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

Multiple Myeloma Clinical Trial

Official title:

An Open-Label, Dose-Escalation, Phase 1/2 Study of the Oral Form of Ixazomib (MLN9708), a Second-Generation Proteasome Inhibitor, Administered in Combination With Lenalidomide and Low-Dose Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Requiring Systemic Treatment

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01217957
• Other study ID #: C16005
• Secondary ID: U1111-1176-7340
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: September 24, 2010
• Last updated: March 12, 2018
• Start date: November 22, 2010
• Est. completion date: February 2, 2018

Study information

• Verified date: March 2018
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

The drug being tested in this study is called ixazomib. Ixazomib was being tested to treat people who had newly diagnosed multiple myeloma who had not previously received systemic treatment. This study was conducted in two Phases. Phase 1 looked at side effects and lab results in people who took ixazomib to determine the MTD and RP2D. Phase 2 looked at overall response rates and side effects in people who took ixazomib.

The study enrolled 15 patients in Phase 1 and 50 patients in Phase 2. Participants in Phase 1 were assigned to cohorts and received ixazomib 1.68, 2.23, 2.97, or 3.95 mg/m^2 in addition to dexamethasone 40 mg and lenalidomide 25 mg. Participants in Phase 2 received ixazomib 4.0 mg fixed dose in addition to dexamethasone 40 mg and lenalidomide 25 mg. In both Phases study treatment was administered in 28-day Cycles as follows: ixazomib Days 1, 8 and 15, dexamethasone Days 1, 8, 15 and 22, and lenalidomide 25 mg Days 1 through 21.

This multi-center trial was conducted in the United States. The overall time to participate in this study was 12, 28-day cycles with the option to continue into a maintenance portion in the absence of disease progression or unacceptable toxicity. Participants made multiple visits to the clinic and a final visit 30 days after last dose of study drug for a follow-up assessment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 65
• Est. completion date: February 2, 2018
• Est. primary completion date: March 8, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

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

Exclusion Criteria

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

• 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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Ixazomib
Ixazomib capsules
• Lenalidomide
Lenalidomide capsules
• Dexamethasone
Dexamethasone tablets

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	Harry and Jeannette Weinberg Cancer Center at Franklin Square Hospital	Baltimore	Maryland
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Rocky Mountain Cancer Center Rose	Denver	Colorado
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	Mayo Clinic Jacksonville	Jacksonville	Florida
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Mt Sinai Medical Center	Miami Beach	Florida
United States	The Medical College of Wisconsin, Inc.	Milwaukee	Wisconsin
United States	W VA University Mary Babb Randolph Cancer Center	Morgantown	West Virginia
United States	Sarah Cannon Cancer Center	Nashville	Tennessee
United States	New York Presbyterian Hospital - Weill-Cornell	New York	New York
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University	Saint Louis	Missouri
United States	Mayo Clinic Arizona	Scottsdale	Arizona
United States	Cancer Center of Central Connecticut	Southington	Connecticut

Sponsors (1)

Lead Sponsor	Collaborator
Millennium Pharmaceuticals, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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	Phase 1: Cmax: Maximum Observed Plasma Concentration for Ixazomib	Cmax: Maximum Observed Plasma Concentration (Cmax) is the peak plasma concentration of ixazomib obtained directly from the plasma concentration-time curve.	Cycle 1, Days 1 and 15
Secondary	Phase 1: Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Ixazomib	Tmax: Time to reach the first maximum observed plasma concentration (Cmax), equal to time (hours) to Cmax, obtained directly from the plasma concentration-time curve.	Cycle 1, Days 1 and 15
Secondary	Phase 1: AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for Ixazomib	AUC(0-168) is a measure of the area under the plasma concentration-time curve from time 0 to 168 hours postdose for Ixazomib.	Cycle 1, Days 1 and 15
Secondary	Phase 1: Rac: Accumulation Ratio of Ixazomib	The accumulation ratio (Rac) was estimated as the ratio of AUC(0-168) on Day 15 to the AUC(0-168) on Day 1. AUC(0-168) is the area under the plasma concentration-time curve from time 0 to 168 hours postdose for ixazomib.	Cycle 1, Day 15
Secondary	Phase 1: Emax: Maximum Observed Inhibition of Whole Blood 20S Proteasome	Emax is the maximum observed inhibition of whole blood 20S proteasome. The pharmacodynamics 20S Proteasome samples were collected and the assays were performed; however, concerns about the third-party laboratory's performance of the blood 20S proteasome activity assay were identified that precluded the ability to confirm the accuracy of the data so no data is reported.	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
Secondary	Phase 1: TEmax: Time to the Maximum Observed Inhibition of Whole Blood 20S Proteasome	TEmax is the time to the maximum observed inhibition of whole blood 20S proteasome. The pharmacodynamics 20S Proteasome samples were collected and the assays were performed; however, concerns about the third-party laboratory's performance of the blood 20S proteasome activity assay were identified that precluded the ability to confirm the accuracy of the data so no data is reported.	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
Secondary	Phase 2: Time to Progression (TTP)	TTP was measured as the time in months from the first dose of study treatment to the date of the first documented progressive disease (PD).	From the first dose of study treatment to the date of first documented progressive disease (Up to 787 days)
Secondary	Phase 2: Overall Survival (OS)	OS was measured as the time in months from the first dose of study treatment to the date of death + 1 day.	From the first dose of study treatment to the date of death (up to 787 days)
Secondary	Phase 2: Overall Response Rate (ORR)	ORR was defined as the percentage of participants with CR, VGPR and Partial Response (PR) assessed by the investigator using IMWG criteria. CR=Negative immunofixation on the serum and urine + Disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow. PR=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by 90% or to < 200 mg per 24 hours. 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.	Up to 787 days
Secondary	Phase 2: Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR)	Response was assessed by the investigator using International Myeloma Working Group (IMWG) Criteria. CR is defined as negative immunofixation on the serum and urine and; disappearance of any soft tissue plasmacytomas and; < 5% plasma cells in bone marrow. VGPR is defined as 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.	After Cycles 3, 6 and 9 (Up to 787 days)
Secondary	Phase 2: Percentage of Participants With Complete Response (CR), Stringent Complete Response (sCR), Very Good Partial Response (VGPR), Near Complete Response (nCR), Partial Response (PR) and Minimal Response (MR)	Response was assessed by the investigator using International Myeloma Working Group (IMWG) Criteria. CR=Negative immunofixation on the serum and urine + Disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow. sCR= CR + Normal free light chain (FLC) ratio and Absence of clonal cells in bone marrow. PR==50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by =90% or to < 200 mg per 24 hours. 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. nCR=Positive immunofixation analysis of serum or urine as the only evidence of disease. Disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow. MR=25% to 49% reduction in serum paraprotein and 50% to 89% reduction in urine light chain excretion for 6 weeks.	Cycles 3, 6, 9 and 12 (Up to 787 days)
Secondary	Phase 2: Time to Best Response	Time to Best Response was measured as the time in months from the first dose of study treatment to the date of first documented documentation of a confirmed response of partial response (PR) or better.	Up to 787 days
Secondary	Phase 2: Duration of Response (DOR)	DOR was measured as the time in months from the date of first documentation of a confirmed response (CR + PR+ VGPR) to the date of the first documented disease progression (PD). Response was assessed by the investigator 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.	Up to 787 days
Secondary	Phase 2: Progression Free Survival (PFS)	PFS was measured as the time in months from the first dose of study treatment to the date of the first documented PD or death.	Up to 787 days
Secondary	Phase 2: 1 Year Survival Rate	1-year survival rate is defined as the percentage of participants still alive at year after the first dose of stud drug.	1 year after first dose of study drug