Clinical Trials /

Low-Intensity Chemotherapy, Ponatinib and Blinatumomab 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 and blinatumomab, 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, ponatinib, and blinatumomab may work better in treating patients with acute lymphoblastic leukemia.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Chronic Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Acute Lymphoblastic Leukemia
  • Official Title: Phase II Study of the Sequential Combination of Low-Intensity Chemotherapy and Ponatinib Followed by Blinatumomab 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
BlinatumomabAnti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody, Anti-CD19/Anti-CD3 Recombinant Bispecific Monoclonal Antibody MT103, Blincyto, MEDI-538, MT-103Treatment (chemotherapy, ponatinib, blinatumomab)
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, blinatumomab)
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, blinatumomab)
FilgrastimG-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, TevagrastimTreatment (chemotherapy, ponatinib, blinatumomab)
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, blinatumomab)
PegfilgrastimFilgrastim SD-01, filgrastim-SD/01, Fulphila, HSP-130, Jinyouli, Neulasta, Neulastim, Pegfilgrastim Biosimilar HSP-130, Pegfilgrastim Biosimilar Pegcyte, SD-01, SD-01 sustained duration G-CSFTreatment (chemotherapy, ponatinib, blinatumomab)
PonatinibAP-24534, AP24534Treatment (chemotherapy, ponatinib, blinatumomab)
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, rituximab biosimilar TQB2303, rituximab-abbs, RTXM83, TruximaTreatment (chemotherapy, ponatinib, blinatumomab)
VincristineLEUROCRISTINE, VCR, VincrystineTreatment (chemotherapy, ponatinib, blinatumomab)

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 and blinatumomab, 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, ponatinib, and blinatumomab may work better in treating patients with acute lymphoblastic leukemia.

Detailed Description

      Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the complete molecular response (CMR) rate of ponatinib and blinatumomab in
      combination with low-intensity chemotherapy in patients with newly diagnosed Philadelphia
      chromosome (Ph)-positive and/or BAR-ABL-positive acute lymphoblastic leukemia (ALL). (Cohort
      1) II. To evaluate the overall response (OR; complete response [CR] + complete response with
      hematologic improvement [CRi]) in patients with relapsed/refractory disease. (Cohort 2)

      SECONDARY OBJECTIVES:

      I. To evaluate other clinical efficacy endpoints (complete cytogenetic response, complete
      molecular response [CMR] [for relapsed/refractory population], event-free survival and
      overall survival) and safety of the combination regimen.

      EXPLORATORY OBJECTIVES:

      I. To characterize the role of ABL1 kinase domain mutations on treatment failure and relapse
      in patients with Ph+ ALL treated with hyper-CVD plus ponatinib and blinatumomab.

      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 and blinatumomab.

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

      IV. To determine the effect on immune cell subsets in patients with Ph+ ALL treated with
      blinatumomab plus ponatinib.

      OUTLINE:

      CYCLES 1 and 3: Patients receive ponatinib orally (PO) once daily (QD) on days 1-21 of cycle
      1 and on days 1-28 of subsequent cycles, cyclophosphamide intravenously (IV) twice daily
      (BID) over 3 hours on days 1-3, rituximab IV over 4-6 hours on days 1 and 11, vincristine IV
      over 15 minutes on days 1 and 11, and pegfilgrastim or filgrastim subcutaneously (SC) daily
      on day 4. Patients also receive methotrexate intrathecally via spinal tap on day 2 and
      cytarabine intrathecally on day 7 in the absence of disease progression or unacceptable
      toxicity.

      CYCLES 2 and 4: Patients receive ponatinib PO QD on days 1-28, methotrexate IV over 24 hours
      on day 1 and intrathecally on day 8, cytarabine IV BID over 2-3 hours on days 2 and 3 and
      intrathecally on day 5, pegfilgrastim or filgrastim SC daily on day 4, and rituximab IV over
      4-6 hours on days 1 and 8 in the absence of disease progression or unacceptable toxicity.

      CYCLES 5-8: Patients receive blinatumomab via central catheter continuously over weeks 1-4
      every 6 weeks. Patients also receive methotrexate intrathecally on day 2 of cycle 5 and on
      day 8 of cycle 6 and cytarabine intrathecally on day 7 of cycle 5 and on day 5 of cycle 6 in
      the absence of disease progression or unacceptable toxicity.

      MAINTENANCE THERAPY:

      CYCLES 1-3, 5-7, 9-11, and 13-15: After c 4 cycles of blinatumomab, if disease has not 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.

      CYCLES 4, 8, and 12: Patients receive blinatumomab via central catheter continuously over
      weeks 1-4 every 6 weeks and ponatinib PO QD on days 1-28.

      Treatment repeats every 28 days for up to 15 cycles in the absence of disease progression or
      unacceptable toxicity. Patients unable to receive blinatumomab, you may receive maintenance
      therapy with vincristine, prednisone, and ponatinib for a total of about 24 cycles at the
      discretion of doctor.

      POST-MAINTENANCE THERAPY: Patients receive ponatinib PO QD on days 1-28. Cycles repeat every
      28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days and then every 6
      months thereafter.
    

Trial Arms

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

Eligibility Criteria

        Inclusion Criteria:

          -  Patients >= 18 years of age with previously untreated Ph-positive ALL (either t(9;22)
             and/or BCR-ABL positive) (includes patients initiated on first cycle of hyper-CVAD
             before cytogenetics known. These patients could have received one or two cycles of
             chemotherapy with or without other TKIs and still eligible. 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 or 3) Patients >= 18
             years of age with relapsed/refractory Ph-positive ALL or lymphoid accelerated or blast
             phase chronic myelogenous leukemia (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

          -  Known 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 within 3
             months; 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. or approved by cardiologist; Significant venous or arterial
             thromboembolism including deep venous thrombosis or pulmonary embolism. Patients with
             a history of treated prior superficial or catheter associated phlebitis will not be
             considered as significant embolism and after discussion with principal investigator
             (PI) will not be excluded from eligibility. Uncontrolled hypertension (diastolic blood
             pressure > 90 mmHg; 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 or 5 half-lives before the first dose of ponatinib in
             patients with newly diagnosed only

          -  History or presence of clinically relevant central nervous system (CNS) pathology such
             as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain
             injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome,
             or psychosis. Patients with active CNS leukemia will NOT be excluded

          -  Current autoimmune disease or history of autoimmune disease with potential CNS
             involvement

          -  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)
Time Frame:Up to 6 years
Safety Issue:
Description:Will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0. 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

June 11, 2020