Clinical Trials /

Ibrutinib and Ixazomib Citrate in Treating Participants With Relapsed or Refractory Waldenstrom Macroglobulinemia

NCT03506373

Description:

This phase II trial studies the side effects of ibrutinib citrate when given with ixazomib, and determines how well they work in treating participants with Waldenstrom macroglobulinemia that has come back or does not respond to treatment. Enzyme inhibitors, such as ibrutinib and ixazomib citrate, may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Waldenstrom Macroglobulinemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ibrutinib and Ixazomib Citrate in Treating Participants With Relapsed or Refractory Waldenstrom Macroglobulinemia
  • Official Title: Phase II Study of Ibrutinib in Combination With Ixazomib in Patients With Waldenstr?m Macroglobulinemia

Clinical Trial IDs

  • ORG STUDY ID: MC178B
  • SECONDARY ID: NCI-2018-00595
  • SECONDARY ID: MC178B
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03506373

Conditions

  • Recurrent Waldenstrom Macroglobulinemia
  • Refractory Waldenstrom Macroglobulinemia

Interventions

DrugSynonymsArms
IbrutinibBTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765Treatment (ixazomib citrate, ibrutinib)
Ixazomib CitrateMLN-9708, MLN9708, NinlaroTreatment (ixazomib citrate, ibrutinib)

Purpose

This phase II trial studies the side effects of ibrutinib citrate when given with ixazomib, and determines how well they work in treating participants with Waldenstrom macroglobulinemia that has come back or does not respond to treatment. Enzyme inhibitors, such as ibrutinib and ixazomib citrate, may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the efficacy (as assessed by complete response [CR] rate) of the combination
      of ixazomib citrate (ixazomib) and ibrutinib in Waldenstrom macroglobulinemia (WM) patients.

      SECONDARY OBJECTIVES:

      I. To assess the overall response rate (ORR=partial response [PR] or better) in WM patients
      treated with ixazomib and ibrutinib.

      II. To assess the time to progression (TTP) in WM patients treated with ixazomib and
      ibrutinib.

      III. To further characterize the safety and toxicity of the combination of ibrutinib and
      ixazomib.

      IV. To assess the overall survival (OS) in WM patients treated with ixazomib and ibrutinib.

      CORRELATIVE OBJECTIVES:

      I. To determine the role of members of the BTK signalosome in achievement or lack thereof of
      response to ibrutinib and ixazomib.

      II. To explore biologic effects of ibrutinib and ixazomib on microenvironment in WM and
      correlate with response to treatment.

      III. Effect of ibrutinib+ixazomib on platelet aggregation. IV. To evaluate the clinical
      pharmacokinetics of the drug combination.

      OUTLINE:

      Participants receive ixazomib citrate orally (PO) on days 1, 8, and 15 and ibrutinib PO daily
      on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, participants are followed up every 3 months for up to 2
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ixazomib citrate, ibrutinib)ExperimentalParticipants receive ixazomib citrate PO on days 1, 8, and 15 and ibrutinib PO daily on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
  • Ibrutinib
  • Ixazomib Citrate

Eligibility Criteria

        Inclusion Criteria:

          -  Histological confirmation of WM for which the patient has received at least one prior
             treatment; patients may have relapsed or refractory disease;(definition: relapse;
             patients who have received prior treatment for WM and now have disease recurrence;
             refractory; patients who have received anti-WM therapy and are noted to have
             progressive disease while on therapy, or those patients who demonstrated disease
             progression within 6 months of the last anti-WM treatment)

          -  Presence of measurable disease as defined by: presence of immunoglobulin M (IgM)
             paraprotein, measurable lymphadenopathy on imaging studies and/or physical exam,
             and/or bone marrow infiltration > 10%

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2

          -  Obtained ? 14 days prior to registration: absolute neutrophil count (ANC) ? 1000/mm^3

          -  Obtained ? 14 days prior to registration: platelet count ? 75,000/mm^3 (NOTE: platelet
             transfusions in order to help patients meet eligibility criteria are not allowed)

          -  Obtained ? 14 days prior to registration: hemoglobin ? 9.0 g/dL

          -  Obtained ? 14 days prior to registration: total bilirubin ? 1.5 x upper limit of
             normal (ULN) unless due to Gilbert?s syndrome, in which case the direct bilirubin must
             be ? 1.5 x ULN

          -  Obtained ? 14 days prior to registration: aspartate transaminase (AST) and alanine
             aminotransferase (ALT) ? 3 x ULN

          -  Obtained ? 14 days prior to registration: calculated creatinine clearance must be ? 30
             ml/min using the Cockcroft Gault formula

          -  Negative pregnancy test done at screening and ? 3 days (72 hours) prior to
             registration, for women of childbearing potential

          -  Provide written informed consent

          -  Willingness to provide mandatory blood specimens and bone marrow specimens for
             correlative research

          -  Willingness to return to enrolling institution for follow-up

        Exclusion Criteria:

          -  Failure to have fully recovered (i.e., ? grade 1 toxicity) from the reversible effects
             of prior treatment for WM

          -  Major surgical procedure (including open biopsy, excluding central line intravenous
             (IV) and port-a-cath placement) within ? 14 days prior to initiating study treatment,
             or anticipation of the need for major surgery during the course of the study treatment

          -  Radiotherapy ? 14 days prior to registration; if the involved field is small, 7 days
             will be considered a sufficient interval between treatment and administration of the
             ixazomib

          -  Systemic treatment, ? 14 days before registration, with strong CYP3A inducers
             (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or St.
             John?s wort

          -  Systemic anti-cancer therapy or participation in other clinical trials, including
             those with other investigational agents not included in this trial, ? 28 days of
             registration and throughout the duration of active treatment in this trial

          -  Patients that have previously been treated with ixazomib, or participated in a study
             with ixazomib whether treated with ixazomib or not; (NOTE: prior ibrutinib treatment
             is allowed as per: patients with prior exposure to ibrutinib will be allowed if they
             do not have disease refractory to ibrutinib; patient receiving ibrutinib will be
             allowed on this trial if they have measurable disease and did not have disease
             progression while receiving ibrutinib; prior bortezomib treatment is allowed as per:
             patients with prior exposure to bortezomib will be allowed if they do not have disease
             refractory to bortezomib)

          -  Central nervous system involvement (Bing-Neel syndrome)

          -  Infection requiring systemic antibiotic therapy or other serious infection ? 7 days
             prior to registration

          -  Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
             hypertension, serious cardiac arrhythmia requiring medication (other than adequately
             rate-controlled atrial fibrillation), symptomatic congestive heart failure, unstable
             angina, stroke/transient ischemic attack (TIA) within the past 6 months or myocardial
             infarction within the past 6 months

          -  Known allergy to any of the study medications, their analogues, or excipients in the
             various formulations of any agent

          -  Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
             absorption or tolerance of ixazomib or ibrutinib, including difficulty swallowing

          -  History of any other prior malignancy; (NOTE: Exception to this are adequately treated
             non-melanoma skin cancers, any in situ cancer, adequately treated stage I or II cancer
             from which the patient is currently in complete remission, or any other cancer from
             which the patient has been disease free for at least two years prior to study
             enrollment)

          -  Patient has ? grade 2 peripheral neuropathy or grade 1 peripheral neuropathy with pain
             on clinical examination during the screening period

          -  Any of the following

               -  Pregnant women

               -  Nursing women

               -  Men or women of child bearing potential (WCBP) who are unwilling to employ
                  effective contraception; effective contraception would be defined as utilizing 2
                  simultaneous methods of contraception from the time of signing consent through 90
                  days after the last dose of the study drugs unless they agree to participate in
                  true abstinence when this is in line with the preferred and usual lifestyle of
                  the subject; (women of child bearing potential [WCBP]: a female who is sexually
                  mature and who: [1] has not undergone a hysterectomy or bilateral oophorectomy;
                  or [2] has not been naturally postmenopausal for at least 24 consecutive months
                  [i.e., has had menses at any time in the preceding 24 consecutive months])

          -  Evidence of any other serious medical condition (such as psychiatric illness,
             infectious diseases, physical or laboratory findings) that may interfere with the
             planned treatment, affect compliance or place the patient at high risk from
             treatment-related complications or potentially interfere with the completion of the
             treatment as per the protocol

          -  Ongoing, active hepatitis B or C virus infection, or known human immunodeficiency
             virus (HIV) positive

          -  Liver disease with Child-Pugh class B or C liver dysfunction

          -  Current treatment with a combination of ibrutinib and strong CYP3A inhibitors
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete response rate (CR)
Time Frame:Up to 5 years
Safety Issue:
Description:Complete response rate to be defined as an objective status of CR at any time, where confirmation of the complete response status is required on two consecutive evaluations with a second immunofixation before calling the patient a CR. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. 95% confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.

Secondary Outcome Measures

Measure:Overall response rate
Time Frame:Up to 5 years
Safety Issue:
Description:Overall response rate will be estimated by the total number of patients who achieve a CR, very good partial response (VGPR), or partial response (PR) divided by the total number of evaluable patients. All evaluable patients will be used for this analysis. Exact binomial 95% confidence intervals for the true overall response rate will be calculated.
Measure:Time to progression
Time Frame:From study registration to the earliest date of documentation of disease progression, assessed up to 5 years
Safety Issue:
Description:The distribution of time to progression will be estimated using the method of Kaplan-Meier.
Measure:Overall survival
Time Frame:Up to 5 years
Safety Issue:
Description:The distribution of overall survival will be estimated using the method of Kaplan-Meier.
Measure:Incidence of adverse effects (AE) graded according to Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.0
Time Frame:Up to 5 years
Safety Issue:
Description:The maximum grade for each type of AE will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the AE(s) to the study treatment will be taken into consideration.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mayo Clinic

Last Updated

March 11, 2019