Metastatic Soft Tissue Sarcoma
Conditions
Brief summary
This study is being done to see if MORAb-004 increases the effectiveness of the chemotherapies gemcitabine and docetaxel in people with metastatic Soft Tissue Sarcoma.
Interventions
DRUGMORAb-004
IV, Days 1 and 8 of every cycle until disease progression
DRUGGemcitabine
IV, Days 1 and 8 of each cycle until disease progression
DRUGDocetaxel
IV, Day 8 of every cycle until disease progression
DRUGPlacebo
Sponsors
Morphotek
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Be at least 18 years of age * Be surgically sterile or consent to use a medically acceptable method of contraception throughout the study period * Have a histologically confirmed diagnosis of mSTS as defined by the 4 specified study subgrouped * Have been treated in the metastatic setting with 0 to 2 prior systemic regimens for mSTS (Systemic treatment regimens given in the neoadjuvant setting and maintenance therapies will not be considered as regimens in the metastatic setting for the purposes of this protocol. Prior anthracycline-based regimen is allowable but not required. Subjects with extra-skeletal small round blue cell sarcomas, including rhabdomyosarcomas, must have exhausted or be intolerant of standard first line anthracycline-based chemotherapy.) * Have measurable disease, as defined by RECIST v 1.1 assess within 2 weeks of study entry and have radiologically documented disease progression greater than or equal to a 10% increase in the sum of the longest diameters of target lesions present within 6 months prior to randomization * Have tumor tissue available for TEM-1 biomarker studies * Be willing and able to provide written informed consent
Exclusion criteria
* Have received more than 2 prior systemic treatment regimens for mSTS * Have received either gemcitabine or docetaxel in any previous treatment for mSTS (regardless of the line of treatment) * Have a diagnosis of primary bone sarcoma of any histological type. * Have a history of clinically significant heart disease, or clinically significant arrhythmia on ECG within the past 6 months * Have a history of allergic reaction to prior monoclonal antibody or biologic agent * Have received previous treatment with MORAb-004 (anti-TEM-1) * Have a medical condition with a high risk of bleeding (e.g., a known bleeding disorder, a coagulopathy, or a tumor that involves the major vessels) or have a recent (within past 6 months) history of a significant bleeding event * Have undergone major surgical procedures or open biopsy, have significant traumatic injury within 30 days prior to the first date of study treatment, or have major surgical procedures anticipated during the study * Have a serious non-healing wound, an ulcer (including gastrointestinal), or a bone fracture
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Radiologic Progression-free Survival (PFS) | From date of first dose until date of first observation of disease progression, or death due to any cause (up to approximately 3 years) | PFS was defined as the time (in weeks) from the date of randomization to the date of first observation of disease progression according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or date of death, regardless of the cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Symptomatic Progression-free Survival | From date of first dose until date of first observation of disease progression, symptomatic progression, or death due to any cause (up to approximately 3 years) | PFS including symptomatic progression was defined as the time (in weeks) from the date of randomization to the date of the first observation of disease progression according to RECIST 1.1, symptomatic progression, or death due to any cause. |
| Part 2: Overall Survival (OS) | From date of first dose until date of death from any cause (up to approximately 3.5 years) | OS was defined as the time (in months) from the date of randomization to the date of death, regardless of the cause. |
| Part 2: Overall Response Rate (ORR) | From date of first dose until disease progression (up to approximately 3.5 years) | ORR was defined as the percentage of subjects with either a complete response (CR) or a partial response (PR) based on RECIST 1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR was defined as at least a 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters. |
| Part 2: Radiologic Progression-free Survival Rate (PFR) | Weeks 12, 24, 48 and 52 | Radiologic progression-free survival rate was defined as the percentage of subjects achieving radiologic PFS at the pre-specified time points. |
| Part 2: Number of Participants Who Had Relationship Between MORAb-004 Exposures and Biomarker Levels | Up to approximately 3 years | — |
Countries
Australia, Belgium, France, Italy, Netherlands, United States
Participant flow
Recruitment details
Participants took part in the study at 31 investigative sites in the United States, Australia, Italy, Netherlands, France and Belgium from 07 August 2012 to 02 August 2016.
Pre-assignment details
In Part 1, a total of 16 participants were enrolled and treated in the study. A total of 225 participants were screened for entry into Part 2 of the study. Of these 225 participants, 46 were screen failures and 209 were randomized into the study, of which 207 participants were treated.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: MORAb-004 4.0 mg/kg + Gemcitabine/Docetaxel Participants received MORAb-004 4 mg/kg, infusion, intravenously on Days 1 and 8 in combination with gemcitabine 900 mg/m\^2, infusion, intravenously on Days 1 and 8 and docetaxel, infusion, intravenously on Day 8 of each 21-day treatment cycle until disease progression (approximately 28 cycles). MORAb-004 was administered after the administration of gemcitabine on Day 1 and after the administration of gemcitabine/docetaxel on Day 8 in each 21-day treatment cycle. | 3 |
| Part 1: MORAb-004 6.0 mg/kg + Gemcitabine/Docetaxel Participants received MORAb-004 6 mg/kg, infusion, intravenously on Days 1 and 8 in combination with gemcitabine 900 mg/m\^2, infusion, intravenously on Days 1 and 8 and docetaxel 75 mg/m\^2, infusion, intravenously on Day 8 of each 21-day treatment cycle until disease progression (approximately 28 cycles). MORAb-004 was administered after the administration of gemcitabine on Day 1 and after the administration of gemcitabine/docetaxel on Day 8 in each 21-day treatment cycle. | 4 |
| Part 1: MORAb-004 8.0 mg/kg + Gemcitabine/Docetaxel Participants received MORAb-004 8 mg/kg, infusion, intravenously on Days 1 and 8 in combination with gemcitabine 900 mg/m\^2, infusion, intravenously on Days 1 and 8 and docetaxel 75 mg/m\^2, infusion, intravenously on Day 8 of each 21-day treatment cycle until disease progression (approximately 28 cycles). MORAb-004 was administered after the administration of gemcitabine on Day 1 and after the administration of gemcitabine/docetaxel on Day 8 in each 21-day treatment cycle. | 9 |
| Part 2: MORAb-004 8.0 mg/kg + Gemcitabine/Docetaxel Participants received MORAb-004 8.0 mg/kg, infusion, intravenously on Days 1 and 8 in combination with gemcitabine 900 mg/m\^2, infusion, intravenously on Days 1 and 8 and docetaxel 75 mg/m\^2, infusion, intravenously on Day 8 of each 21-day treatment cycle for until disease progression (approximately 31 cycles). MORAb-004 was administered after the administration of gemcitabine on Day 1 and after the administration of gemcitabine/docetaxel on Day 8 in each 21-day treatment cycle. | 139 |
| Part 2: Placebo + Gemcitabine/Docetaxel Participants received normal saline (0.9% sodium chloride), infusion, intravenously on Days 1 and 8 in combination with gemcitabine 900 mg/m\^2, infusion, intravenously on Days 1 and 8 and docetaxel 75 mg/m\^2, infusion, intravenously on Day 8 of each 21-day treatment cycle for until disease progression (approximately 31 cycles). Normal saline (0.9% sodium chloride) was administered after the administration of gemcitabine on Day 1 and after the administration of gemcitabine/docetaxel on Day 8 in each 21-day treatment cycle. | 70 |
| Total | 225 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Part 1 | Death | 3 | 1 | 8 | 0 | 0 |
| Part 1 | Discontinuation of study by sponsor | 0 | 0 | 1 | 0 | 0 |
| Part 1 | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 |
| Part 1 | Withdrawal by Subject | 0 | 2 | 0 | 0 | 0 |
| Part 2 | Brain metastases | 0 | 0 | 0 | 1 | 0 |
| Part 2 | Death | 0 | 0 | 0 | 76 | 35 |
| Part 2 | Discontinuation of study by sponsor | 0 | 0 | 0 | 51 | 31 |
| Part 2 | Lost to Follow-up | 0 | 0 | 0 | 3 | 0 |
| Part 2 | Progressive disease | 0 | 0 | 0 | 1 | 0 |
| Part 2 | Withdrawal by Subject | 0 | 0 | 0 | 5 | 4 |
Baseline characteristics
| Characteristic | Part 1: MORAb-004 4.0 mg/kg + Gemcitabine/Docetaxel | Part 1: MORAb-004 6.0 mg/kg + Gemcitabine/Docetaxel | Part 1: MORAb-004 8.0 mg/kg + Gemcitabine/Docetaxel | Part 2: MORAb-004 8.0 mg/kg + Gemcitabine/Docetaxel | Part 2: Placebo + Gemcitabine/Docetaxel | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants | 36 Participants | 21 Participants | 59 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 8 Participants | 103 Participants | 49 Participants | 166 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 2 Participants | 18 Participants | 8 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 4 Participants | 7 Participants | 119 Participants | 61 Participants | 193 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants | 7 Participants | 2 Participants | 11 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 0 Participants | 12 Participants | 9 Participants | 23 Participants |
| Race/Ethnicity, Customized Chinese | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 1 Participants | 3 Participants | 8 Participants | 116 Participants | 57 Participants | 185 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 3 Participants | 63 Participants | 32 Participants | 102 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 6 Participants | 76 Participants | 38 Participants | 123 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 1 / 4 | 8 / 9 | 76 / 140 | 35 / 67 |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 9 / 9 | 140 / 140 | 66 / 67 |
| serious Total, serious adverse events | 0 / 3 | 1 / 4 | 6 / 9 | 106 / 140 | 45 / 67 |
Outcome results
Primary
Part 2: Radiologic Progression-free Survival (PFS)
PFS was defined as the time (in weeks) from the date of randomization to the date of first observation of disease progression according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or date of death, regardless of the cause.
Time frame: From date of first dose until date of first observation of disease progression, or death due to any cause (up to approximately 3 years)
Population: The ITT population consisted of all randomized participants and were analyzed according to the treatment assigned by the IxRS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2: MORAb-004 8.0 mg/kg + Gemcitabine/Docetaxel | Part 2: Radiologic Progression-free Survival (PFS) | 18.7 weeks |
| Part 2: Placebo + Gemcitabine/Docetaxel | Part 2: Radiologic Progression-free Survival (PFS) | 24.1 weeks |
p-value: =0.656295% CI: [0.77, 1.5]Log Rank
Secondary
Part 2: Number of Participants Who Had Relationship Between MORAb-004 Exposures and Biomarker Levels
Time frame: Up to approximately 3 years
Population: The ITT Population consisted of all randomized participants and were analyzed according to treatment assigned by the IxRS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2: MORAb-004 8.0 mg/kg + Gemcitabine/Docetaxel | Part 2: Number of Participants Who Had Relationship Between MORAb-004 Exposures and Biomarker Levels | 0 participants |
| Part 2: Placebo + Gemcitabine/Docetaxel | Part 2: Number of Participants Who Had Relationship Between MORAb-004 Exposures and Biomarker Levels | 0 participants |
Secondary
Part 2: Overall Response Rate (ORR)
ORR was defined as the percentage of subjects with either a complete response (CR) or a partial response (PR) based on RECIST 1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR was defined as at least a 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time frame: From date of first dose until disease progression (up to approximately 3.5 years)
Population: The ITT Population consisted of all randomized participants and were analyzed according to treatment assigned by the IxRS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 2: MORAb-004 8.0 mg/kg + Gemcitabine/Docetaxel | Part 2: Overall Response Rate (ORR) | 19.4 percentage of participants |
| Part 2: Placebo + Gemcitabine/Docetaxel | Part 2: Overall Response Rate (ORR) | 20.0 percentage of participants |
Comparison: Difference equal to (=) (MORAb 8.0 mg/kg + Gemcitabine/Docetaxel) minus (Placebo + Gemcitabine/Docetaxel). Confidence interval based on a normal approximation to the binomial distribution.p-value: =195% CI: [-12, 10.9]Log Rank
Secondary
Part 2: Overall Survival (OS)
OS was defined as the time (in months) from the date of randomization to the date of death, regardless of the cause.
Time frame: From date of first dose until date of death from any cause (up to approximately 3.5 years)
Population: The ITT Population consisted of all randomized participants and were analyzed according to treatment assigned by the IxRS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2: MORAb-004 8.0 mg/kg + Gemcitabine/Docetaxel | Part 2: Overall Survival (OS) | 18.3 months |
| Part 2: Placebo + Gemcitabine/Docetaxel | Part 2: Overall Survival (OS) | 21.1 months |
p-value: 0.315395% CI: [0.82, 1.83]Log Rank
Secondary
Part 2: Radiologic Progression-free Survival Rate (PFR)
Radiologic progression-free survival rate was defined as the percentage of subjects achieving radiologic PFS at the pre-specified time points.
Time frame: Weeks 12, 24, 48 and 52
Population: The ITT Population consisted of all randomized participants and were analyzed according to treatment assigned by the IxRS.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 2: MORAb-004 8.0 mg/kg + Gemcitabine/Docetaxel | Part 2: Radiologic Progression-free Survival Rate (PFR) | 12 weeks | 57.6 percentage of participants |
| Part 2: MORAb-004 8.0 mg/kg + Gemcitabine/Docetaxel | Part 2: Radiologic Progression-free Survival Rate (PFR) | 48 weeks | 24.5 percentage of participants |
| Part 2: MORAb-004 8.0 mg/kg + Gemcitabine/Docetaxel | Part 2: Radiologic Progression-free Survival Rate (PFR) | 24 weeks | 43.3 percentage of participants |
| Part 2: MORAb-004 8.0 mg/kg + Gemcitabine/Docetaxel | Part 2: Radiologic Progression-free Survival Rate (PFR) | 52 weeks | 20.8 percentage of participants |
| Part 2: Placebo + Gemcitabine/Docetaxel | Part 2: Radiologic Progression-free Survival Rate (PFR) | 24 weeks | 51.0 percentage of participants |
| Part 2: Placebo + Gemcitabine/Docetaxel | Part 2: Radiologic Progression-free Survival Rate (PFR) | 12 weeks | 61.8 percentage of participants |
| Part 2: Placebo + Gemcitabine/Docetaxel | Part 2: Radiologic Progression-free Survival Rate (PFR) | 52 weeks | 21.4 percentage of participants |
| Part 2: Placebo + Gemcitabine/Docetaxel | Part 2: Radiologic Progression-free Survival Rate (PFR) | 48 weeks | 25.2 percentage of participants |
Secondary
Part 2: Symptomatic Progression-free Survival
PFS including symptomatic progression was defined as the time (in weeks) from the date of randomization to the date of the first observation of disease progression according to RECIST 1.1, symptomatic progression, or death due to any cause.
Time frame: From date of first dose until date of first observation of disease progression, symptomatic progression, or death due to any cause (up to approximately 3 years)
Population: The ITT population consisted of all randomized participants and were analyzed according to treatment assigned by the IxRS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 2: MORAb-004 8.0 mg/kg + Gemcitabine/Docetaxel | Part 2: Symptomatic Progression-free Survival | 18.1 weeks |
| Part 2: Placebo + Gemcitabine/Docetaxel | Part 2: Symptomatic Progression-free Survival | 24.0 weeks |
p-value: =0.446995% CI: [0.82, 1.57]Log Rank