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ABL001, Dasatinib, and Prednisone in Treating Patients with BCR-ABL Positive B-Cell Acute Lymphoblastic Leukemia or Chronic Myeloid Leukemia

Trial Status: Active

This phase I trial studies the side effects and best dose of ABL001 when given together with dasatinib and prednisone in treating patients with BCR-ABL positive B-cell acute lymphoblastic leukemia or chronic myeloid leukemia. ABL001 and dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Prednisone may help to lessen inflammation and lower the body's immune response. Giving ABL001, dasatinib, and prednisone may work better in treating patients with BCR-ABL positive B-cell acute lymphoblastic leukemia or chronic myeloid leukemia.

Inclusion Criteria

  • Participants must have cytopathologically confirmed BCR-ABL+ B-cell acute lymphoblastic leukemia (ALL) or chronic myeloid leukemia (CML) in lymphoid blast crisis.
  • BCR-ABL positive status may be confirmed by fluorescence in situ hybridization (FISH), karyotype analysis, or molecular testing for p210 (b2a2 or b3a2) or p190 (e1a2 only) transcripts
  • Patients with asymptomatic central nervous system (CNS) disease are eligible and may be treated concurrently with intrathecal chemotherapy.
  • Participants must NOT be suitable for or willing to receive standard intensive induction chemotherapy. The following groups are not considered suitable for standard intensive induction chemotherapy: * Participants who have not received standard intensive induction chemotherapy and are aged >= 50 years. * Participants who have not received standard intensive induction chemotherapy and are aged 18 to 49 years and unfit due to co-morbidity or other factors to receive intensive chemotherapy. Specific criteria that would suggest that a patient is unsuitable for intensive induction chemotherapy include: ** Severe cardiac comorbidity (congestive heart failure or documented cardiomyopathy with ejection fraction [EF] =< 50%). ** Severe pulmonary comorbidity (documented pulmonary disease with carbon monoxide diffusing capability [DLCO] =< 65% or forced expiratory volume in 1 second [FEV1] =< 65%, or dyspnea at rest, or requiring oxygen). ** Eastern Cooperative Oncology Group (ECOG) performance status of 2 due to medical conditions unrelated to leukemia. ** Any other comorbidity that the physician judges to be incompatible with intensive cytotoxic chemotherapy. * Participants aged >= 18 years with disease that is relapsed or refractory to 1 or more cycles of standard intensive induction chemotherapy.
  • ECOG performance status 0-3. ECOG value of 3 is allowed after documented discussion with principal investigator (PI), if poor performance status is attributed to underlying disease.
  • Creatinine =< 1.5 x institutional upper limit of normal within 72 hours of beginning therapy.
  • Amylase and lipase values =< 3.0 x institutional upper limit of normal within 72 hours of beginning therapy.
  • Alkaline phosphatase =< 2.5 x institutional upper limit of normal (unless considered to be not of hepatic origin) within 72 hours of beginning therapy.
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal within 72 hours of beginning therapy.
  • Total bilirubin =< 1.5 x institutional upper limit of normal (=< 3 x upper limit of normal in patients with known or suspected Gilbert's syndrome) within 72 hours of beginning therapy.
  • Direct bilirubin =< 1.5 x institutional upper limit of normal within 72 hours of beginning therapy
  • The effects of ABL001 on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.
  • Women of child-bearing potential must agree to use highly effective methods of contraception during dosing and for 30 days after study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • Allowable methods of birth control: * 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.
  • Sexually active males must use a condom during intercourse while taking the drug and for 30 days after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
  • Ability to understand and the willingness to sign a written informed consent document and comply with all study procedures.

Exclusion Criteria

  • Participants suitable for and willing to receive standard intensive induction chemotherapy.
  • Patients with a known ABL T315I mutation are excluded. ABL kinase mutation analysis is not recommended for newly diagnosed patient. ABL kinase mutation analysis is recommended for patients with relapsed disease or CML progressed to blast phase on prior TKI and results should be reviewed prior to enrollment.
  • Prior treatment of ALL or CML with dasatinib or ABL001. Prior receipt of other tyrosine kinase inhibitor (TKI)s and chemotherapy for the treatment of ALL or CML is permitted.
  • Any TKI therapy must be discontinued for 5 half-lives prior to initiation of protocol therapy.
  • Patient may not have received other chemotherapy, including antibody-based therapy, within 2 weeks of the initiation of protocol therapy with the exception of steroids or hydroxyurea
  • Participants who are receiving any other investigational agents for conditions other than ALL must have discontinued those agents 2 weeks prior to the start of study treatment.
  • 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.
  • History of another active malignancy within 5 years prior to study entry except for previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively.
  • Acute or chronic liver disease (including known active hepatitis B and C infections). Screening for hepatitis is not required. Patients with treated or past exposure viral hepatitis (i.e. evidence of exposure negative viral load) may participate.
  • History of pulmonary arterial hypertension.
  • Significant pleural effusions leading to respiratory compromise and need for intervention (i.e. thoracentesis).
  • Alcohol abuse requiring medical treatment.
  • Participants with a history of acute pancreatitis, chronic pancreatitis, or any ongoing pancreatic disease not considered related to ALL.
  • History of human immunodeficiency virus (HIV). Screening is not required.
  • History of a serious bleeding disorder unrelated to ALL.
  • It is suggested that participants receiving treatment with medications that meet one of the following criteria discontinue the relevant drug prior to the start of treatment with ABL001 and for the duration of the study. If the medication is medically necessary review with PI before enrollment. * Strong inducers of CYP3A4/5. * Moderate and strong inhibitors CYP3A4/5. * CYP3A4/5, CYP2C8 and CYP2C9 substrates with narrow therapeutic index. All other substrates of the enzymes should be used with caution. * H2 antagonists/proton-pump inhibitors. * Grapefruit products are not permitted while on study. * Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians’ Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
  • Corrected QT interval (QTc) of > 480 milliseconds (ms) on baseline electrocardiogram (ECG) (using corrected QT interval per institutional standard).
  • Major surgery within 2 weeks before the first dose of ABL001.
  • Uncontrolled intercurrent illness including, but not limited to: * Uncontrolled infection. * Unstable cardiovascular condition including symptomatic congestive heart failure (New York Heart Association [NYHA] class 3 or 4), unstable angina pectoris, ongoing clinically significant cardiac arrhythmia uncontrolled by medication, and myocardial infarction or stroke within the past 3 months. * Psychiatric illness/social situations that would limit compliance with study requirements. * Currently requiring supplemental oxygen, mechanical ventilation, vasopressors, and/or hemodialysis (life-support). * History of significant congenital or acquired bleeding disorder unrelated to cancer.
  • Unable to comply with an oral regimen.
  • Are pregnant or nursing at the time of screening. Pregnant women are excluded from this study because ABL001 is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ABL001, breastfeeding should be discontinued if the mother is treated with ABL001. These potential risks may also apply to other agents used in this study. Urine or serum pregnancy test must be performed within 14 days of day 1 for women of childbearing potential.

Illinois

Chicago
University of Chicago Comprehensive Cancer Center
Status: ACTIVE
Contact: Wendy Stock

Massachusetts

Boston
Beth Israel Deaconess Medical Center
Status: ACTIVE
Contact: Lourdes M. Mendez
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Marlise Rachael Luskin
Phone: 617-632-3018
Massachusetts General Hospital Cancer Center
Status: ACTIVE
Contact: Hanno Reinhard Hock
Phone: 617-724-1124

New York

Buffalo
Roswell Park Cancer Institute
Status: ACTIVE
Contact: Eunice Sue Wang

PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 dose (RP2D) of asciminib (ABL001) in combination with dasatinib 140 mg daily and prednisone.

II. To further characterize the safety and tolerability of ABL001 at the RP2D in combination with dasatinib and prednisone in an expansion cohort.

SECONDARY OBJECTIVES:

I. To determine efficacy: depth of response to ABL001 in combination with dasatinib and prednisone at day 28 (end cycle 1), day 56 (end cycle 2), and day 84 (end cycle 3).

Ia. Percentage of participants achieving hematologic remission.

Ib. Percentage of participants achieving cytogenetic response.

Ic. Percentage of participants achieving a minimal residual disease (MRD)-negative complete remission (CR) by flow cytometry.

Id. Percentage of participants achieving molecular response: BCR-ABL messenger ribonucleic acid (mRNA) transcript levels of < 10^-3, < 10^-4, < 10^-4.5, and < 10^-5, with BCR-ABL mRNA transcript levels expressed as a percentage compared with a control gene.

EXPLORATORY OBJECTIVES:

I. To determine duration of response: event-free survival (EFS), disease-free survival (DFS), and overall survival (OS).

II. To determine median duration of molecular response in patients who achieve BCR-ABL mRNA transcript levels of < 10^-3, with BCR-ABL mRNA transcript levels expressed as a percentage compared with a control gene.

III. To determine 1-year and 2-year hematologic relapse rate, EFS and OS.

IV. To define mechanisms of clinical resistance to ABL001 in combination with dasatinib and prednisone.

IVa. Single and compound mutations in BCR-ABL associated with clinical resistance to ABL001 plus dasatinib and prednisone will be identified.

IVb. Non-BCR-ABL mediated mechanisms of clinical resistance to ABL001 plus dasatinib and prednisone will be identified.

OUTLINE: This is a dose-escalation study of asciminib.

Patients receive asciminib orally (PO) once daily (QD) on days 1-28, dasatinib PO QD on days 1-28, and prednisone PO QD on days 1-24 and tapered beginning day 25 and stopped on day 32. Treatment repeats every 28 days for up to 84 days in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care allogeneic stem cell transplant.

After completion of study treatment, patients are followed up every 90 days for 5 years.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Marlise Rachael Luskin

  • Primary ID 18-170
  • Secondary IDs NCI-2018-02377
  • Clinicaltrials.gov ID NCT03595917