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.
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
