An open-label phase II dose optimization study of bosutinib at a starting dose of 400 mg daily for adult patients with chronic myeloid leukemia (CML) in chronic phase post frontline TKI failure
Philip A. Thompson
Bosutinib is a type of tyrosine kinase inhibitor (TKI) which is commonly used for the treatment of chronic phase chronic myelogenous leukemia (CP CML). The standard dose of bosutinib often causes temporary, but severe, diarrhea which goes away after bosutinib is stopped or the dose is lowered. The goal of this clinical research study it to learn if a lower dose of bosutinib is as effective as the standard dose. Researchers think that by starting with a lower dose of bosutinib and slowly increasing the dose (if needed), the likelihood and severity of diarrhea and other side effects may be lowered in patients with CP CML. To help researchers learn if the lower dose of bosutinib is as effective as the regular dose, researchers will test your cytogenetic response to the drug. Cytogenetic testing looks at how genetic changes to cells (in this study, the BRC-ABL protein and Philadelphia chromosome) may affect how the disease may react to the study drug.
Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: Bosutinib
Treatment Location: Only at MDACC
Sponsor: Pfizer, inc
Primary: To assess the response rate within 24 weeks in patients in chronic phase receiving an escalating schedule of bosutinib with the starting dose of 400 mg per day, with potential escalation to 500 mg and subsequently 600mg per day. Response is defined as follows: 1. For patients who do not currently have a partial cytogenetic response (PCyR), achievement of major cytogenetic response (MCyR) is considered a response. 2. For patients who are currently in PCyR, achievement of complete cytogenetic response (CCyR), CCyR is considered a response. Secondary: · Safety of dosing schedule. · Frequency of treatment interruptions and dose reductions. · Determine the rate of BCR-ABL/ABL <10% at 3 months and <1% at 6 months on the international scale and the rate of complete cytogenetic response (CCyR) at 6 months after the start of treatment. · Determine the cumulative rate of CCyR. · Determine the rate of major molecular response, MR4, MR4.5 and complete molecular response. · Determine long-term outcomes, including progression-free survival, event-free survival, and overall survival. · Investigate the correlation between ABL kinase domain mutations, if present at the time of enrollment, with outcome. · Determine the rate of development and type of ABL kinase domain mutations during therapy with bosutinib. Exploratory: · As an optional procedure, perform paired whole exome sequencing at baseline and progression to identify novel mutations in protein-coding genes responsible for resistant disease. If patients choose to participate, they will be consented for sample banking on protocol LAB01-473.
IRB Review and Approval Date: 10/28/2016
Recruitment Status: Open
Projected Accrual: N/A
1) Patients with CML in chronic phase who have resistance and/or
intolerance to frontline TKI therapy. Resistance is defined as lack
(lack defined as response not achieved or lost by the given dates
mentioned hereafter) of CHR (complete hematologic response) within 3
months, lack of MCyR within 6 months, and lack of CCyR within 12 months
of therapy with frontline TKIs. In addition, loss of MCyR, CCyR or MMR
at any time during the course of therapy is also considered resistance
to therapy. Intolerance is defined as grade 3 or 4 toxicity that is
unresponsive to or persistent despite adequate management; patients with
persistent (i.e., for more than 2 months) grade 2 non-hematologic
toxicity that is not adequately controlled despite optimal management
are also eligible.
2) Chronic phase disease is defined as: a. <15% blasts in peripheral blood and bone marrow; b. <30% blasts plus promyelocytes in peripheral blood and bone marrow; c. <20% basophils in peripheral blood; d. > or = 100 x 10^9/L platelets (> or = 100,000/mm^3); e. No evidence of extramedullary disease except hepatosplenomegaly; and f. No prior diagnosis of AP or BP-CML. Patients with clonal evolution but no other criteria for accelerated phase are eligible.
3) ECOG performance status of 0, 1, or 2.
4) Age 18 years or older.
5) Adequate organ function with creatinine less than or equal to 2.0 mg/dl, bilirubin less than or equal to 2.0 mg/dl and ALT and AST less than or equal to 3 times institutional upper limit of normal
6) QTcF segment <480msec.
7) Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotrophin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use one of the following effective contraception methods during the study and for 30 days following the last dose of study drug. Effective methods of birth control include: a. birth control pills, shots or implants (placed under the skin by a health care provider) or patches (placed on the skin); b. Intrauterine devices (IUDs); c. condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide. Females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy.
8) Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug.
9) Patients or their legally authorized representative must provide written informed consent.
1) Women that are pregnant or lactating.
2) Known to be HIV+.
3) Active and uncontrolled disease/infection that in the opinion of the treating physician and principal investigator may affect the ability to participate in the trial or put the patient at unduly high risk.
4) Unable or unwilling to sign the informed consent document.
5) No other investigational therapy within the past 14 days.
6) Presence of T315I mutation by ABL1 sequencing
7) Patient is currently in complete cytogenetic remission (CCyR).
Information and next steps
Malignant neoplasms stated as primary lymphoid haematopoietic
Philip A. Thompson
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