Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myelogenous Leukemia

• ClinicalTrials.gov Identifier: NCT02689440
• Recruitment Status: Recruiting
• First Posted: February 24, 2016
• Last Update Posted: January 25, 2022
• Sponsor: M.D. Anderson Cancer Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): M.D. Anderson Cancer Center

Study Description

Brief Summary:

This phase II trial studies how well dasatinib and venetoclax work in treating patients with Philadelphia chromosome positive or BCR-ABL1 positive early chronic phase chronic myelogenous leukemia. Dasatinib and venetoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease	Intervention/treatment	Phase
Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Philadelphia Chromosome Positive, BCR-ABL1 Positive Chronic Myelogenous Leukemia	Drug: Dasatinib; Other: Laboratory Biomarker Analysis; Drug: Venetoclax	Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate the proportion of patients with previously-untreated chronic phase chronic myeloid leukemia (CML) who achieve major molecular response by 12 months of treatment with dasatinib 50 mg orally daily (first 70 patients) and of dasatinib 50 mg daily in combination with venetoclax 200 mg daily starting after 3 months of dasatinib therapy (after protocol amendment).

SECONDARY OBJECTIVES:

I. To estimate the 12 months molecular response (MR)4.5 rate and the cumulative overall rate of MR4.5 (BCR-ABL transcripts [IS] =< 0.01%).

II. To estimate the proportion of patients with MR4.5 at 6-, 12-, 18-, 24-, and 36-months of therapy.

III. To estimate the proportion of patients with sustained MR4.5 of 3 years and more.

IV. To estimate the treatment-free remission rate, time to progression, and overall survival.

V. To assess the safety of this combination.

OUTLINE:

Patients receive dasatinib orally (PO) once daily (QD) for 15 years in the absence of disease progression or unacceptable toxicity. After 3 months of dasatinib treatment, patients also receive venetoclax PO QD on days 1-14 of each month for 3 years in the absence of disease progression or unacceptable toxicity (patients enrolled prior to 4/1/2018 receive only dasatinib).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 140 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Therapy of Early Chronic Phase Chronic Myelogenous Leukemia (CML) With Dasatinib and Venetoclax: A Phase II Study
• Actual Study Start Date: February 19, 2016
• Estimated Primary Completion Date: December 31, 2040
• Estimated Study Completion Date: December 31, 2040

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment (dasatinib, venetoclax); Patients receive dasatinib PO QD for 15 years in the absence of disease progression or unacceptable toxicity. After 3 months of dasatinib treatment, patients also receive venetoclax PO QD on days 1-14 of each month for 3 years in the absence of disease progression or unacceptable toxicity (patients enrolled prior to 4/1/2018 receive only dasatinib).

Drug: Dasatinib; Given PO; Other Names: BMS-354825; Dasatinib Hydrate; Dasatinib Monohydrate; Sprycel; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Venetoclax; Given PO; Other Names: ABT-0199; ABT-199; ABT199; GDC-0199; RG7601; Venclexta; Venclyxto

Outcome Measures

Primary Outcome Measures :

1. Major molecular response (MMR) defined as BCR-ABL transcripts (IS) =< 0.1% [ Time Frame: Up to 12 months ]
   MMR estimates will be presented with 95% credible intervals. MMR and patient and clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test.

Secondary Outcome Measures :

1. Complete cytogenetic response (CCR) defined as 0% Ph-positive metaphases, or fluorescence in situ hybridization =< 2%, or BCR-ABL transcripts (IS) =< 1% [ Time Frame: At 6 months ]
   CCR estimates will be presented with 95% credible intervals.
2. Incidence of toxicities, defined as grade 3 or higher pleural effusion [ Time Frame: Up to 3 years ]
   Safety data of the patients will be summarized using descriptive statistics such as mean, standard deviation, median and range (i.e., duration of hematologic, cytogenetic and molecular response to the drug).
3. Time to progression [ Time Frame: Up to 3 years ]
   Estimated using the Kaplan-Meier method. The two-sided log-rank test will be used to assess the differences of time to events between groups.
4. Overall survival [ Time Frame: Up to 3 years ]
   Estimated using the Kaplan-Meier method. The two-sided log-rank test will be used to assess the differences of time to events between groups.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Diagnosis of Philadelphia chromosome (Ph)-positive or BCR-ABL positive CML in early chronic phase CML (i.e., time from diagnosis is 12 months); except for hydroxyurea and/or 1 to 2 doses of cytarabine patients, patients must have received no or minimal prior therapy, defined as < 1 month (30 days) of prior Food and Drug Administration (FDA) approved tyrosine kinase inhibitor (TKI)
• Patients with clonal evolution and no other criteria for accelerated phase will be eligible for this study
• Eastern Cooperative Oncology Group (ECOG) performance of 0-2
• Total bilirubin < 1.5 x upper limit normal (ULN)
• Serum glutamate pyruvate transaminase (SGPT) < 3 x ULN
• Creatinine < 1.5 x ULN
• Patients must sign an informed consent indicating they are aware of the investigational nature of this study, in keeping with the policies of the hospital

Exclusion Criteria:

• New York Heart Association (NYHA) cardiac class 3-4 heart disease

• Patients meeting the following criteria are not eligible unless cleared by cardiology:

  • Uncontrolled angina within 3 months
  • Diagnosed or suspected congenital long QT syndrome
  • Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes)
  • Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (> 460 msec)

  • History of significant bleeding disorder unrelated to cancer, including:

    • Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)
    • Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)
• Patients with active, uncontrolled psychiatric disorders include: psychosis, major depression, and bipolar disorders
• Subject is known to be positive for human immunodeficiency virus (HIV); (HIV testing is not required)

• Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

  • Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
  • Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment; Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface [HBs] antigen negative-, anti-HBs antibody positive and anti-hepatitis B core [HBc] antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate
• Women of pregnancy potential must practice an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized; prior to study enrollment, women of childbearing potential (WOCBP) must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy; postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential; women must continue birth control for the duration of the trial and at least 3 months after the last dose of study drug; pregnant or breast-feeding women are excluded; all WOCBP must have a negative pregnancy test prior to first receiving investigational product; if the pregnancy test is positive, the patient must not receive investigational product and must not be enrolled in the study

• Patients in late chronic phase (i.e., time from diagnosis to treatment > 12 months), accelerated or blast phase are excluded; the definitions of CML phases are as follows:

  • Early chronic phase:

    • Time from diagnosis to therapy 12 months

    • Late chronic phase:

      • Time from diagnosis to therapy > 12 months

  • Blastic phase:

    • Presence of 30% blasts or more in the peripheral blood or bone marrow

  • Accelerated phase CML:

    • Presence of any of the following features:

      • Peripheral or marrow blasts 15% or more
      • Peripheral or marrow basophils 20% or more
      • Thrombocytopenia < 100 x 10^9/L unrelated to therapy
      • Documented extramedullary blastic disease outside liver or spleen

Contacts and Locations

Contacts

Contact: Hagop Kantarjian; 713-792-7026; hkantarjian@mdanderson.org

Locations

United States, Texas

M D Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Contact: Hagop M. Kantarjian 713-792-7026 hkantarjian@mdanderson.org

Principal Investigator: Hagop M. Kantarjian

Sponsors and Collaborators

M.D. Anderson Cancer Center

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Hagop M Kantarjian; M.D. Anderson Cancer Center

More Information

Additional Information:

MD Anderson Cancer Center Website 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Naqvi K, Jabbour E, Skinner J, Anderson K, Dellasala S, Yilmaz M, Ferrajoli A, Bose P, Thompson P, Alvarado Y, Jain N, Takahashi K, Burger J, Estrov Z, Borthakur G, Pemmaraju N, Paul S, Cortes J, Kantarjian HM. Long-term follow-up of lower dose dasatinib (50 mg daily) as frontline therapy in newly diagnosed chronic-phase chronic myeloid leukemia. Cancer. 2020 Jan 1;126(1):67-75. doi: 10.1002/cncr.32504. Epub 2019 Sep 25.

Naqvi K, Jabbour E, Skinner J, Yilmaz M, Ferrajoli A, Bose P, Thompson P, Alvarado Y, Jain N, Takahashi K, Burger J, Estrov Z, Borthakur G, Pemmaraju N, Paul S, Cortes J, Kantarjian HM. Early results of lower dose dasatinib (50 mg daily) as frontline therapy for newly diagnosed chronic-phase chronic myeloid leukemia. Cancer. 2018 Jul 1;124(13):2740-2747. doi: 10.1002/cncr.31357. Epub 2018 May 3.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT02689440
• Other Study ID Numbers: 2015-1040; NCI-2016-00362 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 2015-1040 ( Other Identifier: M D Anderson Cancer Center ); P30CA016672 ( U.S. NIH Grant/Contract )
• First Posted: February 24, 2016
• Last Update Posted: January 25, 2022
• Last Verified: January 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Philadelphia Chromosome; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Translocation, Genetic; Chromosome Aberrations; Pathologic Processes; Dasatinib; Venetoclax; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action