Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Idasanutlin, Ixazomib Citrate, and Dexamethasone in Treating Patients With Relapsed Multiple Myeloma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02633059
Recruitment Status : Recruiting
First Posted : December 17, 2015
Last Update Posted : July 12, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Brief Summary:
This phase I/II trial studies the side effects and best dose of idasanutlin and ixazomib citrate when given together with dexamethasone in treating patients with multiple myeloma that has returned after a period of improvement. Drugs used in chemotherapy, such as idasanutlin and 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. Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving idasanutlin, ixazomib citrate, and dexamethasone together may work better in treating patients with multiple myeloma.

Condition or disease Intervention/treatment Phase
Loss of Chromosome 17p Recurrent Plasma Cell Myeloma Drug: Dexamethasone Drug: Idasanutlin Drug: Ixazomib Citrate Other: Laboratory Biomarker Analysis Other: Pharmacological Study Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated doses (MTD) of idasanutlin and ixazomib (ixazomib citrate) to be used in combination with dexamethasone in patients with relapsed or refractory multiple myeloma with TP53 (17p) deletion. (Phase I) II. To evaluate the confirmed response rate of ixazomib and idasanutlin used in combination with dexamethasone in patients with relapsed or refractory multiple myeloma with TP53 (17p) deletion. (Phase II)

SECONDARY OBJECTIVES:

I. To describe the toxicities and the confirmed response rate associated with the combination of idasanutlin, ixazomib and dexamethasone. (Phase I) II. To describe the toxicities associated with the combination of idasanutlin, ixazomib and dexamethasone. (Phase II) III. To describe the complete response (CR) and very good partial response (VGPR) rates. (Phase II) IV. To assess progression-free and overall survival. (Phase II)

TERTIARY OBJECTIVES:

I. Assess murine double minute 2 (MDM2) inhibition in bone marrow plasma cells. II. Identify potential biomarkers associated with response. III. To explore the pharmacodynamic effects of idasanutlin.

OUTLINE: This is a phase I, dose-escalation study of idasanutlin and ixazomib citrate followed by a phase II study.

Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15 and idasanutlin PO once daily (QD) on days 1-5 every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive dexamethasone PO on days 1, 8, 15, and 22 every 28 days for 12 courses at the discretion of the treating physician.

After completion of study treatment, patients are followed up for 30 days, every 3 months, and then every 6 months.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 53 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 / 2 Trial of Idasanutlin in Combination With Ixazomib and Dexamethasone in Patients With 17p Deleted, Relapsed Multiple Myeloma
Actual Study Start Date : December 30, 2015
Estimated Primary Completion Date : May 13, 2021
Estimated Study Completion Date : May 13, 2021


Arm Intervention/treatment
Experimental: Treatment (ixazomib citrate, idasanutlin, dexamethasone)
Patients receive ixazomib citrate PO on days 1, 8, and 15 and idasanutlin PO QD on days 1-5 every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive dexamethasone PO on days 1, 8, 15, and 22 every 28 days for 12 courses at the discretion of the treating physician.
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: Idasanutlin
Given PO
Other Names:
  • RG-7388
  • RG7388
  • RO-5503781
  • RO5503781

Drug: Ixazomib Citrate
Given PO
Other Names:
  • MLN-9708
  • MLN9708
  • Ninlaro

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies




Primary Outcome Measures :
  1. Adverse events profile graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (Phase I) [ Time Frame: Up to 30 days after last dose of study treatment ]
    The number and severity of all adverse events (overall and by dose-level) will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion.

  2. Incidence of toxicity graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (Phase I) [ Time Frame: Up to 30 days after last dose of study treatment ]
    Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.

  3. Maximum tolerated dose (MTD) of ixazomib citrate and idasanutlin in combination with dexamethasone (Phase I) [ Time Frame: 28 days ]
    Defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). DLT is graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

  4. Rate of confirmed response, defined as a patient who has achieved a stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) on two consecutive evaluations (Phase II) [ Time Frame: Up to 6 months ]
    Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportion will be calculated.


Secondary Outcome Measures :
  1. Incidence of adverse events graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (Phase II) [ Time Frame: Up to 6 months ]
    The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

  2. Overall survival (Phase II) [ Time Frame: Time from registration to death due to any cause, assessed up to 6 months ]
    The distribution of overall survival will be estimated using the method of Kaplan-Meier.

  3. Progression free survival (Phase II) [ Time Frame: Time from registration to the earliest date of documentation of disease progression or death due to any cause, assessed up to 6 months ]
    The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.

  4. Rate of complete response (CR) (Phase II) [ Time Frame: Up to 6 months ]
    The rate of CR will be estimated by the number of patients with a sCR or CR or divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportions will be calculated.

  5. Rate of partial response (PR) (Phase II) [ Time Frame: Up to 6 months ]
    The rate of PR will be estimated by the number of patients with a VGPR or PR divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportions will be calculated.


Other Outcome Measures:
  1. Changes in macrophage inhibitory cytokine-1 (MIC) levels [ Time Frame: Baseline up to 6 months ]
    Effect of inhibition of mdm2 will be assessed by measuring MIC levels. MIC levels at each time point and changes after treatment will be both graphically and quantitatively summarized and explored. Changes from baseline will be evaluated using Wilcoxon's signed rank test.

  2. Impact of MDM2 inhibition on activation of p53 and clonal selection [ Time Frame: Up to 6 months ]
    Impact of MDM2 inhibition on activation of p53 and clonal selection examined using gene expression profiling and exome sequencing

  3. Potential biomarkers associated with response determined using gene expression profiling [ Time Frame: Up to 6 months ]
    Potential biomarkers associated with response will be assessed in an exploratory manner. Potential markers will be determined using gene expression profiling. The correlation between potential biomarkers and response (responders vs. non-responders) will be evaluated using Fisher's exact and Wilcoxon rank sum tests, where appropriate.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • Diagnosis of multiple myeloma (MM) with deletion 17p (del17p) or monosomy 17 by fluorescence in situ hybridization (FISH) who have received at least one line of therapy
  • Calculated creatinine clearance (using Cockcroft-Gault equation) >= 30 mL/min
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x upper limit of normal (ULN)
  • Total bilirubin =< 1.5 x the upper limit of the normal range (ULN)
  • Absolute neutrophil count (ANC) >= 1500/mm^3
  • Platelet count >= 75,000/mm^3
  • Hemoglobin >= 8.0 g/dL
  • NOTE: white blood count and platelet count criteria must be met without any transfusion or growth factor support
  • Patients with measurable disease defined as at least one of the following:

    • Serum monoclonal protein >= 1.0 g/dL by protein electrophoresis
    • > 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 or 2
  • Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information
  • Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
  • Willing to follow strict birth control measures as suggested below

    • Female patients: if they are of childbearing potential (except if postmenopausal for at least 1 year before the screening visit, OR are surgically sterile), agree to one of the following:

      • Practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR
      • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
    • Male patients: even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following:

      • Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
      • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
  • Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)
  • Willing to provide bone marrow and blood samples for correlative research purposes

Exclusion Criteria:

  • Other malignancy requiring active therapy

    • EXCEPTIONS: Non-melanoma skin cancer, ductal carcinoma in situ (DCIS) or carcinoma-in-situ of the cervix
    • NOTE: if there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer
  • 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 2 peripheral neuropathy, or grade 1 with pain on clinical examination during the screening period
  • Major surgery =< 14 days before study registration
  • All CYP2C8 inhibitors, inducers, and substrates should be discontinued >= 7 days prior to registration; systemic treatment with CYP2C8 inhibitors (anastrozole, montelukast, quercetin, trimethoprim, gemfibrozil, rosiglitazone, pioglitazone), inducers (carbamazepine, phenytoin, rifabutin, rifampin), or substrates (amiodarone, repaglinide, rosiglitazone, sorafenib, torsemide) should be discontinued >= 7 days prior to registration
  • Systemic treatment with strong inhibitors of CYP3A4 (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A4 inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital, Gingko biloba, St. John's wort) are not allowed =< 14 days before registration
  • 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
  • Corrected QT (QTc) > 470 milliseconds (msec) on a 12-lead ECG obtained during the Screening period

    • Note: If a machine reading is above this value, the ECG should be reviewed by a qualified reader and confirmed on a subsequent ECG
  • 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 ixazomib or idasanutlin including difficulty swallowing
  • Diarrhea > grade 1, based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grading, or currently taking antidiarrheals
  • Need for ongoing therapeutic anticoagulation
  • Female patients who are lactating or have a positive serum pregnancy test during the screening period
  • Patients that have previously been treated with ixazomib, or who participated in a blinded 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): NCT02633059


Locations
Layout table for location information
United States, California
City of Hope Comprehensive Cancer Center Recruiting
Duarte, California, United States, 91010
Contact: Michael A. Rosenzweig    626-471-9300    mrosenzweig@coh.org   
Principal Investigator: Michael A. Rosenzweig         
United States, Florida
Mayo Clinic in Florida Recruiting
Jacksonville, Florida, United States, 32224-9980
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Vivek Roy         
United States, Georgia
Emory University Hospital/Winship Cancer Institute Recruiting
Atlanta, Georgia, United States, 30322
Contact: Leonard T Heffner, M.D.    404-778-1900    winship.referrals@emoryhealthcare.org   
Principal Investigator: Leonard T. Heffner, M.D.         
United States, Michigan
University of Michigan Comprehensive Cancer Center Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Craig E. Cole    734-647-8901    colec@med.umich.edu   
Principal Investigator: Craig E. Cole         
Wayne State University/Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Jeffrey A. Zonder    313-576-8732    zonderj@karmanos.org   
Principal Investigator: Jeffrey A. Zonder         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Shaji Kumar         
United States, New Jersey
Hackensack University Medical Center Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Adolfo A. Aleman    551-996-8176    Adolfo.Aleman@Hackensackmeridian.org   
Principal Investigator: Joshua Richter         
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Craig C. Hofmeister    614-293-7807    craig.hofmeiser@osumc.edu   
Principal Investigator: Craig C. Hofmeister         
Sponsors and Collaborators
Mayo Clinic
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Shaji Kumar Mayo Clinic

Layout table for additonal information
Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT02633059     History of Changes
Other Study ID Numbers: MC1582
NCI-2015-02155 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NP29909
X16066
MMRC-061
MC1582 ( Other Identifier: Mayo Clinic )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: December 17, 2015    Key Record Dates
Last Update Posted: July 12, 2018
Last Verified: July 2018

Additional relevant MeSH terms:
Layout table for MeSH terms
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
Ixazomib
BB 1101
Citric Acid
Sodium Citrate
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