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Trial record 1 of 1 for:    NCT 02765854
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Ixazomib and Dexamethasone Versus Ixazomib, Dexamethasone and Lenalidomide, Randomized With NFKB2 Rearrangement

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ClinicalTrials.gov Identifier: NCT02765854
Recruitment Status : Recruiting
First Posted : May 9, 2016
Last Update Posted : September 26, 2019
Sponsor:
Collaborators:
Millennium Pharmaceuticals, Inc.
Multiple Myeloma Research Consortium
Information provided by (Responsible Party):
Leon Bernal-Mizrachi, Emory University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma Drug: Dexamethasone Drug: Ixazomib Drug: Lenalidomide Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : September 1, 2016
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2021


Arm Intervention/treatment
Experimental: Arm B (ixazomib and dexamethasone)
MUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone as in arm A.
Drug: Dexamethasone
Given PO
Other Names:
  • Decadron
  • DexPak
  • Dexasone
  • Baycadron
  • Zema
  • Diodex
  • Hexadrol
  • Maxidex

Drug: Ixazomib
Given PO
Other Names:
  • MLN9708
  • Ninlaro
  • Ixazomib citrate

Experimental: Arm C (ixazomib, dexamethasone, lenalidomide)
MUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone as in arm A and lenalidomide PO daily on days 1-21.
Drug: Dexamethasone
Given PO
Other Names:
  • Decadron
  • DexPak
  • Dexasone
  • Baycadron
  • Zema
  • Diodex
  • Hexadrol
  • Maxidex

Drug: Ixazomib
Given PO
Other Names:
  • MLN9708
  • Ninlaro
  • Ixazomib citrate

Drug: Lenalidomide
Given PO
Other Names:
  • CC-5013
  • Revlimid

Active Comparator: Arm A (ixazomib and dexamethasone)
UNMUTATED NFKB2 REARRANGEMENT: Patients receive ixazomib and dexamethasone.
Drug: Dexamethasone
Given PO
Other Names:
  • Decadron
  • DexPak
  • Dexasone
  • Baycadron
  • Zema
  • Diodex
  • Hexadrol
  • Maxidex

Drug: Ixazomib
Given PO
Other Names:
  • MLN9708
  • Ninlaro
  • Ixazomib citrate




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


Secondary Outcome Measures :
  1. Overall response rate (CR + VGPR + partial response [PR]), stable disease or progression [ Time Frame: At 112 days (4 cycles) ]
    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.

  2. CR, stringent CR, and VGPR rate [ Time Frame: At 224 days (8 cycles) ]
  3. Combined CR + VGPR rate [ Time Frame: At 224 days (8 cycles) ]
  4. PR rate [ Time Frame: At 224 days (8 cycles) ]
  5. 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 ]
    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.

  6. 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 ]
    Analyzed based on the response-evaluable population. DOR will be analyzed using standard survival analysis techniques based on Kaplan-Meier estimates.

  7. 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 ]
  8. 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 ]
  9. Incidence of adverse events [ Time Frame: Up to 30 days post-treatment ]
    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.


Other Outcome Measures:
  1. Gene expression profile [ Time Frame: Up to 30 days post-treatment ]
    Gene expression will be associated with poor response to Id or IRd. Differential gene expression will be computed by pairwise t-tests on the variance-stabilized counts followed by correction for multiple testing using the Benjamini-Hochberg method.

  2. Transcribed mutations via RNA-sequencing [ Time Frame: Baseline ]
    The sequence of mutations associated with poor response to Id or IRd will compared with the mutational analysis of all samples against the results obtained from time 0.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02765854


Contacts
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Contact: Leon Bernal-Mizrachi, MD 404-778-2164 lbernal@emory.edu

Locations
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United States, Georgia
Grady Memorial Hospital Recruiting
Atlanta, Georgia, United States, 30303
Contact: Eduardo Sanabria-Figueroa    404-778-2164    esanab2@emory.edu   
Contact: Shondolyn Richburg       shondolyn.k.richburg@emory.edu   
Emory University/Winship Cancer Institute Recruiting
Atlanta, Georgia, United States, 30322
Contact: Eduardo Sanabria-Figueroa    404-778-2164    esanab2@emory.edu   
Contact: Shondolyn Richburg       shondolyn.k.richburg@emory.edu   
United States, Michigan
University of Michigan/Rogel Cancer Center Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Christine Ye, MD       jchrisye@umich.edu   
United States, Missouri
Washington University/Siteman Cancer Center Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Ravi Vij, MD       rvij@wustl.edu   
Sponsors and Collaborators
Emory University
Millennium Pharmaceuticals, Inc.
Multiple Myeloma Research Consortium
Investigators
Layout table for investigator information
Principal Investigator: Leon Bernal-Mizrachi, MD Emory University/Winship Cancer Institute

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Responsible Party: Leon Bernal-Mizrachi, Principal Investigator, Emory University
ClinicalTrials.gov Identifier: NCT02765854     History of Changes
Other Study ID Numbers: IRB00077815
NCI-2016-00043 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MMRC060 ( Other Identifier: Emory University/Winship Cancer Institute )
First Posted: May 9, 2016    Key Record Dates
Last Update Posted: September 26, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Dexamethasone acetate
Lenalidomide
Ixazomib
BB 1101
Glycine
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal