Clinical Trials /

Carfilzomib and Hyper-CVAD in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoma

NCT02293109

Description:

This phase I trial studies the side effects and best dose of carfilzomib when given together with the hyperfractionated (hyper)-cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (CVAD) chemotherapy regimen in treating patients with newly diagnosed acute lymphoblastic leukemia or lymphoma. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone, 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. Giving carfilzomib with combination chemotherapy may kill more cancer cells.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Lymphoblastic Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Carfilzomib and Hyper-CVAD in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoma
  • Official Title: Phase I Study of Escalating Doses of Carfilzomib With Hyper-CVAD in Patients With Newly Diagnosed Acute Lymphoblastic Leukemia/Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 660258
  • SECONDARY ID: UCDCC#246
  • SECONDARY ID: UCDCC#246
  • SECONDARY ID: NCI-2014-02245
  • NCT ID: NCT02293109

Conditions

  • Contiguous Stage II Adult Lymphoblastic Lymphoma
  • Noncontiguous Stage II Adult Lymphoblastic Lymphoma
  • Stage I Adult Lymphoblastic Lymphoma
  • Stage III Adult Lymphoblastic Lymphoma
  • Stage IV Adult Lymphoblastic Lymphoma
  • Untreated Adult Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
carfilzomibKyprolis, PR-171Treatment (carfilzomib and hyper-CVAD)
cyclophosphamideCPM, CTX, Cytoxan, Endoxan, EndoxanaTreatment (carfilzomib and hyper-CVAD)
vincristine sulfateleurocristine sulfate, VCR, Vincasar PFSTreatment (carfilzomib and hyper-CVAD)
doxorubicin hydrochlorideADM, ADR, AdriaTreatment (carfilzomib and hyper-CVAD)
dexamethasoneAeroseb-Dex, Decaderm, Decadron, DM, DXMTreatment (carfilzomib and hyper-CVAD)
methotrexateamethopterin, Folex, methylaminopterin, Mexate, MTXTreatment (carfilzomib and hyper-CVAD)
cytarabineARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U, cytosine arabinosideTreatment (carfilzomib and hyper-CVAD)
leucovorin calciumCF, CFR, LVTreatment (carfilzomib and hyper-CVAD)
methylprednisoloneDepo-Medrol, Medrol, MePRDL, Solu-Medrol, WyacortTreatment (carfilzomib and hyper-CVAD)
rituximabIDEC-C2B8, IDEC-C2B8 monoclonal antibody, Mabthera, MOAB IDEC-C2B8, RituxanTreatment (carfilzomib and hyper-CVAD)

Purpose

This phase I trial studies the side effects and best dose of carfilzomib when given together with the hyperfractionated (hyper)-cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (CVAD) chemotherapy regimen in treating patients with newly diagnosed acute lymphoblastic leukemia or lymphoma. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone, 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. Giving carfilzomib with combination chemotherapy may kill more cancer cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Safety and tolerability of administering carfilzomib in combination with hyper-CVAD
      chemotherapy.

      II. Recommended dose of carfilzomib in combination with hyper-CVAD chemotherapy for the
      future phase II trial.

      SECONDARY OBJECTIVES:

      I. Rate of remission after 2nd and 4th cycles. II. Incidence of minimal residual disease by
      flow cytometry at 4th cycle.

      OUTLINE: This is a dose escalation study of carfilzomib.

      Patients receive carfilzomib intravenously (IV) over 30 minutes on days 0, 1, 7, and 8.
      Patients also receive hyper-CVAD comprising cyclophosphamide IV over 2 hours every 12 hours
      for 6 doses beginning on day 1, vincristine sulfate IV on days 4 and 11, doxorubicin
      hydrochloride IV over 2-24 hours on day 4, and dexamethasone orally (PO) on days 1-4 and
      11-14 (courses 1 and 3) and methotrexate IV over 24 hours on day 1, cytarabine IV over 2
      hours every 12 hours for 4 doses starting on day 2, leucovorin calcium IV or PO every 6 hours
      beginning 36 hours after the start of methotrexate infusion, and methylprednisolone IV every
      12 hours for 6 doses beginning on day 1 (courses 2 and 4). Patients with cluster of
      differentiation (CD)20 positive disease also receive rituximab twice daily on days 1 and 11
      of courses 1 and 3 and days 1 and 8 of courses 2 and 4. Treatment repeats every 3-4 weeks for
      4 courses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 28 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (carfilzomib and hyper-CVAD)ExperimentalPatients receive carfilzomib IV over 30 minutes on days 0, 1, 7, and 8. Patients also receive hyper-CVAD comprising cyclophosphamide IV over 2 hours every 12 hours for 6 doses beginning on day 1, vincristine sulfate IV on days 4 and 11, doxorubicin hydrochloride IV over 2-24 hours on day 4, and dexamethasone PO on days 1-4 and 11-14 (courses 1 and 3) and methotrexate IV over 24 hours on day 1, cytarabine IV over 2 hours every 12 hours for 4 doses starting on day 2, leucovorin calcium IV or PO every 6 hours beginning 36 hours after the start of methotrexate infusion, and methylprednisolone IV every 12 hours for 6 doses beginning on day 1 (courses 2 and 4). Patients with CD20 positive disease also receive rituximab twice daily on days 1 and 11 of courses 1 and 3 and days 1 and 8 of courses 2 and 4. Treatment repeats every 3-4 weeks for 4 courses in the absence of disease progression or unacceptable toxicity.
  • carfilzomib
  • cyclophosphamide
  • vincristine sulfate
  • doxorubicin hydrochloride
  • dexamethasone
  • methotrexate
  • cytarabine
  • leucovorin calcium
  • methylprednisolone
  • rituximab

Eligibility Criteria

        Inclusion Criteria:

          -  Understand and voluntarily sign an informed consent form

          -  Able to adhere to the study visit schedule and other protocol requirements

          -  Newly diagnosed acute lymphoblastic leukemia/lymphoma

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (3 if it is directly
             disease related and is expected to get better if the acute lymphoblastic
             leukemia/lymphoma [ALL] is under control)

          -  Left ventricular ejection fraction (LVEF) > 40%

          -  Total bilirubin =< 3 mg/dL

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.5 x
             upper limit of normal

          -  Creatinine clearance (CrCl) >= 45 mL/minute within 7 days prior to enrollment either
             measured or calculated using a standard formula (eg, Cockcroft and Gault); in cases
             that creatinine clearance cannot be measured accurately, 24 hour urine can be used

          -  Disease free of other malignancies beside the ALL at the time of the study

          -  Male subjects must agree to practice contraception

          -  Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
             test with a sensitivity of at least 50 mIU/mL within 24 hours prior to the initiation
             of the study and they must agree to ongoing pregnancy testing and to practice
             contraception

        Exclusion Criteria:

          -  Any serious medical condition, laboratory abnormality, or psychiatric illness that
             would prevent the subject from signing the informed consent form

          -  Pregnant or breast feeding females

          -  Active congestive heart failure (New York Heart Association [NYHA] class III to IV),
             symptomatic ischemia, or conduction abnormalities uncontrolled by conventional
             intervention

          -  Unstable angina or myocardial infarction within 6 months prior to enrollment, NYHA
             class III or IV heart failure, uncontrolled angina, history of severe coronary artery
             disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or
             electrocardiographic evidence of acute ischemia or grade 3 conduction system
             abnormalities unless subject has a pacemaker

          -  Uncontrolled hypertension, uncontrolled pulmonary hypertension or uncontrolled
             diabetes within 14 days prior to enrollment

          -  Subjects with pleural effusions requiring thoracentesis or ascites requiring
             paracentesis within 14 days prior to enrollment

          -  Any condition, including the presence of laboratory abnormalities, which places the
             subject at unacceptable risk if he/she were to participate in the study or confounds
             the ability to interpret data from the study

          -  Use of any other experimental drug or therapy within 14 days of baseline

          -  Known history of allergy to Captisol®

          -  Known sero-positive for active viral infection with human immunodeficiency virus
             (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV); patients who are
             sero-positive because of hepatitis B virus vaccine are eligible

          -  Breakpoint cluster region-Abelson positive (BCR-ABL +) patients will be excluded from
             the study
      
Maximum Eligible Age:64 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of carfilzomib with hyper-CVAD, defined as the dose that produces dose limiting toxicity in 17% or fewer (1/6) of patients, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4
Time Frame:Up to 56 days (after second course)
Safety Issue:
Description:The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by NCI CTCAE version 4.0) and nadir or maximum values for the laboratory measures, time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course.

Secondary Outcome Measures

Measure:Rate of remission
Time Frame:Up to 56 days (after second course)
Safety Issue:
Description:All responses will be reported. Response rate among patients with measurable disease will be summarized by exact binomial confidence intervals.
Measure:Rate of minimal residual disease (MRD) in bone marrow aspirate samples
Time Frame:Up to 56 days (after second course)
Safety Issue:
Description:MRD will be defined an aberrant expression of at least 2 antigens in comparison with the known patterns of antigen expression by normal maturing CD19 positive B-cells. A distinct cluster of at least 20 cells showing altered antigen expression will be characterized as an aberrant cell population.
Measure:Rate of MRD in bone marrow aspirate samples
Time Frame:Up to 112 days (after 4th course)
Safety Issue:
Description:MRD will be defined an aberrant expression of at least 2 antigens in comparison with the known patterns of antigen expression by normal maturing CD19 positive B-cells. A distinct cluster of at least 20 cells showing altered antigen expression will be characterized as an aberrant cell population.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of California, Davis

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