Evaluation of ETC-1907206 With Dasatinib in Advanced Haematologic Malignancies
- Conditions
- Ph+ Acute Lymphoblastic Leukemia (Ph+ALL)Ph- Acute Lymphoblastic Leukemia (Ph-ALL)Chronic Myeloid Leukemia Accelerated Phase (CML-AP, Ph+)Chronic Myeloid Leukemia Blast Crisis (CML-BC, Ph+)
- Interventions
- Drug: ETC-1907206Drug: dasatinib
- Registration Number
- NCT03414450
- Lead Sponsor
- EDDC (Experimental Drug Development Centre), A*STAR Research Entities
- Brief Summary
This study evaluates the use of ETC-1907206 in combination with dasatinib in certain types of blood cancers. The first phase of the study (1A) is designed to find the highest tolerated dose of ETC-1907206, while the second phase (1B) will assess the safety and tolerability of the recommended dose of ETC-1907206. ETC-1907206 has been designed to block the activity of an enzyme of the body known as Mnk kinase, which is thought to be involved in the development of a variety of cancers.
- Detailed Description
This study consists of two parts: a Phase 1A dose escalation to identify the MTD and the RD of ETC-1907206 administered in combination with dasatinib and a Phase 1B expansion at the RD.
Phase 1A: A dose escalation with an adaptive design model using ordinal continual reassessment method (oCRM) will be used to characterise the dose toxicity curve of ETC-1907206 when administered orally every other day (EOD) under fasted conditions in combination with oral once daily dasatinib (per locally approved product prescribing instructions) in order to identify the maximum tolerated dose (MTD) and recommended dose (RD) for Phase 1B.
Phase 1B: Open-label, non-randomised, to assess preliminary clinical activity and safety of ETC-1907206 administered orally EOD under fasted conditions at the RD identified in Phase 1A, in combination with dasatinib (per locally approved product prescribing instructions).
Patients will continue in the study until disease progression, the start of new anti-cancer therapy, unacceptable toxicity, death, or the completion of 12 separate 4-week treatment cycles, whichever occurs first.
As long as the Sponsor agrees to continue treatment, patients who complete 12 cycles of treatment and have no evidence of disease progression are allowed to continue on treatment past the end of treatment (EOT) visit until there is disease progression, unacceptable toxicity, the patient decides to withdraw, or it is judged not to be in the patient's interest to continue on the study.
Malignancy assessments of the underlying disease at enrolment (blood and bone marrow), Eastern Cooperative Oncology Group (ECOG) performance status, pharmacokinetic (PK) sampling for ETC-1907206 and dasatinib, sample collection for ETC-1907206 and dasatinib biomarker analysis, and safety and tolerability assessments will be performed during the study.
Recruitment & Eligibility
- Status
- WITHDRAWN
- Sex
- All
- Target Recruitment
- Not specified
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Dose Escalation (Phase 1A) ETC-1907206 An adaptive design using the ordinal Continual Reassessment Method (oCRM) will be used to determine the MTD and RD of ETC-1907206 in combination with dasatinib. Dose Escalation (Phase 1A) dasatinib An adaptive design using the ordinal Continual Reassessment Method (oCRM) will be used to determine the MTD and RD of ETC-1907206 in combination with dasatinib. Dose Expansion (Phase 1B) ETC-1907206 Once the MTD and/or RD has been determined in Phase 1A, an expansion cohort will be enrolled in order to characterize the safety, PK and preliminary clinical activity of ETC-1907206 in combination with dasatinib. Subjects may continue treatment in the study until disease progression, unacceptable toxicity, withdrawal of consent or it is judged not to be in the patient's interest to continue on the study. Dose Expansion (Phase 1B) dasatinib Once the MTD and/or RD has been determined in Phase 1A, an expansion cohort will be enrolled in order to characterize the safety, PK and preliminary clinical activity of ETC-1907206 in combination with dasatinib. Subjects may continue treatment in the study until disease progression, unacceptable toxicity, withdrawal of consent or it is judged not to be in the patient's interest to continue on the study.
- Primary Outcome Measures
Name Time Method Phase 1B PK: AUC from time zero to the last measureable concentration (AUC0-t) pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing Single-dose PK measurement of AUC0-t after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1B PK: First-order rate constant for elimination of drug (kel) pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing Single-dose PK measurement of kel after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1B Safety: Incidence of Adverse Events (AEs) during Phase 1B up to 44 months Incidence and Severity of AEs
Phase 1B PK: Area under the drug concentration-time curve (AUC) from time zero to infinite time (AUC0-inf) pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing Single-dose PK measurement of AUC0-inf after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Maximum Tolerated Dose (MTD) (Phase 1A) the initial 28 days of treatment The MTD is defined as the highest possible dose with a predicted probability of having DLT not exceeding the target toxicity rate. The target toxicity rate (or the target predicted probability of DLT) for this study is set at 25%.
Phase 1B PK: Time to reach maximum plasma concentration (Tmax) pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing Single-dose PK measurement of Tmax after dosing on Day 1 and Day 15 (Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1B PK: Time between drug administration and first observed concentration above lower limit if quantitation in plasma (Tlag) pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing Single-dose PK measurement of Tlag after dosing on Day 1 and Day 15 (Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1B PK: Total clearance (CL) pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing Single-dose PK measurement of CL after dosing on Day 1 and Day 15 (Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1B PK: Volume of distribution (Vd) pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing Single-dose PK measurement of Vd after dosing on Day 1 and Day 15 (Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1B PK: Half-life (T1/2) pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing Single-dose PK measurement of T1/2 after dosing on Day 1 and Day 15 (Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
- Secondary Outcome Measures
Name Time Method Phase 1A PK: Total clearance (CL) pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing Single-dose PK measurement of CL after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1A PK: Volume of distribution (Vd) pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing Single-dose PK measurement of Vd after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1A PK: Half-life (T1/2) pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing Single-dose PK measurement of T1/2 after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1B Clinical Activity: Best Overall Response (BOR) through study completion (44 months) The BOR for each patient is determined by the following hierarchical orders:
* For CML-AP Ph+, CML-BC Ph+ and Ph+ ALL: major molecular response, major cytogenetic response (complete response, partial response), major haematologic response (complete response, complete remission), minor haematologic response,cytogenetic response (minor response, minimal response, no response), progressive disease
* For Ph- ALL: complete haematologic response, complete response with partial haematologic recovery, progressive disease
The response rate will be summarised and two-sided 95% confidence intervals (CIs) on the response rates will be calculated. The best overall response will be listed.Phase 1B Clinical Activity: duration of complete remission (DOCRe) through study completion (44 months) Phase 1B Clinical Activity: objective response rate (ORR) through study completion (44 months) Phase 1B Clinical Activity: time to major molecular response (TTMMR) through study completion (44 months) Phase 1B Clinical Activity: time to complete haematologic response (TTCHR) through study completion (44 months) Phase 1B Clinical Activity: overall survival (OS) through study completion (44 months) Phase 1A Safety: Incidence of Adverse Events (AEs) during Phase 1A up to 24 months Incidence and Severity of AEs
Phase 1A PK: Area under the drug concentration-time curve (AUC) from time zero to infinite time (AUC0-inf) pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing Single-dose PK measurement of AUC0-inf after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1A PK: AUC from time zero to the last measureable concentration (AUC0-t) pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing Single-dose PK measurement of AUC0-t after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1A PK: First-order rate constant for elimination of drug (kel) pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing Single-dose PK measurement of kel after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1A PK: Time to reach maximum plasma concentration (Tmax) pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing Single-dose PK measurement of Tmax after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1A PK: Time between drug administration and first observed concentration above lower limit if quantitation in plasma (Tlag) pre-dose, at 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours (± 6 minutes), and at 24, 30, and 48 hours (± 2 hours) after dosing Single-dose PK measurement of Tlag after dosing on Day 1 and Day 15 Cycle 1) and pre-dose on Day 1 of Cycle 2 and beyond (each Cycle is 28-days in length).
Phase 1B Clinical Activity: time to objective response (TTR) through study completion (44 months) Phase 1B Clinical Activity: time to complete remission (TTCRe) through study completion (44 months) Phase 1B Clinical Activity: duration of objective response (DOR) through study completion (44 months) Phase 1B Clinical Activity: duration of major molecular response (DOMMR) through study completion (44 months) Phase 1B Clinical Activity: duration of complete haematologic response (DOCHR) through study completion (44 months) Phase 1B Clinical Activity: progression-free survival (PFS) through study completion (44 months) Phase 1B Clinical Activity: duration of complete cytogenetic response (DOCCyR) through study completion (44 months) Phase 1B Clinical Activity: time to complete cytogenetic response (TTCCyR) through study completion (44 months)
Trial Locations
- Locations (6)
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Winship Cancer Institute, Emory University
🇺🇸Atlanta, Georgia, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
The Center for Cancer and Blood Disorders
🇺🇸Bethesda, Maryland, United States
Singapore General Hospital
🇸🇬Singapore, Singapore
Oregon Health & Science University
🇺🇸Portland, Oregon, United States