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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.

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.

ETC-1907206 gelatin capsules will be dosed every other day (EOD) and contain 10 mg or 50 mg of ETC-1907206.

ETC-1907206

dasatinib tablets at 140 mg will be dosed every day

dasatinib

Joel Leong, MD, PhD

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.

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.

In Phase 1A, 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.

Evaluation of ETC-1907206 With Dasatinib in Advanced Haematologic Malignancies

A Phase 1A Dose Escalation and Phase 1B Expansion Study to Evaluate the Safety and Tolerability of ETC-1907206 in Combination With Dasatinib in Advanced Haematologic Malignancies

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%.

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Evaluation of ETC-1907206 With Dasatinib in Advanced Haematologic Malignancies	NCT03414450	Ph+ Acute Lymph... Ph- Acute Lymph... Chronic Myeloid... Chronic Myeloid...	ETC-1907206 dasatinib	18 Years -	EDDC (Experimental Drug Development Centre), A*STAR Research Entities
Evaluation of ETC-1907206 With Dasatinib in Advanced Haematologic Malignancies	NCT03414450	Ph+ Acute Lymph... Ph- Acute Lymph... Chronic Myeloid... Chronic Myeloid...	ETC-1907206 dasatinib	18 Years -	EDDC (Experimental Drug Development Centre), A*STAR Research Entities

Spots Global Cancer Trial Database for ph+ acute lymphoblastic leukemia (ph+all)