Ixazomib citrate-thalidomide-low dose dexamethasone induction followed by maintenance therapy with ixazomib citrate or placebo in newly diagnosed multiple myeloma patients not eligible for autologous stem cell transplantation; a randomized phase II trial

• Register: EUCTR
• Last refreshed on: 16 December 2019
• Main ID: EUCTR2013-003266-14-NL
• Date of registration: 23/10/2014
• Prospective Registration: Yes
• Primary sponsor: HOVON Foundation
• Public title: Ixazomib citrate-thalidomide-low dose dexamethasone induction followed by maintenance therapy with ixazomib citrate or placebo in newly diagnosed multiple myeloma patients not eligible for autologous stem cell transplantation; a randomized phase II trial
• Scientific title: Ixazomib citrate-thalidomide-low dose dexamethasone induction followed by maintenance therapy with ixazomib citrate or placebo in newly diagnosed multiple myeloma patients not eligible for autologous stem cell transplantation; a randomized phase II trial - HOVON 126 MM
• Date of first enrolment: 06/11/2014
• Target sample size: 142
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-003266-14
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Denmark, Netherlands, Norway, Sweden

Contacts

• Name: HOVON Data Center
• Affiliation: HOVON

• Name: HOVON Data Center
• Affiliation: HOVON

Key inclusion & exclusion criteria

Inclusion criteria:
-Previously untreated patients with a confirmed diagnosis of symptomatic multiple myeloma according to IMWG criteria
- Measurable disease according to the IMWG criteria
-Age = 66 years or patients = 65 years not eligible for ASCT
- WHO performance status 0-3 for patients <75 years and WHO performance status 0-2 for patients = 75 years
-Absolute neutrophil count (ANC) = 1.0 x109/l and platelet count = 75x109/l , unless related to bone marrow infiltration by malignant plasmacells.
Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment.
-Written informed consent.
-Patient gives consent for extra bone marrow and blood sampling.
-Negative pregnancy test at study entry or at least 1 year post-menopausal or surgically sterile before study entry
-A female patient of childbearing potential, agrees to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug, AND must also adhere to the guidelines of any treatment-specific pregnancy prevention program (for thalidomide) OR agrees to completely abstain from heterosexual intercourse. (Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.)
-Male patients, even if surgically sterilized, (i.e., status post vasectomy) must agree to practice effective barrier contraception during the entire study period and through 90 days after the last dose of study drug, AND must also adhere to the guidelines of any treatment-specific pregnancy prevention program (for thalidomide), OR agrees to completely abstain from heterosexual intercourse (Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 22
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 120

Exclusion criteria:
- Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent
- Systemic AL amyloidosis
- Polyneuropathy, grade 3 or higher or grade 2 with pain on clinical examination during the screening period
- Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months
- Severe pulmonary dysfunction (Modified Medical Research Counsil dyspnea scale classification III-IV)
- Significant hepatic dysfunction (total bilirubin = 1.5 x ULN or transaminases = 3 times normal level) except patients with Gilbert’s syndrome as defined by > 80% unconjugated bilirubin
- Creatinine clearance <30 ml/min or Calculated Glomerular Filtration Rate [ml/min/1.73m2] <30.
- Systemic treatment, within 14 days before the first dose of ixazomib, with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort.
- Pre-treatment with cytostatic drug, IMIDs or proteasome inhibitors. Radiotherapy or a short course of steroids (e.g. 4 day treatment of dexamethasone 40 mg/day or equivalent) are allowed. Radiotherapy should not be given within 14 days before enrollment. In case of radiotherapy, if the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the ixazomib citrate
- Not able and/or not willing to use adequate contraception
- Female patients who are lactating or have a positive serum pregnancy test during the screening period,
- Major surgery within 14 days before enrollment.
- Central nervous system involvement.
- Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.
- Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 ixazomib citraat including difficulty swallowing.
- Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
- Participation in other clinical trials, including those with other investigational agents not included in this trial, within 21days of the start of this trial and throughout the duration of this trial.
- Any serious medical or psychiatric illness, or familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cancer [C04]

Multiple Myeloma
MedDRA version: 21.0 Level: LLT Classification code 10028228 Term: Multiple myeloma System Organ Class: 100000004864

Intervention(s)

Product Name: Ixazomib citrate (4 mg)
Pharmaceutical Form: Capsule
INN or Proposed INN: Ixazomib citrate
CAS Number: 1239908-20-3
Other descriptive name: MLN9708
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 4-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Product Name: Ixazomib citrate (3mg)
Pharmaceutical Form: Capsule
INN or Proposed INN: Ixazomib citrate
CAS Number: 1239908-20-3
Other descriptive name: MLN9708
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 3-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Product Name: Ixazomib citrate (2.3 mg)
Pharmaceutical Form: Capsule
INN or Proposed INN: Ixazomib citrate
CAS Number: 1239908-20-3
Other descriptive name: MLN9708
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.3-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): Maintenance treatment
-Progression free survival (PFS) from randomization, defined as time from randomization to progression or death from any cause, whichever comes first

Induction treatment
-Response rate defined as sCR, CR, VGPR or PR

Main Objective: Maintenance treatment
- To compare progression free survival between maintenance therapy with Ixazomib versus placebo, both following induction therapy with ixazomib citrate – thalidomide – low dose dexamethasone

Induction treatment
- To determine overall response* rate of induction therapy with ixazomib citrate – thalidomide – low dose dexamethasone
* overall response will be defined as (stringent) complete response, very good partial response and partial response

Timepoint(s) of evaluation of this end point: Evaluation will take place when the data of all patients until 8 years after registration are available

Secondary Objective: -To determine toxicity, polyneuropathy in specific, during induction treatment and maintenance treatment
-To determine progression free survival and overall survival from registration
-To compare the efficacy between maintenance treatment with ixazomib citrate versus placebo determined as overall survival from randomization
-To determine the efficacy of maintenance therapy determined as an improvement in response during maintenance treatment
-To determine efficacy of induction therapy determined as time to response
-To determine feasibility, defined as discontinuation rate due to toxicity, during induction treatment and maintenance treatment
-To determine time to next treatment
-To determine PFS on second line therapy
-To determine Quality of Life during induction treatment and maintenance therapy
- To identify clinical, imaging related and molecular markers prognostic and predictive for outcome and toxicity
-To establish second primary malignancies

Secondary Outcome(s)

Secondary end point(s): - Safety and toxicity as defined by type, frequency and severity of adverse events as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4
- PFS from registration
- Overall survival (OS) from registration, measured until death from any cause. Patients alive will be censored at the date of last contact
- OS from randomization.
- Quality of response during maintenance, measured as improvement of response (from start maintenance till progression)
- Time to maximum response, defined as time from registration to maximum response
- Time to death from progression (after initial response), measured from time of first relapse/progression
- Time to next treatment
- PFS from the start of second line therapy
- Quality of life as defined by the EORTC QLQ-C30 and QLQ-MY20 definitions.
- Second Primary Malignancies

Timepoint(s) of evaluation of this end point: Evaluation will take place when the data of all patients until 8 years after registration are available

Secondary ID(s)

HOVON126

Source(s) of Monetary Support

Dutch Cancer Society

Ethics review

Status: Approved
Approval date:
Contact: