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    Clinical Trial Results:
    A Phase 1/2 Study to Assess the Safety and Efficacy of Lorvotuzumab Mertansine (IMGN901) in Combination with Carboplatin/Etoposide in Patients with Advanced Solid Tumors Including Extensive Stage Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2010-022950-17
    Trial protocol
    		 GB  
    Global end of trial date
    12 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 May 2016
    First version publication date
    21 May 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Immunogen 0007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01237678
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ImmunoGen Europe Ltd
    Sponsor organisation address
    24 Chiswell Street, London, United Kingdom, EC1Y 4YX
    Public contact
    James Stec, Director, Scientific Affairs, ImmunoGen Inc., James.Stec@immunogen.com
    Scientific contact
    Dr. Richard Bates, Sr. Manager, Publications, ImmunoGen Inc., Richard.Bates@immunogen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Nov 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Nov 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    12 May 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of phase I of the study was to determine the maximum tolerated dose (MTD) and characterize the dose-limiting toxicities of lorvotuzumab mertansine (IMGN901) when administered in combination with carboplatin + etoposide chemotherapy followed by IMGN901 alone in patients with solid tumors. The primary objective of phase II was to determine the efficacy of IMGN901 in combination with carboplatin + etoposide chemotherapy followed by IMGN901 alone as first-line treatment for patients with extensive stage small cell lung cancer (SCLC). Secondary objectives were to determine the safety and tolerability of IMGN901 in combination with carboplatin + etoposide chemotherapy followed by IMGN901 alone versus carboplatin + etoposide chemotherapy for patients with extensive stage SCLC.
    Protection of trial subjects
    Patients received prophylactic administration of dexamethasone and acetaminophen and/or diphenhydramine (at Investigators discretion) prior to drug infusion in order to minimize/prevent infusion reactions. All patients in cycles 1 and 2 of Phase II received post-infusion prophylaxis with granulocyte-colony stimulating factor (G-CSF), administered per label, starting on Day 4. In cycle 3 and beyond, administration of G-CSF was permitted at the discretion of the Investigator. A Data Monitoring Committee was instituted for the phase II portion of the study in order to ensure ongoing patient safety, which held regular safety review meetings.
    Background therapy
    		 -
    Evidence for comparator
    		 Chemotherapeutic regimens of a platinum agent (carboplatin or cisplatin) in combination with etoposide represents standard-of-care treatment for patients with extensive stage SCLC. Moreover IMGN901 was shown to potentiate the antitumor activity of the carboplatin + etoposide doublet in preclinical models of SCLC.
    Actual start date of recruitment
    17 Nov 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 115
    Country: Number of subjects enrolled
    Spain: 41
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    Canada: 11
    Worldwide total number of subjects
    181
    EEA total number of subjects
    55
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    98
    From 65 to 84 years
    81
    85 years and over
    2

    Subject disposition

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    Recruitment
    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
    Screening details
    		 Patients were screened during a 28-day period. Of the 98 patients randomized to the first Arm of Phase II (IMGN901 + carboplatin + etoposide), 94 subjects were treated; of the 50 patients randomized to the second Arm of Phase II (carboplatin + etoposide), 47 subjects were treated.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase I - IMGN901 + carboplatin + etoposide
    Arm 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lorvotuzumab mertansine
    Investigational medicinal product code
    Other name
    IMGN901
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    IMGN901 was administered as an IV infusion on Days 1 and 8 of a 21-day cycle

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin was administered by IV infusion over 30-60 minutes or as per institutional guidelines on Day 1 of each treatment cycle.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide was administered by IV infusion at a dose of 100 mg/m2 over 30-60 minutes or as per institutional guidelines on Days 1, 2, and 3 of each treatment cycle

    Arm title
    		 Phase II - IMGN901 + carboplatin + etoposide
    Arm 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lorvotuzumab mertansine
    Investigational medicinal product code
    Other name
    IMGN901
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    IMGN901 was administered as an IV infusion on Days 1 and 8 of a 21-day cycle

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin was administered by IV infusion over 30-60 minutes or as per institutional guidelines on Day 1 of each treatment cycle.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide was administered by IV infusion at a dose of 100 mg/m2 over 30-60 minutes or as per institutional guidelines on Days 1, 2, and 3 of each treatment cycle

    Arm title
    		 Phase II - carboplatin + etoposide
    Arm description
    		 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.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin was administered by IV infusion over 30-60 minutes or as per institutional guidelines on Day 1 of each treatment cycle.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide was administered by IV infusion at a dose of 100 mg/m2 over 30-60 minutes or as per institutional guidelines on Days 1, 2, and 3 of each treatment cycle

    Number of subjects in period 1 [1]
    		Phase I - IMGN901 + carboplatin + etoposide Phase II - IMGN901 + carboplatin + etoposide Phase II - carboplatin + etoposide
    Started
    33
    94
    47
    Received intervention
    33
    94
    47
    Completed
    0
    0
    0
    Not completed
    33
    94
    47
         Adverse event, serious fatal
    -
    18
    3
         Consent withdrawn by subject
    3
    1
    5
         Sponsor Decision/Study Closed
    -
    18
    7
         Adverse event, non-fatal
    5
    21
    6
         Completed Cycles 4-6
    -
    11
    21
         Death
    -
    -
    2
         Incorrect Original Diagnosis
    1
    -
    -
         Lack of efficacy
    24
    25
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 181 patients were enrolled in the study: 33 in Phase I and 148 in Phase II. Within the Phase II population, 98 subjects were randomized to the experimental arm (IMGN901+ carboplatin + etoposide), however only 94 subjects were treated. Of the 50 patients randomized to the comparator arm (carboplatin + etoposide), 47 subjects were treated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase I - IMGN901 + carboplatin + etoposide
    Reporting 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.

    Reporting group title
    Phase II - IMGN901 + carboplatin + etoposide
    Reporting 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.

    Reporting group title
    Phase II - carboplatin + etoposide
    Reporting group description
    		 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.

    Reporting group values
    		 Phase I - IMGN901 + carboplatin + etoposide Phase II - IMGN901 + carboplatin + etoposide Phase II - carboplatin + etoposide Total
    Number of subjects
    		 33 94 47 174
    Age Categorical
    A total of 174 patients were included in the analyses (Phase I, 33; Phase II IMGN901 + carboplatin + etoposide, 94; Phase II carboplatin + etoposide, 47) due to a total of 7 patients in Phase II who were randomized but did not receive treatment.
    Units: participants
        <=18 years
    		 0 0 0 0
        Between 18 and 65 years
    		 21 49 26 96
        >=65 years
    		 12 45 21 78
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.3 ± 13.5 64.3 ± 9.2 64.4 ± 9.4 -
    Gender, Male/Female
    Units: participants
        Female
    		 20 40 22 82
        Male
    		 13 54 25 92
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 0 1
        Asian
    		 0 1 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 2 3 2 7
        White
    		 30 90 44 164
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 0 0 1 1
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    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.
    Units: Subjects
        0x
    		 14 22 12 48
        1x
    		 19 62 32 113
        2x
    		 0 10 3 13
    History of Smoking
    Units: Subjects
        Yes
    		 21 93 46 160
        No
    		 12 1 1 14

    End points

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    End points reporting groups
    Reporting group title
    Phase I - IMGN901 + carboplatin + etoposide
    Reporting 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.

    Reporting group title
    Phase II - IMGN901 + carboplatin + etoposide
    Reporting 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.

    Reporting group title
    Phase II - carboplatin + etoposide
    Reporting group description
    		 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.

    Primary: Occurrence of Dose Limiting Toxicities (DLT)

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    End point title
    		 Occurrence of Dose Limiting Toxicities (DLT) [1] [2]
    End point 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)
    End point type
    Primary
    End point timeframe
    21 days (Cycle 1)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analyses were performed.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only DLTs that occurred in the first reporting arm (i.e. Phase I- IMGN901 + carboplatin + etoposide) were considered for decisions regarding dose escalation and determination of MTD/RP2D.
    End point values
    		 Phase I - IMGN901 + carboplatin + etoposide
    Number of subjects analysed
    33
    Units: participants
    number (not applicable)
        Grade 3 febrile neutropenia
    1
        Grade 4 febrile neutropenia
    3
        Grade 4 thrombocytopenia
    4
        Grade 4 granulocytopenia
    1
        Grade 3 lobar pneumonia
    1
    No statistical analyses for this end point

    Primary: Progression Free Survival (PFS) in Phase II

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    End point title
    		 Progression Free Survival (PFS) in Phase II [3] [4]
    End point 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.
    End point type
    Primary
    End point timeframe
    From randomization to objective tumor progression or death (up to post-treatment follow-up 28 days after last dose)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: For design purposes, the number of patients who were progression-free at 6 months were used to test hypotheses against historical 6-month PFS rates typically seen in patients treated with carboplatin/etoposide. The trial was not powered to permit a statistically informative comparison of the randomized treatment groups with respect to PFS.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The trial was not powered to permit a statistically informative comparison of the randomized treatment groups with respect to PFS, therefore only the results from the Phase II experimental arm (Phase II - IMGN901 + carboplatin + etoposide) are presented.
    End point values
    		 Phase II - IMGN901 + carboplatin + etoposide
    Number of subjects analysed
    82
    Units: months
        number (confidence interval 95%)
    6.2 (5.4 to 7.2)
    No statistical analyses for this end point

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

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    End point title
    		 Overview of Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    End point 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.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug on Cycle 1, Day 1 until 28 days after the last study treatment.
    End point values
    		 Phase I - IMGN901 + carboplatin + etoposide Phase II - IMGN901 + carboplatin + etoposide Phase II - carboplatin + etoposide
    Number of subjects analysed
    33
    94
    47
    Units: participants
    number (not applicable)
        Any TEAE
    33
    94
    46
        Related TEAE
    32
    90
    39
        Any SAE
    16
    54
    23
        Related SAE
    8
    30
    9
        TEAEs leading to discontinuation
    8
    50
    6
        Any Grade ≥ 3 TEAE
    29
    92
    42
        Related Grade ≥ 3 TEAE
    22
    83
    33
        Deaths within 28 days of last dose
    1
    14
    5
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) rate at 6 months

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    End point title
    		 Progression Free Survival (PFS) rate at 6 months [5]
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The study was not powered 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 six months in the IMGN901 experimental arm against the historical 6-month PFS rate 0.44 (equivalently a median PFS = 5 months). The control arm was primarily used to serve as an informal validation of historical data. therefore, only data from the Phase II experimental arm are presented.
    End point values
    		 Phase II - IMGN901 + carboplatin + etoposide
    Number of subjects analysed
    82
    Units: percentage
        number (confidence interval 95%)
    39 (28.4 to 50.4)
    No statistical analyses for this end point

    Secondary: Median Overall Survival (OS) in Phase II

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    End point title
    		 Median Overall Survival (OS) in Phase II [6]
    End point 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 alone versus carbolatin/etoposide chemotherapy as first-line treatment for patients with extensive stage small cell lung cancer.
    End point type
    Secondary
    End point timeframe
    From the time of enrollment until death on study due to any cause (up to post-treatment follow-up 28 days after last dose)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point reports only on the two Phase II arms; patients in the dose escalation baseline arm (Phase I - IMGN901 + carboplatin + etoposide) were not included.
    End point values
    		 Phase II - IMGN901 + carboplatin + etoposide Phase II - carboplatin + etoposide
    Number of subjects analysed
    82
    39
    Units: months
        number (confidence interval 95%)
    10.1 (8.7 to 18.1)
    10.97 (7.5 to 11.4)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) rate at 12 months

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    End point title
    		 Overall Survival (OS) rate at 12 months [7]
    End point 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.
    End point type
    Secondary
    End point timeframe
    12 months
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The study was not powered to permit a statistically informative comparison of the randomized treatment groups with respect to OS; therefore only the results from the Phase II experimental arm (Phase II - IMGN901 + carboplatin + etoposide) are presented.
    End point values
    		 Phase II - IMGN901 + carboplatin + etoposide
    Number of subjects analysed
    82
    Units: percentage
        number (confidence interval 95%)
    61 (49.6 to 71.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    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 additional description
    AEs and laboratory results were graded using the NCI CTCAE, version 4.0.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Phase I - IMGN901 + carboplatin + etoposide
    Reporting 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.

    Reporting group title
    Phase II - IMGN901 + carboplatin + etoposide
    Reporting 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.

    Reporting group title
    Phase II - carboplatin + etoposide
    Reporting group description
    		 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.

    Serious adverse events
    		 Phase I - IMGN901 + carboplatin + etoposide Phase II - IMGN901 + carboplatin + etoposide Phase II - carboplatin + etoposide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 33 (48.48%)
    54 / 94 (57.45%)
    23 / 47 (48.94%)
         number of deaths (all causes)
    1
    18
    3
         number of deaths resulting from adverse events
    0
    9
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Renal cancer metastatic
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 94 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 94 (2.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arterial thrombosis limb
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 94 (2.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 94 (2.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 94 (2.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Fatigue
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vulval haemorrhage
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 94 (2.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 33 (0.00%)
    5 / 94 (5.32%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 94 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 94 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal inflammation
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 94 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 94 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 94 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 94 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 94 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 94 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial defibrillation
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 94 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nerve root compression
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 94 (3.19%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 94 (2.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    4 / 33 (12.12%)
    6 / 94 (6.38%)
    5 / 47 (10.64%)
         occurrences causally related to treatment / all
    4 / 4
    6 / 6
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 94 (3.19%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 94 (1.06%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 94 (2.13%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 94 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal heamorrhage
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal heamorrhage
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 94 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 94 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 94 (2.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 94 (2.13%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 33 (0.00%)
    4 / 94 (4.26%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 33 (0.00%)
    6 / 94 (6.38%)
    2 / 47 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    3 / 4
    0 / 1
    Sepsis
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 94 (2.13%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    2 / 2
    1 / 1
    Septic shock
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 94 (3.19%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 94 (3.19%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 94 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 94 (1.06%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase I - IMGN901 + carboplatin + etoposide Phase II - IMGN901 + carboplatin + etoposide Phase II - carboplatin + etoposide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 33 (100.00%)
    91 / 94 (96.81%)
    43 / 47 (91.49%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 33 (6.06%)
    7 / 94 (7.45%)
    0 / 47 (0.00%)
         occurrences all number
    3
    10
    0
    Hypotension
         subjects affected / exposed
    2 / 33 (6.06%)
    10 / 94 (10.64%)
    4 / 47 (8.51%)
         occurrences all number
    2
    10
    6
    Hot flush
         subjects affected / exposed
    0 / 33 (0.00%)
    5 / 94 (5.32%)
    0 / 47 (0.00%)
         occurrences all number
    0
    5
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 33 (9.09%)
    29 / 94 (30.85%)
    10 / 47 (21.28%)
         occurrences all number
    3
    61
    25
    Chills
         subjects affected / exposed
    2 / 33 (6.06%)
    6 / 94 (6.38%)
    2 / 47 (4.26%)
         occurrences all number
    2
    6
    2
    Fatigue
         subjects affected / exposed
    17 / 33 (51.52%)
    46 / 94 (48.94%)
    14 / 47 (29.79%)
         occurrences all number
    35
    77
    23
    Influenza like illness
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    2 / 33 (6.06%)
    13 / 94 (13.83%)
    6 / 47 (12.77%)
         occurrences all number
    5
    16
    12
    Oedema peripheral
         subjects affected / exposed
    3 / 33 (9.09%)
    19 / 94 (20.21%)
    5 / 47 (10.64%)
         occurrences all number
    3
    20
    6
    Pain
         subjects affected / exposed
    5 / 33 (15.15%)
    7 / 94 (7.45%)
    2 / 47 (4.26%)
         occurrences all number
    5
    7
    2
    Pyrexia
         subjects affected / exposed
    8 / 33 (24.24%)
    10 / 94 (10.64%)
    5 / 47 (10.64%)
         occurrences all number
    10
    13
    5
    Malaise
         subjects affected / exposed
    0 / 33 (0.00%)
    6 / 94 (6.38%)
    0 / 47 (0.00%)
         occurrences all number
    0
    6
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 33 (0.00%)
    7 / 94 (7.45%)
    6 / 47 (12.77%)
         occurrences all number
    0
    8
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 33 (18.18%)
    11 / 94 (11.70%)
    10 / 47 (21.28%)
         occurrences all number
    8
    12
    10
    Dysphonia
         subjects affected / exposed
    2 / 33 (6.06%)
    8 / 94 (8.51%)
    2 / 47 (4.26%)
         occurrences all number
    2
    9
    2
    Dyspnoea
         subjects affected / exposed
    5 / 33 (15.15%)
    18 / 94 (19.15%)
    7 / 47 (14.89%)
         occurrences all number
    5
    21
    8
    Epistaxis
         subjects affected / exposed
    2 / 33 (6.06%)
    5 / 94 (5.32%)
    2 / 47 (4.26%)
         occurrences all number
    2
    5
    2
    Oropharyngeal pain
         subjects affected / exposed
    5 / 33 (15.15%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    5
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Haemoptysis
         subjects affected / exposed
    0 / 33 (0.00%)
    6 / 94 (6.38%)
    1 / 47 (2.13%)
         occurrences all number
    0
    7
    1
    Hiccups
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 94 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    0
    0
    3
    Hypoxia
         subjects affected / exposed
    0 / 33 (0.00%)
    5 / 94 (5.32%)
    1 / 47 (2.13%)
         occurrences all number
    0
    5
    1
    Productive cough
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 94 (2.13%)
    4 / 47 (8.51%)
         occurrences all number
    0
    2
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 33 (6.06%)
    8 / 94 (8.51%)
    1 / 47 (2.13%)
         occurrences all number
    2
    10
    1
    Depression
         subjects affected / exposed
    2 / 33 (6.06%)
    5 / 94 (5.32%)
    1 / 47 (2.13%)
         occurrences all number
    2
    5
    2
    Insomnia
         subjects affected / exposed
    6 / 33 (18.18%)
    19 / 94 (20.21%)
    4 / 47 (8.51%)
         occurrences all number
    9
    21
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 33 (6.06%)
    11 / 94 (11.70%)
    0 / 47 (0.00%)
         occurrences all number
    4
    16
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 33 (6.06%)
    8 / 94 (8.51%)
    1 / 47 (2.13%)
         occurrences all number
    7
    8
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 33 (6.06%)
    8 / 94 (8.51%)
    1 / 47 (2.13%)
         occurrences all number
    2
    14
    1
    Blood creatine increased
         subjects affected / exposed
    3 / 33 (9.09%)
    2 / 94 (2.13%)
    3 / 47 (6.38%)
         occurrences all number
    10
    3
    5
    Blood pressure increased
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    7
    0
    0
    Lipase increased
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 94 (3.19%)
    3 / 47 (6.38%)
         occurrences all number
    2
    4
    3
    Lymphocyte count decreased
         subjects affected / exposed
    7 / 33 (21.21%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    29
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    7 / 33 (21.21%)
    11 / 94 (11.70%)
    7 / 47 (14.89%)
         occurrences all number
    14
    23
    22
    Platelet count decreased
         subjects affected / exposed
    2 / 33 (6.06%)
    16 / 94 (17.02%)
    6 / 47 (12.77%)
         occurrences all number
    6
    31
    13
    Weight decreased
         subjects affected / exposed
    2 / 33 (6.06%)
    7 / 94 (7.45%)
    3 / 47 (6.38%)
         occurrences all number
    2
    10
    3
    White blood cell count decreased
         subjects affected / exposed
    7 / 33 (21.21%)
    8 / 94 (8.51%)
    4 / 47 (8.51%)
         occurrences all number
    19
    13
    9
    Blood amylase increased
         subjects affected / exposed
    0 / 33 (0.00%)
    7 / 94 (7.45%)
    2 / 47 (4.26%)
         occurrences all number
    0
    7
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    4
    0
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 33 (0.00%)
    5 / 94 (5.32%)
    0 / 47 (0.00%)
         occurrences all number
    0
    8
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 33 (9.09%)
    13 / 94 (13.83%)
    5 / 47 (10.64%)
         occurrences all number
    3
    16
    5
    Dysgeusia
         subjects affected / exposed
    4 / 33 (12.12%)
    10 / 94 (10.64%)
    6 / 47 (12.77%)
         occurrences all number
    4
    10
    6
    Headache
         subjects affected / exposed
    7 / 33 (21.21%)
    16 / 94 (17.02%)
    5 / 47 (10.64%)
         occurrences all number
    11
    18
    7
    Paraesthesia
         subjects affected / exposed
    2 / 33 (6.06%)
    20 / 94 (21.28%)
    2 / 47 (4.26%)
         occurrences all number
    3
    43
    3
    Peripheral motor neuropathy
         subjects affected / exposed
    2 / 33 (6.06%)
    7 / 94 (7.45%)
    0 / 47 (0.00%)
         occurrences all number
    2
    14
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    17 / 33 (51.52%)
    56 / 94 (59.57%)
    4 / 47 (8.51%)
         occurrences all number
    36
    126
    5
    Restless legs syndrome
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Hyporeflexia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 94 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    0
    0
    5
    Neurotoxicity
         subjects affected / exposed
    0 / 33 (0.00%)
    8 / 94 (8.51%)
    1 / 47 (2.13%)
         occurrences all number
    0
    15
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    24 / 33 (72.73%)
    50 / 94 (53.19%)
    21 / 47 (44.68%)
         occurrences all number
    54
    113
    57
    Leukocytosis
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    3
    0
    0
    Leukopenia
         subjects affected / exposed
    9 / 33 (27.27%)
    10 / 94 (10.64%)
    6 / 47 (12.77%)
         occurrences all number
    15
    12
    19
    Lymphopenia
         subjects affected / exposed
    4 / 33 (12.12%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    11
    0
    0
    Neutropenia
         subjects affected / exposed
    10 / 33 (30.30%)
    53 / 94 (56.38%)
    24 / 47 (51.06%)
         occurrences all number
    24
    118
    74
    Pancytopenia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    16 / 33 (48.48%)
    32 / 94 (34.04%)
    19 / 47 (40.43%)
         occurrences all number
    49
    65
    46
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    8 / 33 (24.24%)
    5 / 94 (5.32%)
    3 / 47 (6.38%)
         occurrences all number
    10
    6
    3
    Constipation
         subjects affected / exposed
    12 / 33 (36.36%)
    30 / 94 (31.91%)
    9 / 47 (19.15%)
         occurrences all number
    14
    35
    12
    Diarrhoea
         subjects affected / exposed
    9 / 33 (27.27%)
    30 / 94 (31.91%)
    8 / 47 (17.02%)
         occurrences all number
    17
    40
    11
    Dyspepsia
         subjects affected / exposed
    6 / 33 (18.18%)
    13 / 94 (13.83%)
    0 / 47 (0.00%)
         occurrences all number
    7
    14
    0
    Dysphagia
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 94 (1.06%)
    4 / 47 (8.51%)
         occurrences all number
    3
    1
    5
    Flatulence
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Nausea
         subjects affected / exposed
    13 / 33 (39.39%)
    40 / 94 (42.55%)
    17 / 47 (36.17%)
         occurrences all number
    17
    56
    25
    Vomiting
         subjects affected / exposed
    11 / 33 (33.33%)
    23 / 94 (24.47%)
    11 / 47 (23.40%)
         occurrences all number
    12
    26
    15
    Abdominal distension
         subjects affected / exposed
    0 / 33 (0.00%)
    5 / 94 (5.32%)
    0 / 47 (0.00%)
         occurrences all number
    0
    8
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 33 (0.00%)
    6 / 94 (6.38%)
    2 / 47 (4.26%)
         occurrences all number
    0
    6
    2
    Stomatitis
         subjects affected / exposed
    0 / 33 (0.00%)
    6 / 94 (6.38%)
    2 / 47 (4.26%)
         occurrences all number
    0
    6
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    10 / 33 (30.30%)
    32 / 94 (34.04%)
    16 / 47 (34.04%)
         occurrences all number
    12
    36
    20
    Dry skin
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Erythema
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Skin lesion
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Pruritis
         subjects affected / exposed
    0 / 33 (0.00%)
    6 / 94 (6.38%)
    1 / 47 (2.13%)
         occurrences all number
    0
    6
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    4 / 33 (12.12%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    5
    0
    0
    Urinary retention
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 33 (24.24%)
    18 / 94 (19.15%)
    5 / 47 (10.64%)
         occurrences all number
    9
    28
    5
    Back pain
         subjects affected / exposed
    4 / 33 (12.12%)
    12 / 94 (12.77%)
    4 / 47 (8.51%)
         occurrences all number
    4
    13
    4
    Bone pain
         subjects affected / exposed
    2 / 33 (6.06%)
    5 / 94 (5.32%)
    3 / 47 (6.38%)
         occurrences all number
    2
    5
    3
    Muscle spasms
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    3
    0
    0
    Muscular weakness
         subjects affected / exposed
    2 / 33 (6.06%)
    6 / 94 (6.38%)
    2 / 47 (4.26%)
         occurrences all number
    2
    10
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    4
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 33 (6.06%)
    7 / 94 (7.45%)
    2 / 47 (4.26%)
         occurrences all number
    3
    15
    2
    Neck pain
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    3
    0
    0
    Pain in extremity
         subjects affected / exposed
    6 / 33 (18.18%)
    11 / 94 (11.70%)
    3 / 47 (6.38%)
         occurrences all number
    8
    13
    3
    Myalgia
         subjects affected / exposed
    0 / 33 (0.00%)
    12 / 94 (12.77%)
    3 / 47 (6.38%)
         occurrences all number
    0
    18
    3
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    3 / 33 (9.09%)
    5 / 94 (5.32%)
    2 / 47 (4.26%)
         occurrences all number
    3
    5
    2
    Urinary tract infection
         subjects affected / exposed
    5 / 33 (15.15%)
    10 / 94 (10.64%)
    7 / 47 (14.89%)
         occurrences all number
    5
    12
    10
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    6 / 94 (6.38%)
    2 / 47 (4.26%)
         occurrences all number
    0
    7
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 33 (18.18%)
    32 / 94 (34.04%)
    16 / 47 (34.04%)
         occurrences all number
    9
    45
    22
    Dehydration
         subjects affected / exposed
    3 / 33 (9.09%)
    15 / 94 (15.96%)
    6 / 47 (12.77%)
         occurrences all number
    5
    23
    7
    Hypercalcaemia
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    4
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    2 / 33 (6.06%)
    5 / 94 (5.32%)
    2 / 47 (4.26%)
         occurrences all number
    6
    8
    2
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    8
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 94 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    3
    0
    0
    Hypokalaemia
         subjects affected / exposed
    9 / 33 (27.27%)
    13 / 94 (13.83%)
    3 / 47 (6.38%)
         occurrences all number
    20
    32
    4
    Hypomagnesaemia
         subjects affected / exposed
    7 / 33 (21.21%)
    16 / 94 (17.02%)
    6 / 47 (12.77%)
         occurrences all number
    15
    36
    6
    Hyponatraemia
         subjects affected / exposed
    8 / 33 (24.24%)
    12 / 94 (12.77%)
    6 / 47 (12.77%)
         occurrences all number
    13
    15
    7
    Hypophospataemia
         subjects affected / exposed
    5 / 33 (15.15%)
    5 / 94 (5.32%)
    1 / 47 (2.13%)
         occurrences all number
    5
    5
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 May 2011
    Substantive changes made to the protocol by Amendment 1 included the following: • The design of phase II was modified to employ a Simon two-stage design - the approximate number of patients enrolled in both phase I and II was updated from 125 to a total of 90-160. • The provision to potentially explore a chemotherapy-naïve cohort of patients in phase I to determine if higher doses of IMGN901 could be tolerated in patients whose bone marrow had not been compromised by prior cytotoxic chemotherapy regimens was added to the protocol. • The inclusion criterion regarding 24-hour creatinine clearance and the exclusion criteria related to neurotoxicity and brain metastases were updated. Specifically, the inclusion of patients with a 24-hour creatinine clearance ≥ 50 mL/min was revised to a 24-hour creatinine clearance ≥ 60 mL/min, and the exclusion of patients with neurotoxicity was changed from ≥ grade 1 neurotoxicity to ≥ grade 2. The criterion relating to CNS metastases was modified to exclude patients with untreated brain metastases in phase II. • The definition of DLT was modified such that isolated, asymptomatic elevations in biochemistry laboratory values lasting ≤ 7 days were not considered dose-limiting. • The dose modification procedures were modified to allow carboplatin to be reduced to AUC = 4 and etoposide to be reduced to 60 mg/m2. • The criteria to continue treatment, begin a new cycle of therapy, and re-initiate therapy after the occurrence of a DLT were modified to state that all non-hematologic toxicities were to be ≤ grade 2 (except alopecia) or returned to baseline. The original protocol had stated that these toxicities had to be ≤ grade 1. • The use of growth factor support for ongoing related toxicities was permitted. • Hematology and clinical chemistries were added on Day 15 of Cycle 1 through 4
    30 Jun 2011
    Substantive changes made to the protocol by Amendment 2 included the following: • The number of cycles of carboplatin + etoposide to be administered was changed from a range of four to six to six, as tolerated, in phase II. • The entrance criteria were changed such that patients with an activity malignancy rather than any malignancy within the previous three years were excluded. Furthermore, the exclusion criterion regarding CNS metastases was modified to provide guidance regarding steroid therapy such that patients with CNS metastases who were previously treated with surgery or radiation and who were receiving stable, decreasing, or no steroids were eligible. • Guidelines allowing for IMGN901 dose reductions for the management of hematologic toxicities were provided. • A DMC was added for review of safety information during the phase II portion of the study.
    04 May 2012
    Substantive changes made to the protocol by Amendment 3 included the following: • The entrance criterion regarding previous radiotherapy was clarified to include cranial irradiation. Furthermore, patients with uncontrolled 3rd space fluid retention were no longer excluded, as patients with SCLC may have pleural effusions that do not necessarily disqualify them from participation in the study. It was further clarified that patients with asymptomatic brain metastases who had been treated were eligible for study participation; those with untreated brain metastases were excluded. • The RP2D for phase II, IMGN901 112 mg/m2 plus carboplatin (AUC5) + etoposide 100 mg/m2, was indicated in the protocol. • It was clarified that the individual study agents may have been discontinued independent of each other. Furthermore, dose level reductions based on the RP2D were clarified. • Wider visit windows were permitted, including 21 rather than seven days for safety follow-up assessments; a delay of up to seven rather than three days due to logistical reasons for starting a new cycle; and seven rather than three days for evaluation of toxicity prior to Day 1 of a new cycle. • The definition of WCBP was updated. • It was clarified that the IMGN901 dose was to be calculated based on the patient’s body weight at first treatment. Adjustments were to be made for significant (≥ 10%) changes in body weight not influenced by fluid retention. • The protocol was clarified to indicate that patients in phase II, Arm 2, were to receive pre-medications prior to carboplatin + etoposide in accordance with institutional guidelines. • The dose modification procedures were clarified.
    30 Aug 2012
    Substantive changes made to the protocol by Amendment 4 included the following: • The requirement for PK sample collection was removed, as sufficient PK data had already been collected in the study. • It was clarified that laboratory abnormalities were to be reported as AEs. • Additional guidance regarding SAE reporting was provided, including identification of events that did not qualify as inpatient hospitalizations; clarification of when death was reported as an SAE rather than an SAE outcome; clarification of what constituted the primary SAE term; and specification that sites were to provide SAE reports to the local IRB/IEC in accordance with local requirements. • Replacement of patients in phase II was allowed by Amendment 4. • The list of critical documents required from an Investigator before initiating the study was updated in accordance with ImmunoGen SOPs.
    11 Apr 2013
    Substantive changes made to the protocol by Amendment 5 included the following: • The IMGN901 dose in phase II was lowered from 112 mg/m2 to 90 mg/m2 based on analysis of data from phase II that showed an increased frequency of peripheral neuropathy in patients treated with IMGN901 112 mg/m2 plus carboplatin + etoposide. • Given the findings noted above, the definition of DLT regarding peripheral neuropathy and procedures for the management of peripheral neuropathy were revised. • An exploratory assessment of CTCs was added. • The sample size was increased in phase II, with an additional 15 patients planned to be enrolled at IMGN 90 mg/m2 dose level in order to permit an analysis to rule out a six-month PFS rate <40%. • The number of sites was increased from up to 40 to up to 50. • The permissible window for delaying the start of a cycle due to logistical reasons was widened. • It was clarified that for patients undergoing PCI, AEs and concomitant medications were to be recorded for 28 days thereafter in order to allow a comparison of safety after PCI between the two treatment arms. • Magnesium was added as a clinical chemistry parameter to be measured. • The definition of the PP population was clarified to indicate that patients included must have been evaluable by RECIST.
    16 Oct 2013
    Substantive changes made to the protocol by Amendment 6 included the following: • It was clarified that for patients in phase II, Arm 2, the EOT visit was to occur after the completion of C6, and follow-up response assessments were to be performed for patients in phase II, Arm 2, who completed six cycles of treatment. • Measurement of cytokines was added as a study assessment. • As an aggregate analysis of safety data from this study indicated an increase in the frequency of serious infectious events, with most occurring in Cycles 1 and 2, and an association of such events with neutropenia, the requirement for prophylactic administration of G-CSF during Cycle 1 and 2 was added.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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