A Study of Ixazomib Administered in Combination With Lenalidomide and Low-Dose Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma

NCT01217957 | Completed Phase 1 Results

• 2 other identifiers: C16005U1111-1176-7340
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 16

Brief Summary

The purpose of Phase 1 of this study was to determine the safety, tolerability, maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of oral ixazomib administered in combination with lenalidomide and low-dose dexamethasone in participants with newly diagnosed multiple myeloma (NDMM). The purpose of Phase 2 of this study was to determine the overall response rate (ORR) and further evaluate the tolerability and toxicity of the combination of oral ixazomib, lenalidomide, and low-dose dexamethasone in patients with NDMM.

Conditions

Multiple Myeloma

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (5)

• Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability

  An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.

  Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days)

• Phase 2: Objective Response Rate (ORR) Following Treatment With the Combination Of Oral Ixazomib, Lenalidomide And Low-Dose Dexamethasone

  ORR was defined as the percentage of participants with Complete (CR) + Very Good Partial Response (VGPR) assessed by the investigatory using International Myeloma Working Group (IMWG) Criteria. CR=Negative immunofixation on the serum and urine and; disappearance of any soft tissue plasmacytomas and; \< 5% plasma cells in bone marrow. VGPR=Serum and urine M-protein detectable by immunofixation but not on electrophoresis or; 90% or greater reduction in serum M-protein plus urine M-protein level \< 100 mg per 24 hours.

  Until occurrence of progressive disease or unacceptable toxicity (Up to 787 days)

• Phase 1: Recommended Phase 2 Dose of Ixazomib Given in Combination With Lenalidomide and Low-Dose Dexamethasone

  RP2D will be determined based on number and type of adverse event and serious adverse events, assessments of clinical laboratory values, neurotoxicity grading, and treatment discontinuation.

  Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days)

• Phase 1: Maximum Tolerated Dose (MTD) of Ixazomib Administered Weekly in Combination With Lenalidomide and Low-Dose Dexamethasone

  MTD of ixazomib will be determined by assessing adverse events and serious adverse events, clinical laboratory values, neurotoxicity grading, and vital sign measurements.

  Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days)

• Phase 2: Percentage of Participants With Grade 3 or Higher AEs, SAEs and Treatment Discontinuation

  An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.

  Until occurrence of progressive disease or unacceptable toxicity (Up to 787 days)

Secondary Outcomes (15)

• Phase 1: Cmax: Maximum Observed Plasma Concentration for Ixazomib

  Cycle 1, Days 1 and 15

• Phase 1: Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Ixazomib

  Cycle 1, Days 1 and 15

• Phase 1: AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for Ixazomib

  Cycle 1, Days 1 and 15

• Phase 1: Rac: Accumulation Ratio of Ixazomib

  Cycle 1, Day 15

• Phase 1: Emax: Maximum Observed Inhibition of Whole Blood 20S Proteasome

  Day 1 predose and at multiple time points (up to 168 hours) postdose and Day 15 predose and at multiple time points (up to 336 hours) postdose

Study Arms (5)

Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + Dexamethasone

EXPERIMENTAL

In phase 1, ixazomib 1.68 mg/m\^2, capsules, orally, once, on Days 1, 8 and 15; plus dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15 and 22; and lenalidomide 25 mg, capsules, orally, once on Days 1 through 21 of a 28-day cycle for up to 12 cycles. Cycle 13 and beyond, single agent ixazomib 1.68 mg/m\^2, capsules, orally, once on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.

Drug: Ixazomib; Drug: Lenalidomide; Drug: Dexamethasone

Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone

EXPERIMENTAL

In phase 1, ixazomib 2.23 mg/m\^2, capsules, orally, once, on Days 1, 8 and 15; plus dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15 and 22; and lenalidomide 25 mg, capsules, orally, once on Days 1 through 21 of a 28-day cycle for up to 12 cycles. Cycle 13 and beyond, single agent ixazomib 2.23 mg/m\^2, capsules, orally, once on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.

Drug: Ixazomib; Drug: Lenalidomide; Drug: Dexamethasone

Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone

EXPERIMENTAL

In phase 1, ixazomib 2.97 mg/m\^2, capsules, orally, once, on Days 1, 8 and 15; plus dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15 and 22; and lenalidomide 25 mg, capsules, orally, once on Days 1 through 21 of a 28-day cycle for up to 12 cycles. Cycle 13 and beyond, single agent ixazomib 2.97 mg/m\^2, capsules, orally, once on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.

Drug: Ixazomib; Drug: Lenalidomide; Drug: Dexamethasone

Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + Dexamethasone

EXPERIMENTAL

In phase 1, ixazomib 3.95 mg/m\^2, capsules, orally, once, on Days 1, 8 and 15; plus dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15 and 22; and lenalidomide 25 mg, capsules, orally, once on Days 1 through 21 of a 28-day cycle for up to 12 cycles. Cycle 13 and beyond, single agent ixazomib 3.95 mg/m\^2, capsules, orally, once on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.

Drug: Ixazomib; Drug: Lenalidomide; Drug: Dexamethasone

Phase 2: Ixazomib 4.0 mg + Lenalidomide + Dexamethasone

EXPERIMENTAL

In phase 2, ixazomib 4.0 mg fixed dose, capsules, orally, once, on Days 1, 8 and 15; plus dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15 and 22; and lenalidomide 25 mg, capsules, orally, once on Days 1 through 21 of a 28-day cycle for up to 12 cycles. Cycle 13 and beyond, single agent ixazomib 4.0 mg fixed dose, capsules, orally, once on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.

Drug: Ixazomib; Drug: Lenalidomide; Drug: Dexamethasone

Interventions

Ixazomib DRUG

Ixazomib capsules

Also known as: MLN9708, NINLARO®

Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + Dexamethasone; Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone; Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone; Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + Dexamethasone; Phase 2: Ixazomib 4.0 mg + Lenalidomide + Dexamethasone

Lenalidomide DRUG

Lenalidomide capsules

Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + Dexamethasone; Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone; Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone; Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + Dexamethasone; Phase 2: Ixazomib 4.0 mg + Lenalidomide + Dexamethasone

Dexamethasone DRUG

Dexamethasone tablets

Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + Dexamethasone; Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone; Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone; Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + Dexamethasone; Phase 2: Ixazomib 4.0 mg + Lenalidomide + Dexamethasone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Each patient must meet all of the following eligibility criteria to be enrolled in the study:
• Male or female patients 18 years or older
• Previously untreated multiple myeloma diagnosed according to standard criteria requiring systemic treatment
• Patients must have measurable disease
• Nonsecretory multiple myeloma based upon standard M-component criteria (i.e., measurable serum/urine M-component) is not allowed unless the baseline serum free light chain level (Freelite™) is evaluated Patients must meet clinical laboratory criteria as specified in study protocol
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• Female and male patients MUST adhere to the guidelines of the lenalidomide pregnancy prevention program
• Must be able to take concurrent aspirin 325 mg daily
• Voluntary written consent

You may not qualify if:

• Peripheral neuropathy that is greater or equal to Grade 2
• Female patients who are lactating or pregnant
• Major surgery or radiotherapy within 14 days before the first dose of study drug
• Serious infection requiring systemic antibiotic therapy within 14 days before the first dose of study drug
• Diarrhea greater than Grade 1 based on the National Cancer Institute Common Terminology Criteria for Adverse Events
• Central nervous system involvement.
• Evidence of current uncontrolled cardiovascular conditions within the past 6 months
• Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection
• Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol
• Known gastrointestinal condition that could interfere with swallowing or the oral absorption or tolerance of ixazomib
• No other prior malignancy within 2 years except nonmelanoma skin cancer or carcinoma in situ of any type if they have undergone complete resection

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (16)

Mayo Clinic Arizona

Scottsdale, Arizona, 85259, United States

Location

Cedars Sinai Medical Center

Los Angeles, California, 90048, United States

Location

Rocky Mountain Cancer Center Rose

Denver, Colorado, 80218, United States

Location

Cancer Center of Central Connecticut

Southington, Connecticut, 06489, United States

Location

Mayo Clinic Jacksonville

Jacksonville, Florida, 32224, United States

Location

Mt Sinai Medical Center

Miami Beach, Florida, 33140, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Harry and Jeannette Weinberg Cancer Center at Franklin Square Hospital

Baltimore, Maryland, 21215, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

New York Presbyterian Hospital - Weill-Cornell

New York, New York, 10021, United States

Location

Sarah Cannon Cancer Center

Nashville, Tennessee, 37203, United States

Location

W VA University Mary Babb Randolph Cancer Center

Morgantown, West Virginia, 26506, United States

Location

The Medical College of Wisconsin, Inc.

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (2)

• Gupta N, Yang H, Hanley MJ, Zhang S, Liu R, Kumar S, Richardson PG, Skacel T, Venkatakrishnan K. Dose and Schedule Selection of the Oral Proteasome Inhibitor Ixazomib in Relapsed/Refractory Multiple Myeloma: Clinical and Model-Based Analyses. Target Oncol. 2017 Oct;12(5):643-654. doi: 10.1007/s11523-017-0524-3.

  PMID: 28803351 DERIVED

• Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Di Bacco A, Estevam J, Gupta N, Hui AM, Rajkumar V, Richardson PG. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014 Dec;15(13):1503-1512. doi: 10.1016/S1470-2045(14)71125-8. Epub 2014 Nov 14.

  PMID: 25456369 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

ixazomib; Lenalidomide; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Results Point of Contact

• Title: Medical Director, Clinical Science
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Monitor

  Millennium Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 24, 2010
• First Posted: October 8, 2010
• Study Start: November 22, 2010
• Primary Completion: March 8, 2013
• Study Completion: February 2, 2018
• Last Updated: March 14, 2018
• Results First Posted: January 27, 2016

Record last verified: 2018-03

Locations

US (16)