Clinical Trials /

Selinexor and Ibrutinib in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Aggressive Non-Hodgkin Lymphoma

NCT02303392

Description:

This phase I trial studies the side effects and best dose of selinexor when given together with ibrutinib in treating patients with chronic lymphocytic leukemia or aggressive non-Hodgkin lymphoma that has returned after a period of improvement or does not respond to treatment. Drugs used in chemotherapy, such as selinexor, 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. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving selinexor together with ibrutinib may be a better treatment for chronic lymphocytic leukemia or aggressive non-Hodgkin lymphoma.

Related Conditions:
  • B-Cell Prolymphocytic Leukemia
  • Chronic Lymphocytic Leukemia
  • Diffuse Large B-Cell Lymphoma
  • Mantle Cell Lymphoma
  • Small Lymphocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Selinexor and Ibrutinib in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Aggressive Non-Hodgkin Lymphoma
  • Official Title: A Dose Escalation Study of Selinexor (KPT-330), a Selective Inhibitor of Nuclear Export, and Ibrutinib, a Bruton's Tyrosine Kinase Inhibitor, in Patients With Relapsed and Refractory Chronic Lymphocytic Leukemia or Aggressive Non-Hodgkin Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: OSU-14087
  • SECONDARY ID: NCI-2014-01493
  • SECONDARY ID: R01CA192928
  • SECONDARY ID: P30CA016058
  • NCT ID: NCT02303392

Conditions

  • Prolymphocytic Leukemia
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Chronic Lymphocytic Leukemia

Interventions

DrugSynonymsArms
SelinexorCRM1 Nuclear Export Inhibitor KPT-330, KPT-330, Selective Inhibitor of Nuclear Export KPT-330, SINE KPT-330Treatment (selinexor, ibrutinib)
IbrutinibBTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765Treatment (selinexor, ibrutinib)

Purpose

This phase I trial studies the side effects and best dose of selinexor when given together with ibrutinib in treating patients with chronic lymphocytic leukemia or aggressive non-Hodgkin lymphoma that has returned after a period of improvement or does not respond to treatment. Drugs used in chemotherapy, such as selinexor, 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. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving selinexor together with ibrutinib may be a better treatment for chronic lymphocytic leukemia or aggressive non-Hodgkin lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose for the combination of selinexor and ibrutinib in
      patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic
      leukemia(SLL)/B-cell prolymphocytic leukemia (PLL) or aggressive non-Hodgkin lymphoma (NHL).

      SECONDARY OBJECTIVES:

      I. To characterize the safety and tolerability of the combination of selinexor and ibrutinib
      in patients with relapsed or refractory CLL/SLL/PLL or aggressive NHL.

      II. To characterize the pharmacokinetic (PK) properties of the combination of selinexor and
      ibrutinib in patients with relapsed or refractory CLL/SLL/PLL or aggressive NHL.

      III. To obtain preliminary evidence on efficacy of the combination of selinexor and ibrutinib
      in patients with relapsed or refractory CLL/SLL/PLL or aggressive NHL.

      IV. To obtain preliminary evidence of response in CLL/SLL/PLL and diffuse large B-cell
      lymphoma (DLBCL) patients receiving the combination of selinexor and ibrutinib as related to
      CLL/SLL/PLL karyotype and immunoglobulin variable heavy chain (IgVH) mutational status and
      DLBCL subtype, respectively.

      V. To evaluate the inhibition of the B-cell receptor signaling pathway in patients with
      relapsed or refractory CLL/SLL/PLL who receive the combination of selinexor and ibrutinib.

      VI. To evaluate the change in localization of tumor suppressor and growth regulation proteins
      in patients with relapsed or refractory CLL/SLL/PLL following treatment with selinexor in
      general and as related to response.

      VII. To preliminarily assess potential causes for primary and secondary resistance to
      selinexor and ibrutinib.

      VIII. To measure intracellular levels of selinexor and metabolites in peripheral blood
      mononuclear cells and to identify how this relates to pharmacodynamics effects and clinical
      outcomes.

      OUTLINE: This is a dose-escalation study of selinexor.

      Patients receive ibrutinib orally (PO) on days 8-28 of course 1 and on days 1-28 on
      subsequent courses and selinexor PO twice daily (BID) weekly on day 1 or bi-weekly on days 1
      and 3. Courses repeat every 28 days in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up at 4 weeks and then every 6
      months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (selinexor, ibrutinib)ExperimentalPatients receive ibrutinib PO on days 8-28 of course 1 and on days 1-28 on subsequent courses and selinexor PO BID weekly on day 1 or bi-weekly on days 1 and 3. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Selinexor
  • Ibrutinib

Eligibility Criteria

        Inclusion Criteria:

          -  A histologically confirmed diagnosis of CLL according the International Workshop on
             CLL/SLL/B-cell PLL or variant of these (IWCLL or World Health Organization [WHO]
             Criteria) and meet criteria for treatment or have need for cytoreduction for stem cell
             transplantation or alternative cell therapy; OR

          -  A histologically confirmed diagnosis of mantle cell lymphoma (MCL) or diffuse large
             B-cell lymphoma (DLBCL) de novo or in the setting of transformation from an indolent
             lymphoma (including DLBCL not otherwise specified) according to the World Health
             Organization criteria for diagnosis of NHL; AND

          -  Patients must have received at least one prior therapy for CLL or NHL, need additional
             treatment, and meet criteria for relapsed or refractory disease; they may not be a
             candidate for curative therapy; relapsed disease is defined as a patient who
             previously achieved a complete remission (CR) or a partial remission (PR), but after a
             period of six or more months demonstrates evidence of disease progression; refractory
             disease is defined as progression within six months of the last anti-leukemic or
             anti-lymphoma therapy, or any response less than a CR or PR

          -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
             =< 2

          -  Patients with NHL must have objective, documented evidence of disease prior to study
             entry

          -  Platelet count >= 50,000/mm^3 in the absence of bone marrow involvement; patients with
             bone marrow involvement only require a platelet count of 30,000/mm^3

          -  Absolute neutrophil count >= 1000/mm^3 in the absence of bone marrow involvement

          -  Creatinine clearance (as calculated by Cockroft Gault equation = [140-age] * mass
             [kg]/[72 * creatinine mg/dL) >= 30mL/min

          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 2.5 times upper
             limit of normal (ULN)

          -  Total bilirubin =< 2.0 x ULN

          -  Female patients capable of reproduction and male patients who have partners capable of
             reproduction must agree to use an effective contraceptive method during the course of
             the study and for 2 months following the completion of their last treatment

          -  Female of childbearing potential must have a negative serum beta-human chorionic
             gonadotropin (HCG) pregnancy test result within 3 days of first study dose; female
             patients who are surgically sterilized or who are > 45 years old and have not
             experienced menses for > 2 years may have beta-HCG pregnancy test waived

          -  Patients who are hepatitis B polymerase chain reaction (PCR) negative who have a
             recent (< 6 month) history of intravenous immunoglobulin (IVIG) therapy are eligible;
             patients with a history of hepatitis B (surface antigen or core antibody positive and
             PCR positive) must take lamivudine or equivalent drug during study therapy and for one
             year after completion of all therapy; patients on IVIG who are core antibody positive
             but PCR negative are not mandated to take prophylaxis

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Patients who are concurrently receiving any other investigational agents

          -  Patients who have received:

               -  Radiation or chemotherapy =< 4 weeks

               -  Mitomycin C, nitrosureas, or radio-immunotherapy =< 6 weeks, or

               -  Immunotherapy or targeted therapy (such as kinase inhibitors) =< 2 weeks prior to
                  cycle 1 day 1(except patients already on ibrutinib)

               -  Palliative steroids for disease related symptoms are allowed as long as dose is
                  tapered down to an equivalent of =< 10 mg of oral prednisone daily on cycle 1 day
                  1

          -  Patients who have underwent autologous or allogeneic stem cell transplant =< 4 weeks
             prior to cycle 1 day 1 or have active graft-versus-host disease are excluded

          -  Patients unable to swallow capsules, those with uncontrolled vomiting or diarrhea or
             disease significantly affecting gastrointestinal function and/or inhibiting small
             intestine absorption such as: malabsorption syndrome, resection of the small bowel, or
             poorly controlled inflammatory bowel disease affecting the small intestine

          -  Patients who are 20% below their ideal body weight

          -  Patients must not be receiving systemic anticoagulation with warfarin; patients must
             be off warfarin for 30 days prior to enrollment; patients who require anticoagulation
             with an agent other than warfarin will not be excluded, but must be reviewed by the
             principal investigator prior to enrollment

          -  As ibrutinib is extensively metabolized by cytochrome P450, family 3, subfamily A,
             polypeptide 4/5 (CYP3A4/5), and patients must not require continued therapy with a
             strong inhibitor or inducer of CYP3A4/5

          -  Patients with active human immunodeficiency virus (HIV) or hepatitis B or C

          -  Patients with secondary malignancy that requires active systemic therapy that will
             interfere with interpretation of efficacy or toxicity of selinexor; (Note: patients
             with basal or squamous skin carcinoma, cervical carcinoma in situ, localized breast
             cancer requiring hormonal therapy or localized prostate cancer (Gleason score < 5 are
             allowed)

          -  Patients with active known central nervous system (CNS) involvement of CLL or
             lymphoma; (patients with history of CNS CLL or lymphoma now in remission are eligible
             for the trial)

          -  Patients who are pregnant or breast feeding; breastfeeding should be discontinued if
             the mother is treated with selinexor

          -  Patients must have recovered all toxicities from prior therapy or radiation to grade 1
             or less (excluding alopecia)

          -  Patients may not have had major surgery within 10 days of enrollment, or minor surgery
             within 7 days of enrollment; examples of minor surgery include dental surgery,
             insertion of a venous access device, skin biopsy, or aspiration of a joint; the
             decision about whether a surgery is major or minor can be made at the discretion of
             the treating physician

          -  Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
             or active infection, symptomatic congestive heart failure, unstable angina pectoris,
             cardiac arrhythmia, or psychiatric illness/social situations that would limit
             compliance with study requirements

          -  Patients with markedly decreased visual acuity
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicity assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4 criteria
Time Frame:Day 28
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Incident of toxicity graded by CTCAE V4
Time Frame:Up to 4 years
Safety Issue:
Description:Toxicities will be tabulated by type and grade and displayed in summary form. In addition, the number of courses started/completed, number of patients requiring dose reductions, and the reason for going off treatment may be summarized to assess treatment tolerability.
Measure:Clinical response defined as those with CR or PR measured by International Working Group Criteria for NHL patients and IWCLL 2008 guidelines for CLL patients
Time Frame:Up to 4 years
Safety Issue:
Description:The degree of response will be summarized within each stratum and at each dose level.
Measure:Overall response rate (ORR)
Time Frame:Up to 4 years
Safety Issue:
Description:Calculated as the number of evaluable responders divided by the total number of evaluable patients. ORR will be presented for those patients treated at the maximum tolerated dose with an exact 90 % confidence interval.
Measure:Progression free survival (PFS)
Time Frame:Date of study enrollment to disease progression or death, whichever occurs first assessed up to 4 years
Safety Issue:
Description:Kaplan-Meier curves and lifetables of PFS will be generated for each stratum. The 1-year point estimates of PFS will be presented along with standard error.
Measure:Overall Survival (OS)
Time Frame:Date of study enrollment to death assessed up to 4 years
Safety Issue:
Description:Kaplan-Meier curves and lifetables of OS will be generated for each stratum. The 1-year point estimates of OS will be presented along with standard error.
Measure:Response as related to CLL karyotype mutational status
Time Frame:Up to 4 years
Safety Issue:
Description:
Measure:Response as related to IgVH mutational status
Time Frame:Up to 4 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Jennifer Woyach

Last Updated

March 25, 2019