Leiomyosarcoma
Conditions
Brief summary
This study will compare the efficacy and safety of unesbulin plus dacarbazine versus placebo plus dacarbazine in participants with unresectable or metastatic, relapsed or refractory LMS who have received at least 1 prior line of systemic therapy.
Interventions
DRUGUnesbulin
Unesbulin will be administered as per the dose and schedule specified in the arm description.
DRUGDacarbazine
Dacarbazine will be administered as per the dose and schedule specified in the arm description.
OTHERPlacebo
Placebo will be administered as per the schedule specified in the arm description.
Sponsors
PTC Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Histological or cytological confirmation of LMS arising at any anatomic site except bone sarcoma, unresectable or metastatic, relapsed or refractory disease measurable per RECIST 1.1 criteria * Disease progression on previous treatment before screening or intolerability to other oncology treatments * Participants with liver metastases may be enrolled * Participants with well-controlled asthma or chronic obstructive pulmonary disease may be enrolled. * Toxicity from prior therapies recovered to Grade ≤1 or participant's baseline, except for alopecia. In addition, endocrinopathies associated with prior immunotherapy-based treatments that are well controlled on replacement medication are not exclusionary. * At least 1 prior systemic cytotoxic or targeted therapy regimen for LMS, which may include but is not limited to single-agent doxorubicin or other anthracycline, doxorubicin plus ifosfamide, trabectedin, pazopanib, or gemcitabine with or without docetaxel. * At least 4 weeks since prior surgery and recovered in the opinion of investigator Key
Exclusion criteria
* Received temozolomide or dacarbazine at any time * Any other systemic anticancer therapy including investigational agents ≤3 weeks before initiation of study treatment. Additionally, participants may not have received radiation ≤3 weeks before initiation of study treatment. * Known intolerance to dacarbazine or one or more of the excipients in unesbulin. * Co-existing active infection or any co-existing medical condition likely to interfere with study procedures * Gastrointestinal disease or other conditions that could affect absorption. Active peptic ulcer disease, active gastritis, or previous history of gastric perforation within the last 2 years * Major surgery, open biopsy, or significant traumatic injury that has not recovered, in the opinion of the investigator, within 28 days of baseline * Immunization with a live vaccine within 30 days before starting study drug due to the risk of serious and life-threatening infections. * Prior malignancies, other than LMS, that required treatment or have shown evidence of recurrence (except for non-melanoma skin cancer or adequately treated cervical carcinoma in situ, prostate cancer in situ or any other low risk malignancy that is approved by the medical monitor) during the 5 years before initiation. * Prior or ongoing clinically significant illness, medical or psychiatric condition, medical history, physical findings, electrocardiogram (ECG) findings, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the participant, or alter the absorption, distribution, metabolism, or excretion of the study drugs, or could impair the assessment of study results. Note: Other inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Per Independent Central Review Using Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 | Up to approximately 2 years | PFS was defined as the time from randomization to the documented disease progression or death due to any cause, whichever occurred first. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). The appearance of one or more new lesions was also considered progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to approximately 2 years | Overall survival was defined as the time in months from the randomization date to the date of death from any cause or date last known alive for those who did not die. |
| Objective Response Rate (ORR) Per Independent Central Review Using RECIST V1.1 | Up to approximately 2 years | ORR was defined as percentage of participants who achieved a confirmed best overall response (BOR) of complete response (CR) or partial response (PR). CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Disease Control Rate (DCR) Per Independent Central Review Using RECIST V1.1 | Up to approximately 2 years | DCR was defined as percentage of participants who achieved a confirmed BOR of CR, PR, or at least 3 months of stable disease (SD). CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. |
| Duration of Response Per Independent Central Review Using RECIST V1.1 | Up to approximately 2 years | Duration of response was defined as the time from the date of first confirmed response of CR or PR to the date of the first documented disease progression or death due to any cause, whichever occurred first. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Disease progression: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | From first dose of study drug up to approximately 2 years | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A TEAE was defined as an AE that had an onset date on or after the first dose of study drug until 30 days after last dose or occurred prior to first dose of study drug and worsened in severity after first dose of study drug. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. |
Countries
Australia, Brazil, Canada, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
Participants were randomized 2:1 to 1 of the following treatment groups: 1. Unesbulin and Dacarbazine or 2. Placebo and Dacarbazine.
Participants by arm
| Arm | Count |
|---|---|
| Unesbulin and Dacarbazine Participants received unesbulin 300 mg tablets administered orally twice weekly in each 3-week treatment cycle in combination with dacarbazine 1000 mg/m\^2 IV once every 21 days. Treatment was continued for each participant until evidence of unacceptable toxicity, disease progression, or treatment discontinuation for another reason. | 238 |
| Placebo and Dacarbazine Participants received placebo matching to unesbulin tablets administered orally twice weekly in each 3-week treatment cycle in combination with dacarbazine 1000 mg/m\^2 IV once every 21 days. Treatment was continued for each participant until evidence of unacceptable toxicity, disease progression, or treatment discontinuation for another reason. | 120 |
| Total | 358 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 15 | 8 |
| Overall Study | Death | 3 | 5 |
| Overall Study | Other Than Specified | 5 | 1 |
| Overall Study | Physician Decision | 6 | 4 |
| Overall Study | Progressive Disease | 104 | 68 |
| Overall Study | Randomized But Not Treated | 1 | 0 |
| Overall Study | Study Terminated by Sponsor | 87 | 29 |
| Overall Study | Withdrawal by Subject | 18 | 5 |
Baseline characteristics
| Characteristic | Placebo and Dacarbazine | Total | Unesbulin and Dacarbazine |
|---|---|---|---|
| Age, Continuous | 58.6 years STANDARD_DEVIATION 11.04 | 57.8 years STANDARD_DEVIATION 11 | 57.4 years STANDARD_DEVIATION 10.98 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 26 Participants | 62 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 87 Participants | 257 Participants | 170 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 39 Participants | 32 Participants |
| Race/Ethnicity, Customized Race American Indian/Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 8 Participants | 25 Participants | 17 Participants |
| Race/Ethnicity, Customized Race Black/African American | 6 Participants | 26 Participants | 20 Participants |
| Race/Ethnicity, Customized Race Missing | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Multiple | 0 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian/Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 12 Participants | 50 Participants | 38 Participants |
| Race/Ethnicity, Customized Race White/Caucasian | 92 Participants | 249 Participants | 157 Participants |
| Sex: Female, Male Female | 93 Participants | 280 Participants | 187 Participants |
| Sex: Female, Male Male | 27 Participants | 78 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 49 / 238 | 27 / 120 |
| other Total, other adverse events | 234 / 238 | 112 / 120 |
| serious Total, serious adverse events | 81 / 238 | 43 / 120 |
Outcome results
Primary
Progression Free Survival (PFS) Per Independent Central Review Using Response Evaluation Criteria in Solid Tumors (RECIST) V1.1
PFS was defined as the time from randomization to the documented disease progression or death due to any cause, whichever occurred first. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). The appearance of one or more new lesions was also considered progression.
Time frame: Up to approximately 2 years
Population: The modified intent-to-treat (mITT) set included randomized participants with 1 to 3 prior lines of therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Unesbulin and Dacarbazine | Progression Free Survival (PFS) Per Independent Central Review Using Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 | 3.6 months |
| Placebo and Dacarbazine | Progression Free Survival (PFS) Per Independent Central Review Using Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 | 2.6 months |
p-value: 0.001795% CI: [0.45, 0.83]Regression, Cox
Secondary
Disease Control Rate (DCR) Per Independent Central Review Using RECIST V1.1
DCR was defined as percentage of participants who achieved a confirmed BOR of CR, PR, or at least 3 months of stable disease (SD). CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: Up to approximately 2 years
Population: The mITT set included randomized participants with 1 to 3 prior lines of therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Unesbulin and Dacarbazine | Disease Control Rate (DCR) Per Independent Central Review Using RECIST V1.1 | 36.4 percentage of participants |
| Placebo and Dacarbazine | Disease Control Rate (DCR) Per Independent Central Review Using RECIST V1.1 | 27.1 percentage of participants |
Secondary
Duration of Response Per Independent Central Review Using RECIST V1.1
Duration of response was defined as the time from the date of first confirmed response of CR or PR to the date of the first documented disease progression or death due to any cause, whichever occurred first. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Disease progression: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.
Time frame: Up to approximately 2 years
Population: The mITT set included randomized participants with 1 to 3 prior lines of therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Unesbulin and Dacarbazine | Duration of Response Per Independent Central Review Using RECIST V1.1 | 6.87 months |
| Placebo and Dacarbazine | Duration of Response Per Independent Central Review Using RECIST V1.1 | NA months |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A TEAE was defined as an AE that had an onset date on or after the first dose of study drug until 30 days after last dose or occurred prior to first dose of study drug and worsened in severity after first dose of study drug. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.
Time frame: From first dose of study drug up to approximately 2 years
Population: The safety analysis set included all participants who received at least 1 dose of study drug (unesbulin/placebo or dacarbazine).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Unesbulin and Dacarbazine | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 236 Participants |
| Placebo and Dacarbazine | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 112 Participants |
Secondary
Objective Response Rate (ORR) Per Independent Central Review Using RECIST V1.1
ORR was defined as percentage of participants who achieved a confirmed best overall response (BOR) of complete response (CR) or partial response (PR). CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Up to approximately 2 years
Population: The mITT set included randomized participants with 1 to 3 prior lines of therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Unesbulin and Dacarbazine | Objective Response Rate (ORR) Per Independent Central Review Using RECIST V1.1 | 8.1 percentage of participants |
| Placebo and Dacarbazine | Objective Response Rate (ORR) Per Independent Central Review Using RECIST V1.1 | 2.1 percentage of participants |
Secondary
Overall Survival
Overall survival was defined as the time in months from the randomization date to the date of death from any cause or date last known alive for those who did not die.
Time frame: Up to approximately 2 years
Population: The mITT set included randomized participants with 1 to 3 prior lines of therapy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Unesbulin and Dacarbazine | Overall Survival | NA months |
| Placebo and Dacarbazine | Overall Survival | NA months |