Mesothelioma
Conditions
Brief summary
The main purpose of the 15743 study is to assess efficacy and safety of anetumab ravtansine versus vinorelbine in progression free survival in patients with stage IV mesothelin overexpressing malignant pleural mesothelioma (MPM). 210 eligible patients will be randomized to receive either anetumab ravtansine every three weeks or weekly vinorelbine. Treatment will continue until centrally confirmed disease progression or until another criterion is met for withdrawal from the study. Patients will enter follow up phase to capture safety and endpoint data as required. Efficacy will be measured by evaluating progression free survival from randomization. Radiological tumor assessments will be performed at defined time points until the patient's disease progresses. Blood samples will be collected for safety, pharmacokinetic and biomarker analysis. Archival or fresh biopsy tissue may also be collected for central pathology review and biomarkers.
Interventions
Starting dose: 6.5 mg/kg administered as IV infusion over 1 h every 3 weeks until disease progression or treatment withdrawal for any reason. Dose reductions are permitted.
DRUGVinorelbine
Starting dose: 30mg/m\^2 administered as an IV infusion over 6 to 10 min every week until disease progression or treatment withdrawal for any reason. Dose reductions are permitted per standard practise.
Sponsors
ImmunoGen and MorphoSys
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histological documentation of malignant pleural mesothelioma (MPM) overexpressing mesothelin * Unresectable locally advanced or metastatic MPM after locally confirmed progression on 1st line treatment with platinum in combination with pemetrexed. * Patients must have measurable disease * Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 * Life expectancy of at least 3 months. * Adequate bone marrow, liver and renal function * Left ventricular ejection fraction (LVEF) ≥ 50% or the lower limit of normal (LLN) according to local institution ranges of normality.
Exclusion criteria
* More than 1 previous systemic anti-cancer therapy line * Patients with corneal epitheliopathy or any eye disorder that may predispose the patients to this condition at the discretion of the investigator in consultation with the ophthalmologist. * Brain metastases, meningeal tumours or other metastases in the central nervous system * Evidence of history of bleeding diathesis. * Ongoing or active infection (bacterial, fungal, or viral) of National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 Grade \> 2. * Pre-existing cardiac conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS), [95% CI] | From randomization till approximately 117 PFS events observed, up to approx. 30 months (data cut-off: 31-May-2017) | Progression-free survival (PFS), defined as time from randomization until disease progression according to mRECIST (Modified Response Evaluation Criteria in Solid Tumors) for Malignant pleural mesothelioma (MPM) per blinded central radiology review, or death. Only descriptive analysis of OS was repeated in the follow-up period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS), [95% CI] | Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause; one-sided log-rank test stratified by time to progression (TTP) on first line treatment. | Overall survival (OS) was defined as time from randomization until death from any cause. |
| Disease Control Rate (DCR) | Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause. | A patient has disease control if the patient has a best tumor response on-study of CR, PR, or SD (Stable disease). DCR was defined as a percentage of patients achieving CR, PR, or SD per mRECIST criteria, as determined by the central radiological reviewer. DCR was calculated in each treatment arm as the number of patients with disease control (a best tumor response on-study of CR, PR, or SD) divided by the number of randomized patients. |
| Duration of Response (DOR) | Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause. | DOR was defined in responders as the time from central documentation of tumor response date of first response in the confirmation sequence) to the earlier of disease progression as determined by the central radiological reviewer, or death without centrally documented progression. A responder was a patient who had a confirmed best tumor response on-study of CR or PR, as determined by the central radiological reviewer per mRECIST criteria. |
| Durable Response Rate (DRR) | Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause. | A durable responder was a responder (i.e. confirmed best tumor response on study of CR or PR) with duration of response of 180 days or more. |
| Percentage of Participants With Confirmed Improvement of Symptoms Characteristic of Mesothelioma | up to approx. 30 months (data cut-off: 31-May-2017) | Improvement rate of symptoms characteristic of mesothelioma was defined as the number of patients with confirmed improvement of symptoms characteristic of mesothelioma (based on the MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma, MDASI-MPM), divided by the number of patients evaluable for improvement of symptoms characteristic of mesothelioma. |
| Objective Response Rate (ORR) | up to approx. 30 months (data cut-off: 31-May-2017) - Time from randomization until death from any cause. | A patient is a responder if the patient has a confirmed best tumor response on-study of CR (Complete response) or PR (Partial response), as determined by the central radiological reviewer per mRECIST criteria. ORR in each treatment arm was defined as the number of responders divided by the number of randomized patients. A responder was a patient who had a confirmed best tumor response on-study of CR or PR, as determined by the central radiological reviewer per mRECIST criteria. |
| Time to Worsening of Pain | up to approx. 30 months (data cut-off: 31-May-2017) | Time to worsening of pain (TTWP) was defined in patients evaluable for assessing worsening of pain, as time from randomization until the first worsening of pain. Patients who died, were lost to follow-up, or ended (MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma) MDASI-MPM assessments without confirmed worsening of pain were censored at the date of their last MDASI-MPM assessment with a non-missing pain score. |
| Percentage of Participants With Confirmed Improvement of Pain | Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause. | Improvement rate of pain was defined as the number of patients with confirmed improvement of pain (based on the pain at its worst item of MDASI-MPM), divided by the number of patients evaluable for improvement of pain. |
| Percentage of Participant With Treatment-emergent Adverse Events (TEAEs) | Up to approx. 55 months (data cut-off: 02-Jul-2019) - Time from randomization until 30 days after last treatment (general AEs), or further until death from any cause (selected AEs). | TEAEs were defined as all AEs starting or worsening within the treatment period. |
| Number of Deaths | Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause. | TEAE(s) associated with a fatal outcome (CTCAE Grade 5) at the time of the data cut-off 06-Apr-2018. |
| Overall Survival (OS) - Addendum | Up to approx. 55 month (data cut-off: 02-JUL-2019) - Time from randomization until death from any cause | Overall survival (OS) was defined as time from randomization until death from any cause; Only descriptive analyses of OS were repeated in with the data as of the 02 JUL 2019. |
| Time to Worsening of Symptoms Characteristic of Mesothelioma | up to approx. 30 months (data cut-off: 31-May-2017) | Time to worsening of symptoms characteristic of mesothelioma (TTWS) was defined in patients evaluable for assessing worsening of symptoms, as the time from randomization until the first worsening of symptoms characteristic of mesothelioma. Patients who died, were lost to follow-up, or ended (MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma) MDASI-MPM assessments without confirmed worsening of symptoms were censored at the date of their last MDASI-MPM assessment with a non-missing (Composite Symptom Score) CSS. |
Countries
Australia, Belgium, Canada, Finland, France, Italy, Netherlands, Poland, Russia, South Korea, Spain, Turkey (Türkiye), United Kingdom, United States
Participant flow
Pre-assignment details
Overall, 315 patients were screened; of these, 67 patients were screening failures.
Participants by arm
| Arm | Count |
|---|---|
| Anetumab Ravtansine (Experimental) Experimental | 166 |
| Vinorelbine (Active Comparator) Active comparator | 82 |
| Total | 248 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Active Follow-up | Death | 8 | 1 |
| Active Follow-up | Deterioration of general conditions | 1 | 0 |
| Active Follow-up | Ongoing but not completed | 4 | 1 |
| Active Follow-up | Progressive disease - clinical | 1 | 2 |
| Active Follow-up | Progressive disease - radiological | 30 | 22 |
| Active Follow-up | Withdrawal by Subject | 4 | 0 |
| Long-term Follow-up | Death | 86 | 44 |
| Long-term Follow-up | Lost to Follow-up | 1 | 2 |
| Long-term Follow-up | Ongoing but not completed | 30 | 17 |
| Long-term Follow-up | Withdrawal by Subject | 6 | 3 |
| Randomization and Treatment Period | Adverse Event | 44 | 13 |
| Randomization and Treatment Period | Death | 7 | 1 |
| Randomization and Treatment Period | Lack of Efficacy | 1 | 0 |
| Randomization and Treatment Period | Not treated | 3 | 10 |
| Randomization and Treatment Period | Ongoing but not completed | 9 | 2 |
| Randomization and Treatment Period | Physician Decision | 0 | 1 |
| Randomization and Treatment Period | Progressive disease - clinical | 12 | 5 |
| Randomization and Treatment Period | Progressive disease - radiological | 54 | 23 |
| Randomization and Treatment Period | Protocol Violation | 1 | 0 |
| Randomization and Treatment Period | Radiological progression | 23 | 15 |
| Randomization and Treatment Period | Withdrawal by Subject | 12 | 12 |
| Safety Follow-up | Death | 12 | 2 |
| Safety Follow-up | Deterioration of general conditions | 15 | 5 |
| Safety Follow-up | Lost to Follow-up | 1 | 0 |
| Safety Follow-up | No follow-up | 5 | 3 |
| Safety Follow-up | Other | 0 | 2 |
| Safety Follow-up | Withdrawal by Subject | 12 | 12 |
Baseline characteristics
| Characteristic | Anetumab Ravtansine (Experimental) | Vinorelbine (Active Comparator) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 100 Participants | 45 Participants | 145 Participants |
| Age, Categorical Between 18 and 65 years | 66 Participants | 37 Participants | 103 Participants |
| Age, Continuous | 66.1 Years STANDARD_DEVIATION 8.1 | 65.6 Years STANDARD_DEVIATION 8.8 | 65.9 Years STANDARD_DEVIATION 8.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 6 Participants | 10 Participants |
| Race (NIH/OMB) White | 157 Participants | 75 Participants | 232 Participants |
| Sex: Female, Male Female | 44 Participants | 20 Participants | 64 Participants |
| Sex: Female, Male Male | 122 Participants | 62 Participants | 184 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 126 / 163 | 55 / 72 |
| other Total, other adverse events | 161 / 163 | 68 / 72 |
| serious Total, serious adverse events | 56 / 163 | 25 / 72 |
Outcome results
Primary
Progression-free Survival (PFS), [95% CI]
Progression-free survival (PFS), defined as time from randomization until disease progression according to mRECIST (Modified Response Evaluation Criteria in Solid Tumors) for Malignant pleural mesothelioma (MPM) per blinded central radiology review, or death. Only descriptive analysis of OS was repeated in the follow-up period.
Time frame: From randomization till approximately 117 PFS events observed, up to approx. 30 months (data cut-off: 31-May-2017)
Population: The primary efficacy analysis (PFS) was performed in the ITT (Intent-to-treat) analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anetumab Ravtansine | Progression-free Survival (PFS), [95% CI] | 4.3 months |
| Vinorelbine | Progression-free Survival (PFS), [95% CI] | 4.5 months |
Comparison: PFS anetumab ravtansine / vinorelbinep-value: 0.859125Log Rank
Secondary
Disease Control Rate (DCR)
A patient has disease control if the patient has a best tumor response on-study of CR, PR, or SD (Stable disease). DCR was defined as a percentage of patients achieving CR, PR, or SD per mRECIST criteria, as determined by the central radiological reviewer. DCR was calculated in each treatment arm as the number of patients with disease control (a best tumor response on-study of CR, PR, or SD) divided by the number of randomized patients.
Time frame: Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause.
Population: The secondary efficacy analysis (DCR) was performed in the ITT (Intent-to-treat) analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anetumab Ravtansine | Disease Control Rate (DCR) | 73.5 percentage of participants |
| Vinorelbine | Disease Control Rate (DCR) | 68.3 percentage of participants |
Secondary
Durable Response Rate (DRR)
A durable responder was a responder (i.e. confirmed best tumor response on study of CR or PR) with duration of response of 180 days or more.
Time frame: Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause.
Population: The secondary efficacy analysis (DRR) was performed in the ITT (Intent-to-treat) analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anetumab Ravtansine | Durable Response Rate (DRR) | 7.2 percentage of participants |
| Vinorelbine | Durable Response Rate (DRR) | 4.9 percentage of participants |
Secondary
Duration of Response (DOR)
DOR was defined in responders as the time from central documentation of tumor response date of first response in the confirmation sequence) to the earlier of disease progression as determined by the central radiological reviewer, or death without centrally documented progression. A responder was a patient who had a confirmed best tumor response on-study of CR or PR, as determined by the central radiological reviewer per mRECIST criteria.
Time frame: Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause.
Population: The secondary efficacy analysis (DOR) was performed in the ITT (Intent-to-treat) analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anetumab Ravtansine | Duration of Response (DOR) | 7.4 months |
| Vinorelbine | Duration of Response (DOR) | 6.7 months |
Secondary
Number of Deaths
TEAE(s) associated with a fatal outcome (CTCAE Grade 5) at the time of the data cut-off 06-Apr-2018.
Time frame: Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause.
Population: The secondary efficacy analysis (TEAEs) was performed in the safety analysis set (SAF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anetumab Ravtansine | Number of Deaths | 10 Number of Deaths |
| Vinorelbine | Number of Deaths | 1 Number of Deaths |
Secondary
Objective Response Rate (ORR)
A patient is a responder if the patient has a confirmed best tumor response on-study of CR (Complete response) or PR (Partial response), as determined by the central radiological reviewer per mRECIST criteria. ORR in each treatment arm was defined as the number of responders divided by the number of randomized patients. A responder was a patient who had a confirmed best tumor response on-study of CR or PR, as determined by the central radiological reviewer per mRECIST criteria.
Time frame: up to approx. 30 months (data cut-off: 31-May-2017) - Time from randomization until death from any cause.
Population: The secondary efficacy analysis (ORR) was performed in the ITT (Intent-to-treat) analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anetumab Ravtansine | Objective Response Rate (ORR) | 8.4 percentage of participants |
| Vinorelbine | Objective Response Rate (ORR) | 6.1 percentage of participants |
Secondary
Overall Survival (OS), [95% CI]
Overall survival (OS) was defined as time from randomization until death from any cause.
Time frame: Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause; one-sided log-rank test stratified by time to progression (TTP) on first line treatment.
Population: The secondary efficacy analysis (OS) was performed in the ITT (Intent-to-treat) analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anetumab Ravtansine | Overall Survival (OS), [95% CI] | 9.5 months |
| Vinorelbine | Overall Survival (OS), [95% CI] | 11.6 months |
Comparison: OS anetumab ravtansine / vinorelbinep-value: 0.65562495% CI: [0.763, 1.506]Log Rank
Secondary
Overall Survival (OS) - Addendum
Overall survival (OS) was defined as time from randomization until death from any cause; Only descriptive analyses of OS were repeated in with the data as of the 02 JUL 2019.
Time frame: Up to approx. 55 month (data cut-off: 02-JUL-2019) - Time from randomization until death from any cause
Population: The secondary efficacy analysis (OS) was performed in the ITT (Intent-to-treat) analysis set.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Anetumab Ravtansine | Overall Survival (OS) - Addendum | 9.5 months |
| Vinorelbine | Overall Survival (OS) - Addendum | 11.6 months |
95% CI: [0.1, 39.3]
95% CI: [0, 35.9]
Secondary
Percentage of Participants With Confirmed Improvement of Pain
Improvement rate of pain was defined as the number of patients with confirmed improvement of pain (based on the pain at its worst item of MDASI-MPM), divided by the number of patients evaluable for improvement of pain.
Time frame: Up to approx. 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause.
Population: The secondary efficacy analysis was performed in the ITT (Intent-to-treat) analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anetumab Ravtansine | Percentage of Participants With Confirmed Improvement of Pain | 40.4 percentage of participants |
| Vinorelbine | Percentage of Participants With Confirmed Improvement of Pain | 32.7 percentage of participants |
p-value: 0.21495% CI: [-9.4, 22.68]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Confirmed Improvement of Symptoms Characteristic of Mesothelioma
Improvement rate of symptoms characteristic of mesothelioma was defined as the number of patients with confirmed improvement of symptoms characteristic of mesothelioma (based on the MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma, MDASI-MPM), divided by the number of patients evaluable for improvement of symptoms characteristic of mesothelioma.
Time frame: up to approx. 30 months (data cut-off: 31-May-2017)
Population: The secondary efficacy analysis was performed in the ITT (Intent-to-treat) analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anetumab Ravtansine | Percentage of Participants With Confirmed Improvement of Symptoms Characteristic of Mesothelioma | 22.5 percentage of participants |
| Vinorelbine | Percentage of Participants With Confirmed Improvement of Symptoms Characteristic of Mesothelioma | 17.9 percentage of participants |
Comparison: Anetumab ravtansine versus vinorelbinep-value: 0.24495% CI: [-8.2, 17.51]Cochran-Mantel-Haenszel
Secondary
Percentage of Participant With Treatment-emergent Adverse Events (TEAEs)
TEAEs were defined as all AEs starting or worsening within the treatment period.
Time frame: Up to approx. 55 months (data cut-off: 02-Jul-2019) - Time from randomization until 30 days after last treatment (general AEs), or further until death from any cause (selected AEs).
Population: The secondary efficacy analysis (TEAEs) was performed in the safety analysis set (SAF).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Anetumab Ravtansine | Percentage of Participant With Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 99.4 Percentage of participants |
| Anetumab Ravtansine | Percentage of Participant With Treatment-emergent Adverse Events (TEAEs) | Any study drug-related TEAE | 88.3 Percentage of participants |
| Anetumab Ravtansine | Percentage of Participant With Treatment-emergent Adverse Events (TEAEs) | Treatment-emergent serious adverse events (TESAEs) | 34.4 Percentage of participants |
| Vinorelbine | Percentage of Participant With Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 98.6 Percentage of participants |
| Vinorelbine | Percentage of Participant With Treatment-emergent Adverse Events (TEAEs) | Any study drug-related TEAE | 90.3 Percentage of participants |
| Vinorelbine | Percentage of Participant With Treatment-emergent Adverse Events (TEAEs) | Treatment-emergent serious adverse events (TESAEs) | 34.7 Percentage of participants |
Secondary
Time to Worsening of Pain
Time to worsening of pain (TTWP) was defined in patients evaluable for assessing worsening of pain, as time from randomization until the first worsening of pain. Patients who died, were lost to follow-up, or ended (MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma) MDASI-MPM assessments without confirmed worsening of pain were censored at the date of their last MDASI-MPM assessment with a non-missing pain score.
Time frame: up to approx. 30 months (data cut-off: 31-May-2017)
Population: The secondary efficacy analysis was performed in the ITT (Intent-to-treat) analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anetumab Ravtansine | Time to Worsening of Pain | 210 days |
| Vinorelbine | Time to Worsening of Pain | NA days |
Comparison: Anetumab ravtansine versus vinorelbinep-value: 0.37891695% CI: [0.557, 1.533]Log Rank
Secondary
Time to Worsening of Symptoms Characteristic of Mesothelioma
Time to worsening of symptoms characteristic of mesothelioma (TTWS) was defined in patients evaluable for assessing worsening of symptoms, as the time from randomization until the first worsening of symptoms characteristic of mesothelioma. Patients who died, were lost to follow-up, or ended (MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma) MDASI-MPM assessments without confirmed worsening of symptoms were censored at the date of their last MDASI-MPM assessment with a non-missing (Composite Symptom Score) CSS.
Time frame: up to approx. 30 months (data cut-off: 31-May-2017)
Population: The secondary efficacy analysis was performed in the ITT (Intent-to-treat) analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anetumab Ravtansine | Time to Worsening of Symptoms Characteristic of Mesothelioma | NA days |
| Vinorelbine | Time to Worsening of Symptoms Characteristic of Mesothelioma | NA days |
Comparison: Anetumab ravtansine versus vinorelbinep-value: 0.31374795% CI: [0.386, 1.779]Log Rank