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

Phase 1 / 2 Trial of Idasanutlin in Combination With Ixazomib and Dexamethasone in Patients With 17p Deleted, Relapsed Multiple Myeloma

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Recurrent Plasma Cell Myeloma; Loss of Chromosome 17p
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Dexamethasone; Drug: Ixazomib Citrate; Drug: Idasanutlin

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.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
  • Florida
    • Jacksonville, Florida, United States, 32224-9980
      • Mayo Clinic in Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital/Winship Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Dexamethasone; Given PO; Other Names: Decadron; Aacidexam; Adexone; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Amplidermis; Anemul mono; Auricularum; Auxiloson; Baycuten; Baycuten N; Cortidexason; Cortisumman; Decacort; Decadrol; 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: Ninlaro; MLN-9708; MLN9708; Drug: Idasanutlin; Given PO; Other Names: RO5503781; RG7388; RG-7388; RO-5503781

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Participants Who Experienced Dose Limiting Toxicities. Maximum Tolerated Dose (MTD) of Ixazomib Citrate and Idasanutlin in Combination With Dexamethasone (Phase I)	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.	28 days
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)	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.	Up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase I)	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.	30 days after the last dose of study treatment, up to 3 years
Incidence of Adverse Events Graded According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (Phase II)	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.	Up to 6 months
Overall Survival (Phase II)	The distribution of overall survival will be estimated using the method of Kaplan-Meier.	Up to 3 years
Progression Free Survival (Phase II)	The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.	Up to 3 years
Rate of Complete Response (CR) (Phase II)	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.	Up to 6 months
Rate of Partial Response (PR) (Phase II)	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.	Up to 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Macrophage Inhibitory Cytokine-1 (MIC) Levels	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.	Baseline up to 6 months
Impact of MDM2 Inhibition on Activation of p53 and Clonal Selection	Impact of MDM2 inhibition on activation of p53 and clonal selection examined using gene expression profiling and exome sequencing	Up to 6 months
Potential Biomarkers Associated With Response Determined Using Gene Expression Profiling	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.	Up to 6 months

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Shaji Kumar, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): December 30, 2015
• Primary Completion (Actual): January 31, 2021
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: December 15, 2015
• First Submitted That Met QC Criteria: December 15, 2015
• First Posted (Estimated): December 17, 2015

Study Record Updates

• Last Update Posted (Actual): September 28, 2023
• Last Update Submitted That Met QC Criteria: September 21, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Dermatologic Agents; Glycine Agents; Dexamethasone; Dexamethasone acetate; BB 1101; Ixazomib; Glycine; Ichthammol
• Other Study ID Numbers: MC1582 (Other Identifier: Mayo Clinic); NCI-2015-02155 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); NP29909 (Other Identifier: Genentech); X16066 (Other Identifier: Millennium Pharmaceuticals, Inc.); MMRC-061 (Other Identifier: MMRF)