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ACTIVE NOT RECRUITING

NCT03836014

PHASE3

Study Comparing Continuous Versus Fixed Duration Therapy With Daratumumab, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma

Sponsor: Assistance Publique - Hôpitaux de Paris

View on ClinicalTrials.gov

Summary

The incorporation of proteasome inhibitors and immunomodulatory drugs into the standard of care has improved the outcome for patients with multiple myeloma (MM) over the past 10 years. However, most patients (\>85%) still eventually relapse around 3-4 years after diagnosis, and ultimately die of their disease, despite salvage therapies. Relapse can occur even when complete remission is achieved after first-line therapy. Currently, daratumumab (Dara) is approved by the american FDA and EMA in combination with lenalidomide (Len) and dexamethasone (Dex) or bortezomib and Dex for the treatment of MM patients who have received at least one prior therapy. Therefore, the Dara-Len-Dex combination is likely to become the most widely used standard of care regimen for MM at the time of first relapse. However, although approval of the latter combination is meant for until disease progression (PD) ("continuous therapy") (CT), the actual optimal duration of relapse treatment is still unknown. Of note, many experts advocate that a "fixed duration" of therapy should be favored, especially if one can show that CT does not translate into a significant overall survival (OS) benefit. As a matter of fact, given the extremely high cost of such novel agents (\>100 KEuros/year/patient), the pharmacoeconomic consequences of a "continuous" versus "fixed" duration therapy are also of utmost importance. Based on this background, the investigator propose to conduct a non-inferiority phase III randomized, multicenter, open label trial for treatment of MM at first relapse, comparing the Dara-Len-Dex combination administered continuously until PD, versus a fixed duration of 24 months. The choice of this duration is justified by the currently available evidence with respect to achievement of a plateau in terms of deep disease response, patients' compliance, and physicians' preference according to different surveys. The primary objective of this study is to estimate the OS rate at 4 years after diagnosis of relapse and initiation of salvage therapy. The primary endpoint is OS at 4 years after randomization. The analysis will be performed on both per-protocol and intent-to-treat sets of patients.

Official title: A Multi-center Phase III Randomized Study Comparing Continuous Versus Fixed Duration Therapy With Daratumumab, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma

Key Details

Gender

All

Age Range

18 Years - Any

Study Type

INTERVENTIONAL

Enrollment

436

Start Date

2019-07-25

Completion Date

2026-07

Last Updated

2024-12-06

Healthy Volunteers

Conditions

Multiple Myeloma in Relapse

Interventions

COMBINATION_PRODUCT

Daratumumab/Lenalidomide/Dexamethasone for 24 months

Conditioning regimen: 16 mg/kg IV : * Weekly (Cycles 1 and C2) * Every two weeks (C3 to C6) * Monthly from C7 up to 24 months in total (Arm 1) Infusion reaction prophylaxis : * Acetaminophen (paracetamol) 650-1000 mg IV or orally (PO) approximately 1 hour or less prior to infusion * An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent but avoid IV use of promethazine) approximately 1hour prior to infusion; after Cycle 6, if a subject has not developed an infusion-related reaction and is intolerant to antihistamines, modifications are acceptable as per investigator discretion * Dexamethasone 40 mg IV (preferred) or PO, approximately 1 hour or less prior infusion. Lenalidomide: Conditioning regimen: 25 mg per os. From day 1 to day 21 of each cycle up to 24 months in total (Arm 1) Dexamethasone: Conditioning regimen: 40 mg at day 1 (preinfusion medication IV preferred), day 8, day 15 and day 22 per os of each cycle up to 24 months in total (Arm 1)

COMBINATION_PRODUCT

Daratumumab/Lenalidomide/Dexamethasone until progression

Conditioning regimen: 16 mg/kg IV : * Weekly (Cycles 1 and C2) * Every two weeks (C3 to C6) * Monthly from C7 until disease progression (Arm 2). Infusion reaction prophylaxis : * Acetaminophen (paracetamol) 650-1000 mg IV or orally (PO) approximately 1 hour or less prior to infusion * An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent but avoid IV use of promethazine) approximately 1hour prior to infusion; after Cycle 6, if a subject has not developed an infusion-related reaction and is intolerant to antihistamines, modifications are acceptable as per investigator discretion * Dexamethasone 40 mg IV (preferred) or PO, approximately 1 hour or less prior infusion. Lenalidomide: Conditioning regimen: 25 mg per os. From day 1 to day 21 of each cycle until disease progression (Arm 2). Dexamethasone: Conditioning regimen: 40 mg at day 1 (preinfusion medication IV preferred), day 8, day 15 and day 22 per os of each cycle until disease progression (Arm 2).

Inclusion Criteria: 1. Adult patients (≥ 18 years old) 2. Documented MM in relapse according to standard criteria and requiring initiation of a first line salvage therapy. 3. Subject must have received one prior line of therapy for MM. 4. Subject must have achieved a response (PR or better) to the prior regimen. 5. Subject must have an ECOG Performance Status score of 0, 1, or 2. 6. For subjects experiencing toxicities resulting from previous therapy (including peripheral neuropathy), the toxicities must have been resolved or stabilized. 7. Signed informed consent 8. Affiliation to a social security system or equivalent (recipient or assign) 9. Effective method of contraception for the duration of treatment and 3 months after the last dose for women of childbearing age and men with a partner of childbearing age: * Progestin-only pill associated with inhibition of ovulation * Hormonal methods of contraception, including oral contraceptive pills containing a combination of estrogen + progesterone, vaginal ring, injectables, implants and intrauterine devices (IUDs) * non-hormonal IUD * Bilateral tubal occlusion * Vasectomized partner with documented azoospermia 90 days after procedure and who received a medical assessment of surgical success * Intrauterine hormone release system (IUS) * Complete Abstinence: Complete abstinence is defined as the complete avoidance of heterosexual intercourse. Complete abstinence is an acceptable form of contraception for all study drugs and must be used throughout the duration of the study and for the duration of time as specified above. It is not necessary to use any other method of contraception when complete abstinence is elected. Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence. Exclusion Criteria: 1. Evidence of refractoriness or intolerance to lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody). If previously treated with a lenalidomide or daratumumab-containing regimen, the subject is excluded if he or she: * Discontinued due to any severe adverse event related to prior lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody) treatment, or * If, at any time point, the subject was refractory to any dose of lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody). Refractoriness to lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody) is defined either as: * Subjects whose disease progressed within 60 days of lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody) administration; or * Subjects whose disease is nonresponsive while on lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody). Nonresponsive disease is defined as either failure to achieve at least a minimal response or development of progressive disease while on lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody). 2. Subject has received an allogenic stem cell transplant (regardless of timing). 3. Subjects planning to undergo a stem cell transplant prior to progression of disease on this study, ie, these subjects should not be enrolled in order to reduce disease burden prior to transplant. 4. Subject has a history of malignancy (other than MM) within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator is considered cured with minimal risk of recurrence within 3 years). 5. Subject has known MM meningeal involvement. 6. Subject has plasma cell leukemia (\>2.0 × 109/L circulating plasma cells by standard differential) or Waldenström's macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis. 7. Subject has any concurrent medical condition or disease (eg, active systemic infection) that is likely to interfere with study procedures or results, or that, in the opinion, of the investigator would constitute a hazard for participating in this study. 8. Subject has known uncontrolled chronic obstructive pulmonary disease (COPD) 9. Subject has clinically significant cardiac disease. 10. Subject is known to be seropositive for human immunodeficiency virus (HIV), hepatitis B or hepatitis C. 11. Creatinine clearance ≤30 mL/min (MDRD method) (lenalidomide dose adjustment will be considered for subjects with creatinine clearance 30-60 mL/min). 12. Hypersensitivity to the active substance or to any of the excipients 13. Pregnancy or lactation women

Locations (1)

Saint Antoine Hospital - Hematology Department

Paris, France