A phase I, multicenter, open-label study of oral ABL001 in patients with chronic myelogenous leukemia or Philadelphia Chromosome-positive acute lymphoblastic leukemia
The goal of this clinical research study is to find the highest tolerable dose of ABL001 taken alone in CML or Ph+ ALL patients, and ABL001 in combination with nilotinib, imatinib, or dasatinib in patients with CML. The safety of this drug taken alone and in combination with nilotinib, imatinib, or dasatinib will also be studied. This is the first study using ABL001 in humans.
Disease Group: Leukemia
Treatment Agent: ABL001,Nilotinib
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Novartis Pharmaceutical Corporation
Primary: 1. Determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of: ABL001 as single agent in CP and AP CML patients ABL001 in combination with nilotinib in CP and AP CML patients ABL001 in combination with imatinib in CP and AP CML patients ABL001 in combination with dasatinib in CP and AP CML patients ABL001 as single agent in BP CML and Ph+ ALL patients Secondary: 1. Characterize the safety and tolerability of ABL001 as single agent and in combination with either nilotinib or imatinib or dasatinib. 2. To assess preliminary anti-CML activity associated with ABL001 as single agent and in combination with either nilotinib or imatinib or dasatinib and anti Ph+ALL activity associated with ABL001 as a single agent. 3. To assess the pharmacokinetic profile of all study drugs in single agent and in combination arms in plasma.
IRB Review and Approval Date: 07/30/2015
Recruitment Status: Open
Projected Accrual: 250
1) Male or female patients >/= 18 years of age who present one of the
following: For Arms 1, 2, 3 & 4, either: a. Patients with Ph+ CML in
chronic or accelerated phase who were previously treated with at least
two different tyrosine kinase inhibitors prior to study entry and are
relapsed, refractory to or intolerant of TKIs as determined by
investigators; or b. Patients with CML in chornic or accelerated phase
who exhibit relapsed disease associated with the presence of the T315I
"gatekeeper mutation" after at least one TKI are also eligible
provided that no other effective therapy exists. There is no restriction
on the number of prior therapies administered to patients, and patients
who are status post bone marrow transplant are eligible provided they
meet the inclusion/exclusion criteria for entry onto the study.
2) **continued from above: For Arm 5: Patients with CML BP or Ph+ ALL who have a cytopathologically confirmed diagnosis and be relapsed or refractory to at least one prior TKI or intolerant to TKIs. TKI failure for Ph+ ALL patients is defined as at least the loss of Molecular Response (MR) 4.5 (BCR-ABL </= 0.0032%); CML-BP is defined according to the following criteria: >/=30% blasts in peripheral blood or bone marrow aspirate or appearance of extramedullary involvement other than hepatosplenomegaly provided by biopsy (i.e. chloroma); Ph+ ALL patients with stable central nervous system (CNS) disease are eligible to participate and may be treated concurrently with intrathecal (or intra Ommaya) chemotherapy. Intrathecal therapy consisting of depocyte or triple therapy with mehtotrexate (up to 15 mg), Ara C (up to 40 mg) and corticosteroids may be administered upt to 2 weeks and 1 weeks, respectively, prior to first dose of ABL001;
3) **continued from above: Ph+ ALL patients who are status post bone marrow transplant are eligible provided they meet the inclusion/exclusion criteria for entry onto the study.
4) Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
5) Willingness and ability to comply with all study procedures.
6) Written informed consent obtained prior to any screening procedures.
1) Wash-Out Period: a) Systemic antineoplastic therapy (including
cytotoxic chemotherapy, alfa-interferon and toxin immunoconjugates) or
any experimental therapy within 14 days or 5 half-lives, whichever is
shorter, before the first dose of study treatment; b) Therapy with TKIs
as single agent within 5 half-lives before the first dose of study
treatment; c) Unconjugated monoclonal anitbody therapies within 28 days
or 5 half-lives, whichever is shorter, before the first dose of study treatment.
2) For patients receiving ABL001 in combination with either nilotinib or imatinib or dasatinib, intolerance to nilotinib, imatinib or dasatinib, respectively.
3) Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment.
4) CNS irradiation for meningeal leukemia, except if radiotherapy occurred > 3 months previously. At least four weeks must have elapsed since prophylactic CNS irradiation given as part of a front-line therapy regimen for ALL.
5) Major surgery within 2 weeks before the first dose of study treatment.
6) The following clinical laboratory results within 3 days before the first dose of study treatment: a. For CML-CP and -AP patients: 1. Absolute neutrophil count (ANC) </= 0.5 x 10(9)/L; 2. Hemoglobin </= 9.0 g/dL; 3. Platelets </= 50 x 10(9)/L; b. For Ph+ ALL and CML-BP patients: 1. Peripheral blood blasts > 50,000 blasts/mm(3); c. Total bilirubin > 1.5 times the upper limit of the normal range (ULN), except for patients with Gilbert’s syndrome, who are excluded if total bilirubin is > 3 times the ULN or if direct bilirubin is > 1.5 times the ULN; d. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the ULN; e. Alkaline phosphatase > 2.5 times the ULN unless considered to be not of hepatic origin; f. Creatinine > 1.5 ULN; g. Amylase values above the institutional ULN; h. Lipase values above the institutional ULN.
7) 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 and for the duration of the study: a. Strong inducers of CYP3A4/5 (monotherapy and all combination arms); b. Strong inhibitors of CYP3A4/5 (combination with nilotinib or dasatinib); c.Moderate inhibitors of CYP3A4/5 (cdombination with nilotinib or dasatinib); d. CYP3A4/5, CYP2C8, and CYP2C9 substrates with narrow therapeutic index (monotherapy and all combination arms); e. CYP2D6 substrates with narrow therapeutic index (combination with nilotinib); f. H2 antagonist/proton-pump inhibitors (combination with dasatinib only); g. Ph+ ALL patients maintained on stable doses of G-CSF or GM-CSF at study entry may continue therapy (monotherapy and combination arm);
8) ***continued from above: h. Medications typically used as part of a maintenance or prephase therapy for Ph+ ALL, such as vincristine, mercaptopurine, thioguaníne, low-dose [<15 mg/m(2)] methotrexate and low-dose [cumulative dose < 1g/m(2)] cyclophosphamide may be given up to one week prior to the first dose of study treatment.
9) Patients who are currently receiving glucocorticoids or hydroxyurea to control peripheral blood leukemic blasts and cannot be discontinued for at least 24 hours prior to obtaining PD biomarkers at screening/baseline and during the study.
10) Grapefruit juice and grapefruit products are not permitted while on study.
11) Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either safely discontinued or switched to a different medication prior to starting study drug administration.
12) 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). Patients who have had a gastrectomy are not excluded.
13) Residual toxic effects of Grade 2 or worse from previous therapy other than neurotoxicity, ototoxicity, and fatigue grade 2 or 3 or alopecia of any grade.
14) Active infection, including pneumonia, requiring systemic therapy or other severe infection within 2 weeks before the first dose of study treatment.
15) History of significant congenital or acquired bleeding disorder unrelated to cancer.
16) Known human immunodeficiency virus (HIV) positive (testing is not required).
17) Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
18) Corrected QT interval (QTc) of > 480 milliseconds (ms) on baseline electrocardiogram (ECG) (using corrected QT interval using Fridericia [QTcF] or if QTcF no available by using Bazett [QTcB]).
19) Uncontrolled cardiovascular condition, including ongoing cardiac arrhythmias, congestive heart failure, angina, or myocardial infarction within the past 3 months.
20) History of another active malignancy within 5 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively.
21) History of acute pancreatitis within 1 year of study entry, chronic pancreatitis, or any ongoing pancreatic disease not considered related to the malignancies under study.
22) Acute or chronic liver disease (including chronic hepatitis B and C infections).
23) History of or ongoing pulmonary arterial hypertension.
24) Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
25) 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 the last dose of study treatment for patients enrolled in Arms 1 and 5, for 14 days after the last dose of study treatment for patients enrolled in Arm 2 (ABL001+nilotinib) and Arm 3 (ABL001+imatinib) and for 30 days after the last dose of study treatment for patients enrolled in Arm 4 (ABL001+dasatinib). Highly effective contraception methods include: a. 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;
26) **Continued from above: b. 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; c. Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject. d. 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.
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