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NCT01217957

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

Completed Phase 1, PHASE2 Results posted Last updated 14 March 2018
What this trial tests

Phase 1, PHASE2 trial testing Ixazomib in Multiple Myeloma in 65 participants. Completed in 2 February 2018.

Timeline
22 November 2010
Primary endpoint
8 March 2013
2 February 2018

Quick facts

Lead sponsorMillennium Pharmaceuticals, Inc.
PhasePhase 1, PHASE2
StatusCompleted
Study typeINTERVENTIONAL
Allocationnon randomized
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment65
Start date22 November 2010
Primary completion8 March 2013
Estimated completion2 February 2018
Sites16 locations across United States

Drugs / interventions tested

Conditions studied

Sponsor

Millennium Pharmaceuticals, Inc. — full company profile →

Who can join

18 and older, any sex, with Multiple Myeloma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability Primary · Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days)

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 prol

Any AE
GroupValue95% CI
Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + Dexamethasone3
Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone3
Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone6
Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + Dexamethasone3
SAE
GroupValue95% CI
Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + Dexamethasone2
Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone3
Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone1
Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + Dexamethasone2
Phase 2: Objective Response Rate (ORR) Following Treatment With the Combination Of Oral Ixazomib, Lenalidomide And Low-Dose Dexamethasone Primary · Until occurrence of progressive disease or unacceptable toxicity (Up to 787 days)

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.

GroupValue95% CI
Phase 2: Ixazomib 4.0 mg + Lenalidomide + Dexamethasone5944 – 73
Phase 2: Ixazomib 4.0mg/2.23 + Lenalidomide + Dexamethasone6247 – 75
Phase 1: Recommended Phase 2 Dose of Ixazomib Given in Combination With Lenalidomide and Low-Dose Dexamethasone Primary · Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days)

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.

GroupValue95% CI
Phase 1: Ixazomib + Lenalidomide + Dexamethasone2.23
Phase 1: Maximum Tolerated Dose (MTD) of Ixazomib Administered Weekly in Combination With Lenalidomide and Low-Dose Dexamethasone Primary · Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days)

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

GroupValue95% CI
Phase 1: Ixazomib + Lenalidomide + Dexamethasone2.97
Phase 2: Percentage of Participants With Grade 3 or Higher AEs, SAEs and Treatment Discontinuation Primary · Until occurrence of progressive disease or unacceptable toxicity (Up to 787 days)

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 prol

Grade 3 or Higher AEs
GroupValue95% CI
Phase 2 :Ixazomib 4.0 mg + Lenalidomide + Dexamethasone76
Phase 2: Ixazomib 4.0 mg/2.23 + Lenalidomide + Dexamethasone75
SAEs
GroupValue95% CI
Phase 2 :Ixazomib 4.0 mg + Lenalidomide + Dexamethasone40
Phase 2: Ixazomib 4.0 mg/2.23 + Lenalidomide + Dexamethasone43
AEs Resulting in Treatment Discontinuation
GroupValue95% CI
Phase 2 :Ixazomib 4.0 mg + Lenalidomide + Dexamethasone8
Phase 2: Ixazomib 4.0 mg/2.23 + Lenalidomide + Dexamethasone8
Phase 1: Cmax: Maximum Observed Plasma Concentration for Ixazomib Secondary · Cycle 1, Days 1 and 15

Cmax: Maximum Observed Plasma Concentration (Cmax) is the peak plasma concentration of ixazomib obtained directly from the plasma concentration-time curve.

Day 1 (n=1, 3, 4, 1)
GroupValue95% CI
Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + DexamethasoneNA± NA
Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone22.303± 13.0184
Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone94.779± 34.5442
Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + DexamethasoneNA± NA
Day 15 (n=2, 3, 4, 1)
GroupValue95% CI
Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + Dexamethasone11.999± NA
Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone31.368± 31.9963
Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone53.517± 22.1412
Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + DexamethasoneNA± NA
Phase 1: Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Ixazomib Secondary · Cycle 1, Days 1 and 15

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.

Day 1 (n=1, 3, 4, 1)
GroupValue95% CI
Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + Dexamethasone1.020NA – NA
Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone1.5201.00 – 8.00
Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone1.0600.50 – 1.08
Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + Dexamethasone0.250NA – NA
Day 15 (n=2, 3, 4, 1)
GroupValue95% CI
Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + Dexamethasone4.1651.05 – 7.28
Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone1.0000.98 – 2.03
Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone1.0151.00 – 2.02
Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + Dexamethasone2.000NA – NA
Phase 1: AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for Ixazomib Secondary · Cycle 1, Days 1 and 15

AUC(0-168) is a measure of the area under the plasma concentration-time curve from time 0 to 168 hours postdose for Ixazomib.

Day 1 (n=1, 3, 4, 1)
GroupValue95% CI
Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + DexamethasoneNA± NA
Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone587.667± 350.1861
Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone923.484± 156.2679
Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + DexamethasoneNA± NA
Day 15 (n=2, 3, 3, 1)
GroupValue95% CI
Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + Dexamethasone834.608± NA
Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone1083.998± 104.0256
Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone1831.324± 262.7420
Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + DexamethasoneNA± NA
Phase 1: Rac: Accumulation Ratio of Ixazomib Secondary · Cycle 1, Day 15

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.

GroupValue95% CI
Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + DexamethasoneNA± NA
Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone1.849± 0.8359
Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone2.051± 0.6469
Phase 2: Time to Progression (TTP) Secondary · From the first dose of study treatment to the date of first documented progressive disease (Up to 787 days)

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).

GroupValue95% CI
Phase 2: Ixazomib 4.0 mg + Lenalidomide + DexamethasoneNANA – NA
Phase 2: Ixazomib 4.0 mg/2.23 + Lenalidomide + DexamethasoneNANA – NA
Phase 2: Overall Survival (OS) Secondary · From the first dose of study treatment to the date of death (up to 787 days)

OS was measured as the time in months from the first dose of study treatment to the date of death + 1 day.

GroupValue95% CI
Phase 2: Ixazomib 4.0 mg + Lenalidomide + DexamethasoneNANA – NA
Phase 2: Ixazomib 4.0 mg/2.23 + Lenalidomide + DexamethasoneNANA – NA
Phase 2: Overall Response Rate (ORR) Secondary · Up to 787 days

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.

GroupValue95% CI
Phase 2: Ixazomib 4.0 mg + Lenalidomide + Dexamethasone8875 – 95
Phase 2: Ixazomib 4.0 mg/2.23 + Lenalidomide + Dexamethasone8877 – 96

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to 787 days. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Phase 1: Ixazomib + Lenalidomide + Dexamethasone
Serious: 8/15 (53%)
Deaths:
Phase 2: Ixazomib 4.0 mg + Lenalidomide + Dexamethasone
Serious: 20/50 (40%)
Deaths:

Serious adverse events (46 terms)

ReactionSystemPhase 1: Ixazomib + Lenali…Phase 2: Ixazomib 4.0 mg +…
PneumoniaInfections and infestations
DehydrationMetabolism and nutrition disorders
Back painMusculoskeletal and connective tissue disorders
DiarrhoeaGastrointestinal disorders
Non-cardiac chest painGeneral disorders
Cardiac failure congestiveCardiac disorders
DiverticulitisInfections and infestations
Bone abscessInfections and infestations
Postoperative wound infectionInfections and infestations
Pneumonia respiratory syncytial viralInfections and infestations
SepsisInfections and infestations
NauseaGastrointestinal disorders
VomitingGastrointestinal disorders
ConstipationGastrointestinal disorders
Gastrooesophageal reflux diseaseGastrointestinal disorders
Abdominal herniaGastrointestinal disorders
FaecalomaGastrointestinal disorders
Intestinal perforationGastrointestinal disorders
Gastrointestinal haemorrhageGastrointestinal disorders
AstheniaGeneral disorders
FatigueGeneral disorders
PyrexiaGeneral disorders
Hernia obstructiveGeneral disorders
Oedema peripheralGeneral disorders
HypotensionVascular disorders
Other adverse events (121 terms — click to expand)

ReactionSystemPhase 1: Ixazomib + Lenali…Phase 2: Ixazomib 4.0 mg +…
InsomniaPsychiatric disorders
NeutropeniaBlood and lymphatic system disorders
Upper respiratory tract infectionInfections and infestations
CoughRespiratory, thoracic and mediastinal disorders
Pain in extremityMusculoskeletal and connective tissue disorders
DysgeusiaNervous system disorders
Rash macularSkin and subcutaneous tissue disorders
HypocalcaemiaMetabolism and nutrition disorders
HypokalaemiaMetabolism and nutrition disorders
Muscle spasmsMusculoskeletal and connective tissue disorders
ArthralgiaMusculoskeletal and connective tissue disorders
HeadacheNervous system disorders
LeukopeniaBlood and lymphatic system disorders
LymphopeniaBlood and lymphatic system disorders
MalaiseGeneral disorders
Blood creatinine increasedInvestigations
Weight increasedInvestigations
Vision blurredEye disorders
Alanine aminotransferase increasedInvestigations
Decreased appetiteMetabolism and nutrition disorders
HypophosphataemiaMetabolism and nutrition disorders
Sinus congestionRespiratory, thoracic and mediastinal disorders
Rash pruriticSkin and subcutaneous tissue disorders
TachycardiaCardiac disorders
Abdominal distensionGastrointestinal disorders
Bone painMusculoskeletal and connective tissue disorders
Musculoskeletal painMusculoskeletal and connective tissue disorders
MyalgiaMusculoskeletal and connective tissue disorders
ParaesthesiaNervous system disorders
TremorNervous system disorders
EpistaxisRespiratory, thoracic and mediastinal disorders
Dry eyeEye disorders
Abdominal painGastrointestinal disorders
Dry mouthGastrointestinal disorders
StomatitisGastrointestinal disorders
PainGeneral disorders
Aspartate aminotransferase increasedInvestigations
Blood alkaline phosphatase increasedInvestigations
Muscular weaknessMusculoskeletal and connective tissue disorders
Musculoskeletal chest painMusculoskeletal and connective tissue disorders

Most-reported serious reactions: Pneumonia, Dehydration, Back pain, Diarrhoea, Non-cardiac chest pain, Cardiac failure congestive, Diverticulitis, Bone abscess.

Data from ClinicalTrials.gov NCT01217957 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. 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.
    Kumar SK, Berdeja JG, Niesvizky R, Lonial S, et al · · 2014 · cited 206× · PMID 25456369 · DOI 10.1016/s1470-2045(14)71125-8
  2. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients.
    Richardson PG, Baz R, Wang M, Jakubowiak AJ, et al · · 2014 · cited 162× · PMID 24920586 · DOI 10.1182/blood-2014-01-548826
  3. Spotlight on ixazomib: potential in the treatment of multiple myeloma.
    Muz B, Ghazarian RN, Ou M, Luderer MJ, et al · · 2016 · cited 87× · PMID 26811670 · DOI 10.2147/dddt.s93602
  4. The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.
    Tundo GR, Sbardella D, Santoro AM, Coletta A, et al · · 2020 · cited 78× · PMID 32442437 · DOI 10.1016/j.pharmthera.2020.107579
  5. The 26S proteasome is a multifaceted target for anti-cancer therapies.
    Grigoreva TA, Tribulovich VG, Garabadzhiu AV, Melino G, et al · · 2015 · cited 55× · PMID 26295307 · DOI 10.18632/oncotarget.4619
  6. Ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up including ixazomib maintenance.
    Kumar SK, Berdeja JG, Niesvizky R, Lonial S, et al · · 2019 · cited 40× · PMID 30696949 · DOI 10.1038/s41375-019-0384-1
  7. Pharmacokinetics and safety of ixazomib plus lenalidomide-dexamethasone in Asian patients with relapsed/refractory myeloma: a phase 1 study.
    Gupta N, Goh YT, Min CK, Lee JH, et al · · 2015 · cited 32× · PMID 26337806 · DOI 10.1186/s13045-015-0198-1
  8. Population Pharmacokinetic Analysis of Ixazomib, an Oral Proteasome Inhibitor, Including Data from the Phase III TOURMALINE-MM1 Study to Inform Labelling.
    Gupta N, Diderichsen PM, Hanley MJ, Berg D, et al · · 2017 · cited 31× · PMID 28290121 · DOI 10.1007/s40262-017-0526-4

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Data sources for this page

Drug Landscape aggregates and links these public records for informational use only. Always verify against the primary source before clinical or regulatory decisions. Canonical URL: https://druglandscape.com/trial/NCT01217957.

Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing