Ixazomib and Pevonedistat in Treating Patients With Multiple Myeloma That Has Come Back or Does Not Respond to Treatment

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Active, not recruiting

CT.gov ID

NCT03770260

Collaborator

(none)

Enrollment

Locations

Arm

Anticipated Duration (Months)

4.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase Ib trial studies side effects and best dose of pevonedistat when given together with ixazomib in treating patients with multiple myeloma that has come back or does not respond to treatment. Pevonedistat and ixazomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma	Drug: Ixazomib Citrate Drug: Pevonedistat	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

Determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of MLN4924 (pevonedistat) in combination with MLN9708 (ixazomib citrate [ixazomib]) in relapsed and/or refractory multiple myeloma (RRMM) patients after more than one previous line of treatment. (Dose-escalation phase) II. Describe the safety profile and tolerability of the combination of MLN9708 (ixazomib) and MLN4924 (pevonedistat) in the proteasome inhibitor (PI)-sensitive and PI-refractory populations. (Dose-expansion phase) III. Determine the anti-tumor activity and overall response rates (ORR) in patients with RRMM with the use of MLN9708 (ixazomib) and MLN4924 (pevonedistat) in combination. (Dose-expansion phase)

SECONDARY OBJECTIVE:

Attain pharmacokinetic (PK) characterization of MLN4924 (pevonedistat) in combination with MLN9708 (ixazomib) for the purpose of understanding concentration-effect relationships of both agents. (Dose-escalation phase)

EXPLORATORY OBJECTIVE:

To correlate and predict disease response using the following tests: NAD(P)H dehydrogenase (quinone) 1 (NQO1) and cystine/glutamate transporter (SLC7A11) (nuclear factor [erythroid-derived 2]-like 2 [NRF2] target genes): evaluated on whole blood as markers of MLN4924 (pevonedistat) activity.

OUTLINE: This is a dose-escalation study of pevonedistat.

Patients receive ixazomib citrate orally (PO) once daily (QD) on days 1, 8, and 15 of each cycle and pevonedistat intravenously (IV) over 60 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then every 2-3 months for up to 2 years.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

42 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

MLN9708 (Ixazomib) and MLN4924 (Pevonedistat) in Relapsed/Refractory Multiple Myeloma Patients: A Phase 1b Trial

Actual Study Start Date :

Apr 23, 2019

Anticipated Primary Completion Date :

Apr 23, 2023

Anticipated Study Completion Date :

Apr 23, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (ixazomib citrate, pevonedistat) Patients receive ixazomib citrate PO QD on days 1, 8, and 15 of each cycle and pevonedistat IV over 60 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Ixazomib Citrate Given PO Other Names: MLN-9708 MLN9708 Ninlaro Drug: Pevonedistat Given IV Other Names: MLN4924 Nedd8-Activating Enzyme Inhibitor MLN4924

Arm

Intervention/Treatment

Experimental: Treatment (ixazomib citrate, pevonedistat)

Patients receive ixazomib citrate PO QD on days 1, 8, and 15 of each cycle and pevonedistat IV over 60 minutes on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Ixazomib Citrate

Given PO

Other Names:

MLN-9708

MLN9708

Ninlaro

Drug: Pevonedistat

Given IV

Other Names:

MLN4924

Nedd8-Activating Enzyme Inhibitor MLN4924

Outcome Measures

Primary Outcome Measures

Incidence of adverse events [Up to 30 days]
Descriptive statistics will be provided for selected safety data by dose and time as appropriate.
Maximum tolerated dose of pevonedistat and ixazomib citrate [Up to cycle 1]
All patients who receive any amount of the study drug will be evaluable for toxicity. The primary analysis will occur after all patients have either discontinued the study or completed at least 6 months of treatment.
Overall response rates [Up to 2 years]
Best overall response categories will be tabulated by dose cohort and overall for the IMWG categories of stringent complete response, complete response, very good partial response, partial response (PR), stable disease, progressive disease, and relapse and the European Group for Blood and Marrow Transplantation (EBMT) category of minimal response. A two-sided 95% exact binominal confidence intervals (CI) will be calculated for each category. The myeloma response rate (responses >= PR) will also be tabulated by dose cohort and overall. The myeloma response rate and each of the best overall response categories will be compared between dose cohorts with Chi-square test.

Secondary Outcome Measures

Pharmacokinetics (PK) characterization of pevonedistat in combination with ixazomib citrate [Cycle 1, day 1 at pre-dose, 0.5, 1, 2, 2.5, 5, 8, and 21 hours]
Descriptive statistics will be provided for selected PK data by dose and time as appropriate. Pevonedistat concentrations in these samples will be quantitatively measured using a liquid chromatography/tandem mass spectrometry (liquid Chromatography with tandem mass spectrometry [LC/MS/MS]) method in place at Covance under contract with Takeda. For pevonedistat, the individual PK parameters from a single dose will be estimated for maximum concentration (Cmax), area under the curve (AUC), half-life (t1/2), apparent CL/F, and apparent volume of distribution (V/F) using non-compartmental or compartmental PK methods with the software WinNonlin. Advanced population PK methods may be employed to assess the link between drug exposure and biological effects and efficacy.

Other Outcome Measures

Biomarker analysis of NQO1 and SLC7A11 [Up to 2 years]
Descriptive statistics will first be used to summarize their gene expression in whole blood by Reverse transcription-polymerase chain reaction (RT-PCR). Biomarker data will also be displayed graphically, where appropriate. Depending on whether data is normally distributed, Person or Spearman's correlation coefficient will be used to measure the correlations of NQO1 and SLC7A11 with the dosage of pevonedistat, and then tested with Wald's test. General Linear Model (GLM) will be used to compare each of the biomarkers (NQO1 and SLC7A11) between different dose levels of pevonedistat with and without adjusting for other factors. Logistics regression model will be further employed to test the adjusted effect of each biomarkers (NQO1 and SLC7A11) on the response rate after adjusting for dosage of pevonedistat as well as other factors.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must have RRMM with measurable disease, as defined by at least one of the following:
Serum monoclonal protein >= 0.5 g/dL
Urinary monoclonal protein excretion of >= 200 mg/24 hours
Kappa or lambda light chain level >= 10 mg/dL with an abnormal free light chain ratio
At least two prior lines of therapy and all patients should have at least been exposed to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody.
For proteasome-sensitive expansion cohort: Patients with MM who relapsed or are refractory to a prior line of therapy not including a proteasome inhibitor
For proteasome-relapsed/refractory expansion cohort: Patients with MM who have relapsed after prior PI exposure or are PI-refractory, defined as nonresponsive to treatment or progresses within 60 days of last exposure to a PI
Age >= 18 years
Because no dosing or adverse event (AE) data are currently available on the use of MLN4924 (pevonedistat) in combination with MLN9708 (ixazomib) in patients < 18 years of age, and as this disease is exceptionally uncommon in this age group, children are excluded from this study
Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
Leukocytes >= 3,000/mcL
Absolute neutrophil count >= 1,000/mcL
Platelets >= 75,000/mcL
Bilirubin =< institutional upper limit of normal (ULN).
Patients with Gilbert's syndrome may enroll if direct bilirubin =< 1.5 x ULN
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN
Creatinine clearance (CrCl) by Cockcroft-Gault >= 30 mL/min
Known human immunodeficiency virus (HIV) positive patients who meet the following criteria will be considered eligible:
CD 4 count > 350 cells/mm^3
Undetectable viral load
Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents (e.g. excluding ritonavir)
No history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections
The effects of MLN4924 (pevonedistat) and MLN9708 (ixazomib) on the developing human fetus are unknown. For this reason and because NAE inhibitory agents are known to be teratogenic, women of child-bearing potential and men must meet the following criteria:
Female patients who are:
Postmenopausal for at least one year before the screening visit, OR
Surgically sterile, OR
If of childbearing potential, agree to practice 1 highly effective method and 1 additional (barrier) method of contraception, at the same time, from the time of signing the informed consent until 4 months after the last dose of the ixazomib and pevonedistat (female and male condoms should not be used together), or agree to abstain from heterosexual intercourse, when this is in line with the preferred and usual lifestyle of the subject (Periodic abstinence [e.g,, calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception)
Male patients, even if surgically sterilized, who:
Agree to practice effective barrier contraception during the entire time enrolled on study through 4 months after completion of ixazomib and pevonedistat administration (female and male condoms should not be used together), OR
Agree to abstain from heterosexual intercourse, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception)
Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible

Exclusion Criteria:

Diagnosed or treated for another malignancy within 2 years before randomization 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 resection
Patients who are receiving any other investigational agents, within 30 days of the start of this trial and throughout the duration of this trial
Patients with known central nervous system involvement should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other AEs
History of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN4924 (pevonedistat) or MLN9708 (ixazomib) (including boron or boron-containing products)
Patients with uncontrolled intercurrent illness
Pregnant women are excluded from this study because MLN4924 (pevonedistat) is an NAE inhibitory agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with MLN4924 (pevonedistat), breastfeeding should be discontinued if the mother is treated with MLN4924 (pevonedistat). These potential risks may also apply to the use of MLN9708 (ixazomib) in this study
Major surgery within 14 days before the first dose of any study drug or a scheduled surgery during study period
Patients with uncontrolled coagulopathy or bleeding disorder
Known hepatic impairment as defined by known hepatic cirrhosis, hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection
Note: Patients who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load
Known cardiopulmonary disease defined as:
Unstable angina;
Congestive heart failure (New York Heart Association [NYHA] class III or IV);
Myocardial infarction within 6 months prior to first dose (patients who had ischemic heart disease such as acute coronary syndrome [ACS], myocardial infarction, and/or revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll);
Symptomatic cardiomyopathy
Clinically significant arrhythmia:
History of polymorphic ventricular fibrillation or torsade de pointes,
Permanent atrial fibrillation, defined as continuous atrial fibrillation for

= 6 months,

Persistent atrial fibrillation, defined as sustained atrial fibrillation lasting > 7 days and/or requiring cardioversion in the 4 weeks before screening,
Grade 3 atrial fibrillation defined as symptomatic and incompletely controlled medically, or controlled with device (e.g., pacemaker), or ablation in the past 6 months and
Patients with paroxysmal atrial fibrillation or grade < 3 atrial fibrillation for period of at least 6 months are permitted to enroll provided that their rate is controlled on a stable regimen
Clinically significant pulmonary hypertension requiring pharmacologic therapy
Uncontrolled high blood pressure (i.e., systolic blood pressure > 180 mmHg, diastolic blood pressure > 95 mmHg)
Prolonged rate corrected QT (QTc) interval >= 500 msec, calculated according to institutional guidelines
Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram
Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, and pulmonary fibrosis
Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 (ixazomib), including difficulty swallowing
Peripheral neuropathy that is grade >= 3, or grade 2 with pain on clinical examination during the screening period
Patients that have previously been treated with MLN9708 (ixazomib)
Systemic treatment, within 14 days before the first dose of MLN9708 (ixazomib), with strong CYP3A inducers (rifampin, rifapentine, rifabutin, ritonavir, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort. Clinically significant metabolic enzyme inducers are not permitted during this study
Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the MLN9708 (ixazomib)
Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s)
Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Smilow Cancer Center/Yale-New Haven Hospital	New Haven	Connecticut	United States	06510
2	Yale University	New Haven	Connecticut	United States	06520
3	Moffitt Cancer Center-International Plaza	Tampa	Florida	United States	33607
4	Moffitt Cancer Center - McKinley Campus	Tampa	Florida	United States	33612
5	Moffitt Cancer Center	Tampa	Florida	United States	33612
6	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia	United States	30322
7	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
8	Duke University Medical Center	Durham	North Carolina	United States	27710
9	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210