Clinical trial NCT04965155: A Trial for Relapsed Multiple Myeloma Patients (Isatuximab-dexamethasone)
Official title: Isatuximab and Autologous Hematopoietic Stem Cell Transplantation for Relapsed Multiple Myeloma Patients (Isabel Study)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Relapsed Multiple Myeloma
Lead sponsor: EMN Trial Office S.r.l. Impresa Sociale
Sponsor class: OTHER
First posted: 2021-07-16
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Isatuximab-dexamethasone pre and post transplant
Primary purpose: TREATMENT

Brief summary: This is an open label phase II study designed to assess the efficacy and safety of the combination isatuximab-dexamethasone pre and post transplant in relapsed MM patients. Before enrolment, patients have already received a reinduction therapy, as per local protocols, in order to achieve an optimal cytoreduction. Since carfilzomib-based regimens (eg. carfilzomib-lenalidomide-dexamethasone or carfilzomib-dexamethasone) are the current standard in Italy, for uniformity the use of one of these combinations is recommended. However, any cytoreductive treatment, excluding anti-CD38 antibodies containing regimens, as per local practice, is acceptable. During this period, if necessary, it will be possible to mobilize and collect peripheral blood stem cells. After the pre-enrollment cytoreduction period (reinduction therapy), patients have achieved at least a PR according to IMWG Response criteria.

After study enrolment, patients will receive 3 courses of isatuximab in combination with dexamethasone; after cycle 3 patients will receive ASCT, that will be conditioned with melphalan and will be followed by reinfusion of cryopreserved autologous stem cells. At 2 months after ASCT, patients will start maintenance, consisting in the administration of isatuximab in combination with dexamethasone for 12 cycles. Starting from cycle 13 onwards, only isatuximab will be administered until progression or intolerance.


Eligibility criteria: Inclusion Criteria:

1. Patient has given voluntary written informed consent
2. Patient is willing and able to comply with the study visits and procedures required per protocol
3. Subject must have at least 18 and = 70 years of age
4. Patient has a life-expectancy = 3 months
5. Subject has received an ASCT in the first line of therapy with a progression/relapse after at least 24 months
6. Subject must have received any cytoreductive treatment, excluding anti-CD38 antibodies containing regimens, as per local practice for the first relapse, according to local guidelines. Carfilzomib-based combinations are recommended (eg. carfilzomib-lenalidomidedexamethasone or carfilzomib-dexamethasone). After the salvage duration phase (reinduction therapy), subject has achieved at least a PR according to IMWG Response criteria.
7. Subject must have documented relapsed MM as per IMWG criteria, and achieved at least a partial remission with treatments as per local guidelines
8. Subject must have at least 2.0 x 106 CD34+/Kg cryopreserved autologous stem cells
9. Subject must have an ECOG Performance Status score of 0, 1
10. Subject must have the following laboratory values:

    * Platelet count =50 x 109/L (=30 x 109 /L if myeloma involvement in the bone marrow is \> 50%) within 14 days prior to drug administration)
    * Absolute neutrophil count (ANC) = 1 x 109/L without the use of growth factors
    * Corrected serum calcium =14 mg/dL (3.5 mmol/L)
    * Alanine transaminase (ALT): = 3 x the ULN
    * Total bilirubin: = 2 x the ULN
    * Calculated or measured creatinine clearance: = 30 mL/minute
11. Female subjects are eligible to participate if they are not pregnant, not breastfeeding, and at least one of the following conditions applies:

    * they are not females of childbearing potential (FCBP), OR
    * they are FCBP who have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting study medication and before each cycle of study treatment and must either commit to continue abstinence from heterosexual intercourse or apply a highly effective method of birth control during the intervention period and for at least 5 months after the last dose of study treatment. Of note: contraception duration should take also into consideration any backbone therapy
12. Male subjects must agree to use contraception on this protocol during the intervention period and for at least 5 months after the last dose of study treatment and refrain from donating sperm during this period

Exclusion Criteria:

1. Previous therapy with daratumumab, isatuximab or any other anti-CD38 monoclonal antibody
2. MM localization to the central nervous system
3. Subjects who have received any investigational drug within 14 days or 5 half-lives of the investigational drug from eligibility confirmation, whichever is longer
4. Subjects who have received an allogeneic stem cell transplant
5. Subject with a history of malignancy (other than multiple myeloma) within 3 years before the date of eligibility confirmation (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the investigator, in agreement with the medical monitor, is considered cured with minimal risk of recurrence within 3 years)
6. Subject is known to be seropositive for human immunodeficiency virus (HIV) or with an active hepatitis A, B and C infection, defined as a positive test for hepatitis B surface antigen \[HBsAg\] and a positivity for HAV-RNA, HBV-DNA or HCV-RNA
7. Subject with any concurrent, clinically significant, uncontrolled 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 with active tuberculosis and severe infections requiring treatment with an antibiotic parenteral administration
9. Subject with hypersensitivity or history of intolerance to steroids, mannitol, pregelatinized starch, sodium stearyl fumarate, histidine (as base and hydrochloride salt), arginine hydrochloride, poloxamer 188, sucrose or any of the other components of study therapy that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents
10. Subject with pulmonary deficit, defined as FEV1 \<65% and/or DLCO \<65%
11. Subject with clinically significant cardiac disease, including:

    * LVEF \<50%
    * Myocardial infarction within 6 months before eligibility confirmation, or unstable or
    * Uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV)
    * Cardiac arrhythmia (Common Terminology Criteria for Adverse Events \[CTCAE\] Version 5 Grade 2 or higher) or clinically significant ECG abnormalities
    * Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) \>500 msec

Primary outcomes:
measure: MRD negativity
timeFrame: Within 12 months after ASCT
Secondary outcomes:
measure: Response rate
timeFrame: 5/6 years
measure: TTP (time to progression)
timeFrame: 5/6 years
measure: PFS (progression free survival)
timeFrame: 5/6 years
measure: TNT (time to next therapy)
timeFrame: 5/6 years
measure: PFS2 (progression free survival 2)
timeFrame: 5/6 years
measure: OS (overall survival)
timeFrame: 5/6 years
measure: DOR (duration of response)
timeFrame: 5/6 years
measure: Time to PR (time to partial response)
timeFrame: 5/6 years
measure: Time to VGPR (time to very good partial response)
timeFrame: 5/6 years
measure: Time to CR (time to complete response)
timeFrame: 5/6 years
measure: Time to sCR (time to stringent complete response)
timeFrame: 5/6 years
measure: Rate of 1 year sustained MRD (minimal residue disease) negativity
timeFrame: 5/6 years
measure: MRD (minimal residue disease) negativity
timeFrame: 5/6 years
measure: 24 months MRD negativity rate
timeFrame: 5/6 years
measure: Analysis of safety
timeFrame: 5/6 years
measure: Dose reduction rate
timeFrame: 5/6 years
measure: Time to discontinuation of study drug
timeFrame: 5/6 years
measure: Relative dose estimations for each study drugs
timeFrame: 5/6 years
Other outcomes:
Locations:
city: Ancona
country: Italy
facility: AOU Ospedali Riuniti Umberto I
city: Bari
country: Italy
facility: AOU Policlinico di Bari
city: Bologna
country: Italy
facility: AOU di Bologna
city: Bolzano
country: Italy
facility: Ospedale di Bolzano - Azienda Sanitaria dell'Alto Adige
city: Genova
country: Italy
facility: AOU Policlinico S. Martino
city: Milano
country: Italy
facility: I.R.C.C.S. Ospedale S. Raffaele
city: Napoli
country: Italy
facility: AOU Federico II
city: Padova
country: Italy
facility: AO di Padova
city: Perugia
country: Italy
facility: AO di Perugia-Ospedale S. Maria della Misericordia
city: Roma
country: Italy
facility: Policlinico Umberto I - Università 'Sapienza'
city: Terni
country: Italy
facility: AO S. Maria
city: Torino
country: Italy
facility: AOU Città della Salute e della Scienza di Torino
city: Trieste
country: Italy
facility: AOU Ospedali Riuniti di Trieste
city: Udine
country: Italy
facility: Ospedale S. Maria della Misericordia di Udine
Study officials:
References: