ABL001 is an investigational drug which has not been approved by the health authorities to date and is being developed to treat people with CML in chronic phase. Bosutinib is one of the TKIs with proven clinical benefit in CP-CML patients previously treated with one or more tyrosine kinase inhibitor(s) and is currently approved for this indication in many countries, including the European Union.The purpose of this study is to compare the benefits and side effects of ABL001 versus bosutinib in patients with CML. CML is characterized by an abnormal chromosome called the “Philadelphia chromosome”. The Philadelphia chromosome creates an abnormal protein (BCR-ABL) that causes some white blood cells (leukemia cells) to grow.
Patients may be treated with either ABL001 or bosutinib. They have a 2 in 3 chance of being treated with ABL001 and a 1 in 3 chance of being treated with bosutinib in order to learn more about the safety profile of the experimental therapy, whereas the safety of bosutinib therapy is well documented.
About 222 patients will participate in this study worldwide in various countries.
Patients will be asked to take one 40 mg tablet of ABL001 two times a day (without food) or one 500 mg tablet of bosutinib once a day (with food) for up to 168 weeks.
Patients will come to the doctor’s study site about 37 times (including screening visit period of a maximum 42 days) up to 168 weeks. After completing treatment or discontinuing the study early, a visit called end of treatment visit will take place followed by a safety follow-up telephone call and then patients will enter the survival follow-up phase.
Two-hundred and twenty-two (222) patients with CML-CP who had prior treatment with two or more ATP binding site TKIs will be randomized on a 2:1 basis to receive either ABL001 or bosutinib. Patients with known history of T315I and/or V299L mutations at study entry will be excluded from the trial since bosutinib, the comparator, is not approved for these patients.
Dr. Ali Bazarbachi will identify eligible patients from his own practice.
If interested, they will be referred to the research fellow who will be responsible to conduct the consenting process at American University of Beirut in a private room.
Research fellow will review the document with the subjects, answer all questions they may have, and ensure that the subjects are made aware of all the procedures and the potential risks and benefits associated with the study and its duration.
Patient/impartial witness/legal representative should voluntary sign and date the informed consent form.
A copy of the signed informed consent document must be filed with the investigator study file and a signed copy should be given to the subjects.
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Male or female patients with a diagnosis of CML-CP ≥ 18 years of age
2. Patients must meet all of the following laboratory values at the screening visit:
< 15% blasts in peripheral blood and bone marrow
< 30% blasts plus promyelocytes in peripheral blood and bone marrow
< 20% basophils in the peripheral blood
≥ 50 x 109/L (≥ 50,000/mm3) platelets
·Transient prior therapy related thrombocytopenia (< 50,000/mm3 for ≤ 30 days prior
to screening) is acceptable
· No evidence of extramedullary leukemic involvement, with the exception of
3. BCR-ABL ratio ≥ 1% IS according to central laboratory at the screening examination
4. Prior treatment with a minimum of 2 prior ATP-binding site TKIs (i.e. imatinib, nilotinib,
dasatinib, radotinib or ponatinib)
5. Failure or intolerance to the last previous TKI therapy at the time of screening (adapted
from the 2013 ELN Guidelines Bacarrani 2013)
· Failure is defined for CML-CP patients (CP at the time of initiation of last therapy) as
follows. Patients must meet at least 1 of the following criteria.
· Three months after the initiation of therapy: No CHR or > 95% Ph+ metaphases
· Six months after the initiation of therapy: BCR-ABL ratio > 10% IS and/or > 65%
Twelve months after initiation of therapy: BCR-ABL ratio > 10% IS and/or > 35%
· At any time after the initiation of therapy, loss of CHR, CCyR or PCyR
· At any time after the initiation of therapy, the development of new BCR-ABL
· At any time after the initiation of therapy, confirmed loss of MMR in 2
consecutive tests, of which one must have a BCR-ABL ratio ≥ 1% IS
· At any time after the initiation of therapy, new clonal chromosome abnormalities
in Ph+ cells: CCA/Ph+
Intolerance is defined as:
· Non-hematologic 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 dose reduction is not considered in the best
interest of the patient if response is already suboptimal)
· Hematologic 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 doses recommended by manufacturer
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
7. Adequate end organ function as defined by (as per central laboratory tests):
· Total bilirubin ≤ 1.5 x ULN except for patients with Gilbert’s syndrome who may
only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
· Aspartate transaminase (AST) ≤ 3.0 x ULN
· Alanine transaminase (ALT) ≤ 3.0 x ULN
· Serum amylase ≤ ULN
· Serum lipase ≤ ULN
· Alkaline phosphatase ≤ 2.5 x ULN
· Creatinine clearance ≥ 50 mL/min as calculated using Cockcroft-Gault formula
8. Patients must avoid consumption of grapefruit, Seville oranges or products containing the
juice of each during the entire study and preferably 7 days before the first dose of study
medications, due to potential CYP3A4 interaction with the study medications. Orange
juice is allowed.
9. Written informed consent obtained prior to any screening procedures.
10. Patients must have the following electrolyte values within normal limits (as per central
laboratory tests) or corrected to be within normal limits with supplements prior to first
dose of study medication:
· Total calcium (corrected for serum albumin)
Patients eligible for this study must not meet any of the following criteria:
1. Known presence of the T315I or V299L mutation at any time prior to study entry
2. Known second chronic phase of CML after previous progression to AP/BC
3. Previous treatment with a hematopoietic stem-cell transplantation
4. Patient planning to undergo allogeneic hematopoietic stem cell transplantation
5. Cardiac or cardiac repolarization abnormality, including any of the following:
· History within 6 months prior to starting study treatment of myocardial infarction
(MI), angina pectoris, coronary artery bypass graft (CABG)
· Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left
bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II
and third degree AV block)
· QTcF at screening ≥450 ms (male patients), ≥460 ms (female patients)
· Long QT syndrome, family history of idiopathic sudden death or congenital long QT
syndrome, or any of the following:
· Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or
hypomagnesemia, history of cardiac failure, or history of clinically
· Concomitant medication(s) with a known risk to prolong the QT interval and/or
known to cause Torsades de Pointes that cannot be discontinued or replaced 7
days prior to starting study drug by safe alternative medication.
· Inability to determine the QTcF interval
6. Severe and/or uncontrolled concurrent medical disease that in the opinion of the
investigator could cause unacceptable safety risks or compromise compliance with the
protocol (e.g. uncontrolled diabetes, active or uncontrolled infection, pulmonary
7. History of acute pancreatitis within 1 year of study entry or past medical history of chronic
8. History of elevation in amylase or lipase (> ULN) within 1 year other than that which may
have occurred with gallstones, trauma, or medical procedures
9. History of acute or chronic liver disease
10. Known presence of significant congenital or acquired bleeding disorder unrelated to
11. History of other active malignancy within 3 years prior to study entry with the exception
of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated
12. Known history of Human Immunodeficiency Virus (HIV), chronic Hepatitis B (HBV), or
chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBs Ag)
and Hepatitis B core antibody (HBcAb / anti HBc) will be performed at screening
13. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the
absorption of study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea,
malabsorption syndrome, small bowel resection, or gastric bypass surgery)
14. Treatment with medications that meet one of the following criteria and that cannot be
discontinued at least one week prior to the start of treatment with study treatment
· Moderate or strong inducers of CYP3A
· Moderate or strong inhibitors of CYP3A and/or P-gp
· Substrates of CYP3A4/5, CYP2C8, or CYP2C9 with narrow therapeutic index
15. Previous treatment with or known/ suspected hypersensitivity to ABL001 or any of its
16. Previous treatment with or known/ suspected hypersensitivity to bosutinib or any of its
17. Participation in a prior investigational study within 30 days prior to randomization or
within 5 half-lives of the investigational product, whichever is longer
18. Pregnant or nursing (lactating) women
19. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 3 days after last dose of ABL001. Highly effective contraception
· Total abstinence (when this is in line with the preferred and usual lifestyle of the
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception
· Female sterilization (have had surgical bilateral oophorectomy (with or without
hysterectomy) total hysterectomy or tubal ligation at least six weeks before taking
study treatment). In case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment
· Male sterilization (at least 6 months prior to screening). The vasectomized male
partner should be the sole partner for that subject.
· Use of oral, injected or implanted hormonal methods of contraception or placement of
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal
contraception that have comparable efficacy (failure rate <1%), for example hormone
vaginal ring or transdermal hormone contraception.
· In case of use of oral contraception women should have been stable on the same pill
for a minimum of 3 months before taking study treatment.
20. Women are considered post-menopausal and not of child bearing potential if they have
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment is she considered
not of child bearing potential.
21. Sexually active males unless they use a condom during intercourse while taking the drug
during treatment and for 3 days after stopping treatment and should not father a child in
this period. A condom is required to be used also by vasectomized men as well as during
intercourse with a male partner in order to prevent delivery of the drug via semen.