Study of Tinostamustine, First-in-Class Alkylating HDACi Fusion Molecule, in Relapsed/Refractory Hematologic Malignancies
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|ClinicalTrials.gov Identifier: NCT02576496|
Recruitment Status : Recruiting
First Posted : October 15, 2015
Last Update Posted : November 5, 2020
|Condition or disease||Intervention/treatment||Phase|
|Hematological Malignancies Multiple Myeloma Hodgkin's Lymphoma Peripheral T-cell Lymphoma Cutaneous T Cell Lymphoma T-cell Prolymphocytic Leukemia||Drug: Tinostamustine||Phase 1|
Tinostamustine is a new chemical entity, a first-in-class fusion molecule of an alkylator, bendamustine and a histone-deacetylase inhibitor (HDACi), vorinostat. It is anticipated that tinostamustine may have activity in various hematological malignancies and solid tumors.
The study consists of 2 stages:
- Stage 1: Dose Escalation to determine Maximum Tolerated Dose (MTD) at the optimal infusion time and the pharmacokinetic (PK) profiles; is expected to enroll between 21 and 48 patients. Stage 1 has now been completed.
- Stage 2: Expansion in five Cohorts, in which approximately 12-16 patients will be enrolled per cohort, for a maximum of 70 patients.
In Stage 1, tinostamustine doses were escalated following the standard 3+3 design. The decision to escalate to the next dose level occurred after all cohort patients completed 3 weeks (21 days) of observation and have been evaluated for safety and toxicity.The starting dose was a 1 hour infusion of 20 mg/m2, and the maximum dose level was 150 mg/m2. Reduced infusion times of 45 minutes and 30 minutes were assessed once the maximum tolerated dose at a 1-hour infusion was determined.
In Stage 2, five cohorts of patients (with relapsed/refractory multiple myeloma (MM); relapsed/refractory Hodgkin's lymphoma; relapsed/refractory peripheral T-cell lymphoma (PTCL); relapsed/refractory cutaneous T-cell lymphoma (CTCL); and relapsed/refractory T-cell Prolymphocytic leukemia (T-PLL) will be enrolled and treated at the recommended Phase 2 dose (RP2D) based on results of Stage 1. For MM patients, treatment will occur on Day 1 and Day 15 of a 28 day cycle. For lymphoma patients, treatment will occur on Day 1 of a 21 day cycle. Patients in each stage of the study are expected to receive a median of four Cycles of therapy, and the maximum number of treatment Cycles allowed is 12.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||111 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1 Trial to Investigate the Safety, Pharmacokinetic Profiles and the Efficacy of Tinostamustine, a First-in-Class Alkylating Histone Deacetylase Inhibition (HDACi) Fusion Molecule, in Relapsed/Refractory Hematologic Malignancies|
|Study Start Date :||March 2016|
|Estimated Primary Completion Date :||March 2021|
|Estimated Study Completion Date :||October 2021|
Experimental: Tinostamustine (EDO-S101)
EDO-S101, IV, 20mg/m2 up to 150mg/m2 Day1 of each 21 day cycle-Stage 1; EDO-S101,IV, 40mg/m2 up to 60mg/m2 on Day 1 and Day 15 of 28 day cycle in multiple myeloma patients and IV, 40mg/m2 up to 100mg/m2 on Day 1 of 21 day cycle in lymphoma patients-Stage 2
- Overall response rate [ Time Frame: 10-20 months from beginning of stage 2 ]Determine overall response rate
- Clinical benefit rate by cohort [ Time Frame: 10-20 months from beginning of stage 2 ]Determine clinical benefit rate by cohort
- Safety of selected doses in expanded population [ Time Frame: 36 months from beginning stage 2 ]Number of participants with treatment-related adverse events as assessed by CTCAE V4.03
- Time to objective response [ Time Frame: 10-20 months after beginning stage 2 ]Evaluate time to objective response by cohort
- Duration of response [ Time Frame: 10-20 months after beginning stage 2 ]Evaluate duration of response
- Progression free survival (PFS) [ Time Frame: 32-36 months after beginning stage 2 ]Determine time to progression free survival time for patients who received the RP2D
- Overall Survival (OS) [ Time Frame: 32-36 months after beginning stage 2 ]Determine the overall survival time for patients who received the RP2D
- Maximum Plasma Concentration (Cmax) [ Time Frame: 10-20 months after beginning stage 2 ]Determine Cmax using the PK population
- Time to Reach Maximum Concentration (Tmax) [ Time Frame: 10-20 months after beginning stage 2 ]Determine Tmax using the PK population
- Time taken for the plasma concentration to fall by half its original value (t1/2) [ Time Frame: 10-20 months after beginning stage 2 ]Determine t1/2 using the PK population
- Area Under Curve (AUC) [ Time Frame: 10-20 months after beginning stage 2 ]Determine area under the plasma drug concentration-time curve using the PK population
- QT (QTc) analysis [ Time Frame: 10-20 months after beginning stage 2 ]To perform a concentration corrected QT analysis
- Number of patients with treatment-emergent adverse events (TEAEs). TEAEs will be assessed by NCI-CTCAE 4.03 [ Time Frame: 10-20 months after beginning stage 2 ]Patient safety data will be summarized by disease cohort as well as overall disease cohorts pooled (i.e., MM, Hodgkin's lymphoma, non-Hodgkin's lymphoma, PTCL, T- PLL)
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02576496
|Principal Investigator:||Pier L Zinzani, MD,PhD||University of Bologna Medical Center, Bologna|