdom	SM2 5PT
48	Royal Marsden, London	London		United Kingdom	SW3 6JJ

Sponsors and Collaborators

• ImmunoGen, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: ImmunoGen, Inc.
• ClinicalTrials.gov Identifier: NCT01237678
• Other Study ID Numbers: Immunogen 0007
• First Posted: Nov 9, 2010
• Last Update Posted: Jan 18, 2018
• Last Verified: Dec 1, 2017

• Keywords provided by ImmunoGen, Inc.: Immunogen; Lung; Small Cell Lung Cancer; Carboplatin; ADC
• Additional relevant MeSH terms: Lung Neoplasms; Small Cell Lung Carcinoma; Carboplatin; Etoposide; Lorvotuzumab mertansine

Study Results

Participant Flow

Recruitment Details	Participants were recruited from, and treated at, 45 study sites in the U.S., Canada, Spain, and the U.K. between November 2010 and May 2015.
Pre-assignment Detail	Patients were screened during a 28-day period

Arm/Group Title	Phase I - IMGN901 + Carboplatin + Etoposide	Phase II - IMGN901 + Carboplatin + Etoposide	Phase II - Carboplatin + Etoposide
Arm/Group Description	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.	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.	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.
Period Title: Phase I - IMGN901+Carboplatin+Etoposide
STARTED	33	0	0
Received Intervention	33	0	0
COMPLETED	0	0	0
NOT COMPLETED	33	0	0
Period Title: Phase I - IMGN901+Carboplatin+Etoposide
STARTED	0	98	50
Received Intervention	0	94	47
COMPLETED	0	0	0
NOT COMPLETED	0	98	50

Baseline Characteristics

Arm/Group Title	Phase I - IMGN901 + Carboplatin + Etoposide	Phase II - IMGN901 + Carboplatin + Etoposide	Phase II - Carboplatin + Etoposide	Total
Arm/Group Description	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.	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.	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.	Total of all reporting groups
Overall Participants	33	94	47	174
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	21 63.6%	49 52.1%	26 55.3%	96 55.2%
>=65 years	12 36.4%	45 47.9%	21 44.7%	78 44.8%
Sex: Female, Male (Count of Participants)
Female	20 60.6%	40 42.6%	22 46.8%	82 47.1%
Male	13 39.4%	54 57.4%	25 53.2%	92 52.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 3%	0 0%	0 0%	1 0.6%
Asian	0 0%	1 1.1%	0 0%	1 0.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	2 6.1%	3 3.2%	2 4.3%	7 4%
White	30 90.9%	90 95.7%	44 93.6%	164 94.3%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	1 2.1%	1 0.6%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
0	14 42.4%	22 23.4%	12 25.5%	48 27.6%
1	19 57.6%	62 66%	32 68.1%	113 64.9%
2	0 0%	10 10.6%	3 6.4%	13 7.5%
History of Smoking (participants) [Number]
Yes	21 63.6%	93 98.9%	46 97.9%	160 92%
No	12 36.4%	1 1.1%	1 2.1%	14 8%

Outcome Measures

1. Primary Outcome

Title	Occurrence of Dose Limiting Toxicities (DLT)
Description	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)
Time Frame	21 days (Cycle 1)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	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
Arm/Group Description
Measure Participants	6	6	3	6	12
Grade 3 febrile neutropenia	0 0%	1 1.1%	0 0%	0 0%	0 NaN
Grade 4 febrile neutropenia	1 3%	1 1.1%	0 0%	1 0.6%	0 NaN
Grade 4 thrombocytopenia	0 0%	2 2.1%	0 0%	1 0.6%	1 NaN
Grade 4 granulocytopenia	0 0%	1 1.1%	0 0%	0 0%	0 NaN
Grade 3 lobar pneumonia	0 0%	0 0%	0 0%	0 0%	1 NaN

2. Primary Outcome

Title	Progression Free Survival (PFS) in Phase II
Description	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.
Time Frame	From randomization to objective tumor progression or death (up to post-treatment follow-up 28 days after last dose, up to 22 months)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase II - IMGN901 + Carboplatin + Etoposide
Arm/Group Description	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.
Measure Participants	82
Median (95% Confidence Interval) [months]	6.2

3. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of IMGN901
Description	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.
Time Frame	21 days (Cycle 1)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase I - IMGN901 + Carboplatin + Etoposide
Arm/Group Description	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.
Measure Participants	33
Number [mg/m^2]	112

4. Secondary Outcome

Title	Overview of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Description	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.
Time Frame	From the first dose of study drug on Cycle 1, Day 1 until 28 days after the last study treatment (up to 22 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I - IMGN901 + Carboplatin + Etoposide	Phase II - IMGN901 + Carboplatin + Etoposide	Phase II - Carboplatin + Etoposide
Arm/Group Description	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.	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.	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.
Measure Participants	33	94	47
Any TEAE	33 100%	94 100%	46 97.9%
Related TEAE	32 97%	90 95.7%	39 83%
Any SAE	16 48.5%	54 57.4%	23 48.9%
Related SAE	8 24.2%	30 31.9%	9 19.1%
TEAEs leading to discontinuation	8 24.2%	50 53.2%	6 12.8%
Any Grade ≥ 3 TEAE	29 87.9%	92 97.9%	42 89.4%
Related Grade ≥ 3 TEAE	22 66.7%	83 88.3%	33 70.2%
Deaths within 28 days of last dose	1 3%	14 14.9%	5 10.6%

5. Secondary Outcome

Title	Progression Free Survival (PFS) Rate at 6 Months
Description	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.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase II - IMGN901 + Carboplatin + Etoposide
Arm/Group Description	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.
Measure Participants	82
Number (95% Confidence Interval) [percentage of participants]	39 118.2%

6. Secondary Outcome

Title	Median Overall Survival (OS) in Phase II
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase II - IMGN901 + Carboplatin + Etoposide	Phase II - Carboplatin + Etoposide
Arm/Group Description	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.	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.
Measure Participants	82	39
Median (95% Confidence Interval) [months]	10.1	10.97

7. Secondary Outcome

Title	Overall Survival (OS) Rate at 12 Months
Description	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.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase II - IMGN901 + Carboplatin + Etoposide
Arm/Group Description	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.
Measure Participants	82
Number (95% Confidence Interval) [percentage of participants alive]	61 184.8%

Adverse Events

Time Frame	Reported SAEs include events from the first dose of study drug on Cycle 1, Day 1 until 28 days after the last study treatment.
Adverse Event Reporting Description	AEs and laboratory results were graded using the NCI CTCAE, version 4.0.
Arm/Group Title	Phase I - IMGN901 + Carboplatin + Etoposide		Phase II - IMGN901 + Carboplatin + Etoposide		Phase II - Carboplatin + Etoposide
Arm/Group Description	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.		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.		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.
All Cause Mortality
	Phase I - IMGN901 + Carboplatin + Etoposide		Phase II - IMGN901 + Carboplatin + Etoposide		Phase II - Carboplatin + Etoposide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase I - IMGN901 + Carboplatin + Etoposide		Phase II - IMGN901 + Carboplatin + Etoposide		Phase II - Carboplatin + Etoposide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/33 (48.5%)		54/94 (57.4%)		23/47 (48.9%)
Blood and lymphatic system disorders
Anaemia	0/33 (0%)		2/94 (2.1%)		0/47 (0%)
Febrile neutropenia	4/33 (12.1%)		6/94 (6.4%)		5/47 (10.6%)
Neutropenia	0/33 (0%)		3/94 (3.2%)		1/47 (2.1%)
Pancytopenia	1/33 (3%)		0/94 (0%)		0/47 (0%)
Thrombocytopenia	1/33 (3%)		1/94 (1.1%)		2/47 (4.3%)
Cardiac disorders
Atrial defibrillation	1/33 (3%)		0/94 (0%)		1/47 (2.1%)
Cardiac arrest	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Cardiac disorder	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Gastrointestinal disorders
Constipation	1/33 (3%)		1/94 (1.1%)		0/47 (0%)
Diarrhoea	0/33 (0%)		2/94 (2.1%)		2/47 (4.3%)
Diverticular perforation	1/33 (3%)		0/94 (0%)		0/47 (0%)
Pancreatitis	1/33 (3%)		0/94 (0%)		0/47 (0%)
Abdominal pain	0/33 (0%)		0/94 (0%)		1/47 (2.1%)
Abdominal pain upper	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Gastrointestinal heamorrhage	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Haematemesis	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Ileus	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Upper gastrointestinal heamorrhage	0/33 (0%)		0/94 (0%)		1/47 (2.1%)
Vomiting	0/33 (0%)		0/94 (0%)		1/47 (2.1%)
General disorders
Non-cardiac chest pain	1/33 (3%)		2/94 (2.1%)		0/47 (0%)
Pain	1/33 (3%)		2/94 (2.1%)		0/47 (0%)
Pyrexia	0/33 (0%)		2/94 (2.1%)		0/47 (0%)
Disease progression	0/33 (0%)		1/94 (1.1%)		1/47 (2.1%)
Fatigue	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Hepatobiliary disorders
Hepatic cirrhosis	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Infections and infestations
Bacteraemia	1/33 (3%)		0/94 (0%)		0/47 (0%)
Cellulitis	0/33 (0%)		2/94 (2.1%)		0/47 (0%)
Clostridium difficile colitis	2/33 (6.1%)		0/94 (0%)		0/47 (0%)
Lobar pneumonia	1/33 (3%)		0/94 (0%)		0/47 (0%)
Lower respiratory tract infection	0/33 (0%)		2/94 (2.1%)		0/47 (0%)
Neutropenic sepsis	0/33 (0%)		4/94 (4.3%)		1/47 (2.1%)
Pneumonia	0/33 (0%)		6/94 (6.4%)		2/47 (4.3%)
Sepsis	2/33 (6.1%)		2/94 (2.1%)		1/47 (2.1%)
Septic shock	0/33 (0%)		3/94 (3.2%)		0/47 (0%)
Respiratory tract infection	0/33 (0%)		1/94 (1.1%)		1/47 (2.1%)
Device related infection	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Viral infection	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Injury, poisoning and procedural complications
Femur fracture	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Spinal compression fracture	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Fracture	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Investigations
Ejection fraction decreased	0/33 (0%)		0/94 (0%)		1/47 (2.1%)
Neutrophil count decreased	0/33 (0%)		0/94 (0%)		1/47 (2.1%)
Transaminases increased	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Metabolism and nutrition disorders
Dehydration	0/33 (0%)		3/94 (3.2%)		1/47 (2.1%)
Hypercalcaemia	1/33 (3%)		0/94 (0%)		0/47 (0%)
Hypomagnesaemia	1/33 (3%)		0/94 (0%)		0/47 (0%)
Hyponatraemia	0/33 (0%)		0/94 (0%)		1/47 (2.1%)
Electrolyte imbalance	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Failure to thrive	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Muscular weakness	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to central nervous system	0/33 (0%)		1/94 (1.1%)		1/47 (2.1%)
Renal cancer metastatic	0/33 (0%)		0/94 (0%)		1/47 (2.1%)
Nervous system disorders
Convulsion	1/33 (3%)		1/94 (1.1%)		0/47 (0%)
Nerve root compression	1/33 (3%)		0/94 (0%)		0/47 (0%)
Peripheral sensory neuropathy	0/33 (0%)		3/94 (3.2%)		0/47 (0%)
Peripheral sensorimotor neuropathy	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Polyneuropathy	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Syncope	0/33 (0%)		1/94 (1.1%)		1/47 (2.1%)
Psychiatric disorders
Completed suicide	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Confusional state	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Delirium	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Hallucination	0/33 (0%)		0/94 (0%)		1/47 (2.1%)
Reproductive system and breast disorders
Vulval haemorrhage	1/33 (3%)		0/94 (0%)		0/47 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/33 (0%)		2/94 (2.1%)		0/47 (0%)
Pulmonary embolism	0/33 (0%)		5/94 (5.3%)		0/47 (0%)
Dyspnoea	0/33 (0%)		0/94 (0%)		1/47 (2.1%)
Haemoptysis	0/33 (0%)		1/94 (1.1%)		2/47 (4.3%)
Hypoxia	0/33 (0%)		0/94 (0%)		1/47 (2.1%)
Laryngeal inflammation	0/33 (0%)		0/94 (0%)		1/47 (2.1%)
Pleural effusion	0/33 (0%)		1/94 (1.1%)		1/47 (2.1%)
Pulmonary oedema	0/33 (0%)		0/94 (0%)		1/47 (2.1%)
Respiratory distress	0/33 (0%)		0/94 (0%)		1/47 (2.1%)
Respiratory failure	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Vascular disorders
Deep vein thrombosis	2/33 (6.1%)		0/94 (0%)		0/47 (0%)
Hypotension	0/33 (0%)		2/94 (2.1%)		0/47 (0%)
Hypertension	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Peripheral ischaemia	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Arterial thrombosis limb	0/33 (0%)		1/94 (1.1%)		0/47 (0%)
Other (Not Including Serious) Adverse Events
	Phase I - IMGN901 + Carboplatin + Etoposide		Phase II - IMGN901 + Carboplatin + Etoposide		Phase II - Carboplatin + Etoposide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/33 (100%)		91/94 (96.8%)		43/47 (91.5%)
Blood and lymphatic system disorders
Anaemia	24/33 (72.7%)		50/94 (53.2%)		21/47 (44.7%)
Leukocytosis	2/33 (6.1%)		0/94 (0%)		0/47 (0%)
Leukopenia	9/33 (27.3%)		10/94 (10.6%)		6/47 (12.8%)
Lymphopenia	4/33 (12.1%)		0/94 (0%)		0/47 (0%)
Neutropenia	10/33 (30.3%)		53/94 (56.4%)		24/47 (51.1%)
Pancytopenia	2/33 (6.1%)		0/94 (0%)		0/47 (0%)
Thrombocytopenia	16/33 (48.5%)		32/94 (34%)		19/47 (40.4%)
Cardiac disorders
Sinus tachycardia	0/33 (0%)		5/94 (5.3%)		0/47 (0%)
Gastrointestinal disorders
Abdominal pain	8/33 (24.2%)		5/94 (5.3%)		3/47 (6.4%)
Constipation	12/33 (36.4%)		30/94 (31.9%)		9/47 (19.1%)
Diarrhoea	9/33 (27.3%)		30/94 (31.9%)		8/47 (17%)
Dyspepsia	6/33 (18.2%)		13/94 (13.8%)		0/47 (0%)
Dysphagia	3/33 (9.1%)		1/94 (1.1%)		4/47 (8.5%)
Flatulence	2/33 (6.1%)		0/94 (0%)		0/47 (0%)
Nausea	13/33 (39.4%)		40/94 (42.6%)		17/47 (36.2%)
Vomiting	11/33 (33.3%)		23/94 (24.5%)		11/47 (23.4%)
Abdominal distension	0/33 (0%)		5/94 (5.3%)		0/47 (0%)
Abdominal pain upper	0/33 (0%)		6/94 (6.4%)		2/47 (4.3%)
Stomatitis	0/33 (0%)		6/94 (6.4%)		2/47 (4.3%)
General disorders
Asthenia	3/33 (9.1%)		29/94 (30.9%)		10/47 (21.3%)
Chills	2/33 (6.1%)		6/94 (6.4%)		2/47 (4.3%)
Fatigue	17/33 (51.5%)		46/94 (48.9%)		14/47 (29.8%)
Influenza like illness	2/33 (6.1%)		0/94 (0%)		0/47 (0%)
Mucosal inflammation	2/33 (6.1%)		13/94 (13.8%)		6/47 (12.8%)
Oedema peripheral	3/33 (9.1%)		19/94 (20.2%)		5/47 (10.6%)
Pain	5/33 (15.2%)		7/94 (7.4%)		2/47 (4.3%)
Pyrexia	8/33 (24.2%)		10/94 (10.6%)		5/47 (10.6%)
Malaise	0/33 (0%)		6/94 (6.4%)		0/47 (0%)
Non-cardiac chest pain	0/33 (0%)		7/94 (7.4%)		6/47 (12.8%)
Infections and infestations
Oral candidiasis	3/33 (9.1%)		5/94 (5.3%)		2/47 (4.3%)
Urinary tract infection	5/33 (15.2%)		10/94 (10.6%)		7/47 (14.9%)
Upper respiratory tract infection	0/33 (0%)		6/94 (6.4%)		2/47 (4.3%)
Injury, poisoning and procedural complications
Fall	3/33 (9.1%)		0/94 (0%)		0/47 (0%)
Investigations
Alanine aminotransferase increased	2/33 (6.1%)		11/94 (11.7%)		0/47 (0%)
Aspartate aminotransferase increased	2/33 (6.1%)		8/94 (8.5%)		1/47 (2.1%)
Blood alkaline phosphatase increased	2/33 (6.1%)		8/94 (8.5%)		1/47 (2.1%)
Blood creatine increased	3/33 (9.1%)		2/94 (2.1%)		3/47 (6.4%)
Blood pressure increased	2/33 (6.1%)		0/94 (0%)		0/47 (0%)
Gamma-glutamyltransferase increased	3/33 (9.1%)		0/94 (0%)		0/47 (0%)
Lipase increased	2/33 (6.1%)		3/94 (3.2%)		3/47 (6.4%)
Lymphocyte count decreased	7/33 (21.2%)		0/94 (0%)		0/47 (0%)
Neutrophil count decreased	7/33 (21.2%)		11/94 (11.7%)		7/47 (14.9%)
Platelet count decreased	2/33 (6.1%)		16/94 (17%)		6/47 (12.8%)
Weight decreased	2/33 (6.1%)		7/94 (7.4%)		3/47 (6.4%)
White blood cell count decreased	7/33 (21.2%)		8/94 (8.5%)		4/47 (8.5%)
Blood amylase increased	0/33 (0%)		7/94 (7.4%)		2/47 (4.3%)
Metabolism and nutrition disorders
Decreased appetite	6/33 (18.2%)		32/94 (34%)		16/47 (34%)
Dehydration	3/33 (9.1%)		15/94 (16%)		6/47 (12.8%)
Hypercalcaemia	3/33 (9.1%)		0/94 (0%)		0/47 (0%)
Hyperglycaemia	2/33 (6.1%)		5/94 (5.3%)		2/47 (4.3%)
Hypoalbuminaemia	3/33 (9.1%)		0/94 (0%)		0/47 (0%)
Hypocalcaemia	2/33 (6.1%)		0/94 (0%)		0/47 (0%)
Hypokalaemia	9/33 (27.3%)		13/94 (13.8%)		3/47 (6.4%)
Hypomagnesaemia	7/33 (21.2%)		16/94 (17%)		6/47 (12.8%)
Hyponatraemia	8/33 (24.2%)		12/94 (12.8%)		6/47 (12.8%)
Hypophospataemia	5/33 (15.2%)		5/94 (5.3%)		1/47 (2.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	8/33 (24.2%)		18/94 (19.1%)		5/47 (10.6%)
Back pain	4/33 (12.1%)		12/94 (12.8%)		4/47 (8.5%)
Bone pain	2/33 (6.1%)		5/94 (5.3%)		3/47 (6.4%)
Muscle spasms	2/33 (6.1%)		0/94 (0%)		0/47 (0%)
Muscular weakness	2/33 (6.1%)		6/94 (6.4%)		2/47 (4.3%)
Musculoskeletal chest pain	2/33 (6.1%)		0/94 (0%)		0/47 (0%)
Musculoskeletal pain	2/33 (6.1%)		7/94 (7.4%)		2/47 (4.3%)
Neck pain	2/33 (6.1%)		0/94 (0%)		0/47 (0%)
Pain in extremity	6/33 (18.2%)		11/94 (11.7%)		3/47 (6.4%)
Myalgia	0/33 (0%)		12/94 (12.8%)		3/47 (6.4%)
Nervous system disorders
Dizziness	3/33 (9.1%)		13/94 (13.8%)		5/47 (10.6%)
Dysgeusia	4/33 (12.1%)		10/94 (10.6%)		6/47 (12.8%)
Headache	7/33 (21.2%)		16/94 (17%)		5/47 (10.6%)
Paraesthesia	2/33 (6.1%)		20/94 (21.3%)		2/47 (4.3%)
Peripheral motor neuropathy	2/33 (6.1%)		7/94 (7.4%)		0/47 (0%)
Peripheral sensory neuropathy	17/33 (51.5%)		56/94 (59.6%)		4/47 (8.5%)
Restless legs syndrome	2/33 (6.1%)		0/94 (0%)		0/47 (0%)
Hyporeflexia	0/33 (0%)		0/94 (0%)		3/47 (6.4%)
Neurotoxicity	0/33 (0%)		8/94 (8.5%)		1/47 (2.1%)
Psychiatric disorders
Anxiety	2/33 (6.1%)		8/94 (8.5%)		1/47 (2.1%)
Depression	2/33 (6.1%)		5/94 (5.3%)		1/47 (2.1%)
Insomnia	6/33 (18.2%)		19/94 (20.2%)		4/47 (8.5%)
Renal and urinary disorders
Dysuria	4/33 (12.1%)		0/94 (0%)		0/47 (0%)
Urinary retention	2/33 (6.1%)		0/94 (0%)		0/47 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	6/33 (18.2%)		11/94 (11.7%)		10/47 (21.3%)
Dysphonia	2/33 (6.1%)		8/94 (8.5%)		2/47 (4.3%)
Dyspnoea	5/33 (15.2%)		18/94 (19.1%)		7/47 (14.9%)
Epistaxis	2/33 (6.1%)		5/94 (5.3%)		2/47 (4.3%)
Oropharyngeal pain	5/33 (15.2%)		0/94 (0%)		0/47 (0%)
Pulmonary embolism	2/33 (6.1%)		0/94 (0%)		0/47 (0%)
Haemoptysis	0/33 (0%)		6/94 (6.4%)		1/47 (2.1%)
Hiccups	0/33 (0%)		0/94 (0%)		3/47 (6.4%)
Hypoxia	0/33 (0%)		5/94 (5.3%)		1/47 (2.1%)
Productive cough	0/33 (0%)		2/94 (2.1%)		4/47 (8.5%)
Skin and subcutaneous tissue disorders
Alopecia	10/33 (30.3%)		32/94 (34%)		16/47 (34%)
Dry skin	2/33 (6.1%)		0/94 (0%)		0/47 (0%)
Erythema	2/33 (6.1%)		0/94 (0%)		0/47 (0%)
Skin lesion	2/33 (6.1%)		0/94 (0%)		0/47 (0%)
Pruritis	0/33 (0%)		6/94 (6.4%)		1/47 (2.1%)
Vascular disorders
Hypertension	2/33 (6.1%)		7/94 (7.4%)		0/47 (0%)
Hypotension	2/33 (6.1%)		10/94 (10.6%)		4/47 (8.5%)
Hot flush	0/33 (0%)		5/94 (5.3%)		0/47 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.