Clinical Trials /

Ixazomib and Dexamethasone Versus Ixazomib, Dexamethasone and Lenalidomide, Randomized With NFKB2 Rearrangement

NCT02765854

Description:

This randomized phase II trial studies how well ixazomib and dexamethasone or ixazomib, dexamethasone, and lenalidomide work based on the presence of the rearrangement of a gene called nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (NFKB2) in treating patients with multiple myeloma that has returned after a period of improvement or does not respond to treatment. Ixazomib may stop the growth of cancer cells by blocking enzymes called proteasomes needed for cell growth. Drugs used in chemotherapy, such as 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. Lenalidomide may stimulate the immune system against cancer cells and may also prevent the growth of new blood vessels that tumors need to grow. It is not yet known whether ixazomib and dexamethasone, or ixazomib, dexamethasone, and lenalidomide are more effective in treating multiple myeloma.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Ixazomib and Dexamethasone Versus Ixazomib, Dexamethasone and Lenalidomide, Randomized With NFKB2 Rearrangement
  • Official Title: Phase II Trial of Ixazomib and Dexamethasone Versus Ixazomib, Dexamethasone and Lenalidomide, Randomized With NFKB2 Rearrangement. (Proteasome Inhibitor NFKB2 Rearrangement Driven Trial, PINR)

Clinical Trial IDs

  • ORG STUDY ID: IRB00077815
  • SECONDARY ID: NCI-2016-00043
  • SECONDARY ID: MMRC060
  • NCT ID: NCT02765854

Conditions

  • Recurrent Plasma Cell Myeloma
  • Refractory Plasma Cell Myeloma

Interventions

DrugSynonymsArms
DexamethasoneDecadron, DexPak, Dexasone, Baycadron, Zema, Diodex, Hexadrol, MaxidexArm A (ixazomib and dexamethasone)
IxazomibMLN9708, Ninlaro, Ixazomib citrateArm A (ixazomib and dexamethasone)
LenalidomideCC-5013, RevlimidArm C (ixazomib, dexamethasone, lenalidomide)

Purpose

This randomized phase II trial studies how well ixazomib and dexamethasone or ixazomib, dexamethasone, and lenalidomide work based on the presence of the rearrangement of a gene called nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (NFKB2) in treating patients with multiple myeloma that has returned after a period of improvement or does not respond to treatment. Ixazomib may stop the growth of cancer cells by blocking enzymes called proteasomes needed for cell growth. Drugs used in chemotherapy, such as 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. Lenalidomide may stimulate the immune system against cancer cells and may also prevent the growth of new blood vessels that tumors need to grow. It is not yet known whether ixazomib and dexamethasone, or ixazomib, dexamethasone, and lenalidomide are more effective in treating multiple myeloma.

Detailed Description

      PRIMARY OBJECTIVES:

      To test whether the NFKB2 rearrangement can guide the selection of treatment (ixazomib
      [ixazomib citrate] plus dexamethasone [Id] or ixazomib plus lenalidomide and dexamethasone
      [IRd]) by conducting the following comparisons:

      I. To compare the response rate at 4 cycles between patients treated with Id and patients
      treated with IRd and confirm the lack of significant difference in overall response.

      II. To compare the response rate at 4 cycles between non-rearranged and rearranged NFKB2
      treated with Id and confirm that NFKB2 rearrangement is associated with reduce response rate.

      III. To compare the responses rate at 4 cycles of patients with rearranged NFKB2 treated with
      Id or IRd and confirm that adding lenalidomide increases the response rate in this
      population.

      SECONDARY OBJECTIVES:

      I. To determine time to treatment failure (TTF).

      II. To determine the frequency and severity of adverse events (AE) in IRd treated cohort.

      III. To identify novel transcribed mutations associated with Id and IRd resistance in
      patients with multiple myeloma (MM).

      IV. To determine the prevalence of NFKB2 rearrangement in relapsed/refractory MM patients
      screened in the study.

      V. To determine the prevalence of NFKB2 rearrangement according to the type of previous
      therapies received in all patients screened in the study.

      VI. To determine the toxicity profile of the study drugs according to the presence of NFKB2
      rearrangement.

      VII. Delineate transcribed mutations associated with relapse or refractoriness to Id or IRd
      treatment by ribonucleic acid (RNA)-sequencing.

      OUTLINE:

      ARM A (UNMUTATED NFKB2 REARRANGEMENT): Patients receive ixazomib orally (PO) on days 1, 8,
      and 15 and dexamethasone PO on days 1, 8, 15, and 22.

      Patients with mutated NFKB2 rearrangement are randomized in to 1 of 2 treatment arms.

      ARM B (MUTATED NFKB2 REARRANGEMENT): Patients receive ixazomib and dexamethasone as in arm A.

      ARM C (MUTATED NFKB2 REARRANGEMENT): Patients receive ixazomib and dexamethasone as in arm A
      and lenalidomide PO daily on days 1-21.

      In all arms, cycles repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      Patients may proceed to autologous stem cell transplant after 4 cycles of treatment.

      After completion of study, patients are followed up monthly.
    

Trial Arms

NameTypeDescriptionInterventions
Arm B (ixazomib and dexamethasone)ExperimentalMUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone as in arm A.
  • Dexamethasone
  • Ixazomib
Arm C (ixazomib, dexamethasone, lenalidomide)ExperimentalMUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone as in arm A and lenalidomide PO daily on days 1-21.
  • Dexamethasone
  • Ixazomib
  • Lenalidomide
Arm A (ixazomib and dexamethasone)Active ComparatorUNMUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone.
  • Dexamethasone
  • Ixazomib

Eligibility Criteria

        Inclusion Criteria:

          -  Voluntary written consent must be given before performance of any study related
             procedure not part of standard medical care, with the understanding that consent may
             be withdrawn by the patient at any time without prejudice to future medical care

          -  Females of childbearing potential (FCBP)* must have a negative serum or urine
             pregnancy test with a sensitivity of at least 50 milli-International Units (mIU)/mL
             within 10-14 days prior to and again within 24 hours of starting lenalidomide and
             ixazomib and must either commit to continued abstinence from heterosexual intercourse
             or begin TWO acceptable methods of birth control, one highly effective method and one
             additional effective method AT THE SAME TIME, at least 28 days before she starts
             taking lenalidomide through 90 days after the last dose of study drug; FCBP must also
             agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual
             contact with a FCBP even if they have had a vasectomy from the time of signing the
             informed consent form through 90 days after the last dose of study drug; in the event
             that the male patients choose to agree to practice true abstinence, this must follow
             the timelines detailed above; all patients assigned to the lenalidomide treatment
             group must be registered in and must comply with all requirements of the Revlimid Risk
             Evaluation and Mitigation Strategy (REMS) program

               -  *A female of childbearing potential is a sexually mature woman who:

                    -  1) has not undergone a hysterectomy or bilateral oophorectomy; or

                    -  2) has not been naturally postmenopausal for at least 24 consecutive months

          -  Multiple myeloma diagnosed according to standard criteria either currently or at the
             time of initial diagnosis

          -  The patient has confirmed relapsed or refractory MM

          -  For patients that relapse following a response to prior treatment with bortezomib or
             carfilzomib, six months must have elapsed since the last dose of treatment

          -  The patient has received 1 to 3 prior lines of therapy. By definition, a single line
             of therapy may consist of 1 or more agents, and may include induction, hematopoietic
             stem cell transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a
             single short course of steroids (ie, less than or equal to the equivalent of
             dexamethasone 40 mg/day for 4 days) would not be considered prior lines of therapy

          -  Patients must have measurable disease defined by at least 1 of the following
             measurements:

               -  Serum M-protein ≥ 1.0 g/dL (≥ 10 g/L) for an immunoglobulin (Ig)G myeloma, ≥ 0.1
                  g/dL for an immunoglobulin D (IgD) myeloma or 0.5 g/dL (≥ 5g/L) for an
                  immunoglobulin A (IgA) myeloma

               -  Urine light chain ≥ 200 mg/24 hours

               -  Serum free light chain ≥ 10 mg/dL provided the free light chain (FLC) ratio is
                  abnormal

               -  Patients with oligo- or non-secretory disease must have bone marrow involvement
                  with at least 30% plasmacytosis on aspiration

          -  Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance
             status 0, 1, or 2

          -  Absolute neutrophil count (ANC) ≥ 1,000/mm³

          -  Platelet count ≥ 75,000/mm³; in the case that platelets are between 50,000-75,000, the
             patient can be enrolled if the plasma cell count in the bone marrow is superior to ≥
             50%; to meet this hematological eligibility no transfusion support and hematological
             growth factor are not allowed within 7 days before study enrollment

          -  Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN)

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

          -  Serum creatinine ≤ 2.5 mg/dL or a calculated creatinine clearance ≥ 50 mL/min

        Exclusion Criteria:

          -  The patient is refractory to carfilzomib or bortezomib; (refractory is defined as
             patients who never achieved a response and progressed while on carfilzomib or
             bortezomib or within 60 days of completing treatment)

          -  Prior treatment with any investigational proteasome inhibitor within 6 months of study
             entry

          -  Female patients who are breast feeding or have a positive serum pregnancy test during
             the screening period

          -  Failure to have fully recovered (ie, > grade 1 toxicity) from the reversible effects
             of prior chemotherapy

          -  Diarrhea > grade 1 according to National Cancer Institute (NCI) Common Terminology
             Criteria for Adverse Events (CTCAE) version (v)4.03

          -  Prior chemotherapy and/or immunotherapy within 14 days before enrollment; major
             surgery within 14 days before enrollment and minor surgery within 7 days prior to
             cycle 1 day 1

          -  Radiotherapy within 14 days before enrollment; if the involved field covered ≤ 5% of
             the bone marrow reserve, the patient may be enrolled irrespective of the end date of
             radiotherapy

          -  Central nervous system involvement

          -  Infection requiring systemic antibiotic therapy or other serious infection within 14
             days before study enrollment

          -  Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
             hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
             unstable angina, or myocardial infarction within the past 6 months

          -  Systemic treatment, within 14 days before the first dose of ixazomib, with strong
             cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A) inducers (rifampin,
             rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo
             biloba or St. John's wort

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

          -  Any serious medical or psychiatric illness that could, in the investigator's opinion,
             potentially compromise the patient's ability to understand the patient information, to
             give informed consent, to comply with the treatment according to this protocol or
             complete the study

          -  Diagnosed or treated for another malignancy within 2 years before study enrollment or
             previously diagnosed with another malignancy and have any evidence of residual
             disease; patients with non-melanoma skin cancer or carcinoma in situ of any type are
             not excluded if they have undergone complete resection

          -  Patient has ≥ grade 2 peripheral neuropathy or neuropathy with pain, regardless of
             grade that is seen on clinical examination during the screening period

          -  Known intolerance to immunomodulatory drugs (IMiDs)

          -  History of allergic reaction/hypersensitivity to any of the study medications, their
             analogues or excipients in the various formulations

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

          -  Participation in other clinical trials, including those with other investigational
             agents not included in this trial, such as monoclonal antibodies, within 30 days of
             the start of this trial and throughout the duration of this trial

          -  Corticosteroid doses > 10 mg/day of prednisone or equivalent within 14 days prior to
             cycle 1 day 1

          -  Autologous or allogeneic stem cell or bone marrow transplant within 3 months prior to
             cycle 1 day 1

          -  Cytotoxic therapy within 21 days prior to cycle 1 day (D) 1

          -  Patients that have previously been treated with ixazomib, or participated in a study
             with ixazomib whether treated with ixazomib or not
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response rate of very good partial response (VGPR) or better
Time Frame:At 112 days (4 cycles)
Safety Issue:
Description:Estimates of the complete response (CR) + VGPR rates will be presented with 2-sided 95% exact binomial confidence intervals.

Secondary Outcome Measures

Measure:Overall response rate (CR + VGPR + partial response [PR]), stable disease or progression
Time Frame:At 112 days (4 cycles)
Safety Issue:
Description:Analyzed based on the response-evaluable population. Overall response rate will be presented with 2-sided 95% exact binomial confidence interval in the subset of high-risk patients determined by cytogenetics.
Measure:CR, stringent CR, and VGPR rate
Time Frame:At 224 days (8 cycles)
Safety Issue:
Description:
Measure:Combined CR + VGPR rate
Time Frame:At 224 days (8 cycles)
Safety Issue:
Description:
Measure:PR rate
Time Frame:At 224 days (8 cycles)
Safety Issue:
Description:
Measure:Time to response (TTR)
Time Frame:From the date of first dose of study treatment to the date of the first documentation of a confirmed response, assessed up to 2 years
Safety Issue:
Description:Analyzed based on the response-evaluable population. TTR will be analyzed using standard survival analysis techniques based on Kaplan-Meier estimates. TTR may also be measured in the population of patients with a confirmed response.
Measure:Duration of response (DOR)
Time Frame:From the date of first documentation of a confirmed response to the date of first documented progressive disease (PD), assessed up to 30 days post-treatment
Safety Issue:
Description:Analyzed based on the response-evaluable population. DOR will be analyzed using standard survival analysis techniques based on Kaplan-Meier estimates.
Measure:Incidence of thrombotic thrombocytopenic purpura (TTP)
Time Frame:From the date of first dose of study treatment to the date of first documentation of PD, assessed up to 30 days post-treatment
Safety Issue:
Description:
Measure:Progression-free survival
Time Frame:From the date of first dose of study treatment to the date of first documented PD or death, assessed up to 2 years
Safety Issue:
Description:
Measure:Incidence of adverse events
Time Frame:Up to 30 days post-treatment
Safety Issue:
Description:Toxicity information recorded will include the type, severity, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity. Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to further define the safety profile of Id or IRd combinations. Treatment-emergent events will be tabulated.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Emory University

Last Updated

September 24, 2019