ELDORADO: a Randomized Phase II Trial of Elranatamab or Daratumumab in Combination With Lenalidomide, Bortezomib, and Dexamethasone (RVd Lite) in Newly Diagnosed, Transplant Ineligible/Deferred Multiple Myeloma
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 160
- 试验地点
- 6
- 主要终点
- Proportion Patients who test Negative for Minimal Residual Disease (MRD) at 10^-5 after 4 Treatment Cycles
研究概览
简要总结
This research study is being done to compare the efficacy and safety of the combination of elranatamab, lenalidomide, bortezomib, dexamethasone versus the combination of daratumumab, lenalidomide, bortezomib, dexamethasone for patients with newly diagnosed, transplant ineligible/deferred multiple myeloma.
详细描述
The ELDORADO trial is a phase 2, randomized, open label, multicenter study that will enroll approximately 160 patients (10 patient safety run and 150 patients for randomization) to compare the efficacy and safety of the combination of elranatamab, lenalidomide, bortezomib, dexamethasone versus the standard combination of daratumumab and hyaluronidase, lenalidomide, bortezomib, dexamethasone in newly diagnosed, transplant ineligible/deferred multiple myeloma patients. Pfizer, Inc. is supporting this research by providing the study drug, elranatamab, and funding for research activities. Patients will receive treatment for 24 cycles. For patients who meet certain testing parameters, some patients may be able to discontinue treatment and be observed. Other patients may continue with the treatment that they have been receiving until disease progression. Patients may discontinue treatment if they experience unacceptable adverse events, their condition changes rendering them unacceptable for further treatment, they experience intercurrent illness that prevents further administration of treatment, they demonstrate an inability or unwillingness to comply with the medication regimen and/or documentation requirements, or they withdraw from the study. Patients will be followed for a period of 5 years from when the last participant discontinues treatment. The majority of this follow up will not be in person and will be through review of the patients' charts. The U.S. FDA has not approved the combination of elranatamab or daratumumab with lenalidomide, bortezomib, and dexamethasone (elra-RVd lite or dara-RVd lite) as a treatment for any disease. Elranatamab is a bispecific antibody, meaning it can attach to two different things at the same time. Elranatamab, specifically, connects to cancer cells, as well as to a certain type of immune cells, called T cells, to help the immune system attack and destroy the cancer cells. Daratumumab recognizes and attaches to a protein found on the surface of cancer cells, called CD38. This aids the immune system in identifying and destroying cancer cells. Lenalidomide is an immunomodulatory drug. Immunomodulatory drugs help control or adjust how the immune system works, whether it is too weak or too aggressive to more effectively fight infections and cancers. Bortezomib is a proteasome inhibitor, meaning it blocks proteasome in cells. Proteasome aids in cell growth and development. When proteasome is blocked, damaged proteins build up, stressing a cancer cell, and eventually cause cell death. Dexamethasone is a glucocorticoid (a substance that stops inflammation caused by immune system disorders) that has shown significant activity in myeloma. It is believed to aid in anti-myeloma effects, which may lead to the destruction of myeloma cancer cells.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must be at least 18 years of age
- •Newly diagnosed multiple myeloma, with monoclonal plasma cells in the bone marrow ≥10% or a biopsy proven plasmacytoma and either CRAB criteria or biomarker of malignancy
- •a. CRAB criteria, one or more of the following: i. Hypercalcemia: serum calcium (>1 mg/dL) higher than the upper limit of normal or >11 mg/dL ii. Renal insufficiency: creatinine clearance <40 mL/min (calculated per local practice) or serum creatinine >2 mg/dL iii. Anemia: hemoglobin value >2 g/dL below the lower limit of normal or hemoglobin <10 g/dL iv. Bone lesions: one or more lytic lesions on skeletal radiography, CT, or PET CT b. Biomarker of malignancy (one or more of the following): i. Clonal bone marrow plasma cells ≥60% ii. Involved:uninvolved serum free light chain ratio ≥100 iii. >1 focal lesion on magnetic resonance imaging (MRI)
- •Measurable disease as defined by one of the following:
- •Serum monoclonal protein ≥0.5 g/dL. For IgA monoclonal protein, total IgA >500 mg/dL is allowable.
- •Urine monoclonal protein ≥200 mg/24 hours
- •Involved serum free light chain ≥100 mg/L with abnormal free light chain ratio
- •Not considered eligible for high dose melphalan and autologous stem cell transplant per treating investigator or plan for deferred high dose melphalan and autologous stem transplant
- •ECOG performance status of 0-2
- •ANC ≥1000/μL. G-CSF is not permitted within 14 days of screening.
- •Platelet count ≥75,000/µL. Platelet count ≥50,000/µL is permitted if bone marrow is >50% involved. Platelet transfusion and thrombopoietin receptor agonists are not permitted within 7 days of screening.
- •Hemoglobin ≥ 8 g/dL. Red blood cell transfusions are permitted to meet eligibility criteria.
- •Calculated creatinine clearance of ≥ 30 mL/min, not requiring dialysis, with calculation per local practice.
- •Serum bilirubin values < 1.5 x ULN. Isolated bilirubin x 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%. Patients with elevated bilirubin due to Gilbert's syndrome may be permitted with PI approval (e.g. total bilirubin <3 mg/dL and normal direct bilirubin); and
- •Serum aspartate transaminase (ALT) and aspartate transaminase (AST) values < 2.5 × the upper limit of normal (ULN) of the institutional laboratory reference range.
- •Must be able to comply with thromboembolism prophylaxis with e.g. acetylsalicylic acid (ASA), apixaban, rivaroxaban, lower molecular weight heparin, or equivalent.
- •Females of childbearing potential (FCBP) must:
- •Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy within 10-14 days, with the second test within 24 hours of starting lenalidomide. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact.
- •Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use and be able to comply with two reliable forms of contraception as defined by lenalidomide Risk Evaluation and Mitigation Strategy (REMS) program.
- •Male subjects must follow the lenalidomide REMS.
- •Ability and the willingness to undergo repeat bone marrow biopsy assessments.
- •Ability to understand and the willingness to sign a written informed consent document.
排除标准
- •Prior or current systemic therapy for any plasma cell disorder. An exception is emergency use of corticosteroids (equivalent to dexamethasone 40 mg daily for four days). After discussion with the principal investigator. one cycle of standard of care myeloma therapy (without anti-CD38 monoclonal antibody) is permissible to allow for stabilization of disease, during screening/prior to enrollment.
- •Pregnancy, currently breastfeeding, or planned breastfeeding.
- •Participant plans to father a child while enrolled in the study or within 100 days after last dose of study treatment.
- •Prior history of malignancies, other than MM, unless the patient has completed definitive treatment and has been free of the disease for ≥3 years. Patients who are free of disease <3 years may enroll after approval of the PI (e.g. localized breast cancer considered to have very low risk of recurrence). Exceptions include the following (i.e. the following are eligible to participate):
- •Basal or squamous cell carcinoma of the skin
- •Carcinoma in situ of the cervix
- •Ductal carcinoma in situ of the breast
- •Incidental histologic finding of prostate cancer (T1a or T1b) managed with surveillance
- •Other malignancies of clinically localized disease may be permitted to enroll after discussion with the Sponsor-Investigator
- •Patients with plasma cell leukemia at time of screening, POEMS syndrome, or primary AL amyloidosis are excluded from this trial.
- •Seropositive for HIV infection.
- •Hepatitis B viral load positive.
- •Hepatitis C viral load positive.
- •Peripheral neuropathy ≥grade
- •Patient has a history of significant cardiovascular, neurological, endocrine, gastrointestinal, respiratory, or inflammatory illness that could preclude study participation, pose an undue medical hazard, or interfere with the interpretation of the study results, including, but not limited to:
- •Congestive heart failure (New York Heart Association [NYHA] Class 3 or 4)
- •Unstable angina
- •Clinically significant, uncontrolled cardiac arrhythmia such a 2nd degree or 3rd degree atrioventricular block
- •Recent (within the preceding 6 months) myocardial infarction or stroke
- •Severe non-ischemic cardiomyopathy.
- •Uncontrolled hypertension
- •Diabetes mellitus with >2 episodes of ketoacidosis in the preceding 12 months
- •Chronic obstructive pulmonary disease (COPD) requiring >2 hospitalizations in the preceding 12 months.
- •Acute diffuse infiltrative pulmonary disease.
- •Active bacterial, viral, or fungal infection
- •Stroke, transient ischemic attack, or seizure within six months of starting treatment.
- •Patient has any other medical, psychiatric, or social condition that would preclude participation in the study, pose an undue medical hazard, interfere with the conduct of the study, or interfere with interpretation of the study results.
- •Major surgery within 4 weeks prior to C1D
- •Kyphoplasty or vertebroplasty are not considered major surgery.
- •Received an investigational drug (or vaccine) or used an invasive investigational medical device within four weeks before screening or is currently enrolled in an interventional investigational study.
- •Live or live-attenuated vaccine within 30 days prior to C1D1.
研究组 & 干预措施
Elranatamab with lenalidomide, bortezomib, and dexamethasone (elra-RVd lite)
The first 10 patients will enroll in the elranatamab arm for a one 14-day safety run-in cycle. Elranatamab and dexamethasone will be administered at pre-determined doses on days 1, 4, and 8 of the cycle. After randomization occurs, patients in the elra-RVd lite arm will complete 24 cycles (each cycle is 28 days) of treatment. On day 1 of each cycle and day 15 of cycle 1, the pre-determined dose of elranatamab will be administered via subcutaneous injection. On days 1-21 of each cycle, patients will take the pre-determined dose of oral lenalidomide. One days 1, 8, and 15 of cycles 1-8, the pre-determined dose of bortezomib will be administered via subcutaneous injection. After completion of 24 treatment cycles, patients who have had two MRD negative tests, one year apart, may discontinue treatment and enter the observation phase of the trial. Patients who have not had two MRD negative tests one year apart, may continue elranatamab lenalidomide treatment for another 24 cycles.
干预措施: Elranatamab (PF-06863135) (Drug)
Elranatamab with lenalidomide, bortezomib, and dexamethasone (elra-RVd lite)
The first 10 patients will enroll in the elranatamab arm for a one 14-day safety run-in cycle. Elranatamab and dexamethasone will be administered at pre-determined doses on days 1, 4, and 8 of the cycle. After randomization occurs, patients in the elra-RVd lite arm will complete 24 cycles (each cycle is 28 days) of treatment. On day 1 of each cycle and day 15 of cycle 1, the pre-determined dose of elranatamab will be administered via subcutaneous injection. On days 1-21 of each cycle, patients will take the pre-determined dose of oral lenalidomide. One days 1, 8, and 15 of cycles 1-8, the pre-determined dose of bortezomib will be administered via subcutaneous injection. After completion of 24 treatment cycles, patients who have had two MRD negative tests, one year apart, may discontinue treatment and enter the observation phase of the trial. Patients who have not had two MRD negative tests one year apart, may continue elranatamab lenalidomide treatment for another 24 cycles.
干预措施: Lenalidomide (Drug)
Elranatamab with lenalidomide, bortezomib, and dexamethasone (elra-RVd lite)
The first 10 patients will enroll in the elranatamab arm for a one 14-day safety run-in cycle. Elranatamab and dexamethasone will be administered at pre-determined doses on days 1, 4, and 8 of the cycle. After randomization occurs, patients in the elra-RVd lite arm will complete 24 cycles (each cycle is 28 days) of treatment. On day 1 of each cycle and day 15 of cycle 1, the pre-determined dose of elranatamab will be administered via subcutaneous injection. On days 1-21 of each cycle, patients will take the pre-determined dose of oral lenalidomide. One days 1, 8, and 15 of cycles 1-8, the pre-determined dose of bortezomib will be administered via subcutaneous injection. After completion of 24 treatment cycles, patients who have had two MRD negative tests, one year apart, may discontinue treatment and enter the observation phase of the trial. Patients who have not had two MRD negative tests one year apart, may continue elranatamab lenalidomide treatment for another 24 cycles.
干预措施: Bortezomib for Injection (Drug)
Elranatamab with lenalidomide, bortezomib, and dexamethasone (elra-RVd lite)
The first 10 patients will enroll in the elranatamab arm for a one 14-day safety run-in cycle. Elranatamab and dexamethasone will be administered at pre-determined doses on days 1, 4, and 8 of the cycle. After randomization occurs, patients in the elra-RVd lite arm will complete 24 cycles (each cycle is 28 days) of treatment. On day 1 of each cycle and day 15 of cycle 1, the pre-determined dose of elranatamab will be administered via subcutaneous injection. On days 1-21 of each cycle, patients will take the pre-determined dose of oral lenalidomide. One days 1, 8, and 15 of cycles 1-8, the pre-determined dose of bortezomib will be administered via subcutaneous injection. After completion of 24 treatment cycles, patients who have had two MRD negative tests, one year apart, may discontinue treatment and enter the observation phase of the trial. Patients who have not had two MRD negative tests one year apart, may continue elranatamab lenalidomide treatment for another 24 cycles.
干预措施: Dexamethasone (Drug)
Daratumumab with lenalidomide, bortezomib, and dexamethasone (dara-RVd lite)
After randomization occurs, patients in the dara-RVd lite arm will complete 24 cycles (each cycle is 28 days) of treatment. On days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 of cycles 3-6, and day 1 of cycles 7+, the pre-determined dose of daratumumab will be administered via subcutaneous injection. On days 1-21 of each cycle, patients will take the pre-determined dose of oral lenalidomide. One days 1, 8, and 15 of cycles 1-8, the pre-determined dose of bortezomib will be administered via subcutaneous injection. On days 1, 2, 8, 9, 15, 16 of cycles 3+, as well as days 22 and 23 of cycles 1 and 2, patients will take the pre-determined dose of oral dexamethasone.
干预措施: Bortezomib for Injection (Drug)
Daratumumab with lenalidomide, bortezomib, and dexamethasone (dara-RVd lite)
After randomization occurs, patients in the dara-RVd lite arm will complete 24 cycles (each cycle is 28 days) of treatment. On days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 of cycles 3-6, and day 1 of cycles 7+, the pre-determined dose of daratumumab will be administered via subcutaneous injection. On days 1-21 of each cycle, patients will take the pre-determined dose of oral lenalidomide. One days 1, 8, and 15 of cycles 1-8, the pre-determined dose of bortezomib will be administered via subcutaneous injection. On days 1, 2, 8, 9, 15, 16 of cycles 3+, as well as days 22 and 23 of cycles 1 and 2, patients will take the pre-determined dose of oral dexamethasone.
干预措施: Daratumumab and Hyaluronidase-fihj (Drug)
Daratumumab with lenalidomide, bortezomib, and dexamethasone (dara-RVd lite)
After randomization occurs, patients in the dara-RVd lite arm will complete 24 cycles (each cycle is 28 days) of treatment. On days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 of cycles 3-6, and day 1 of cycles 7+, the pre-determined dose of daratumumab will be administered via subcutaneous injection. On days 1-21 of each cycle, patients will take the pre-determined dose of oral lenalidomide. One days 1, 8, and 15 of cycles 1-8, the pre-determined dose of bortezomib will be administered via subcutaneous injection. On days 1, 2, 8, 9, 15, 16 of cycles 3+, as well as days 22 and 23 of cycles 1 and 2, patients will take the pre-determined dose of oral dexamethasone.
干预措施: Lenalidomide (Drug)
Daratumumab with lenalidomide, bortezomib, and dexamethasone (dara-RVd lite)
After randomization occurs, patients in the dara-RVd lite arm will complete 24 cycles (each cycle is 28 days) of treatment. On days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 of cycles 3-6, and day 1 of cycles 7+, the pre-determined dose of daratumumab will be administered via subcutaneous injection. On days 1-21 of each cycle, patients will take the pre-determined dose of oral lenalidomide. One days 1, 8, and 15 of cycles 1-8, the pre-determined dose of bortezomib will be administered via subcutaneous injection. On days 1, 2, 8, 9, 15, 16 of cycles 3+, as well as days 22 and 23 of cycles 1 and 2, patients will take the pre-determined dose of oral dexamethasone.
干预措施: Dexamethasone (Drug)
结局指标
主要结局
Proportion Patients who test Negative for Minimal Residual Disease (MRD) at 10^-5 after 4 Treatment Cycles
时间窗: Day 1 of Cycle 1 (each cycle is 28 days) to Day 28 of Cycle 4.
Evaluated at 1 x 10\^-5 using next generation sequencing (NGS) to detect clonal sequences. The proportions will be compared using the Cochran-Mantzel-Haenszel test, stratified by the randomization stratification factors. A one-sided significance level of 0.05 will be used. Patients without successful baseline minimal residual disease (MRD) testing will not be evaluated for MRD response. Proportion patients who test negative for MRD at 10\^-5 after 4 treatment cycles will be compared between the elran-RVd lite arm and the dara-RVd lite arm.
Proportion Patients who test Negative for Minimal Residual Disease (MRD) at 10^-5 after 4 Treatment Cycles
时间窗: Day 1 of Cycle 1 (each cycle is 28 days) to Day 28 of Cycle 4.
Evaluated at 1 x 10\^-5 using next generation sequencing (NGS) to detect clonal sequences. The proportions will be compared using the Cochran-Mantzel-Haenszel test, stratified by the randomization stratification factors. A one-sided significance level of 0.05 will be used. Patients without successful baseline minimal residual disease (MRD) testing will not be evaluated for MRD response. Proportion patients who test negative for MRD at 10\^-5 after 4 treatment cycles will be compared between the elran-RVd lite arm and the dara-RVd lite arm.
次要结局
- Progression-Free Survival (PFS)(Day 1 of Cycle 1 (each cycle is 28 days) to documentation of disease progression or death from any cause (up to 5 years). Patients who have not progressed or died are censored at the date last known progression-free.)
- Overall Survival (OS)(Day 1 of Cycle 1 (each cycle is 28 days) to documentation of death due to any cause or censored at the date last known alive, up to 5 years from study registration.)
- Overall Response Rate (ORR)(Day of initiation of first response to the first documentation of disease progression or death, up to 5 years after registration. Patients who have not progressed or died are censored at the date last known progression-free.)
- Proportion Patients who test Negative for Minimal Residual Disease (MRD) at 10^-5 after 12 Treatment Cycles(Day 1 of Cycle 1 (each cycle is 28 days) to Day 28 of Cycle 12.)
- Proportion Patients who test Negative for Minimal Residual Disease (MRD) at 10^-6 after 4 Treatment Cycles(Day 1 of Cycle 1 (each cycle is 28 days) to Day 28 of Cycle 4.)
- Proportion Patients who Remain Negative for Minimal Residual Disease (MRD) at 10^-5 for 12 Months(Day of first negative MRD test to study completion (up to 5 years).)
- Proportion Patients who Remain Negative for Minimal Residual Disease (MRD) at 10^-6 for 12 Months(Day of first negative MRD test to study completion (up to 5 years).)
- Proportion Patients who test Negative for Minimal Residual Disease (MRD) at 10^-6 after 12 Treatment Cycles(Day 1 of Cycle 1 (each cycle is 28 days) to Day 28 of Cycle 12.)
- Depth of Response using Peripheral Blood Mass Spectrometry(Day 1 of cycle 1 (each cycle is 28 days) to day 28 of cycle 24.)
- Number of Patients who Experience Adverse Events (AEs)(Day 1 of cycle 1 (each cycle is 28 days) to day 28 of the patient's last treatment cycle (up to 48 cycles).)
- Progression-Free Survival (PFS)(Day 1 of Cycle 1 (each cycle is 28 days) to documentation of disease progression or death from any cause (up to 5 years). Patients who have not progressed or died are censored at the date last known progression-free.)
- Overall Survival (OS)(Day 1 of Cycle 1 (each cycle is 28 days) to documentation of death due to any cause or censored at the date last known alive, up to 5 years from study registration.)
- Overall Response Rate (ORR)(Day of initiation of first response to the first documentation of disease progression or death, up to 5 years after registration. Patients who have not progressed or died are censored at the date last known progression-free.)
- Proportion Patients who test Negative for Minimal Residual Disease (MRD) at 10^-5 after 12 Treatment Cycles(Day 1 of Cycle 1 (each cycle is 28 days) to Day 28 of Cycle 12.)
- Proportion Patients who test Negative for Minimal Residual Disease (MRD) at 10^-6 after 4 Treatment Cycles(Day 1 of Cycle 1 (each cycle is 28 days) to Day 28 of Cycle 4.)
- Proportion Patients who Remain Negative for Minimal Residual Disease (MRD) at 10^-5 for 12 Months(Day of first negative MRD test to study completion (up to 5 years).)
- Proportion Patients who Remain Negative for Minimal Residual Disease (MRD) at 10^-6 for 12 Months(Day of first negative MRD test to study completion (up to 5 years).)
- Proportion Patients who test Negative for Minimal Residual Disease (MRD) at 10^-6 after 12 Treatment Cycles(Day 1 of Cycle 1 (each cycle is 28 days) to Day 28 of Cycle 12.)
- Depth of Response using Peripheral Blood Mass Spectrometry(Day 1 of cycle 1 (each cycle is 28 days) to day 28 of cycle 24.)
- Number of Patients who Experience Adverse Events (AEs)(Day 1 of cycle 1 (each cycle is 28 days) to day 28 of the patient's last treatment cycle (up to 48 cycles).)
研究者
Andrew Yee, MD
Principle Investigator
Massachusetts General Hospital