The primary objective of this study is to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of unesbulin in combination with dacarbazine for the treatment of advanced LMS and determine the overall safety profile of unesbulin in combination with dacarbazine. This study will employ the time-to-event continual reassessment method (TITE-CRM) for dose finding. Treatment will be initiated at dose level 2 (DL2) (Dacarbazine 1000 milligrams per square meter \[mg/m\^2\] intravenously \[IV\] every 21 days in combination with unesbulin 200 milligrams \[mg\] orally twice weekly) for the first participant. This dose level represents the investigator's best assessment of the MTD based on available toxicity data for both agents. For subsequent participants, the dose level at which treatment is initiated will be selected based on the TITE-CRM using the most up to date dose-limiting toxicity (DLT) information from all participants previously treated. To enroll additional participants at the RP2D, the study is amended to include an expansion cohort of up to 12 participants (some of whom could be ongoing participants who reconsent). Treatment will continue for each participant until evidence of unacceptable toxicity, disease progression, or treatment discontinuation for another reason.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
41
Unesbulin will be administered as per the dose and schedule specified in the arm.
Dacarbazine will be administered as per the dose and schedule specified in the arm.
Mayo Clinic Florida
Jacksonville, Florida, United States
John Hopkins
Baltimore, Maryland, United States
Washington University Medical Campus
St Louis, Missouri, United States
Columbia University Medical Center
New York, New York, United States
MTD and RP2D of Unesbulin in Combination With Dacarbazine
MTD will be determined using the TITE-CRM for dose-finding. MTD is defined as the dose associated with a target probability of DLT of 0.25.
Time frame: First 2 cycles of treatment (6 weeks)
Number of Participants With Adverse Events
Time frame: From screening until end of study (up to approximately 1.5 years)
Objective Response Rate (ORR) (Percentage of Participants With Objective Response) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Objective Response is defined as confirmed best response of complete response (CR) or partial response (PR).
Time frame: From Baseline until the date of objectively documented progression per RECIST v1.1 or the date of initiation of subsequent therapy or palliative local therapy, whichever occurs first (up to approximately 1.5 years)
Time to Response as Determined by the Investigator Using RECIST v1.1
Time to response is defined as the first time either PR or CR occurs.
Time frame: From Baseline until the date of first occurrence of CR or PR (up to approximately 1.5 years)
Duration of Response (DOR)
DOR is defined as the time from the date of first confirmed response to the date of the first documented tumor progression (per RECIST v1.1) or death due to any cause, whichever occurs first.
Time frame: Time from the date of first confirmed response to the date of the first documented tumor progression or death due to any cause, whichever occurs first (up to approximately 1.5 years)
Progression-Free Survival (PFS)
PFS is defined as the time from the first dose of study drug to the date of the first documented tumor progression as determined by the investigator using RECIST v1.1 or death due to any cause, whichever occurs first.
Time frame: Time from the first dose of study drug to the date of the first documented tumor progression or death due to any cause, whichever occurs first (up to approximately 1.5 years)
Best Overall Response Rate (Disease Control Rate) (Percentage of Participants With Best Overall Response)
Best overall response is defined as CR, PR and stable disease (SD).
Time frame: From Baseline until the date of objectively documented progression per RECIST v1.1 or the date of initiation of subsequent therapy or palliative local therapy, whichever occurs first (up to approximately 1.5 years)
Overall Survival (OS)
OS is defined as the time from the first dose of study drug to the date of death from any cause.
Time frame: Time from the first dose of study drug to the date of death from any cause (up to approximately 1.5 years)
Maximum Observed Plasma Concentration (Cmax) of Unesbulin, Dacarbazine, and Inactive Metabolite of Dacarbazine (5-amino-imidazole-4-carboxamide [AIC])
Pharmacokinetic (PK) variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.
Time frame: Unesbulin: Predose (within 1 hour [hr]); 1,2,3 to 824, 48, 72 hrs postdose (during any cycle); Dacarbazine and AIC: Predose (within 1 hr); 0.5,1 hr post start of infusion; 0.25,0.5,1,3,7,23 hrs postdose on Cycle 1 Day 1,Cycle 2 Day 1 (each cycle=21 days)
Time to Reach Maximum Plasma Concentration (Tmax) of Unesbulin, Dacarbazine, and Inactive Metabolite of Dacarbazine (AIC)
PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.
Time frame: Unesbulin: Predose (within 1 hr); 1,2,3 to 824, 48, 72 hrs postdose (during any cycle); Dacarbazine and AIC: Predose (within 1 hr); 0.5,1 hr post start of infusion; 0.25,0.5,1,3,7,23 hrs postdose on Cycle 1 Day 1,Cycle 2 Day 1 (each cycle=21 days)
Area Under the Plasma Concentration-Time Curve (AUC) of Unesbulin, Dacarbazine, and Inactive Metabolite of Dacarbazine (AIC)
PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.
Time frame: Unesbulin: Predose (within 1 hr); 1,2,3 to 824, 48, 72 hrs postdose (during any cycle); Dacarbazine and AIC: Predose (within 1 hr); 0.5,1 hr post start of infusion; 0.25,0.5,1,3,7,23 hrs postdose on Cycle 1 Day 1, Cycle 2 Day 1 (each cycle=21 days)
Half-Life (t1/2) of Unesbulin, Dacarbazine, and Inactive Metabolite of Dacarbazine (AIC)
PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.
Time frame: Unesbulin: Predose (within 1 hr); 1,2,3 to 824, 48, 72 hrs postdose (during any cycle); Dacarbazine and AIC: Predose (within 1 hr); 0.5,1 hr post start of infusion; 0.25,0.5,1,3,7,23 hrs postdose on Cycle 1 Day 1, Cycle 2 Day 1 (each cycle=21 days)
Apparent Clearance (CL/F) of Unesbulin, Dacarbazine, and Inactive Metabolite of Dacarbazine (AIC)
PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.
Time frame: Unesbulin: Predose (within 1 hr); 1,2,3 to 824, 48, 72 hrs postdose (during any cycle); Dacarbazine and AIC: Predose (within 1 hr); 0.5,1 hr post start of infusion; 0.25,0.5,1,3,7,23 hrs postdose on Cycle 1 Day 1, Cycle 2 Day 1 (each cycle=21 days)
Apparent Volume of Distribution (Vz/F) of Unesbulin, Dacarbazine, and Inactive Metabolite of Dacarbazine (AIC)
PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.
Time frame: Unesbulin: Predose (within 1 hr); 1,2,3 to 824, 48, 72 hrs postdose (during any cycle); Dacarbazine and AIC: Predose (within 1 hr); 0.5,1 hr post start of infusion; 0.25,0.5,1,3,7,23 hrs postdose on Cycle 1 Day 1, Cycle 2 Day 1 (each cycle=21 days)
Accumulation Ratio (R) of Unesbulin, Dacarbazine, and Inactive Metabolite of Dacarbazine (AIC)
PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.
Time frame: Unesbulin: Predose (within 1 hr); 1,2,3 to 824, 48, 72 hrs postdose (during any cycle); Dacarbazine and AIC: Predose (within 1 hr); 0.5,1 hr post start of infusion; 0.25,0.5,1,3,7,23 hrs postdose on Cycle 1 Day 1, Cycle 2 Day 1 (each cycle=21 days)
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