Evaluation of ETC-1907206 With Dasatinib in Advanced Haematologic Malignancies

NCT03414450 | Withdrawn Phase 1 FDA Drug

• 1 other identifier: D3-005
• Study Type: interventional
• Target: N/A
• Locations: 2 countries
• Sites: 6

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.

Conditions

Ph- Acute Lymphoblastic Leukemia (Ph-ALL); Chronic Myeloid Leukemia Accelerated Phase (CML-AP, Ph+); Chronic Myeloid Leukemia Blast Crisis (CML-BC, Ph+)

Keywords

Mnk kinase inhibitor, Mnk kinase

Outcome Measures

Primary Outcomes (10)

• Maximum Tolerated Dose (MTD) (Phase 1A)

  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%.

  the initial 28 days of treatment

• Phase 1B Safety: Incidence of Adverse Events (AEs) during Phase 1B

  Incidence and Severity of AEs

  up to 44 months

• Phase 1B PK: Area under the drug concentration-time curve (AUC) from time zero to infinite time (AUC0-inf)

  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).

  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

• Phase 1B PK: AUC from time zero to the last measureable concentration (AUC0-t)

  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).

  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

• Phase 1B PK: First-order rate constant for elimination of drug (kel)

  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).

  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

• Phase 1B PK: Time to reach maximum plasma concentration (Tmax)

  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).

  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

• Phase 1B PK: Time between drug administration and first observed concentration above lower limit if quantitation in plasma (Tlag)

  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).

  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

• Phase 1B PK: Total clearance (CL)

  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).

  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

• Phase 1B PK: Volume of distribution (Vd)

  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).

  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

• Phase 1B PK: Half-life (T1/2)

  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).

  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

Secondary Outcomes (23)

• Phase 1A Safety: Incidence of Adverse Events (AEs) during Phase 1A

  up to 24 months

• 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

• 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

• 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

• 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

Study Arms (2)

Dose Escalation (Phase 1A)

EXPERIMENTAL

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.

Drug: ETC-1907206; Drug: dasatinib

Dose Expansion (Phase 1B)

EXPERIMENTAL

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.

Drug: ETC-1907206; Drug: dasatinib

Interventions

ETC-1907206 DRUG

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

Also known as: ETC-206

Dose Escalation (Phase 1A); Dose Expansion (Phase 1B)

dasatinib DRUG

dasatinib tablets at 140 mg will be dosed every day

Also known as: Sprycel

Dose Escalation (Phase 1A); Dose Expansion (Phase 1B)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Each patient (male or female) must meet all of the following criteria to be enrolled in this study:
• Capable of understanding the written informed consent, provides signed and witnessed written informed consent, and agrees to comply with protocol requirements.
• Age 18 years or older (US sites) or 21 years or older (Singapore site) at Baseline.
• Bone marrow (BM) cytogenetic analysis with at least 20 metaphase cells, confirmed advanced haematologic malignancies in any of the 4 following disease populations at Screening:
• CML-AP, Ph+
• CML-BC, Ph+
• Ph+ ALL
• Ph- ALL with relapsed and refractory disease who have exhausted all available therapy (for patients who develop T315I mutation related resistance, the definition requires failure of ponatinib treatment if drug is accessible).
• Meets definition for one of the following study subgroups:
• CML-AP:
• ≥ 15% and \< 30% blast in peripheral blood or bone marrow, or
• ≥ 20% basophils in peripheral blood or bone marrow or
• ≥ 30% blasts + promyelocytes in peripheral blood or bone marrow (but \< 30% blasts) or
• \< 100 x 10\^9 platelets/L in peripheral blood unrelated to therapy or
• Cytogenetic, genetic evidence of clonal evolution and

You may not qualify if:

• Patients meeting any of the following criteria will be excluded from the study:
• Is a male patient with sexual partner(s) of childbearing potential who is unwilling to use a highly effective method of contraception, one of which includes a condom. Sexually active male patients must use a condom during intercourse throughout the study and for 12 weeks after the end of treatment and should not father a child in this period. A condom is required to be used also by vasectomised males in order to prevent potential delivery of the study drug via seminal fluid. Female partners of male patients must be advised to also use one of the following contraception methods:
• intrauterine device or intrauterine system;
• prior sterilisation; or
• total abstinence from male/female intercourse.
• Is a female patient of childbearing potential, defined as a female physiologically capable of becoming pregnant (including a female whose career, lifestyle, or sexual orientation precludes intercourse with a male partner, and females whose partners have been sterilised by vasectomy or other means), unless they are using a highly effective method for birth control throughout the study and for 12 weeks after the end of treatment. Highly effective methods for birth control include the following:
• Total abstinence: This is an acceptable method when this is consistent with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Female sterilisation: The patient has had a surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks prior to taking study drug. In case of an oophorectomy alone, the reproductive status of the patient must have been confirmed by follow-up hormone level assessment.
• Male partner sterilisation: The patient has the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate. (For female patients on the study, the vasectomised male partner should be the sole partner for that patient.) These patients must also agree to the use an intrauterine device or intrauterine system AND a barrier method of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam, gel, film, or cream, or vaginal suppository. Reliable contraception must be maintained throughout the study and for 12 weeks after study drug discontinuation.
• Females considered post-menopausal and not of childbearing potential: The definition applies to females who have had 12 months of natural (spontaneous) amenorrhoea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or 6 months of spontaneous amenorrhoea with serum follicle-stimulating hormone (FSH) levels \> 40 million international units per milliliter (mIU/mL) (for US only: and estradiol \< 20 pg/mL) or have had surgical bilateral oophorectomy (with or without hysterectomy) at least 6 weeks prior to starting treatment. In the case of oophorectomy alone, only when the reproductive status of the patient has been confirmed by follow-up hormone level assessment is she considered not of childbearing potential.
• Is a pregnant or nursing (lactating) female, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test (\> 5 mIU/mL).
• Has dasatinib intolerance (haematologic and non-haematologic). Defined as: CTCAE Grade \>2
• Has received anti-cancer therapy within 2 weeks or 5 half-lives, whichever is shorter (except for hydroxyurea, steroids, allopurinol, febuxostat, rasburicase, and intravenous hydration), prior to starting study drug or the side effects of such therapy have not resolved to Grade ≤1 within 2 weeks prior to starting study drug.
• Is receiving concomitant anti-cancer therapy (except for hydroxyurea, steroids, anagrelide, allopurinol, febuxostat, rasburicase, and intravenous hydration during the first week of the study drug\[s\] administration, or corticosteroids when appropriate).
• Has used other investigational drugs within 2 weeks or 5 half-lives (whichever is shorter) prior to the first dose of study drug.

Sponsors & Collaborators

• EDDC (Experimental Drug Development Centre), A*STAR Research Entities: lead
• Chiltern International Inc.: collaborator

Study Sites (6)

Winship Cancer Institute, Emory University

Atlanta, Georgia, 30322, United States

Location

The Center for Cancer and Blood Disorders

Bethesda, Maryland, 20874, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Singapore General Hospital

Singapore, 169608, Singapore

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Accelerated Phase

Interventions

Dasatinib

Condition Hierarchy (Ancestors)

Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Study Officials

• Joel Leong, MD, PhD

  D3 (Drug Discovery and Development)

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: January 14, 2018
• First Posted: January 30, 2018
• Study Start: April 25, 2018
• Primary Completion: February 1, 2022
• Study Completion: February 1, 2023
• Last Updated: October 25, 2018

Record last verified: 2018-10

Locations

US (5); SG (1)