Clinical Trials /

Evaluation of ETC-1907206 With Dasatinib in Advanced Haematologic Malignancies

NCT03414450

Description:

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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Chronic Myeloid Leukemia
Recruiting Status:

Withdrawn

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Evaluation of ETC-1907206 With Dasatinib in Advanced Haematologic Malignancies
  • 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

Clinical Trial IDs

  • ORG STUDY ID: D3-005
  • NCT ID: NCT03414450

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

DrugSynonymsArms
ETC-1907206ETC-206Dose Escalation (Phase 1A)
dasatinibSprycelDose Escalation (Phase 1A)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation (Phase 1A)ExperimentalAn 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.
  • ETC-1907206
  • dasatinib
Dose Expansion (Phase 1B)ExperimentalOnce 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
  • dasatinib

Eligibility Criteria

        INCLUSION CRITERIA:

        Each patient (male or female) must meet all of the following criteria to be enrolled in
        this study:

          1. Capable of understanding the written informed consent, provides signed and witnessed
             written informed consent, and agrees to comply with protocol requirements.

          2. Age 18 years or older (US sites) or 21 years or older (Singapore site) at Baseline.

          3. 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).

          4. 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.

          5. ECOG performance status of 0 to 2 at Baseline.

          6. Life expectancy of at least 3 months at Baseline.

          7. 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):

               1. Total bilirubin ≤ 1.5 x upper limit of normal (ULN), unless resulting from
                  haemolysis or documented Gilbert syndrome.

               2. Transaminases [aspartate aminotransferase (AST) and/or alanine aminotransferase
                  (ALT) ≤ 2.5 x ULN]. [< 5 x ULN if liver infiltration with tumour present]

               3. Prothrombin time (PT) < 1.5 ULN.

               4. Calculated creatinine clearance ≥ 60 mL/min (Cockcroft and Gault formula).

               5. No clinically relevant abnormalities in the urinalysis results.

               6. Haematology:

                    -  Haemoglobin > 10 g/dL (transfusion allowed to reach the level)

                    -  Neutrophils > 1,000/µL

                    -  Platelets > 75,000/µL.

               7. Pancreatic status:

                    -  Lipase ≤ 1.5 x ULN

                    -  Amylase ≤ 1.5 x ULN.

          8. Capable of taking oral medication and following direction regarding taking study drug
             (either by himself/herself or by caregiver).

          9. 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).

         10. 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.

         11. 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.

         12. 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.

        EXCLUSION CRITERIA:

        Patients meeting any of the following criteria will be excluded from the study:

          1. 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.

          2. 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.

          3. 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).

          4. Has dasatinib intolerance (haematologic and non-haematologic). Defined as: CTCAE Grade
             >2

          5. 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.

          6. 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).

          7. Has used other investigational drugs within 2 weeks or 5 half-lives (whichever is
             shorter) prior to the first dose of study drug.

          8. Has undergone autologous or allogenic stem cell transplantation < 60 days prior to the
             first dose of study drug;

          9. Has any evidence of on-going graft-versus-host disease (GVHD).

         10. 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).

         11. Has central nervous system (CNS) metastases.

         12. Has significant bleeding disorder unrelated to the disease.

         13. Has a history of long QT syndrome or prolonged QT interval corrected based on
             Fridericia's method (QTcF) > 450 ms.

         14. Has ECG evidence of complete left bundle branch block, or ventricular pacing.

         15. 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).

         16. 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.

         17. Is receiving treatment with drugs known to be associated with Torsade de Pointes.

         18. Has ophthalmic signs or symptoms, such as flashes and colour perception changes.

         19. Has evidence of electrolyte imbalance such as hypokalaemia, hypocalcaemia, and
             hypomagnesaemia of NCI-CTCAE Grade ≥ 2 (NCI CTCAE version 4.03).

         20. Has symptomatic chronic heart failure; unstable angina pectoris, cardiac arrhythmia.

         21. Has cardiac left ventricular ejection fraction (LVEF) < 40% (assessed by transthoracic
             echocardiography).

         22. Has a history of myocardial infarction and/or thromboembolism in the past 6 months.

         23. 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.

         24. Has a known history of human immunodeficiency virus (HIV) sero positivity and/or is
             receiving combination anti retroviral therapy.

         25. 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.

         26. Has history of seizure disorders or CNS leukaemia.

         27. 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.

         28. Cannot start treatment with dasatinib 140 mg daily, oral.

         29. Is unwilling or unable to comply with the protocol
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) (Phase 1A)
Time Frame:the initial 28 days of treatment
Safety Issue:
Description: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%.

Secondary Outcome Measures

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

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:D3 (Drug Discovery and Development), Biomedical Sciences Institute

Trial Keywords

  • Mnk kinase inhibitor, Mnk kinase

Last Updated

March 13, 2018