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Ixazomib in Treating Patients With Relapsed Multiple Myeloma That Is Not Refractory to Bortezomib

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ClinicalTrials.gov Identifier: NCT01415882
Recruitment Status : Recruiting
First Posted : August 12, 2011
Last Update Posted : December 5, 2019
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Janssen Scientific Affairs, LLC
Information provided by (Responsible Party):
Mayo Clinic

Tracking Information
First Submitted Date  ICMJE August 5, 2011
First Posted Date  ICMJE August 12, 2011
Last Update Posted Date December 5, 2019
Actual Study Start Date  ICMJE February 4, 2016
Estimated Primary Completion Date September 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 8, 2016)
Proportion of confirmed responses with ixazomib citrate alone (Arm A only-closed to accrual as of addendum 5), ixazomib citrate with dexamethasone (Arms B + C), or ixazomib citrate with dexamethasone and cyclophosphamide (Arm D) [ Time Frame: Up to 2 years ]
A confirmed response is defined as stringent complete response, CR, very good partial response, or PR noted as the objective status on 2 separate evaluations while receiving ixazomib citrate with or without dexamethasone. 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 by the exact binomial method.
Original Primary Outcome Measures  ICMJE
 (submitted: August 10, 2011)
Proportion of confirmed response (stringent complete response [sCR], CR, very good partial response [VGPR], PR) with single agent proteasome inhibitor MLN9708 [ Time Frame: up to 4 months ]
A confirmed response is defined as sCR, CR, VGPR, or PR noted as the objective status on 2 separate evaluations while receiving single agent proteasome inhibitor MLN9708. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients.
Change History Complete list of historical versions of study NCT01415882 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 12, 2015)
  • Confirmed response rate with the addition of dexamethasone (Arm A only) [ Time Frame: Up to 2 years ]
    Estimated by the number of patients who achieve a confirmed response at any time (with single agent ixazomib citrate or ixazomib citrate plus dexamethasone) divided by the number of evaluable patients. 95% confidence intervals for the true confirmed response rate will be calculated by the exact binomial method.
  • Event-free survival [ Time Frame: From registration to disease progression while receiving ixazomib citrate and dexamethasone, death due to any cause, or subsequent treatment for multiple myeloma, assessed up to 2 years ]
    Date of progression will be defined as the date that the criteria for progressive disease were first met after initiation of dexamethasone. The distribution of event-free survival will be estimated using the method of Kaplan-Meier.
  • Incidence of adverse events, graded according to NCI CTCAE version 3.0 [ Time Frame: Up to 30 days after the last day of study drug treatment ]
    The maximum grade for each type of adverse event, regardless of causality, will be recorded and reported for each patient, and frequency tables will be reviewed to determine adverse event patterns.
  • Overall survival [ Time Frame: From registration to death due to any cause, assessed up to 2 years ]
    The distribution of survival time will be estimated using the method of Kaplan-Meier.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 10, 2011)
  • To determine the overall response rate of MLN9708 in combination with dexamethasone by bone marrow aspirate and biopsy, myeloma FISH, metaphase cytogenetics, PCLI, and flow cytometry at 2 and 4 months. [ Time Frame: no longer than 2 years ]
  • Survival out to 2 years [ Time Frame: Every 6 months for 2 years ]
  • Disease-free survival [ Time Frame: Every 6 months for 2 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ixazomib in Treating Patients With Relapsed Multiple Myeloma That Is Not Refractory to Bortezomib
Official Title  ICMJE Phase 2 Trial of Ixazomib Combinations in Patients With Relapsed Multiple Myeloma
Brief Summary This randomized phase II trial studies how well ixazomib (ixazomib citrate) works in treating patients with multiple myeloma that has returned after a period of improvement but is not resistant to bortezomib. 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 confirmed overall response rate (>= partial response [PR]) of MLN9708 (ixazomib citrate), used as a single agent in patients with relapsed multiple myeloma, who are proteasome inhibitor naïve (including bortezomib) naive OR have received less than 6 cycles of therapy with bortezomib and had a better than PR with no progression at the time of discontinuation. (Arm A - Permanently closed to accrual as of Addendum 5) II. To determine the confirmed overall response rate (>= PR) of MLN9708 at a 4 mg dose level in combination with dexamethasone in patients with relapsed multiple myeloma, who are proteasome inhibitor naïve (including bortezomib) naïve OR have received less than 6 cycles of therapy with bortezomib and had a better than PR with no progression at the time of discontinuation. (Arm B) III. To determine the confirmed overall response rate (>= PR) of MLN9708 at a 5.5 mg dose level in combination with dexamethasone in patients with relapsed multiple myeloma, who are proteasome inhibitor naïve (including bortezomib) naïve OR have received less than 6 cycles of therapy with bortezomib and had a better than PR with no progression at the time of discontinuation. (Arm C) IV. To determine the confirmed overall response rate (>= PR) of MLN9708 in combination with cyclophosphamide and dexamethasone in patients with relapsed multiple myeloma, who are proteasome inhibitor naive (including bortezomib) naïve OR have received less than 6 cycles of therapy with bortezomib and had a better than PR with no progression at the time of discontinuation. (Arm D)

SECONDARY OBJECTIVES:

I. To determine the overall response rate of MLN9708 in combination with dexamethasone, when dexamethasone is added to MLN9708 for lack of response or for progression. (Arm A) II. To determine the event free survival and overall survival among patients with relapsed myeloma following treatment with MLN9708 with dexamethasone added for lack of response or progression. (Arm A) III. To determine the event free survival and overall survival among patients with relapsed myeloma following treatment with MLN9708 at two different doses, in combination with dexamethasone. (Arms B and C) IV. To determine the event free survival and overall survival among patients with relapsed myeloma following treatment with MLN9708 in combination with cyclophosphamide and dexamethasone. (Arms D)

OUTLINE: Patients are randomized to 1 of 3 treatment arms (Arm A permanently closed to accrual as of Addendum 5).

ARM A: Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15. Patients with lack of minor response by the end of the second course or lack of partial response by the end of the fourth course also receive dexamethasone PO on days 1, 2, 8, 9, 15, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive ixazomib citrate PO on days 1, 8 and 15 and dexamethasone PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive higher dose of ixazomib citrate PO on days 1, 8, and 15 and dexamethasone PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM D: Patients receive ixazomib citrate PO on days 1, 8, and 15, cyclophosphamide PO and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM E: Patient receive isazomib citrate PO on days 1,8 and 15, cyclophosphamide PO on days 1,8,15 and 22. Daratumumab IV Days 1, 8, 15, 22 for cycles 1-2; Days 1, 15 for cycles 3-6; and Day 1 for subsequent cycles. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Dexamethasone IV (PO only if IV unavailable) days 1,8,15 and 22. *Dexamethasone is started Day 1 Cycle 1

**Dexamethasone should be given IV (PO only if IV is unavailable), approximately 1 hour or less prior to daratumumab infusion. On days when subjects receive this dose of dexamethasone in the clinic, dexamethasone will not be self-administered at home. On days when daratumumab is not scheduled, PO may be taken at home.

After completion of study treatment, patients are followed up every 6 or 12 months for 2 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Recurrent Plasma Cell Myeloma
  • Refractory Plasma Cell Myeloma
Intervention  ICMJE
  • Drug: Cyclophosphamide
    Given PO
    Other Names:
    • (-)-Cyclophosphamide
    • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
    • Carloxan
    • Ciclofosfamida
    • Ciclofosfamide
    • Cicloxal
    • Clafen
    • Claphene
    • CP monohydrate
    • CTX
    • CYCLO-cell
    • Cycloblastin
    • Cycloblastine
    • Cyclophospham
    • Cyclophosphamid monohydrate
    • Cyclophosphamidum
    • Cyclophosphan
    • Cyclophosphane
    • Cyclophosphanum
    • Cyclostin
    • Cyclostine
    • Cytophosphan
    • Cytophosphane
    • Cytoxan
    • Fosfaseron
    • Genoxal
    • Genuxal
    • Ledoxina
    • Mitoxan
    • Neosar
    • Revimmune
    • Syklofosfamid
    • WR- 138719
  • Drug: Dexamethasone
    Given PO
    Other Names:
    • Aacidexam
    • Adexone
    • Aknichthol Dexa
    • Alba-Dex
    • Alin
    • Alin Depot
    • Alin Oftalmico
    • Amplidermis
    • Anemul mono
    • Auricularum
    • Auxiloson
    • Baycuten
    • Baycuten N
    • Cortidexason
    • Cortisumman
    • Decacort
    • Decadrol
    • Decadron
    • Decalix
    • Decameth
    • Decasone R.p.
    • Dectancyl
    • Dekacort
    • Deltafluorene
    • Deronil
    • Desamethasone
    • Desameton
    • Dexa-Mamallet
    • Dexa-Rhinosan
    • Dexa-Scheroson
    • Dexa-sine
    • Dexacortal
    • Dexacortin
    • Dexafarma
    • Dexafluorene
    • Dexalocal
    • Dexamecortin
    • Dexameth
    • Dexamethasonum
    • Dexamonozon
    • Dexapos
    • Dexinoral
    • Dexone
    • Dinormon
    • Fluorodelta
    • Fortecortin
    • Gammacorten
    • Hexadecadrol
    • Hexadrol
    • Lokalison-F
    • Loverine
    • Methylfluorprednisolone
    • Millicorten
    • Mymethasone
    • Orgadrone
    • Spersadex
    • Visumetazone
  • Drug: Ixazomib Citrate
    Given PO
    Other Names:
    • MLN-9708
    • MLN9708
    • Ninlaro
  • Other: Laboratory Biomarker Analysis
    Correlative studies
Study Arms  ICMJE
  • Experimental: Arm A (ixazomib citrate and dexamethasone, closed to accrual)
    Patients receive ixazomib citrate PO on days 1, 8, and 15. Patients with lack of minor response by the end of the second course or lack of partial response by the end of the fourth course also receive dexamethasone PO on days 1, 2, 8, 9, 15, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Dexamethasone
    • Drug: Ixazomib Citrate
    • Other: Laboratory Biomarker Analysis
  • Experimental: Arm B (ixazomib citrate and dexamethasone)
    Patients receive ixazomib citrate PO on days 1, 8 and 15 and dexamethasone PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Dexamethasone
    • Drug: Ixazomib Citrate
    • Other: Laboratory Biomarker Analysis
  • Experimental: Arm C (higher-dose ixazomib citrate and dexamethasone)
    Patients receive higher doses of ixazomib citrate PO on days 1, 8, and 15 and dexamethasone PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Dexamethasone
    • Drug: Ixazomib Citrate
    • Other: Laboratory Biomarker Analysis
  • Experimental: Arm D (ixazomib citrate, dexamethasone, and cyclophosphamide)
    Patients receive ixazomib citrate PO on days 1, 8, and 15, cyclophosphamide PO and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Dexamethasone
    • Drug: Ixazomib Citrate
    • Other: Laboratory Biomarker Analysis
  • Experimental: Arm E (Ixazomib, cyclophosphamide, daratumab, dexa
    Patient receive ixazomib citrate PO on days 1, 8 &15, cyclophosphamide PO on days 1, 8,15,& 22 (Discontinue after 12 cycles), Daratumumab IV on days 1,8,15 & 22 for cycles 1-2; days 1,15 for cycles 3-6; day 1 for subsequent cycles, Dexamethasone PO on days 1,8,15 & 22.
    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Dexamethasone
    • Drug: Ixazomib Citrate
    • Other: Laboratory Biomarker Analysis
Publications * Kumar SK, LaPlant BR, Reeder CB, Roy V, Halvorson AE, Buadi F, Gertz MA, Bergsagel PL, Dispenzieri A, Thompson MA, Crawley J, Kapoor P, Mikhael J, Stewart K, Hayman SR, Hwa YL, Gonsalves W, Witzig TE, Ailawadhi S, Dingli D, Go RS, Lin Y, Rivera CE, Rajkumar SV, Lacy MQ. Randomized phase 2 trial of ixazomib and dexamethasone in relapsed multiple myeloma not refractory to bortezomib. Blood. 2016 Nov 17;128(20):2415-2422. Epub 2016 Oct 4.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 8, 2016)
144
Original Estimated Enrollment  ICMJE
 (submitted: August 10, 2011)
33
Estimated Study Completion Date  ICMJE September 1, 2020
Estimated Primary Completion Date September 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Calculated creatinine clearance (using Cockcroft-Gault equation) >= 30 mL/min
  • Absolute neutrophil count >= 1000/mL
  • Untransfused platelet count >= 75000/mL
  • Hemoglobin >= 8.0 g/dL
  • Total bilirubin =< 1.5 x the upper limit of the normal range (ULN)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN
  • Patients with relapsed multiple myeloma who have already received one or more standard treatment regimens
  • Measurable disease of multiple myeloma as defined by at least ONE of the following:

    • Serum monoclonal protein >= 1.0 g/dL
    • >= 200 mg of monoclonal protein in the urine on 24 hour electrophoresis
    • Serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2
  • Patients should be proteasome inhibitor naïve (including bortezomib and carfilzomib) OR have received less than 6 cycles of therapy with a bortezomib or carfilzomib containing regimen and were not refractory to the bortezomib or carfilzomib based regimen (less than a PR or progression on or within 60 days of discontinuation)
  • Provide informed written consent
  • Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
  • Willing to return to consenting Mayo Clinic institution for follow-up during the Active Monitoring Phase of the study; Note: during the Active Monitoring Phase of a study (i.e., active treatment and observation), participants must be willing to return to the consenting institution for follow-up
  • Recovered (i.e., < grade 1 toxicity) from the reversible effects of prior antineoplastic therapy

Exclusion Criteria:

  • Recent prior chemotherapy:

    • Alkylators (e.g. melphalan, cyclophosphamide) =< 14 days prior to registration
    • Anthracyclines =< 14 days prior to registration
    • High dose corticosteroids, immune modulatory drugs (thalidomide or lenalidomide) =< 7 days prior to registration
  • Prior therapy with any proteasome inhibitor other than bortezomib or carfilzomib
  • Concomitant high dose corticosteroids other than what is part of treatment protocol (concurrent use of corticosteroids); EXCEPTION: patients may be on chronic steroids (maximum dose 20 mg/day prednisone equivalent) if they are being given for disorders other than myeloma, i.e., adrenal insufficiency, rheumatoid arthritis, etc
  • 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 nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
  • Any of the following:

    • Pregnant women or women of reproductive ability who are unwilling to use 2 effective methods of contraception from the time of signing the informed consent form through 90 days after the last dose of study drug
    • Nursing women
    • Men who are unwilling to use a condom (even if they have undergone prior vasectomy) while having intercourse with any women, while taking the drug and for 30 days after stopping treatment
  • Other co-morbidity which would interfere with patient's ability to participate in trial, e.g. uncontrolled infection, uncompensated heart or lung disease
  • Other concurrent chemotherapy, radiotherapy, or any ancillary therapy considered investigational; NOTE: bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment
  • Patient has >= grade 3 peripheral neuropathy, or grade 2 with pain on clinical examination during the screening period
  • Major surgery within 14 days before study registration
  • Systemic treatment with strong inhibitors of cytochrome P450, family 1, subfamily A (CYP3A) inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days before the first dose of study treatment
  • Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure, angina, or myocardial infarction within the past 6 months; Note: prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevant
  • Known human immunodeficiency virus (HIV) positive
  • Known hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection
  • Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
  • Known allergy 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 MLN9708 including difficulty swallowing
  • Diarrhea > grade 1, based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grading, in the absence of antidiarrheals
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01415882
Other Study ID Numbers  ICMJE MC1181
NCI-2011-02303 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
11-001516 00
Mod11-001516-50
MC1181 ( Other Identifier: Mayo Clinic )
P30CA015083 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mayo Clinic
Study Sponsor  ICMJE Mayo Clinic
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • Janssen Scientific Affairs, LLC
Investigators  ICMJE
Principal Investigator: Shaji Kumar Mayo Clinic
PRS Account Mayo Clinic
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP