Clinical trial NCT01335685: Study of Oral Ixazomib in Combination With Melphalan and Prednisone in Participants With Newly Diagnosed Multiple Myeloma
Official title: An Open-Label, Dose-Escalation, Phase 1/2 Study of the Oral Form of Ixazomib (MLN9708), a Next-Generation Proteasome Inhibitor, Administered in Combination With a Standard Care Regimen of Melphalan and Prednisone in Patients With Newly Diagnosed Multiple Myeloma Requiring Systemic Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2011-04-14
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this phase 1/2, open-label study was to evaluate the effect of oral formulation of Ixazomib when added to standard melphalan and prednisone (MP) treatment. Both phases of the study included participants who had newly diagnosed multiple myeloma and were ineligible for high-dose therapy plus stem cell transplantation because of age (≥65 years of age) or coexisting conditions and for whom standard MP treatment was indicated.

Detailed description: The drug tested in this study was called ixazomib (MLN9708). Ixazomib was tested to treat the people with newly diagnosed multiple myeloma requiring systemic treatment who were not eligible for stem cell transplantation. This study determined the safety, tolerability, efficacy, quality of life (QOL), and pharmacokinetics (PK)/pharmacodynamics (PD) of ixazomib.

The study enrolled 61 patients. The study was conducted in 2 parts: 1) phase 1 dose escalation and 2) phase 2 expansion at maximum tolerated dose. Participants were enrolled to receive:

* Ixazomib 3.0 mg, 3.7 mg, 4.0 mg, or 5.5. mg depending on the treatment assignment

This multicenter trial was conducted in the Unites states, Canada, United Kingdom, Spain and Czech Republic. The overall time to participate in this study is 5.5 years. Participants made multiple visits to the clinic and were followed up every 16 weeks after end of treatment until disease progression if stopped treatment before disease progression and then every 16 weeks up to start of next therapy or death whichever occurs first.

Eligibility criteria: Inclusion Criteria:

* Is indicated with standard melphalan prednisone (MP) treatment and is not a candidate for high-dose therapy plus stem cell transplantation (HDT-SCT) for 1 of the following reasons: the participant is 65 years of age or older OR the participant is less than 65 years of age but has significant comorbid condition(s) that are likely to have a negative impact on tolerability of HDT-SCT
* Is diagnosed with symptomatic multiple myeloma or asymptomatic myeloma with myeloma-related organ damage according to standard criteria
* Has measurable disease as specified in study protocol
* Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
* Has adequate hematologic, liver, and renal function

Exclusion Criteria

* Has peripheral neuropathy that is greater or equal to Grade 2
* Has major surgery or radiotherapy within 14 days before the first dose of study drug
* Has uncontrolled infection requiring systematic antibiotics
* Has diarrhea (\> Grade 1)
* Has prior systemic therapy for multiple myeloma, including investigational drugs (prior treatment with corticosteroids or localized radiation therapy dose not disqualify the participantt)
* Has central nervous system involvement
* Has cardiac status as described in protocol
* Has known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption of tolerance of IXAZOMIB - Diagnosis of smoldering multiple myeloma, Waldenstrom's macroglobulinemia, POEMS syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome
* Has Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection
* Is diagnosed or treated for another malignancy within 2 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease with the exception of nonmelanoma skin cancer or any completely resected carcinoma in situ
* Has serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Ixazomib (Phase 1)
timeFrame: Cycle 1, phase 1 (Up to 42 days)
measure: Very Good Partial Response (VGPR) or Better Response Rate (Phase 2)
timeFrame: Day 1 of every other cycle from Day 1 of Cycle 2 (each cycle of 28 days) until death (Up to 5.5 years)
Secondary outcomes:
measure: Maximum Inhibition Rate (Emax) (Phase 1)
timeFrame: At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study
measure: Time of Occurrence of Emax (TEmax) (Phase 1)
timeFrame: At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study
measure: Cmax: Maximum Observed Plasma Concentration for Ixazomib (Phase 1)
timeFrame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib (Phase 1)
timeFrame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D
measure: AUCtau: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Ixazomib (Phase 1)
timeFrame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D
measure: Terminal Elimination Rate Constant (λz) for Ixazomib (Phase 1)
timeFrame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D
measure: Terminal Phase Elimination Half-life (T1/2) for Ixazomib (Phase 1)
timeFrame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D
measure: Observed Accumulation Ratio for AUCtau (Rac) (Phase 1)
timeFrame: Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D
measure: Overall Response Rate (ORR)
timeFrame: Day 1 of every other cycle from Day 1 of Cycle 2 (each cycle of 28 days) up to 61 cycles, at end of treatment (Up to 5.5 years)
measure: Time to First Response (Phase 2)
timeFrame: From the date of enrollment to the date of the first documented response for up to 5.5 years
measure: Duration of Response (DOR) (Phase 2)
timeFrame: From the time from the date of first documentation of PR or better to the date of first documented disease progression for up to 5.5 years
measure: Time to Progression (TTP) (Phase 2)
timeFrame: From the date of enrollment to the date of the first documented disease progression for up to 5.5 years
measure: Time to Next Therapy (Phase 2)
timeFrame: From the date of enrollment to the date of subsequent antineoplastic therapy for up to 5.5 years
measure: Progression Free Survival (Phase 2)
timeFrame: From the date of enrollment to the date of the first documented disease progression or death due to any cause for up to 5.5 years
measure: Overall Survival (Phase 2)
timeFrame: From date of enrollment to date of death, approximately 5.5 years (Approximate median follow-up: 43.6 months)
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
timeFrame: From first dose of study drug through 30 days after last dose of study drug or until the start of subsequent antineoplastic therapy for up to 5.6 years
measure: Assessments of Quality of Life (Phase 2)
timeFrame: Baseline, Day 1 of each treatment cycle, and Day 1 of each maintenance cycle, up to 5.5 years
Other outcomes:
Locations:
city: Lebanon
country: United States
state: New Hampshire
city: Morgantown
country: United States
state: West Virginia
city: Vancouver
country: Canada
state: British Columbia
city: Toronto
country: Canada
state: Ontario
city: Quebec
country: Canada
city: Brno
country: Czechia
city: Praha 2
country: Czechia
city: Badalona
country: Spain
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Salamanca
country: Spain
city: San Sebastian
country: Spain
city: Sevilla
country: Spain
city: Bournemouth
country: United Kingdom
city: Brighton
country: United Kingdom
city: Cambridge
country: United Kingdom
city: London
country: United Kingdom
city: Nottingham
country: United Kingdom
city: Oxford
country: United Kingdom
city: Uxbridge
country: United Kingdom
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: San-Miguel JF, Echeveste Gutierrez MA, Spicka I, Mateos MV, Song K, Craig MD, Blade J, Hajek R, Chen C, Di Bacco A, Estevam J, Gupta N, Byrne C, Lu V, van de Velde H, Lonial S. A phase I/II dose-escalation study investigating all-oral ixazomib-melphalan-prednisone induction followed by single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma. Haematologica. 2018 Sep;103(9):1518-1526. doi: 10.3324/haematol.2017.185991. Epub 2018 Jun 28.