The purpose of this study is to determine the effect of ixazomib maintenance therapy on progression free survival (PFS) compared with placebo, in participants with NDMM who have had a major response (complete response [CR], very good partial response [VGPR], or partial response [PR]) to initial therapy and who have not undergone SCT.
Active, not recruiting
Phase 3
| Drug | Synonyms | Arms |
|---|---|---|
| Placebo | Placebo | |
| Ixazomib | Ixazomib |
The drug being tested in this study is called ixazomib citrate. Ixazomib citrate is being
tested to slow PD and improve overall survival in people who have NDMM who have had a major
positive response to initial therapy and have not undergone SCT. This study will look at the
effect of ixazomib citrate has on the length of time that participants are free of PD and
their overall survival.
The study will enroll approximately 700 participants. Participants will be randomly assigned
(by chance, like flipping a coin) to one of the two treatment groups-which will remain
undisclosed to the participant and study doctor during the study (unless there is an urgent
medical need):
- Ixazomib citrate 3 mg
- Placebo (dummy inactive pill) - this is a capsule that looks like the study drug but has
no active ingredient
All participants will be asked to take one capsule on Days 1, 8 and 15 of each 28-day cycle,
for up to 26 cycles.
This multi-center trial will be conducted worldwide. The overall time to participate in this
study is approximately 76 to 104 months. Participants will make 28 visits to the clinic
during the treatment period and will continue to make follow-up visits every 4 weeks until
the next line of therapy begins. Participants will also be contacted by telephone every 12
weeks after last treatment visit for a follow-up assessment.
| Name | Type | Description | Interventions |
|---|---|---|---|
| Placebo | Experimental | Ixazomib placebo-matching capsule, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 (Up to data cut-off 12 August 2019). |
|
| Ixazomib | Placebo Comparator | Ixazomib 3 mg, capsule, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib 3 or 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 (Up to data cut-off 12 August 2019). |
|
Inclusion Criteria:
1. Adult male or female participants 18 years or older with a confirmed diagnosis of
symptomatic newly diagnosed multiple myeloma (NDMM) according to standard criteria.
2. Completed 6 to 12 months (+- 2 weeks) of initial therapy, during which the participant
was treated to best response, defined as the best response maintained for 2 cycles
after the M-protein nadir is reached.
3. Documented major response (PR, VGPR, CR) according to the International Myeloma
Working Group (IMWG) uniform response criteria, version 2011, after this initial
therapy.
4. Female participants who:
- Are postmenopausal for at least 1 year before the screening visit, OR
- Are surgically sterile, OR
- If they are of childbearing potential, agree 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, OR
- Agree to practice true abstinence, when this is in line with the preferred and
usual lifestyle of the participant. (Periodic abstinence (eg, calendar,
ovulation, symptothermal, postovulation methods] and withdrawal are not
acceptable methods of contraception.)
Male participants, even if surgically sterilized (that is, status postvasectomy), who:
- Agree to practice effective barrier contraception during the entire study
Treatment period and through 90 days after the last dose of study drug, OR
- Agree to practice true abstinence, when this is in line with the preferred and
usual lifestyle of the participant. (Periodic abstinence [example, calendar,
ovulation, symptothermal, postovulation methods for the female partner] and
withdrawal are not acceptable methods of contraception.)
5. Voluntary written consent must be given before performance of any study-related
procedure not part of standard medical care, with the understanding that consent may
be withdrawn by the participant at any time without prejudice to future medical care.
6. Complete documentation of the details of the initial therapy before randomization
including cytogenetics and International Staging System (ISS) is available.
7. Eastern Cooperative Oncology Group Performance Status of 0 to 2.
8. Suitable venous access for the study-required blood sampling and consent for the
specific amounts that will be taken.
9. Is willing and able to adhere to the study visit schedule and other protocol
requirements including blood sampling and bone marrow aspiration.
10. Must meet the following clinical laboratory criteria at study entry:
- Absolute neutrophil count (ANC) greater than or equal to (>=) 1,000 per cubic
millimeter (/mm^3) without growth factor support and platelet count >=
75,000/mm^3. Platelet transfusions to help participants meet eligibility criteria
are not allowed within 3 days before randomization.
- Total bilirubin less than or equal to (<=) 1.5*the upper limit of the normal
range (ULN).
- Alanine aminotransferase and aspartate aminotransferase <= 3*ULN.
- Calculated creatinine clearance >= 30 milliliter per minute (mL/min) (using the
Cockcroft-Gault equation).
Exclusion Criteria:
1. Multiple myeloma that has relapsed after, or was not responsive to, initial therapy.
2. Prior stem cell transplant (SCT).
3. Radiotherapy within 14 days before randomization.
4. Diagnosed or treated for another malignancy within 5 years before randomization or
previous diagnosis with another malignancy. Participants with nonmelanoma skin cancer
or carcinoma in situ of any type are not excluded if they have undergone complete
resection.
5. Female participants who are lactating and breastfeeding or have a positive serum
pregnancy test during the Screening period.
6. Major surgery within 14 days before randomization.
7. Central nervous system involvement.
8. Infection requiring intravenous (IV) antibiotic therapy or other serious infection
within 14 days before randomization.
9. Diagnosis of Waldenstrom's macroglobulinemia, polyneuropathy, organomegaly,
endocrinopathy, monoclonal gammopathy, and skin changes syndrome (POEMS), plasma cell
leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative
syndrome.
10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
hypertension, uncontrolled cardiac arrhythmias, uncontrolled congestive heart failure,
unstable angina, or myocardial infarction within the past 6 months.
11. Systemic treatment with strong cytochrome P450 3A (CYP3A) inducers (rifampin,
rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital) or use of Ginkgo
biloba or St. John's wort within 14 days before randomization.
12. Ongoing or active infection, known human immunodeficiency virus (HIV) positive, active
hepatitis B or C infection.
13. Comorbid systemic illnesses or other severe concurrent disease that, in the judgment
of the investigator, would make the participant inappropriate for entry into this
study or interfere significantly with the proper assessment of safety and toxicity of
the prescribed regimens (example, PN that is Grade 1 with pain or Grade 2 or higher of
any cause).
14. Psychiatric illness or social situation that would limit compliance with study
requirements.
15. Known allergy to any of the study medications, their analogues, or excipients in the
various formulations of any agent.
16. Inability to swallow oral medication, inability or unwillingness to comply with the
drug administration requirements, or gastrointestinal (GI) procedure that could
interfere with the oral absorption or tolerance of treatment.
17. Treatment with any investigational products within 30 days before randomization.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Progression Free Survival (PFS) |
| Time Frame: | From the randomization until progressive disease (PD) or death or data cut-off date (12 Aug 2019) (Up to approximately 42 months) |
| Safety Issue: | |
| Description: | PFS is defined as the time from the date of randomization to the date of first documentation of PD or death from any cause, as evaluated by an independent review committee (IRC) according to International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurs first. Per IMWG criteria, PD: serum M-component increase ≥0.5 g/dl or urine M-component increase ≥200 mg/24-hour/ difference between involved and uninvolved FLC levels increase >10 mg/dl or bone marrow plasma cell ≥10%/ development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia. |
| Measure: | Overall Survival (OS) |
| Time Frame: | From the date of randomization every 12 weeks after PD on next-line therapy until death (Up to approximately 76 to 104 months) |
| Safety Issue: | |
| Description: | OS will be measured as the time from the date of randomization to the date of death. |
| Measure: | Percentage of Participants Who Achieve or Maintain Any Best Response Category During the Treatment Period |
| Time Frame: | Up to 24 months |
| Safety Issue: | |
| Description: | Response will be assessed according to IMWG criteria. Best response includes PR, VGPR and CR. |
| Measure: | Time to Progression (TTP) |
| Time Frame: | From the date of randomization to the date of first documented PD (Up to approximately 76 to 104 months) |
| Safety Issue: | |
| Description: | TTP is defined as the time from the date of randomization to the date of first documentation of PD, using IMWG criteria. |
| Measure: | Progression Free Survival 2 (PFS2) |
| Time Frame: | From the date of randomization to every 12 weeks until 2nd PD or death (Up to approximately 76 to 104 months) |
| Safety Issue: | |
| Description: | PFS2 is defined as the time from the date of randomization to objective PD on next-line treatment using IMWG criteria, or death due to any cause, whichever occurs first. |
| Measure: | Time to Next Line Therapy (TTNT) |
| Time Frame: | From the date of randomization to the date of the first dose of the next-line of therapy (Up to approximately 76 to 104 months) |
| Safety Issue: | |
| Description: | TTNT is defined as the time from the date of randomization to the date of the first dose of next-line antineoplastic therapy. |
| Measure: | Time to End of the Next-line of Therapy After Study Treatment |
| Time Frame: | From the date of randomization to the date of last dose of the next-line of therapy (Up to approximately 76 to 104 months) |
| Safety Issue: | |
| Description: | Time to end of the next line of therapy is defined as the time from the date of randomization to the date of last dose of the next line of antineoplastic therapy following study treatment. |
| Measure: | Duration of Next-line Therapy |
| Time Frame: | From the date of the first dose of the line of antineoplastic therapy coming after study treatment to the date of the last dose (Up to approximately 76 to 104 months) |
| Safety Issue: | |
| Description: | Duration of next-line therapy is defined as the time from the date of the first dose of the line of antineoplastic therapy coming after study treatment to the date of the last dose. |
| Measure: | Percentage of Participants Who Develop A New Primary Malignancy |
| Time Frame: | From the randomization date till death or termination of the study (Up to approximately 76 to 104 months) |
| Safety Issue: | |
| Description: |
| Measure: | Percentage of Participants With Conversion From Minimal Residual Disease (MRD) Positive to MRD Negative, or the Maintenance of MRD Negativity |
| Time Frame: | Screening, Cycle 13, and Cycle 26 (Cycle length is equal to [=] 28 days) |
| Safety Issue: | |
| Description: | Bone marrow aspirates and blood samples will be sent to a central laboratory and will be assessed for MRD using flow cytometry. MRD negativity is defined as absence of MRD and MRD positivity is defined as presence of MRD. |
| Measure: | Correlation of MRD Status With PFS and OS |
| Time Frame: | Screening, Cycle 13, and Cycle 26 (Cycle length=28 days) |
| Safety Issue: | |
| Description: | PFS is defined as the time from the date of randomization to the date of first documentation of PD or death from any cause, as evaluated by an IRC according to IMWG criteria, or death due to any cause, whichever occurs first. OS will be measured as the time from the date of randomization to the date of death. |
| Measure: | OS in a High-risk Population |
| Time Frame: | From the date of randomization to every 12 weeks after PD on next-line therapy until death (Up to approximately 76 to 104 months) |
| Safety Issue: | |
| Description: | High-risk population will include but not be limited to participants carrying deletion (del)17, t(4;14), t(14;16). OS will be measured as the time from the date of randomization to the date of death. |
| Measure: | PFS in a High-risk Population |
| Time Frame: | From the date of randomization to every 4 weeks during follow-up until PD or death (Up to approximately 76 to 104 months) |
| Safety Issue: | |
| Description: | High-risk population will include but not be limited to participants carrying del17, t(4;14), t(14;16). PFS is defined as the time from the date of randomization to the date of first documentation of PD or death from any cause. |
| Measure: | Eastern Cooperative Oncology Group (ECOG) Performance Status |
| Time Frame: | Cycle 2 and every 28 days ( Up to 24 months) (Cycle length =28 days) |
| Safety Issue: | |
| Description: | ECOG performance status assess participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory ( greater than [>] 50 percent [%] of waking hours), capable of all self-care, unable to carry out any work activities; 3=capable of only limited self-care, confined to bed/chair >50% of waking hours; 4=completely disabled, cannot carry on any self-care, totally confined to bed/chair; 5=dead. |
| Measure: | Percentage of Participants With Serious Adverse Events (SAEs) and Adverse Events (AEs) |
| Time Frame: | First dose of study drug through 30 days after last dose of study drug (Up to 25 months) |
| Safety Issue: | |
| Description: | A SAE is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. AEs are defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 30 days after the last dose of study drug. |
| Measure: | Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) |
| Time Frame: | Baseline and every 28 days (Up to 24 months) |
| Safety Issue: | |
| Description: | The EORTC QLQ-C30 is completed by the participant. The EORTC QLQ-30 contains 30 questions that incorporate 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The participant answers questions about their health during the past week. There are 28 questions answered on a 4-point scale where 1 =Not at all (best) to 4 =Very Much (worst) and 2 questions answered on a 7-point scale where 1 =Very poor (worst) to 7 =Excellent (best). |
| Measure: | Number of Participants With Any Markedly Abnormal Standard Safety Laboratory Values |
| Time Frame: | From First dose date of study drug through 30 days after the last dose of study drug (Up to 25 months) |
| Safety Issue: | |
| Description: | Clinical laboratory evaluations will be performed by a central laboratory. The number of participants with any markedly abnormal standard safety laboratory values collected throughout study. |
| Measure: | Correlation Between Frailty Status and PFS and OS |
| Time Frame: | Up to approximately 76 to 104 months |
| Safety Issue: | |
| Description: | Participant's frailty status is classified as fit, unfit or frail on the bases of 4 components: age, the Charlson comorbidity scoring system without age weighting, the Katz index of independence in activities of daily living, and the Lawton instrumental activities of daily living scale. The sum of the 4 frailty scores equals the total frailty score. A total frailty score of 0 corresponds to a frailty status of fit; a total score of 1, to unfit; and a total score of 2 or more, to frail. PFS is defined as the time from the date of randomization to the date of first documentation of PD or death from any cause, as evaluated by an IRC according to IMWG criteria, or death due to any cause, whichever occurs first. OS will be measured as the time from the date of randomization to the date of death. |
| Measure: | Pharmacokinetic Parameter: Plasma Concentration of Ixazomib |
| Time Frame: | Cycle 1 (1 and 4 hours post-dose Day 1, Days 8 and 15 pre-dose); Cycle 2 and 5 (Days 1 and 8 pre-dose) and Cycles 3, 4, 6-10 (Day 1 pre-dose) (Cycle length =28 days) |
| Safety Issue: | |
| Description: | Plasma concentrations of the complete hydrolysis product of ixazomib citrate (ixazomib) will be measured using a validated Liquid Chromatography-tandem Mass Spectrometry (LC/MS/MS) assay. |
| Measure: | Time to Resolution of Peripheral Neuropathy (PN) Events |
| Time Frame: | From the initial onset date of PN up to the resolution date for resolved events (Up to 25 Months) |
| Safety Issue: | |
| Description: | PN is defined as the treatment-emergent adverse event in the high-level term of peripheral neuropathies not elsewhere classified (NEC) according to the Medical Dictionary for Regulatory Activities (MedDRA). A PN event is considered as resolved if its final outcome is resolved with no subsequent PN event of the same preferred term occurring on the resolution date or the day before and after. Time to resolution is defined as the time from the initial onset date (inclusive) to the resolution date for resolved events. |
| Measure: | Time to Improvement of PN Events |
| Time Frame: | From the initial onset date of PN up to the improvement of event (Up to 25 Months) |
| Safety Issue: | |
| Description: | PN is defined as the treatment-emergent adverse event in the high-level term of peripheral neuropathies NEC according to the MedDRA. A PN event is considered as resolved if its final outcome is resolved with no subsequent PN event of the same preferred term occurring on the improvement date or the day before and after. Time to improvement is defined as the time from the initial onset date (inclusive) to the improvement of event. |
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | Millennium Pharmaceuticals, Inc. |
November 10, 2020
