Clinical Trials /

Low-Intensity Chemotherapy and Ponatinib in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Acute Lymphoblastic Leukemia

NCT03147612

Description:

This phase II trial studies how well low-intensity chemotherapy and ponatinib work in treating patients with Philadelphia chromosome-positive and/or BCR-ABL positive acute lymphoblastic leukemia that may have come back or is not responding to treatment. Drugs used in chemotherapy, such as cyclophosphamide, vincristine, dexamethasone, methotrexate, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with rituximab, may induce changes in body's immune system and may interfere with the ability of cancer cells to grow and spread. Ponatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Granulocyte colony stimulating factor helps the bone marrow make recover after treatment. Giving low-intensity chemotherapy and ponatinib may work better in treating patients with acute lymphoblastic leukemia.

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Low-Intensity Chemotherapy and Ponatinib in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Acute Lymphoblastic Leukemia
  • Official Title: Phase II Study of the Combination of Low-Intensity Chemotherapy and Ponatinib in Patients With Philadelphia Chromosome (Ph)-Positive and/or BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL)

Clinical Trial IDs

  • ORG STUDY ID: 2016-0402
  • SECONDARY ID: NCI-2018-01186
  • SECONDARY ID: 2016-0402
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03147612

Conditions

  • Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia With BCR-ABL1
  • Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Philadelphia Chromosome Positive
  • Recurrent Acute Lymphoblastic Leukemia
  • Refractory Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (chemotherapy, ponatinib)
Cytarabine.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Treatment (chemotherapy, ponatinib)
FilgrastimFILGRASTIM, LICENSE HOLDER UNSPECIFIED, G-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, TevagrastimTreatment (chemotherapy, ponatinib)
MethotrexateAbitrexate, Alpha-Methopterin, Amethopterin, Brimexate, CL 14377, CL-14377, Emtexate, Emthexat, Emthexate, Farmitrexat, Fauldexato, Folex, Folex PFS, Lantarel, Ledertrexate, Lumexon, Maxtrex, Medsatrexate, Metex, Methoblastin, Methotrexate LPF, Methotrexate Methylaminopterin, Methotrexatum, Metotrexato, Metrotex, Mexate, Mexate-AQ, MTX, Novatrex, Rheumatrex, Texate, Tremetex, Trexeron, Trixilem, WR-19039Treatment (chemotherapy, ponatinib)
PegfilgrastimFilgrastim SD-01, filgrastim-SD/01, Fulphila, HSP-130, Jinyouli, Neulasta, Neulastim, Pegfilgrastim Biosimilar HSP-130, SD-01, SD-01 sustained duration G-CSFTreatment (chemotherapy, ponatinib)
PonatinibAP-24534, AP24534Treatment (chemotherapy, ponatinib)
RituximabABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, RTXM83Treatment (chemotherapy, ponatinib)
VincristineLEUROCRISTINE, VCR, VincrystineTreatment (chemotherapy, ponatinib)

Purpose

This phase II trial studies how well low-intensity chemotherapy and ponatinib work in treating patients with Philadelphia chromosome-positive and/or BCR-ABL positive acute lymphoblastic leukemia that may have come back or is not responding to treatment. Drugs used in chemotherapy, such as cyclophosphamide, vincristine, dexamethasone, methotrexate, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with rituximab, may induce changes in body's immune system and may interfere with the ability of cancer cells to grow and spread. Ponatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Granulocyte colony stimulating factor helps the bone marrow make recover after treatment. Giving low-intensity chemotherapy and ponatinib may work better in treating patients with acute lymphoblastic leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the complete molecular response (CMR) rate of ponatinib in combination with
      low-intensity chemotherapy in elderly patients with newly diagnosed Philadelphia chromosome
      (Ph)-positive and/or BAR-ABL-positive acute lymphoblastic leukemia (ALL).

      II. To evaluate the overall response (OR; complete response [CR] + complete response with
      hematologic improvement [CRi]) in patients with relapsed/refractory disease.

      SECONDARY OBJECTIVES:

      I. To evaluate other clinical efficacy endpoints (complete cytogenetic response, complete
      molecular response, event-free survival and overall survival) and safety of the combination
      regimen.

      EXPLORATORY OBJECTIVES:

      I. To characterize the frequency of ABL1 kinase domain mutations at diagnosis and to
      determine their influence on relapse-free survival in patients with Ph+ ALL treated with
      hyper-CVD plus ponatinib.

      II. To determine the impact of recurrent genomic alterations and ribonucleic acid (RNA)
      expression at diagnosis on relapse free survival (RFS) in patients with Ph+ ALL treated with
      hyper-CVD plus ponatinib.

      III. To investigate the impact of next-generation sequencing-based minimal residual disease
      assessment on relapse-free survival in patients with Ph+ ALL.

      OUTLINE:

      COURSES 1, 3, 5, 7: Patients receive ponatinib orally (PO) once daily (QD) on days 1-14 of
      course 1 and days 1-28 of subsequent courses, cyclophosphamide intravenously (IV) twice daily
      (BID) over 3 hours on days 1, 2, and 3, rituximab IV over 4-6 hours on days 1 and 11, receive
      vincristine IV over 15 minutes on days 1 and 11, pegfilgrastim or filgrastim subcutaneously
      (SC) daily on day 4, methotrexate intrathecally via spinal tap on day 2 of courses 1, 3, and
      5, and cytarabine intrathecally on day 7 of courses 1, 3, and 5.

      COURSES 2, 4, 6, 8: Patients receive ponatinib PO QD on days 1-28, methotrexate IV over 24
      hours on day 1 and intrathecally on day 8 of courses 2, 4, and 8, cytarabine IV BID over 2-3
      hours on days 2 and 3 and intrathecally on day 5 of courses 2, 4, and 6, pegfilgrastim or
      filgrastim SC daily on day 4, and rituximab IV over 4-6 hours on days 1 and 8.

      MAINTENANCE THERAPY: After course 8, if disease has gotten worse, patients receive
      vincristine IV over 15 minutes on day 1, prednisone PO on days 1-5, and ponatinib PO QD on
      days 1-28. Courses repeat every 28 days for up to 2 years in the absence of disease
      progression or unacceptable toxicity.

      POST-MAINTENANCE THERAPY: Patients receive ponatinib PO QD on days 1-28. Courses repeat every
      28 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (chemotherapy, ponatinib)ExperimentalSee Detailed Description.
  • Cyclophosphamide
  • Cytarabine
  • Filgrastim
  • Methotrexate
  • Pegfilgrastim
  • Ponatinib
  • Rituximab
  • Vincristine

Eligibility Criteria

        Inclusion Criteria:

          -  Patients >= 60 years of age with previously untreated Ph-positive ALL (either t(9;22)
             and/or BCR-ABL positive) (includes patients initiated on first course of hyper-CVAD
             before cytogenetics known) or with lymphoid acelerated or blast phase chronic
             myelogenous leukemia (CML). patients < 60 years of age may be enrolled if they are
             considered unfit for intensive chemotherapy

          -  Patients >= 60 years of age with previously treated Ph-positive ALL, after 1-2 courses
             of chemotherapy with or without other TKIs. Patients < 60 years of age may be enrolled
             if they are considered unfit for intensive chemotherapy. If they achieved CR, they are
             assessable only for event-free and overall survival, or If they failed to achieve CR,
             they are assessable for CR, event-free, and overall survival

          -  Patients >= 18 years of age with relapsed/refractory Ph-positive ALL or lymphoid
             accelerated or blast phase CML

          -  Performance status =< 2 (Eastern Cooperative Oncology Group [ECOG] scale)

          -  Total serum bilirubin =< 2 x upper limit of normal (ULN), unless due to Gilbert's
             syndrome

          -  Alanine aminotransferase (ALT) =< 3 x ULN

          -  Aspartate aminotransferase (AST) =< 3 x ULN

          -  Serum lipase and amylase =< 1.5 x ULN

          -  Creatinine =< 2.0 mg/dl

          -  Female patients who: are postmenopausal for at least 1 year before the screening
             visit, OR are surgically sterile, OR if they are of childbearing potential, agree to
             practice 2 effective methods of contraception, at the same time, from the time of
             signing the informed consent through 4 months after the last dose of study drug, or
             agree to completely abstain from heterosexual intercourse

          -  Male patients, even if surgically sterilized (i.e., status post-vasectomy), who: agree
             to practice effective barrier contraception during the entire study treatment period
             and through 4 months after the last dose of study drug, or agree to completely abstain
             from heterosexual intercourse

          -  Adequate cardiac function as assessed clinically by history and physical examination

          -  Signed informed consent

        Exclusion Criteria:

          -  Active serious infection not controlled by oral or intravenous antibiotics

          -  Active hepatitis B. Patients with chronic hepatitis B who are on appropriate viral
             suppressive therapy may be allowed after discussion with the principal investigator
             (PI)

          -  History of acute pancreatitis within 1 year of study or history of chronic
             pancreatitis

          -  History of alcohol abuse

          -  Uncontrolled hypertriglyceridemia (triglycerides > 450mg/dL)

          -  Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or
             squamous cell carcinoma) that in the investigator's opinion will shorten survival to
             less than 1 year

          -  Active grade III-V cardiac failure as defined by the New York Heart Association
             criteria

          -  Uncontrolled, or active cardiovascular disease, specifically including, but not
             restricted to: myocardial infarction (MI), stroke, or revascularization; unstable
             angina or transient ischemic attack; congestive heart failure prior to enrollment, or
             left ventricular ejection fraction (LVEF) less than lower limit of normal per local
             institutional standards prior to enrollment; diagnosed or suspected congenital long QT
             syndrome; clinically significant atrial or ventricular arrhythmias as determined by
             the treating physician; prolonged corrected QT (QTc) interval on pre-entry
             electrocardiogram (> 470 msec) unless corrected after electrolyte replacement.
             Significant venous thromboembolism including deep venous thrombosis or pulmonary
             embolism. Uncontrolled hypertension (diastolic blood pressure > 90 mmHg; systolic >
             140mmHg). Patients with hypertension should be under treatment on study entry to
             effect blood pressure control

          -  Any history of venous thromboembolism including deep venous thrombosis or pulmonary
             embolism; uncontrolled hypertension (diastolic blood pressure > 90mmHg; systolic >
             140mmHg). Patients with hypertension should be under treatment on study entry to
             effect blood pressure control

          -  Taking any medications or herbal supplements that are known to be strong inhibitors of
             CYP3A4 within at least 14 days before the first dose of ponatinib

          -  Treatment with any investigational antileukemic agents or chemotherapy agents in the
             last 7 days before study entry, unless full recovery from side effects has occurred or
             patient has rapidly progressive disease judged to be life-threatening by the
             investigator

          -  Pregnant and lactating women will not be eligible; women of childbearing potential
             should have a negative pregnancy test prior to entering on the study and be willing to
             practice methods of contraception. Women do not have childbearing potential if they
             have had a hysterectomy or are postmenopausal without menses for 12 months. In
             addition, men enrolled on this study should understand the risks to any sexual partner
             of childbearing potential and should practice an effective method of birth control

          -  History of significant bleeding disorder unrelated to cancer, including: diagnosed
             congenital bleeding disorders (e.g., von Willebrand's disease); and diagnosed acquired
             bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)

          -  Patients with documented significant pleural or pericardial effusions unless they are
             thought to be secondary to their leukemia
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete molecular response (CMR) in newly diagnosed Philadelphia chromosome (Ph)-positive and/or BCR-ABL-positive participants
Time Frame:Up to 84 days (3 courses)
Safety Issue:
Description:The CMR rate within the first 3 courses for cohort 1 or rate within the first 2 courses for cohort 2 will be estimated along with the 95% credible intervals. Similar analyses will be performed for estimating the rate of complete cytogenetic response and major molecular response rates.

Secondary Outcome Measures

Measure:Complete cytogenetic response
Time Frame:Up to 6 years
Safety Issue:
Description:Will be estimated along with the 95% credible intervals.
Measure:CMR for relapsed/refractory population
Time Frame:Up to 6 years
Safety Issue:
Description:Will be estimated along with the 95% credible intervals.
Measure:Event-free survival (EFS)
Time Frame:From the first day of treatment until any failure (resistant disease, relapse, or death), assessed up to 6 years
Safety Issue:
Description:The Kaplan-Meier method will be used to assess EFS probabilities for each cohort.
Measure:Overall survival (OS)
Time Frame:From the first day of treatment to time of death from any cause, assessed up to 6 years
Safety Issue:
Description:The Kaplan-Meier method will be used to assess OS probabilities for each cohort.
Measure:Incidence of adverse events (AEs) per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0
Time Frame:Up to 6 years
Safety Issue:
Description:The proportion of patients with AEs will be estimated, along with the Bayesian 95% credible interval.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated