Ph+ Acute Lymphoblastic Leukemia (Ph+ALL)Phase 1NCT03414450

Evaluation of ETC-1907206 With Dasatinib in Advanced Haematologic Malignancies

A Phase 1 study testing ETC-1907206 and dasatinib in people with Ph+ Acute Lymphoblastic Leukemia (Ph+ALL) and Ph- Acute Lymphoblastic Leukemia (Ph-ALL), run by EDDC (Experimental Drug Development Centre), A*STAR Research Entities at 6 sites in 2 countries.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Ph+ Acute Lymphoblastic Leukemia (Ph+ALL), Ph- Acute Lymphoblastic Leukemia (Ph-ALL), Chronic Myeloid Leukemia Accelerated Phase (CML-AP, Ph+)
What is being tested?: ETC-1907206 and dasatinib
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 0 participants
Where: 6 sitesin 2 countries
Study dates: 25 Apr 2018to Feb 2023
Phase: Phase 1
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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+

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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
No extramedullary disease.
CML-BC:
≥ 30% blasts in peripheral blood or bone marrow, or
extramedullary disease other than hepatosplenomegaly.
Ph+ ALL:
≥ 30% blasts in blood or bone marrow and
no prior history of CML.
Ph- ALL:
≥ 10% blasts in bone marrow.
ECOG performance status of 0 to 2 at Baseline.
Life expectancy of at least 3 months at Baseline.
Adequate organ function at Baseline, including the following (noting that repeated tests at Baseline should not be performed unless there are sufficient reasons to assume the patient would meet the inclusion criteria with re testing):
Total bilirubin ≤ 1.5 x upper limit of normal (ULN), unless resulting from haemolysis or documented Gilbert syndrome.
Transaminases [aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 x ULN]. [< 5 x ULN if liver infiltration with tumour present]
Prothrombin time (PT) < 1.5 ULN.
Calculated creatinine clearance ≥ 60 mL/min (Cockcroft and Gault formula).
No clinically relevant abnormalities in the urinalysis results.
Haematology:
Haemoglobin > 10 g/dL (transfusion allowed to reach the level)
Neutrophils > 1,000/µL
Platelets > 75,000/µL.
Pancreatic status:
Lipase ≤ 1.5 x ULN
Amylase ≤ 1.5 x ULN.
Capable of taking oral medication and following direction regarding taking study drug (either by himself/herself or by caregiver).
Negative serum pregnancy test at Baseline plus a negative urine pregnancy test on Day 1, Cycle 1 prior to treatment (applies to females of childbearing potential only).
A minimum of 2 weeks (14 days), or 5 half-lives (whichever is shorter) since last receipt of any anti-cancer therapy (except dasatinib, hydroxyurea, anagrelide or steroids), or 4 weeks from radiation or major surgery to the first administration of the study drug.
All non-haematological AEs of any prior anti-cancer therapy, surgery, or radiotherapy have to be resolved to NCI CTCAE Grade ≤ 1 (except alopecia) within 2 weeks prior to starting study drug.
Willing to submit the blood samples and bone marrow samples for PK and pharmacodynamic (PD) analyses.
CML-AP Ph+, CML-BC Ph+, Ph- ALL, and Ph+ ALL patients with relapsed and refractory disease who have exhausted all available therapy.
Subgroup-specific intolerance definition: [Intolerance to tyrosine kinase inhibitors (TKIs) or other approved treatments for CML-AP, CML-BC and Ph+ ALL; to approved treatments for Ph- ALL] defined as:
Non-haematologic intolerance:
Patients with Grade 3 or 4 toxicity while on therapy, or with persistent Grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless a dose reduction is not considered in the best interest of the patient if response is already suboptimal) in absence of: major haematologic response (MaHR) for accelerated phase (AP), blast crisis (BC) or Ph+ ALL patients; complete remission (CR) or complete haematological response with partial haematologic recovery of peripheral blood count (CRh) for Ph- ALL.
Haematologic intolerance:
Patients with Grade 3 or 4 toxicity [absolute neutrophil count (ANC) or platelets] while on therapy that is recurrent after dose reduction to the lowest dose recommended by drug manufacturers in the absence of: MaHR for AP, BC or Ph+ ALL patients; CR or CRh for Ph- ALL.
NOTE: For dasatinib, non-haematologic and haematologic intolerance is defined as: CTCAE Grade > 2 requiring discontinuation.

Who cannot join

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:

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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.
Has undergone autologous or allogenic stem cell transplantation < 60 days prior to the first dose of study drug;
Has any evidence of on-going graft-versus-host disease (GVHD).
Has evidence of another malignancy not in remission or history of such a malignancy within the last 3 years (except for treated basal or squamous cell carcinoma of the skin, or in situ cancer of the cervix).
Has central nervous system (CNS) metastases.
Has significant bleeding disorder unrelated to the disease.
Has a history of long QT syndrome or prolonged QT interval corrected based on Fridericia's method (QTcF) > 450 ms.
Has ECG evidence of complete left bundle branch block, or ventricular pacing.
Has abnormalities in the 12-lead ECG that in the opinion of the Investigator increase the risk of participating in the study (e.g., sinus rhythm with PR interval > 240 ms or second degree or higher atrioventricular (AV) block confirmed by a repeat ECG).
Has blood pressure and heart rate (HR) higher than 160/100 mmHg and 100 beats per minute (bpm), respectively, or lower than 80/50 mm Hg and 45 bpm, respectively, confirmed by a repeat assessment.
Is receiving treatment with drugs known to be associated with Torsade de Pointes.
Has ophthalmic signs or symptoms, such as flashes and colour perception changes.
Has evidence of electrolyte imbalance such as hypokalaemia, hypocalcaemia, and hypomagnesaemia of NCI-CTCAE Grade ≥ 2 (NCI CTCAE version 4.03).
Has symptomatic chronic heart failure; unstable angina pectoris, cardiac arrhythmia.
Has cardiac left ventricular ejection fraction (LVEF) < 40% (assessed by transthoracic echocardiography).
Has a history of myocardial infarction and/or thromboembolism in the past 6 months.
Has uncontrolled diabetes mellitus, neurologic or psychiatric condition, an ongoing systemic (including opportunistic) clinically significant infections or any other significant or unstable concurrent medical illness that in the opinion of the Investigator would preclude protocol therapy.
Has a known history of human immunodeficiency virus (HIV) sero positivity and/or is receiving combination anti retroviral therapy.
Has a history of gastric bypass surgery or with pre-existing gastrointestinal disorders that may interfere with proper absorption of the drug, as per Investigator's judgement.
Has history of seizure disorders or CNS leukaemia.
Is receiving cytochrome P450 3A4 (CYP3A4) inhibitors within 7 days prior to the first dose of ETC-1907206 or receiving CYP3A4 inducers within 14 days prior to the first dose of ETC-1907206 and dasatinib.
Cannot start treatment with dasatinib 140 mg daily, oral.
Is unwilling or unable to comply with the protocol

Trial locations and contacts

6 sites in 2 countries.

Country

City, postcode or hospital

6 sites in 2 countries

United States5 sites

Winship Cancer Institute, Emory University
Atlanta, Georgia, 30322
The Center for Cancer and Blood Disorders
Bethesda, Maryland, 20874
MD Anderson Cancer Center
Houston, Texas, 77030
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
Oregon Health & Science University
Portland, Oregon, 97239

Other trials in United States

Singapore1 site

Singapore General Hospital
Singapore, 169608

Other trials in Singapore

About this study

Official title: 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

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.

Read the 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.

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+)
Being tested: ETC-1907206, dasatinib
Keywords: Mnk kinase inhibitor, Mnk kinase
Medical subject headings: Leukemia, Myeloid, Accelerated Phase

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

ETC-1907206Drug
Also called ETC-206
ETC-1907206 gelatin capsules will be dosed every other day (EOD) and contain 10 mg or 50 mg of ETC-1907206.
dasatinibDrug
Also called Sprycel
dasatinib tablets at 140 mg will be dosed every day

Study groups in NCT03414450
Study group	Role	What they receive
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. Receives: 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. Receives: Drug: ETC-1907206; Drug: dasatinib

What is being measured

The primary outcome is the main question the study is designed to answer.

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%.
Measured: the initial 28 days of treatment
Phase 1B Safety: Incidence of Adverse Events (AEs) during Phase 1B
Incidence and Severity of AEs
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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
Incidence and Severity of AEs
Measured: up to 24 months
Phase 1A 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).
Measured: 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)
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).
Measured: 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)
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).
Measured: 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)
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).
Measured: 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 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).
Measured: 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: 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).
Measured: 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: 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).
Measured: 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: 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).
Measured: 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 Clinical Activity: Best Overall Response (BOR)
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.
Measured: through study completion (44 months)
Phase 1B Clinical Activity: objective response rate (ORR)
Measured: through study completion (44 months)
Phase 1B Clinical Activity: duration of objective response (DOR)
Measured: through study completion (44 months)
Phase 1B Clinical Activity: duration of major molecular response (DOMMR)
Measured: through study completion (44 months)
Phase 1B Clinical Activity: duration of complete haematologic response (DOCHR)
Measured: through study completion (44 months)
Phase 1B Clinical Activity: duration of complete remission (DOCRe)
Measured: through study completion (44 months)
Phase 1B Clinical Activity: duration of complete cytogenetic response (DOCCyR)
Measured: through study completion (44 months)
Phase 1B Clinical Activity: time to objective response (TTR)
Measured: through study completion (44 months)
Phase 1B Clinical Activity: time to major molecular response (TTMMR)
Measured: through study completion (44 months)
Phase 1B Clinical Activity: time to complete haematologic response (TTCHR)
Measured: through study completion (44 months)
Phase 1B Clinical Activity: time to complete remission (TTCRe)
Measured: through study completion (44 months)
Phase 1B Clinical Activity: time to complete cytogenetic response (TTCCyR)
Measured: through study completion (44 months)
Phase 1B Clinical Activity: progression-free survival (PFS)
Measured: through study completion (44 months)
Phase 1B Clinical Activity: overall survival (OS)
Measured: through study completion (44 months)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

25 Apr 2018Feb 2023

First posted30 Jan 2018
Study start25 Apr 2018
Primary completionFeb 2022 (estimated)
Study completionFeb 2023 (estimated)

Why it stopped: Withdrawal requested by D3

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Other trials for Ph+ Acute Lymphoblastic Leukemia (Ph+ALL)Studies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Sequential
Model description: 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.
Masking: None (open label)
Enrolment: 0 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03414450
Sponsor's protocol ID: D3-005
Status last verified: Oct 2018
First submitted: 14 Jan 2018
Last updated: 25 Oct 2018
Results posted: No
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Undecided

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 25 Oct 2018. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: 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
ClinicalTrials.gov ID: NCT03414450
Acronym / sponsor ID: D3-005
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+)
Keywords: Mnk kinase inhibitor, Mnk kinase
Phase: Phase 1
Study type: Interventional
Recruitment status: WithdrawnReason stopped: Withdrawal requested by D3
Enrolment: 0 participants (actual)
Lead sponsor: EDDC (Experimental Drug Development Centre), A*STAR Research EntitiesOther government
Collaborators: Chiltern International Inc.
Study start: 25 Apr 2018 (actual)
Primary completion: Feb 2022 (estimated)
Study completion: Feb 2023 (estimated)
First posted: 30 Jan 2018 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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.

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Sequential
Masking: None (open label)
Number of arms: 2
Model description: 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.

Arm	Type	Receives
Dose Escalation (Phase 1A)	Experimental	Drug: ETC-1907206, Drug: dasatinibAn 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)	Experimental	Drug: ETC-1907206, Drug: dasatinibOnce 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.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (51 listed)

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:
Meets definition for one of the following study subgroups:

Key exclusion criteria (37 listed)

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:
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:
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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
ETC-1907206Also: ETC-206ETC-1907206 gelatin capsules will be dosed every other day (EOD) and contain 10 mg or 50 mg of ETC-1907206.	Drug	Dose Escalation (Phase 1A), Dose Expansion (Phase 1B)
dasatinibAlso: Spryceldasatinib tablets at 140 mg will be dosed every day	Drug	Dose Escalation (Phase 1A), Dose Expansion (Phase 1B)

Primary outcome

Maximum Tolerated Dose (MTD) (Phase 1A)
Time frame: 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 Safety: Incidence of Adverse Events (AEs) during Phase 1B
Time frame: 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)
Time frame: 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 1B PK: AUC from time zero to the last measureable concentration (AUC0-t)
Time frame: 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)
Time frame: 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 PK: Time to reach maximum plasma concentration (Tmax)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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).

23 secondary outcomes

Phase 1A Safety: Incidence of Adverse Events (AEs) during Phase 1A
Time frame: up to 24 months
Phase 1A PK: Area under the drug concentration-time curve (AUC) from time zero to infinite time (AUC0-inf)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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 between drug administration and first observed concentration above lower limit if quantitation in plasma (Tlag)
Time frame: 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: Total clearance (CL)
Time frame: 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: Volume of distribution (Vd)
Time frame: 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: Half-life (T1/2)
Time frame: 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 Clinical Activity: Best Overall Response (BOR)
Time frame: through study completion (44 months)
Phase 1B Clinical Activity: objective response rate (ORR)
Time frame: through study completion (44 months)
Phase 1B Clinical Activity: duration of objective response (DOR)
Time frame: through study completion (44 months)
Phase 1B Clinical Activity: duration of major molecular response (DOMMR)
Time frame: through study completion (44 months)
Phase 1B Clinical Activity: duration of complete haematologic response (DOCHR)
Time frame: through study completion (44 months)
Phase 1B Clinical Activity: duration of complete remission (DOCRe)
Time frame: through study completion (44 months)
Phase 1B Clinical Activity: duration of complete cytogenetic response (DOCCyR)
Time frame: through study completion (44 months)
Phase 1B Clinical Activity: time to objective response (TTR)
Time frame: through study completion (44 months)
Phase 1B Clinical Activity: time to major molecular response (TTMMR)
Time frame: through study completion (44 months)
Phase 1B Clinical Activity: time to complete haematologic response (TTCHR)
Time frame: through study completion (44 months)
Phase 1B Clinical Activity: time to complete remission (TTCRe)
Time frame: through study completion (44 months)
Phase 1B Clinical Activity: time to complete cytogenetic response (TTCCyR)
Time frame: through study completion (44 months)
Phase 1B Clinical Activity: progression-free survival (PFS)
Time frame: through study completion (44 months)
Phase 1B Clinical Activity: overall survival (OS)
Time frame: through study completion (44 months)

Results and safety

The study was withdrawn before enrolling participants, so there are no results.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 25 Oct 2018.
Individual participant dataSharing planned: Undecided

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Joel Leong, MD, PhD study chair

D3 (Drug Discovery and Development)

6 sites in 2 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 51 inclusion and 37 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 25 Oct 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in United States, Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Tolerated Dose (MTD) (Phase 1A) (time frame: the initial 28 days of treatment). The study lists 10 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03414450.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Oct 2018.