Phase II Study of IRD (Ixazomib, Lenalidomide, Dexamethasone) Post Autologous Stem Cell Transplantation Followed by Maintenance Ixazomib or Lenalidomide for Multiple Myeloma

Multiple Myeloma Clinical Trial

Official title:

A Phase II Study of IRD (Ixazomib, Lenalidomide, & Dexamethasone) for Consolidation Therapy Post Autologous Stem Cell Transplantation Followed by Maintenance Ixazomib or Lenalidomide for Multiple Myeloma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02253316
• Other study ID #: 201411060
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: January 20, 2015
• Est. completion date: August 31, 2024

Study information

• Verified date: July 2023
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this research study is to evaluate a treatment regimen called IRD which will be given to participants after their stem cell transplant in an effort to help prolong the amount of time the participants are disease-free after transplant. IRD is a three-drug regimen consisting of ixazomib, lenalidomide (also called Revlimid), and dexamethasone. After 4 cycles of IRD, the participants will be randomized to receive maintenance therapy either with ixazomib or lenalidomide.

Description:

Based on the further need to improve progression-free survival and overall survival post-autologous stem cell transplantation (ASCT) for multiple myeloma and the benefits seen of consolidation/maintenance treatment with immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor bortezomib, the natural next step is to evaluate combination regimens of immunomodulatory drugs and proteasome inhibitors as consolidation/maintenance post-ASCT. The regimen consisting of ixazomib, lenalidomide, and dexamethasone (IRD) has been shown to have low toxicity, and the availability of an oral formulation of ixazomib allows for easier administration when compared to bortezomib.

In this study, following consolidation with IRD, patients will be randomized to maintenance therapy with lenalidomide or ixazomib in order to collect pilot data comparing the toxicity and efficacy of maintenance therapy with immunomodulatory drugs and proteasome inhibitors.

09/23/2019: Upon review of the interim analysis, there will be no further randomizations into the maintenance portion of the trial. All patients will be enrolled into the lenalidomide arm with the exception of those who discontinue lenalidomide during the consolidation phase due to toxicity. Patients who discontinue lenalidomide may be enrolled into the ixazomib arm following approval from the principal investigator.

09/30/2021: Following analysis 4 in 2021, analysis of the primary endpoint, all patients receiving lenalidomide maintenance will be transitioned off-study. Patients receiving ixazomib may remain on trial until disease progression or unacceptable toxicity at the discretion of the treating physician and the site principal investigator.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 236
• Est. completion date: August 31, 2024
• Est. primary completion date: February 5, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria

Each patient must meet all of the following inclusion criteria to begin IRD Consolidation:

• Between the ages of 18 and 70 years of age (inclusive) at time of enrollment

• 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

• Confirmed diagnosis of symptomatic multiple myeloma. (Patients with multiple myeloma with secondary amyloidosis are eligible.)

• Received at least two cycles of any regimen as initial systemic therapy for multiple myeloma and are within 2-16 months of the first dose of initial therapy

• Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or 2

• Adequate organ function as defined below:

Absolute neutrophil count (ANC) >= 1,000 mm^3 Platelet count >= 75,000/mm^3; platelet transfusions to help patient meet eligibility criteria are not allowed within 7 days before study enrollment Total bilirubin <= 1.5 x upper limit of normal range (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=3 x ULN Calculated creatinine clearance >= 30 mL/min

• Women of childbearing potential must follow pregnancy testing requirements as outlined in the Revlimid REMS program material. This is defined as either committing to continued abstinence from heterosexual intercourse or beginning TWO acceptable methods of contraception (one highly effective method and one additional effective method AT THE SAME TIME) at least 28 days prior to the start of lenalidomide, for the duration of study participation, and for 28 days following the last dose of lenalidomide. Women of childbearing potential must also agree to ongoing pregnancy testing.

• Men must agree to use a latex condom during sexual contact with a woman of childbearing potential even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.

• All study participants must be registered into the mandatory Revlimind REMS program and be willing to comply with its requirements. Per standard Revlimid REMS program requirements, all physicians who prescribe lenalidomide for research subjects enrolled into this trial, must be registered in, and must comply with, all requirements of the Revlimid REMS program.

Exclusion Criteria

Patients meeting any of the following exclusion criteria are not to be enrolled in the study:

• Female patients who are lactating or have a positive serum pregnancy test during the screening period

• Evidence of MM disease progression any time prior to enrollment. Progression from smoldering/asymptomatic MM to symptomatic MM is not exclusionary.

• Tandem autologous transplantation

• History of plasma cell leukemia or MM CNS involvement

• Administration or planned administration of any other concomitant chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy which would be considered a treatment of multiple myeloma until Day +28 post-transplant through discontinuation from study. Patients may be on corticosteroids if they are being given for disorders other than multiple myeloma (e.g., adrenal insufficiency, rheumatoid arthritis, etc.)

• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.

• Prior organ transplant requiring immunosuppressive therapy

• Active hepatitis A, B or C virus infection, or known human immunodeficiency virus (HIV) positive

• Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent

• Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib

• Concurrent hematologic or non-hematologic malignancy requiring treatment (other than multiple myeloma and secondary amyloidosis)

• Cardiac syncope, uncompensated NYHA Class 3 or 4 congestive heart failure, myocardial infarction within the previous six months, unstable angina pectoris, clinically significant repetitive ventricular arrhythmias despite antiarrhythmic treatment, severe orthostatic hypotension, or clinically important autonomic disease

• Grade >= 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period

• Major surgery within 14 days prior to enrollment

• Infection requiring systemic antibiotic therapy or other serious infection within 14 days prior to enrollment

• Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days prior to enrollment and throughout the duration of this trial

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Biological:
• Ixazomib

Drug:
• Lenalidomide

• Dexamethasone

Locations

Country	Name	City	State
United States	Emory University - Winship Cancer Institute	Atlanta	Georgia
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Colorado Blood Cancer Institute	Denver	Colorado
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	City of Hope	Duarte	California
United States	Tennessee Oncology, PLLC	Nashville	Tennessee
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of California, San Francisco	San Francisco	California

Sponsors (3)

Lead Sponsor	Collaborator
Washington University School of Medicine	Millennium Pharmaceuticals, Inc., Multiple Myeloma Research Consortium

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Improvement in Minimal Residual Disease (MRD)	For the purposes of this study, a patient will be considered as having minimal residual disease if a positive result (1x10E06) is obtained using the Adaptive Clonoseq MRD testing.	After 4 cycles of IRD consolidation treatment (approximately Day 112 of consolidation treatment)
Secondary	MRD-negative Rate After ASCT	For the purposes of this study, a patient will be considered as having minimal residual disease if a positive result (1x10E06) is obtained using the Adaptive Clonoseq MRD testing	Prior to beginning consolidation treatment (Day -28 to Day 0)
Secondary	Toxicity of IRD Consolidation	For the purposes of this study, toxicity will be defined as inability to receive 4 cycles of IRD consolidation due to toxicity.	After 4 cycles of IRD consolidation treatment (approximately Day 112 of consolidation treatment)
Secondary	Response Rate of IRD Consolidation	For the purposes of this study, response rate is defined as the improvement in complete response rate. Response will be determined by the International Myeloma Working Group (IMWG) Uniform Response Criteria.	After 4 cycles of IRD consolidation treatment (approximately Day 112 of consolidation treatment)
Secondary	Progression-free Survival of IRD Consolidation	Progression-free survival (PFS) will be defined as time from ASCT to progression, relapse, or death, whichever occurs first, and those event-free survivors will be censored at withdrawal or study closeout.	Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study)
Secondary	Overall Survival of IRD Consolidation	Overall survival (OS) will be defined as time from ASCT to death due to any causes, and survivors will be censored at withdrawal or study closeout.	Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study)
Secondary	Compare Toxicity Between the Two Maintenance Arms	The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.	30 days after the completion of maintenance treatment (estimated to be Day 1125 of maintenance treatment)
Secondary	Compare Response Rate Between the Two Maintenance Arms	Response will be determined by the International Myeloma Working Group (IMWG) Uniform Response Criteria. Response includes stringent complete response (sCR) and complete response (CR).; sCR requires all of the following: CR as defined below; Normal free light chain ratio (0.26-1.65); Absence of clonal cells in the bone marrow by immunohistochemistry or immunofluorescence; CR requires all of the following: Disappearance of monoclonal protein by both protein electrophoresis and immunofixation studies from the blood and urine; If serum and urine monoclonal protein are unmeasurable, Normal free light chain ratio (0.26-1.65); <5% plasma cells in the bone marrow; Disappearance of soft tissue plasmacytoma	Through completion of maintenance treatment (estimated to be day 1095 of maintenance treatment)
Secondary	Compare Progression-free Survival Between the Two Maintenance Arms	Progression-free survival (PFS) will be defined as time from ASCT to progression, relapse, or death, whichever occurs first, and those event-free survivors will be censored at withdrawal or study closeout.	Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study)
Secondary	Compare Overall Survival Between the Two Maintenance Arms	Overall survival (OS) will be defined as time from ASCT to death due to any causes, and survivors will be censored at withdrawal or study closeout.	Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study)
Secondary	Rate of MRD-positive to MRD-negative Conversion Between the Two Maintenance Arms		Cycle 13 Day 1 of maintenance treatment (Approximately Day 364 of maintenance treatment)
Secondary	Association of Progression-free Survival With MRD-negativity	Progression-free survival (PFS) will be defined as time from ASCT to progression, relapse, or death, whichever occurs first, and those event-free survivors will be censored at withdrawal or study closeout.	Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study)
Secondary	Association of Progression-free Survival With MRD-positivity	Progression-free survival (PFS) will be defined as time from ASCT to progression, relapse, or death, whichever occurs first, and those event-free survivors will be censored at withdrawal or study closeout.	Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study)
Secondary	Association of Overall Survival With MRD-negativity	Overall survival (OS) will be defined as time from ASCT to death due to any causes, and survivors will be censored at withdrawal or study closeout.	Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study)
Secondary	Association of Overall Survival With MRD-positivity	Overall survival (OS) will be defined as time from ASCT to death due to any causes, and survivors will be censored at withdrawal or study closeout.	Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study)

External Links

•   Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine