Clinical Trials /

Ibrutinib, Fludarabine Phosphate, Cyclophosphamide, and Obinutuzumab in Treating Patients With Chronic Lymphocytic Leukemia

NCT02629809

Description:

This phase II trial studies how well ibrutinib, fludarabine phosphate, cyclophosphamide, and obinutuzumab work in treating patients with chronic lymphocytic leukemia. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, 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 monoclonal antibodies, such as obinutuzumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving ibrutinib, fludarabine phosphate, cyclophosphamide, and obinutuzumab together may work better in treating chronic lymphocytic leukemia.

Related Conditions:
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ibrutinib, Fludarabine Phosphate, Cyclophosphamide, and Obinutuzumab in Treating Patients With Chronic Lymphocytic Leukemia
  • Official Title: First-Line Therapy With Ibrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (GA-101) (iFCG) for Patients With Chronic Lymphocytic Leukemia (CLL) With Mutated IGHV Gene and Non-Del(17p)

Clinical Trial IDs

  • ORG STUDY ID: 2015-0281
  • SECONDARY ID: NCI-2016-00016
  • SECONDARY ID: 2015-0281
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02629809

Conditions

  • Chronic Lymphocytic Leukemia
  • Immunoglobulin Heavy Chain Locus Variable Region Mutation
  • Small Lymphocytic Lymphoma

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 (iFCG)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (iFCG)
IbrutinibBTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765Treatment (iFCG)
ObinutuzumabAnti-CD20 Monoclonal Antibody R7159, GA-101, GA101, Gazyva, huMAB(CD20), R7159, RO 5072759Treatment (iFCG)

Purpose

This phase II trial studies how well ibrutinib, fludarabine phosphate, cyclophosphamide, and obinutuzumab work in treating patients with chronic lymphocytic leukemia. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, 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 monoclonal antibodies, such as obinutuzumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving ibrutinib, fludarabine phosphate, cyclophosphamide, and obinutuzumab together may work better in treating chronic lymphocytic leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Estimate therapeutic activity (achievement of complete remission [CR] or CR with
      incomplete marrow recovery [CRi] and bone marrow minimal residual disease [MRD] negativity
      after 3 courses) of first-line treatment with ibrutinib, fludarabine (fludarabine phosphate),
      cyclophosphamide, obinutuzumab (GA101) (iFCG) in patients with chronic lymphocytic leukemia
      (CLL) who have mutated immunoglobulin heavy chain variable region (IGHV) and
      non-del(chromosome 7, p arm [17p]) fluorescence in-situ hybridization (FISH).

      SECONDARY OBJECTIVES:

      I. Estimate the rate of conversion of bone marrow MRD-positive after 3 courses of iFCG to
      bone marrow MRD-negative with 9 additional courses of ibrutinib and obinutuzumab (iG).

      II. Determine the safety of this combination in the proposed patient population.

      III. Determine the progression-free survival (PFS). IV. Determine the overall survival (OS).
      V. Determine the long-term incidence of secondary myelodysplastic syndrome (MDS)/acute
      myeloid leukemia (AML), and Richter's transformation.

      VI. Perform ribonucleic acid (RNA) profiling to identify molecules responsible for response
      and/or relapse.

      VII. Investigate impact on breakpoint cluster region (BCR) pathway and deoxyribonucleic acid
      DNA damage response pathway proteins during therapy.

      OUTLINE:

      INDUCTION COURSE 1: Patients receive obinutuzumab intravenously (IV) over 4-6 hours on days
      1, 2, 8 and 15, fludarabine phosphate IV over 15 minutes and cyclophosphamide IV over 30
      minutes on days 2-4. Patients also receive ibrutinib orally (PO) once daily (QD) on days
      1-28.

      INDUCTION COURSES 2 and 3: Patients receive obinutuzumab IV over 4-6 hours on day 1,
      fludarabine phosphate IV over 15 minutes and cyclophosphamide IV over 30 minutes on days 1-3.
      Patients also receive ibrutinib PO QD on days 1-28.

      MAINTENANCE: Patients receive 1 of 5 maintenance regimens as determined by disease status.

      REGIMEN I COURSES 4 and 6: Patients achieving CR/CRi and bone marrow MRD-negative receive
      maintenance therapy comprising obinutuzumab IV over 4-6 hours on day 1, and ibrutinib PO QD
      on days 1-28. Treatment repeats every 28 days for up to 3 courses in the absence of disease
      progression or unacceptable toxicity.

      REGIMEN I COURSES 7 and 12: Patients remaining bone marrow MRD-negative receive maintenance
      therapy comprising ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 6
      courses in the absence of disease progression or unacceptable toxicity.

      REGIMEN I COURSES 7 and 12: Patients converting bone marrow MRD-positive receive maintenance
      therapy comprising obinutuzumab IV over 4-6 hours on day 1, and ibrutinib PO QD on days 1-28.
      Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or
      unacceptable toxicity.

      REGIMEN II COURSES 4 and 12: Patients achieving less than CR/CRi and/or bone marrow
      MRD-positive receive maintenance therapy comprising obinutuzumab IV over 4-6 hours on day 1,
      and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 9 courses in the
      absence of disease progression or unacceptable toxicity.

      REGIMEN II AFTER 12 COURSES: Patients still bone marrow MRD-positive receive maintenance
      therapy comprising ibrutinib PO QD on days 1-28. Treatment repeats every 28 days in the
      absence of disease progression or unacceptable toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (iFCG)ExperimentalSee Detailed Description.
  • Cyclophosphamide
  • Fludarabine Phosphate
  • Ibrutinib
  • Obinutuzumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with a diagnosis of CLL/small lymphocytic lymphoma (SLL), with mutated (> 2%
             deviation from germ line) IGHV gene, who meet criteria to initiate first-line
             treatment per International Workshop on CLL Working Group (IWCLL) 2008 guidelines

          -  Patients must not have received prior CLL-directed therapy

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Absolute neutrophil count > 500 mL

          -  Platelet count > 50,000/mL

          -  Serum total bilirubin =< 1.5 x upper limit of normal (ULN) or =< 3 x ULN for patients
             with Gilbert's disease

          -  Estimated creatinine clearance >= 30 mL/min (calculated or measured by 24 hour urine
             collection)

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN

          -  Women of childbearing potential must have a negative serum or urine beta human
             chorionic gonadotropin (beta-hCG) pregnancy test result within 14 days prior to the
             first dose of study drugs and must agree to use an effective contraception method
             during the study and for 30 days following the last dose of study drug; women of
             non-childbearing potential are those who are postmenopausal greater than 1 year or who
             have had a bilateral tubal ligation or hysterectomy; men who have partners of
             childbearing potential must agree to use an effective contraceptive method during the
             study and for 30 days following the last dose of study drug

          -  Free of prior malignancies for 3 years with exception of patients diagnosed with basal
             cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or
             breast, who are eligible even if they are currently treated or have been treated
             and/or diagnosed in the past 2 years prior to study enrolment; if patients have
             another malignancy that was treated within the last 2 years, such patients can be
             enrolled, after consultation with the principal investigator, if the likelihood of
             requiring systemic therapy for this other malignancy within 2 years is less than 10%,
             as determined by an expert in that particular malignancy at MD Anderson Cancer Center

          -  Patients or their legally authorized representative must provide written informed
             consent

          -  Prothrombin time (PT)/international normalization ratio (INR) < 1.5 x ULN

          -  Partial thromboplastin time (PTT) < 1.5 x ULN

          -  Activated partial thromboplastin time (aPTT) < 1.5 x ULN

        Exclusion Criteria:

          -  Major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy,
             experimental therapy within 3 weeks prior to the first dose of the study drugs and/or
             monoclonal antibody =< 6 weeks prior to first administration of study treatment

          -  Patients with del(17p) by FISH (or known tumor protein p53 [TP53] mutation)

          -  Patients with unmutated (=< 2% homology with germ line) IGHV

          -  Uncontrolled active systemic infection (viral, bacterial, and fungal)

          -  Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, QT
             prolongation or familial history of QT prolongation, congestive heart failure, or
             myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac
             disease as defined by the New York Heart Association Functional Classification

          -  History of stroke or cerebral hemorrhage within 6 months

          -  Patient is pregnant or breast-feeding

          -  Current or chronic hepatitis B or C infection, or known seropositivity for human
             immunodeficiency virus (HIV); subjects who are positive for hepatitis B or C core
             antibody or hepatitis B or C surface antigen must have a negative polymerase chain
             reaction (PCR) result before enrollment; those who are PCR positive will be excluded;
             Note: Patients who are receiving intravenous immunoglobulins may become seropositive
             for hepatitis B antibodies; these patients are allowed on the study without additional
             testing

          -  Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune
             thrombocytopenia) requiring steroid therapy

          -  Concurrent use of investigational therapeutic agent

          -  Patients may not receive other concurrent chemotherapy, radiotherapy, or
             immunotherapy; localized radiotherapy to an area not compromising bone marrow function
             does not apply

          -  Malabsorption syndrome or other condition that precludes enteral route of
             administration

          -  Concomitant use of warfarin or other vitamin K antagonists

          -  Requires treatment with a strong cytochrome P450 (CYP), family 3, subfamily A (3A)
             inhibitor

          -  Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that in the opinion of the investigator may increase the risk associated
             with study participation or investigational product administration or may interfere
             with the interpretation of study results and/or would make the patient inappropriate
             for enrollment into this study

          -  Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Efficacy of the combination of ibrutinib, fludarabine phosphate, cyclophosphamide, and obinutuzumab defined as achievement of complete remission/complete remission with incomplete marrow recovery and bone marrow minimal residual disease-negative status
Time Frame:84 days
Safety Issue:
Description:Simon's optimal two-stage design will be employed. The proportion of patients achieving complete remission/complete remission with incomplete marrow recovery and bone marrow minimal residual disease-negative will be estimated along with the 95% confidence interval.

Secondary Outcome Measures

Measure:Bone marrow minimal residual disease-negative status
Time Frame:84 days
Safety Issue:
Description:Will estimate the proportion of patients achieving bone marrow minimal residual disease negative, along with the 95% confidence interval. For the patients who did not achieve primary endpoint after 3 courses of ibrutinib, fludarabine phosphate, cyclophosphamide, obinutuzumab, will estimate the rate of conversion to bone marrow minimal residual disease-negative with an additional 9 courses of ibrutinib and obinutuzumab treatment, along with the 95% confidence interval.
Measure:Incidence of treatment emergent toxicities using a Bayesian design by Thall, Simon and Estey assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03
Time Frame:From the prior chemotherapy course to up to 84 days
Safety Issue:
Description:Toxicities are defined as (prolonged grade >= 3 neutropenia or thrombocytopenia) at least possibly related to the study drugs lasting > 42 days from the prior chemotherapy course; febrile neutropenia; hospitalization due to infection; early death (within first 30 days of starting treatment). Safety data will be summarized using frequency and percentage, by organ type, grade and attribution.
Measure:Progression-free survival
Time Frame:Up to 6 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate the probabilities of progression-free survival.
Measure:Overall survival
Time Frame:Up to 6 years
Safety Issue:
Description:Log-rank tests will be used to compare subgroups of patients in terms of overall survival.
Measure:Long-term incidence rate of secondary myelodysplastic syndrome/acute myeloid leukemia
Time Frame:Up to 6 years
Safety Issue:
Description:Long-term incidence rate of secondary myelodysplastic syndrome/acute myeloid leukemia will be estimated along with 95% confidence interval.
Measure:Long-term incidence rate of Richter's transformation
Time Frame:Up to 6 years
Safety Issue:
Description:Long-term incidence rate of Richter's transformation will be estimated along with 95% confidence interval.
Measure:Rate of complete remission (CR)/CR with incomplete marrow recovery (CRi) in subgroups of patients defined by fluorescence in situ hybridization (FISH) subtypes
Time Frame:Up to 6 years
Safety Issue:
Description:Will also assess if the combination therapy results in improvement in the rate of CR/CRi in subgroups of patients defined by FISH subtypes.

Details

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

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