Clinical trial NCT03993912: Compare Lenalidomide and Subcutaneous Daratumumab vs Lenalidomide and Dexamethasone in Frail Subjects With Previously Untreated Multiple Myeloma Who Are Ineligible for High Dose Therapy
Official title: A Phase III Study Comparing Lenalidomide and Subcutaneous Daratumumab (R-Dara SC) vs Lenalidomide and Dexamethasone (Rd) in Frail Subjects With Previously Untreated Multiple Myeloma Who Are Ineligible for High Dose Therapy
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Multiple Myeloma
Keywords: Newly diagnosed Multiple Myeloma
Frail elderly patients
Dexamethasone-sparing regimen
Daratumumab
Toxicity
Lead sponsor: University Hospital, Lille
Sponsor class: OTHER
First posted: 2019-06-21
Enrollment: 294
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase 3, randomized (study drug assigned by chance), open-label (participants and researchers are aware about the treatment, participants are receiving), active-controlled (study in which the experimental treatment or procedure is compared to a standard treatment or procedure), parallel-group (each group of participants will be treated at the same time), and multicenter (when more than one hospital team work on a medical research study) study in participants with newly diagnosed multiple myeloma (a blood cancer of plasma cells) and who are not candidates for high dose chemotherapy (treatment of disease, usually cancer, by chemical agents) and autologous stem cell transplant (ASCT). The primary hypothesis of this study is that subcutaneous Daratumumab in combination with Lenalidomide will prolong progression-free survival and likely induce less toxicity as compared with Lenalidomide and dexamethasone, in elderly frail subjects with newly diagnosed Multiple myeloma who are ineligible for high dose chemotherapy and ASCT

Detailed description: The primary hypothesis of this study is that subcutaneous Daratumumab in combination with Lenalidomide will prolong progression-free survival and likely induce less toxicity as compared with Lenalidomide and dexamethasone, in elderly frail subjects with newly diagnosed Multiple myeloma who are ineligible for high dose chemotherapy and ASCT

Eligibility criteria: Inclusion Criteria:

1. Subject must be at least 65 years of age.
2. Subject must have documented multiple myeloma satisfying the CRAB criteria and measurable disease.
3. Newly diagnosed and not considered candidate for high-dose chemotherapy with SCT.
4. Subject must have a Frailty Score ≥ 2
5. Subject must have within 5 days prior to first drug intake (C1D1) pretreatment clinical laboratory values meeting the following criteria during the Screening Phase:

   * hemoglobin ≥7.5 g/dL
   * absolute neutrophil count ≥1.0 x 109/L
   * platelet count ≥70 x 109/L
   * aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN)
   * alanine aminotransferase (ALT) ≤2.5 x ULN
   * total bilirubin ≤2.0 x ULN
   * creatinine clearance≥30mL/min
6. Measurable ISS with β2-microglobulin and albumin values for randomization
7. A man who is sexually active with a woman of childbearing potential must agree to use a latex or synthetic condom, even if they had a successful vasectomy. All men must also not donate sperm during the study, for 4 weeks after the last dose of lenalidomide, and for 4 months after the last dose of daratumumab. Women participating in this study must be postmenopausal.
8. Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF.
9. Subjects affiliated with an appropriate social security system.

Exclusion Criteria:

1. Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, or smoldering multiple myeloma.
2. Subject has a diagnosis of Waldenström's disease, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
3. Subject has prior or current systemic therapy or SCT for multiple myeloma
4. Subject has a history of malignancy (other than multiple myeloma) within 5 years before the date of randomization
5. Subject has had radiation therapy within 14 days of randomization.
6. Subject has had plasmapheresis within 28 days of randomization.
7. Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.
8. Subject has known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume \[FEV\] in 1 second \<60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years (intermittent asthma is allowed).
9. Subject is known to be seropositive for history of human immunodeficiency virus (HIV)
10. Seropositive for hepatitis B.
11. (Known to be) seropositive for hepatitis C
12. Subject has any concurrent medical or psychiatric condition or disease that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.
13. Subject has clinically significant cardiac disease, including:

    * myocardial infarction within 1 year before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function
    * uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities
    * screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) \>470 msec
14. Subject has known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients
15. Subject has plasma cell leukemia or POEMS syndrome
16. Subject is known or suspected of not being able to comply with the study protocol. Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject or that could prevent, limit, or confound the protocol-specified assessments.
17. Subject has had major surgery within 2 weeks before randomization or has not fully recovered from surgery.
18. Subject has received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before randomization or is currently enrolled in an interventional investigational study.
19. Refusal to consent or protected by legal regime ( guardianship, trusteeship)
20. Subject has contraindications to required prophylaxis for deep vein thrombosis and pulmonary embolism
21. Incidence of gastrointestinal disease that may significantly alter the absorption of oral drugs.

Primary outcomes:
measure: Comparison of the efficacy of Daratumumab SC injection when combined with Lenalidomide (R-Dara SC) vs Lenalidomide and Dexamethasone (Rd): PFS
timeFrame: From date of randomization until the date of first documented progression or date of toxicity or date of death from any cause, whichever came first, assessed up to 84months
Secondary outcomes:
measure: Time-to-treatment failure
timeFrame: From date of randomization until the date of first documented progression or date of toxicity or date of death from any cause, whichever came first, assessed up to 84months
measure: Time-to-next treatment
timeFrame: From date of randomization until the date of first documented progression or date of toxicity or date of death from any cause, whichever came first, assessed up to 84months
measure: PFS2 time
timeFrame: From date of randomization until the date of first documented progression or date of toxicity or date of death from any cause, whichever came first, assessed up to 84months
measure: Overall survival (OS) time
timeFrame: From date of randomization until the date of death from any cause, whichever came first, assessed up to 84months
measure: Complete remission (CR)
timeFrame: From date of randomization until the date of first documented progression whichever came first, assessed up to 84months
measure: Very good partial response (VGPR) or better.
timeFrame: From date of randomization until the date of first documented progression or date of toxicity or date of death from any cause, whichever came first, assessed up to 84months
measure: Overall response (CR + VGPR + partial response [PR]).
timeFrame: From date of randomization until the date of first documented progression or date of toxicity or date of death from any cause, whichever came first, assessed up to 84months
measure: Occurrence of grade 3 or more side effects.
timeFrame: From date of randomization until the date of first documented progression or date of toxicity or date of death from any cause, whichever came first, assessed up to 84months
measure: Safety and tolerability of Daratumumab SC when administered in combination with Revlimid: NCI-CTCAE V5.0.
timeFrame: From date of randomization until the date of first documented progression or date of toxicity or date of death from any cause, whichever came first, assessed up to 84months
measure: Evaluation of quality of life based on MY20 questionnaires
timeFrame: From date of randomization until the date of first documented progression or date of toxicity or date of death from any cause, whichever came first, assessed up to 84months
measure: Evaluation of quality of life based on EORTC C30 questionnaires
timeFrame: From date of randomization until the date of first documented progression or date of toxicity or date of death from any cause, whichever came first, assessed up to 84months
measure: Evaluation of quality of life based on EQ-5D questionnaires
timeFrame: From date of randomization until the date of first documented progression or date of toxicity or date of death from any cause, whichever came first, assessed up to 84months
measure: Minimal residual disease (MRD) negative rate at 12 months.
timeFrame: after 12 months of treatment
measure: Event Free Survival
timeFrame: From date of randomization until the date of first documented progression or date of toxicity or date of death from any cause, whichever came first, assessed up to 84months
Other outcomes:
Locations:
city: Besançon
country: France
facility: Chru Jean Minjoz
city: Blois
country: France
facility: Ch Blois Simone Veil
city: Bourg-en-Bresse
country: France
facility: Ch Fleyriat
city: Brest
country: France
facility: Chru Brest Site Hopital Morvan
city: Caen
country: France
facility: Chu de Caen Normandie
city: Cesson-Sévigné
country: France
facility: Hopital Prive Sevigne - Cesson
city: Dijon
country: France
facility: Chu Dijon Bourgogne
city: Grenoble
country: France
facility: Chu de Grenoble
city: La Rochelle
country: France
facility: Gpe Hospitalier La Rochelle-Re-Aunis
city: Le Coudray
country: France
facility: Ch Chartres Louis Pasteur-Le Coudray
city: Lille
country: France
facility: Hôpital Claude Huriez, CHU
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Mont-de-Marsan
country: France
facility: Chi Mont de Marsan Et Pays Des Sources
city: Montpellier
country: France
facility: Chu Montpellier
city: Nantes
country: France
facility: Chu de Nantes Site Hotel Dieu Hme
city: Nice
country: France
facility: Chu de Nice Hopital de L'Archet
city: Pessac
country: France
facility: Hopital Haut-Leveque - Chu
city: Périgueux
country: France
facility: Centre Hospitalier de Perigueux
city: Rennes
country: France
facility: Chru Rennes Site Pontchaillou
city: Saint-Malo
country: France
facility: Centre Hospitalier Saint-Malo
city: Saint-Quentin
country: France
facility: Centre Hospitalier de Saint Quentin
city: Toulouse
country: France
facility: Oncopole Chu Toulouse
city: Tours
country: France
facility: Chu de Tours
Study officials:
affiliation: University Hospital, Lille
name: Thierry Facon, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References: