Clinical Trials /

A Study of Ixazomib and Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma

NCT03323151

Description:

Patients with mantle cell lymphoma (MCL) that has relapsed (come back) or refractory (progressed on treatment) will receive ixazomib and ibrutinib. Ibrutinib has been approved by the Food and Drug Administration (FDA) as treatment for patients with mantle cell lymphoma who have received at least one prior therapy. Ixazomib is in a class of medications called proteasome inhibitors. Cancer cells depend on proteasome to provide this protein metabolism (turnover) function to regulate their growth and survival. Ixazomib disrupts a cancer cells' ability to survive by blocking the proteasome and disrupting protein metabolism. This may help to slow down the growth of cancer or may cause cancer cells to die. The purpose of this study is to see whether the addition of ixazomib to ibrutinib chemotherapy is effective in treating people who have relapsed or refractory MCL and to examine the side effects associated with ixazomib in combination with ibrutinib.

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Ixazomib and Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma
  • Official Title: A Phase I/II Study of Ixazomib and Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: PrE0404
  • SECONDARY ID: X16077
  • NCT ID: NCT03323151

Conditions

  • Mantle-Cell Lymphoma

Interventions

DrugSynonymsArms
IxazomibNinlaroPhase I: Ixazomib & Ibrutinib
IxazomibNinlaroPhase II: Ixazomib & Ibrutinib-Naive
IbrutinibImbruvicaPhase I: Ixazomib & Ibrutinib
IbrutinibImbruvicaPhase II: Ixazomib & Ibrutinib-Naive

Purpose

Patients with mantle cell lymphoma (MCL) that has relapsed (come back) or refractory (progressed on treatment) will receive ixazomib and ibrutinib. Ibrutinib has been approved by the Food and Drug Administration (FDA) as treatment for patients with mantle cell lymphoma who have received at least one prior therapy. Ixazomib is in a class of medications called proteasome inhibitors. Cancer cells depend on proteasome to provide this protein metabolism (turnover) function to regulate their growth and survival. Ixazomib disrupts a cancer cells' ability to survive by blocking the proteasome and disrupting protein metabolism. This may help to slow down the growth of cancer or may cause cancer cells to die. The purpose of this study is to see whether the addition of ixazomib to ibrutinib chemotherapy is effective in treating people who have relapsed or refractory MCL and to examine the side effects associated with ixazomib in combination with ibrutinib.

Detailed Description

      MCL is a rare subtype of non-Hodgkin lymphoma that is considered incurable with conventional
      therapy. For relapsed patients, Ibrutinib, lenalidomide, and bortezomib are all approved by
      the FDA but are not curative. Novel approaches are required to improve outcomes for patients
      with relapsed/refractory MCL.

      This is an open-label study that will be done in 2 phases. Phase I will test different doses
      of ixazomib and ibrutinib to determine the maximum safe and tolerated dose. In Phase I,
      patients who have already received ibrutinib, may participate if they meet certain criteria
      (i.e., have not received ibrutinib for at least 3 months).

      Phase II will find out the effects, good and/or bad, of ixazomib in combination with
      ibrutinib. In Phase II, patients will be separated into 2 groups, patients who have never
      received ibrutinib and patients who have received ibrutinib. This study is designed to
      examine the effectiveness of this drug in treating patients with MCL.

      Patients will be treated until progression or unacceptable toxicity.

      Tumor assessments will be performed approximately every 3 months for the first year of
      treatment, then every 6 months until progression.

      Mandatory bone marrow and tumor tissue samples (i.e., obtained during a previous procedure or
      biopsy) are required at baseline. Mandatory research blood samples will also be collected.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I: Ixazomib & IbrutinibExperimentalIxazomib and Ibrutinib will be given by mouth until progression or unacceptable toxicity.
  • Ixazomib
  • Ibrutinib
Phase II: Ixazomib & Ibrutinib-NaiveExperimentalPatients who are Ibrutinib-Naive will receive Ixazomib and Ibrutinib by mouth until progression or unacceptable toxicity.
  • Ixazomib
  • Ibrutinib
Phase II: Ixazomib & Ibrutinib Pre-TreatedExperimentalPatients previously treated with Ibrutinib will receive Ixazomib and Ibrutinib by mouth until progression or unacceptable toxicity.
  • Ixazomib
  • Ibrutinib

Eligibility Criteria

        -  Relapsed or refractory, pathologically proven mantle cell lymphoma. Must have a
             current or prior tissue sample that is IHC positive for cyclin D 1 or that is positive
             by FISH or cytogenetics for t(11;14).

          -  Must have been refractory to and/or relapsed/progressed after at least 1 prior
             therapy.

          -  Prior autologous or allogeneic transplant are allowed. Patients may not have active
             grade II-IV acute graft-versus-host disease (GVHD) or moderate/severe chronic GVHD by
             NIH criteria and may not require immunosuppressive medications and/or corticosteroids
             for the management of acute or chronic GVHD.

          -  Phase I: Prior proteasome inhibitor and/or Bruton's tyrosine kinase (BTK) inhibitors
             are allowed but patients may not have been exposed to the combination of proteasome
             inhibitor and BTK inhibitor. Patients who have progressed on ibrutinib that are felt
             to be at high risk for rapid progression on this study shall not be eligible for the
             phase I portion of the study. NOTE: Ibrutinib pre-treated patients must meet all
             eligibility criteria AND must have discontinued prior ibrutinib at least 3 months
             prior to starting study therapy.

          -  Phase II: Prior proteasome inhibitor and/or Bruton's tyrosine kinase inhibitors are
             allowed but patients may not have been exposed to the combination of proteasome
             inhibitor and BTK inhibitor. NOTE: Patients must have tolerated prior ibrutinib (i.e.,
             not discontinued therapy due to toxicity).

          -  Age ≥ 18 years.

          -  Eastern Oncology Oncology Group (ECOG) performance status of 0-2.

          -  Ability to understand and willingness to sign Institutional Review Board
             (IRB)-approved informed consent.

          -  Willing to provide archived tumor tissue and blood samples for research.

          -  Adequate organ function as measured by the following criteria

               -  Absolute Neutrophil Count (ANC) ≥ 750/mm³

               -  Platelets ˃50,000/mm³

               -  Serum Creatinine ≤ 2x Upper Limit Normal (ULN)

               -  ALT and AST ≤ 3x ULN

               -  Total Bilirubin ≤ 1.5x ULN

          -  Patients must not have received systemic treatment for MCL for at least 14 days prior
             to enrollment, except for steroids which may be used to manage acute symptoms related
             to disease up to 48 hours prior to starting study therapy. Radiation therapy must be
             concluded at least 14 days prior to enrollment.

          -  Women must not be pregnant or breastfeeding since we do not know the effects of
             ixazomib and ibrutinib on the fetus or breastfeeding child. All sexually active
             females of childbearing potential must have a blood test to rule out pregnancy within
             2 weeks prior to registration.

          -  Sexually active women of child-bearing potential with a non-sterilized male partner
             and sexually active men must agree to use 2 methods of adequate contraception
             (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the
             duration of study participation, and for 3 months following last dose of study drugs.

          -  Patients must have resolved all prior non-hematologic toxicities assessed as related
             to prior therapy to ≤ grade 1.

          -  Patients must have measurable disease (i.e., ≥ 1.5 cm in largest diameter) by
             conventional imaging modalities. Patients with spleen or extranodal involvement as the
             only measurable site of disease must have a discrete splenic lesion ≥ 1.5 cm in
             largest diameter.

          -  Patients may not have current/active Central Nervous System (CNS) involvement with
             mantle cell lymphoma (patients with prior CNS involvement are eligible as long as they
             have had no evidence of active CNS disease for at least 6 months).

          -  Patients may not have another malignancy that could interfere with the evaluation of
             safety or efficacy of this combination. Patients with a prior malignancy will be
             allowed without study chair approval in the following circumstances:

               -  Not currently active and diagnosed at least 3 years prior to the date of
                  enrollment.

               -  Non-invasive diseases such as low risk cervical cancer or any cancer in situ

               -  Localized disease in which chemotherapy would not be indicated (such as Stage I
                  colon, lung, prostate or breast cancer). Patients with other malignancies not
                  meeting these criteria must be discussed with PrECOG prior to enrollment.

          -  Patients requiring long-term anticoagulation must be managed on an anticoagulant
             besides warfarin. Patients who require warfarin are not eligible.

          -  Patients with a clinically significant bleeding episode as judged by the investigator
             within 3 months of registration are not eligible, except patients who suffer bleeding
             due to trauma.

          -  Patients may not have had major surgery within 14 days, or minor surgery within 3
             days, before registration.

          -  Patients may not have any active infection requiring oral or intravenous antimicrobial
             therapy at the time of therapy initiation. Patients with a recent self-limited
             infection that has clinically resolved may complete a prescribed course of
             antimicrobial therapy after study initiation as long as they are asymptomatic with no
             clinical evidence of infection for at least 7 days prior to treatment. Patients with a
             recent serious (grade ≥ 3) infection requiring hospitalization must have completed all
             antimicrobial therapy within 14 days of therapy initiation.

          -  Patients may not have evidence of uncontrolled cardiovascular conditions, including
             uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive
             heart failure (New York Heart Association (NYHA) class III or higher, unstable angina,
             or myocardial infarction within the past 6 months. Patients with a history of any
             significant cardiovascular disease that has been controlled for at least 14 days
             before registration are allowed (except for patients who have had a myocardial
             infarction within 6 months).

          -  No systemic treatment, within 14 days before the first dose of ibrutinib with moderate
             or strong inhibitors of CYP3A (Strong Inhibitors: ketoconazole, itraconazole,
             voriconazole, posaconazole, clarithromycin, and telithromycin; Moderate Inhibitors:
             fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir,
             fosamprenavir, crizotinib, imatinib, verapamil, ciprofloxacin, grapefruit juice
             products, and Seville oranges) or strong CYP3A inducers for ibrutinib and ixazomib
             (carbamazepine, rifampin, phenytoin, St. John's wort).

          -  Patients with ongoing or active systemic infection, active hepatitis B or C virus
             infection, or known Human Immunodeficiency Virus (HIV) positive are not eligible.
             Testing is not required in absence of clinical suspicion.

          -  Patients with a history of hepatitis B or C must have a negative peripheral blood
             Polymerase Chain Reaction (PCR) and may not be positive for Hepatitis B surface
             antigen. Patients with cirrhosis or other evidence of liver damage due to Hepatitis B
             or C are not eligible.

          -  Patients with any serious medical or psychiatric illness that could, in the
             investigator's opinion, potentially interfere with the completion of the treatment
             according to the protocol are not eligible.

          -  Patients with a known allergy to any of the study medications, their analogues, or
             excipients in the various formulations of any agent are not eligible.

          -  Patients with known gastrointestinal (GI) disease or prior GI procedure that could
             interfere with the oral absorption or tolerance of ixazomib or ibrutinib including
             difficulty swallowing are not eligible.

          -  Patients with ≥ Grade 2 peripheral neuropathy, or Grade 1 peripheral neuropathy with
             pain on clinical examination during the screening period are not eligible.

          -  Patients may not participate in any other therapeutic clinical trials, including those
             with other investigational agents not included in this trial throughout the duration
             of this study.

          -  As ibrutinib will not be provided by the study, the patient must be able to obtain
             ibrutinib through other means (i.e., commercially or through patient assistance
             programs). This must be confirmed prior to registration.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: Maximum Tolerated Dose (MTD)
Time Frame:15 months
Safety Issue:
Description:MTD of ixazomib in mg in combination with ibrutinib in mg

Secondary Outcome Measures

Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame:Phase I: 15 months; Phase II: 60 months
Safety Issue:
Description:Number of patients with abnormal laboratory values and/or adverse events related to treatment
Measure:Overall Response Rate (ORR)
Time Frame:Phase I: 15 months; Phase II: 60 months
Safety Issue:
Description:ORR assessed in accordance with Lugano classification
Measure:Progression-Free Survival (PFS)
Time Frame:Phase I: 15 months; Phase II: 60 months
Safety Issue:
Description:PFS assessed in accordance with Lugano classification
Measure:Overall Survival (OS)
Time Frame:Phase I: 15 months; Phase II: 60 months
Safety Issue:
Description:OS assessed in accordance with Lugano classification

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:PrECOG, LLC.

Trial Keywords

  • Relapsed Mantle-Cell Lymphoma
  • Refractory Mantle-Cell Lymphoma
  • Ixazomib
  • Ibrutinib
  • Proteasome Inhibitor
  • Bruton's Tyrosine Kinase Inhibitor

Last Updated

April 30, 2018