Testing the Addition of Ixazomib/Placebo to Lenalidomide in Patients With Evidence of Residual Multiple Myeloma, OPTIMUM Trial
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| ClinicalTrials.gov Identifier: NCT03941860 |
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Recruitment Status :
Active, not recruiting
First Posted : May 8, 2019
Last Update Posted : June 7, 2023
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Sponsor:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI)
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Brief Summary:
This phase III trial studies how well lenalidomide in combination with ixazomib works compared to lenalidomide alone in treating patients with evidence of residual multiple myeloma after stem cell transplantation. Lenalidomide may help shrink or slow the growth of multiple myeloma. Ixazomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving lenalidomide and ixazomib together may work better than giving lenalidomide alone in treating patients with evidence of residual multiple myeloma after a stem cell transplantation.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Multiple Myeloma | Procedure: Biospecimen Collection Procedure: Bone Marrow Aspirate Procedure: Bone Marrow Biopsy Procedure: Computed Tomography Drug: Ixazomib Citrate Drug: Lenalidomide Other: Placebo Administration Procedure: Positron Emission Tomography Other: Quality-of-Life Assessment Other: Questionnaire Administration | Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 510 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, Investigator) |
| Primary Purpose: | Treatment |
| Official Title: | Optimizing Prolonged Treatment In Myeloma Using MRD Assessment (OPTIMUM) |
| Actual Study Start Date : | June 1, 2021 |
| Estimated Primary Completion Date : | December 31, 2023 |
| Estimated Study Completion Date : | December 31, 2023 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Multiple myeloma
MedlinePlus related topics:
Multiple Myeloma
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm A (lenalidomide, ixazomib citrate)
Patients receive lenalidomide PO QD on days 1-28 and ixazomib citrate PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
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Procedure: Biospecimen Collection
Undergo collection of blood samples
Other Names:
Procedure: Bone Marrow Aspirate Undergo bone marrow aspirate
Other Names:
Procedure: Bone Marrow Biopsy Undergo bone marrow biopsy
Other Names:
Procedure: Computed Tomography Undergo CT scan
Other Names:
Drug: Ixazomib Citrate Given PO
Other Names:
Drug: Lenalidomide Given PO
Other Names:
Other: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies |
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Placebo Comparator: Arm B (lenalidomide, placebo)
Patients receive lenalidomide PO QD on days 1-28 and a placebo PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspirate and/or biopsy and PET and CT scan at screening and on study as well as undergo collection of blood samples throughout the trial.
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Procedure: Biospecimen Collection
Undergo collection of blood samples
Other Names:
Procedure: Bone Marrow Aspirate Undergo bone marrow aspirate
Other Names:
Procedure: Bone Marrow Biopsy Undergo bone marrow biopsy
Other Names:
Procedure: Computed Tomography Undergo CT scan
Other Names:
Drug: Lenalidomide Given PO
Other Names:
Other: Placebo Administration Given PO Procedure: Positron Emission Tomography Undergo PET scan
Other Names:
Other: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies |
Primary Outcome Measures :
- Overall survival (OS) [ Time Frame: From randomization to death due to any cause, or censored at date last known alive, assessed up to 15 years ]Will be estimated using the Kaplan-Meier (KM) method and compared using a stratified log-rank test. Stratified cox proportional hazards regression will produce a treatment hazard ratio estimate (ixazomib-lenalidomide/placebo-lenalidomide.
- Change in Functional Assessment of Cancer Therapy (FACT)/Gynecologic Oncology Group-Neurotoxicity (GOG-Ntx) Trial Outcome Index (TOI) score [ Time Frame: Baseline up to 12 cycles ]Descriptive statistics (mean, standard deviation [SD], median, range) will be used to evaluate the distribution of levels and changes for the set of health-related quality of life (QOL) evaluations. Linear mixed effects models will be used to perform repeated measured regression analysis with the assumed covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit.
- Change in FACT-Multiple Myeloma (MM) TOI score [ Time Frame: Baseline up to 24 cycles ]Descriptive statistics (mean, SD, median, range) will be used to evaluate the distribution of levels and changes for the set of health-related QOL evaluations. Levels and changes will also be assessed graphically. Linear mixed effects models will be used to perform repeated measured regression analysis with the assumed covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit.
Secondary Outcome Measures :
- Progression-free survival (PFS) [ Time Frame: From randomization until the earlier of progression or death due to any cause, or censored at date of last disease evaluation, assessed up to 15 years ]Will be estimated using the KM method and compared using the stratified log-rank test. Only deaths that occur within 3 months of the last disease evaluation are considered events.
- Best response on treatment [ Time Frame: Up to 60 cycles post-randomization ]Will be based on standard International Myeloma Working Group (IMWG) criteria and tabulated by category. Response rates (stringent complete response [sCR], complete response [CR], very good partial response [VGPR]) will be compared using the chi-squared test for proportions.
- Minimal residual disease (MRD) conversion rate [ Time Frame: At 12 and 24 cycles post-randomization ]
- Incidence of adverse events [ Time Frame: Up to 15 years ]Will be assessed by worst grade and type determined using Common Terminology Criteria for Adverse Events. Will compare the rates of worst grade 3 or higher non-hematologic treatment-related events using the chi-squared test for proportions. Will plan to examine comprehensively adverse events experienced by study participants using the Tox-T method.
- Change in FACT- General (G) score [ Time Frame: Baseline up to 12 cycles ]Descriptive statistics (mean, SD, median, range) will be used to evaluate the distribution of levels and changes for the set of health-related QOL evaluations. Levels and changes will also be assessed graphically. Linear mixed effects models will be used to perform repeated measured regression analysis with the assumed covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit. The t-test will be used to assess the change in FACT-G score between treatment arms. Also, FACT-G scores after 12 cycles of treatment will be compared between MRD positive and negative groups at that time point.
- Time to worsening of FACT/GOG-Ntx TOI [ Time Frame: Baseline to a decrease of 8 points (minimally important differences [MID]), respectively, or censored at the date of last assessment ]Will be analyzed with the KM method and compared using the log-rank test. Time to worsening of symptoms with PFS and OS will be assessed with Kendall's Tau adjusted for censored observations.
- Change in levels of all instruments [ Time Frame: Baseline up to 1 year after treatment discontinuation ]Descriptive statistics (mean, SD, median, range) will be used to evaluate the distribution of levels and changes for the set of health-related QOL evaluations. Levels and changes will also be assessed graphically. Linear mixed effects models will be used to perform repeated measured regression analysis with the assumed covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit.
- FACT/GOG-Ntx TOI recovery rate [ Time Frame: Up to 1 year after treatment discontinuation ]The recovery rate will be estimated in the patients experiencing a MID decrease (the proportion of patients with the FACT/GOG-Ntx TOI score returning to baseline level). Will provide rates on each arm including exact binomial 95% confidence intervals.
- Time to improvement of the FACT-MM TOI [ Time Frame: Baseline to an increase of 10 points (MID), respectively, or censored at the date of last assessment ]Will be analyzed with the KM method and compared using the log-rank test.
- FACT-MM TOI response rate [ Time Frame: Up to 1 year after treatment discontinuation ]Will be defined as the proportion of patients experiencing a MID improvement since baseline at each assessment time point. Will provide rates on each arm including exact binomial 95% confidence intervals.
Other Outcome Measures:
- Time to progression [ Time Frame: From randomization to progression, or censored at date of last disease evaluation, assessed up to 15 years ]Will be estimated in each arm using the Kaplan-Meier method.
- Duration of response [ Time Frame: From time of observed response (VGPR or better) to the time of progression in the respective group of responders, assessed up to 15 years ]Will be estimated in each arm using the Kaplan-Meier method.
- Treatment duration [ Time Frame: From randomization to date off treatment, or censored at the date of last treatment, assessed up to 15 years ]Will be estimated using the Kaplan-Meier method. Patients will be classified into dichotomous groups based on a 75% relative dose intensity cutoff (< 75% vs >= 75% represents poor vs good treatment adherence). The proportion of patients with poor lenalidomide treatment adherence will be compared between arms using the chi-squared test for proportions. In addition, multivariable logistic regression analysis will be conducted to identify the baseline factors associated with calculated good treatment adherence.
- Cumulative dose [ Time Frame: Up to 15 years ]Will be calculated overall and by cycle. Data will be summarized by treatment arm with descriptive statistics and graphically over time.
- Dose intensity [ Time Frame: Up to 15 years ]Will be calculated as cumulative dose received divided by treatment duration. Will be calculated overall and by cycle. Data will be summarized by treatment arm with descriptive statistics and graphically over time.
- Relative dose intensity [ Time Frame: Up to 15 years ]Will be calculated as the dose intensity divided by planned dose intensity. Data will be summarized by treatment arm with descriptive statistics and graphically over time.
- Presence, frequency, interference, amount, and/or severity of select Patient Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE) [ Time Frame: Up to 1 year after treatment discontinuation ]Will be tabulated at each cycle
- Adherence Starts with Knowledge (ASK)-12 scores [ Time Frame: Up to 12 cycles ]Will be assessed at each assessment time point. Linear regression analysis at these 2 time points separately will be conducted with QOL score as outcome and treatment adherence group as the main effect adjusting for baseline QOL score along with other disease and demographic characteristics. Descriptive statistics will be used to summarize ASK-12 scores tabulated every 6 cycles on study therapy. The relationship between likelihood of medication adherence and calculated treatment adherence dichotomous groups will be evaluated in 2 x 2 tables. In addition, multivariable logistic regression analysis will be conducted to identify the baseline factors associated with low likelihood of medication adherence over 12- and 24-cycles of treatment.
- ASK-12 scores [ Time Frame: Up to 24 cycles ]Will be assessed at each assessment time point. Linear regression analysis at these 2 time points separately will be conducted with QOL score as outcome and treatment adherence group as the main effect adjusting for baseline QOL score along with other disease and demographic characteristics. Descriptive statistics will be used to summarize ASK-12 scores tabulated every 6 cycles on study therapy. The relationship between likelihood of medication adherence and calculated treatment adherence dichotomous groups will be evaluated in 2 x 2 tables. In addition, multivariable logistic regression analysis will be conducted to identify the baseline factors associated with low likelihood of medication adherence over 12- and 24-cycles of treatment.
- PRO compliance rate [ Time Frame: Up to 2 years ]Will be defined as the proportion of patients who submit the given PRO instrument among those eligible at each time point which excludes those missing by design (due to death or disease progression, early treatment discontinuation). Descriptive statistics will be used to summarize selected PRO-CTCAEs tabulated at each cycle overall and by arm. PRO-CTCAEs will be mapped with provider reported adverse events (AEs) and differences in incidence and worst severity will be evaluated. PRO-CTCAE ratings will further be evaluated in relation to patient bother by treatment side effects to identify the toxicities that are most highly associated with treatment tolerability issues.
- PRO completion rate [ Time Frame: Up to 2 years ]Will be defined as the proportion of patients who complete given PRO instrument based on the instrument's scoring system among those eligible at each time point. Descriptive statistics will be used to summarize selected PRO-CTCAEs tabulated at each cycle overall and by arm. PRO-CTCAEs will be mapped with provider reported AEs and differences in incidence and worst severity will be evaluated. PRO-CTCAE ratings will further be evaluated in relation to patient bother by treatment side effects to identify the toxicities that are most highly associated with treatment tolerability issues.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- STEP 0: PRE-REGISTRATION
- Patient must be >= 18 years of age
- Patient must be previously diagnosed with multiple myeloma (MM) and be on lenalidomide maintenance with >= 5mg daily for at least 6 months and no more than 18 months after an early autologous stem cell transplantation (SCT =< 12 months of diagnosis). Patient must not be off lenalidomide maintenance therapy for more than 30 days prior to start of treatment on Step 1 of this protocol
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Patient must be able to undergo a diagnostic bone marrow aspirate following pre-registration to Step 0
- NOTE: A bone marrow aspirate specimen must be submitted to Mayo Clinic Hematology Laboratory for central assessment of minimal residual disease (MRD) status to confirm patient's eligibility for Step 1 randomization. Mayo Clinic will forward results to the submitting institution within three (3) business days of receipt of the bone marrow specimen
- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
- Patient must have been able to maintain at least 5mg daily dose of lenalidomide without growth factor support
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
- STEP 1 RANDOMIZATION
- Patient must meet Step 0 eligibility criteria at the time of Step 1 randomization
- Patients must have evidence of residual disease by central MRD testing or by presence of monoclonal protein in serum or urine
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Patient must have serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and serum free light chain (FLC) performed =< 28 days prior to randomization
- NOTE: UPEP (on a 24-hour collection) is required, no substitute method is acceptable. Urine must be followed monthly if the baseline urine M-spike is >= 200 mg/24 hour (hr). Please note that if both serum and urine M-components are present, both must be followed in order to evaluate response
- Hemoglobin >= 8 g/dL (obtained =< 14 days prior to randomization)
- Untransfused platelet count >= 75,000 cells/mm^3 (obtained =< 14 days prior to randomization)
- Absolute neutrophil count (ANC) >= 1000 cells/mm^3 (obtained =< 14 days prior to randomization)
- Calculated creatinine clearance >= 30 mL/min (obtained =< 14 days prior to randomization)
- Total bilirubin =< 1.5 times the upper limit of normal (ULN) (obtained =< 14 days prior to randomization)
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 times the upper limit of normal (ULN) (obtained =< 14 days prior to randomization)
- Patient must agree to register into the mandatory Revlimid Risk Evaluation and Mitigation Strategies (REMS) registered trademark program and be willing and able to comply with the requirements of Revlimid REMS registered trademark
- Patients of childbearing potential must either abstain from sexual intercourse for the duration of their participation in the study or agree to use TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME for 1) at least 28 days before starting study treatment; 2) while participating in the study; 3) during dose interruptions; and 4) for at least 90 days after the last dose of protocol treatment. Patients must also agree to not breastfeed during this same time period. Men must agree to either abstain from sexual intercourse for the duration of their participation in the study or use a latex condom during sexual contact with a partner of childbearing potential while participating in the study and for 90 days after the last dose of protocol treatment even if they have had a successful vasectomy. Patients must also agree to abstain from donating sperm while on study treatment and for 28 days after the last dose of protocol treatment even if they have had a successful vasectomy. All patients must agree to abstain from donating blood during study participation and for at least 28 days after the last dose of protocol treatment
Exclusion Criteria:
- Patient must not have primary refractory or progressive disease on a proteasome inhibitor-based regimen during induction therapy prior to stem cell transplant
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Patient must not be on other concurrent chemotherapy, or any ancillary therapy considered investigational
- NOTE: Bisphosphonates are considered to be supportive care rather than therapy and are allowed while on protocol treatment
- Patient must not have uncontrolled psychiatric illness or social situations that would limit compliance with study requirements
- Patient must not have another malignancy requiring treatment or have received treatment within two years before pre-registration or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
- Patients must not have known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib or lenalidomide including difficulty swallowing
- Patient must not have known hepatitis B surface antigen-positive status or known or suspected active hepatitis C infection, but testing specifically for the trial is not required
- Patient must not be off lenalidomide maintenance therapy for more than 30 days prior to start of treatment on Step 1 of this protocol
- Patients must not have grade 2 or higher peripheral neuropathy or grade 1 peripheral neuropathy with pain per Common Terminology Criteria for Adverse Events (CTCAE)
- Patients must not have uncontrolled intercurrent illness
- Patients must not have grade 2 or higher diarrhea per CTCAE in the absence of antidiarrheals
- Patients must not have been on systemic treatment, within 14 days before the first dose of ixazomib, with strong CYP3A inducers (such as rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort
- Patient must not be pregnant due to potential harm to the fetus from ixazomib and lenalidomide. All patients of childbearing potential must have a blood test or urine study with a sensitivity of at least 25 mIU/mL within 10-14 days prior to the first dose of lenalidomide and again within 24 hours prior to the first dose of lenalidomide. Patients of childbearing potential must also agree to ongoing pregnancy testing while on treatment. A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03941860
Locations
Show 223 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Shaji K Kumar | ECOG-ACRIN Cancer Research Group |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT03941860 |
| Other Study ID Numbers: |
NCI-2019-02790 NCI-2019-02790 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) EAA171 ( Other Identifier: ECOG-ACRIN Cancer Research Group ) EAA171 ( Other Identifier: CTEP ) U10CA180820 ( U.S. NIH Grant/Contract ) |
| First Posted: | May 8, 2019 Key Record Dates |
| Last Update Posted: | June 7, 2023 |
| Last Verified: | May 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page. |
| URL: | https://grants.nih.gov/policy/sharing.htm |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Multiple Myeloma Neoplasms, Plasma Cell Neoplasms by Histologic Type Neoplasms Hemostatic Disorders Vascular Diseases Cardiovascular Diseases Paraproteinemias Blood Protein Disorders Hematologic Diseases Hemorrhagic Disorders Lymphoproliferative Disorders Immunoproliferative Disorders Immune System Diseases Lenalidomide |
Ixazomib Glycine Immunologic Factors Physiological Effects of Drugs Angiogenesis Inhibitors Angiogenesis Modulating Agents Growth Substances Growth Inhibitors Antineoplastic Agents Molecular Mechanisms of Pharmacological Action Protease Inhibitors Enzyme Inhibitors Glycine Agents Neurotransmitter Agents |