Evaluation iNduction, Consolidation and Maintenance Treatment With Isatuximab , Carfilzomib, LEnalidomide and Dexamethasone

NCT ID: NCT03104842

Last Updated: 2024-05-29

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 246 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-08-15
• Study Completion Date: 2026-09-30

Brief Summary

A Clinical Phase II, multicenter, Open-label study evaluating iNduction, consolidation and maintenance treatment with Isatuximab (SAR650984), Carfilzomib, LEnalidomide and Dexamethasone (I-KRd) in Primary diagnosed high-risk multiple myeloma paTients

Conditions

Multiple Myeloma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm B No-Transplantation

Patients \> 70 years or ineligible for stem cell transplantation will enter study arm B They will undergo 12 cycles of Treatment : Carfilzomib, Lenalidomid, Isatuximab (I-KRd) (6 Cycles Induction, 2 Cycles Intensification, 4 Cycles Consolidation),to be followed by I-KR maintenance util PD or Toxicity

Group Type: EXPERIMENTAL

Isatuximab

Intervention Type: DRUG

Antibody Intravenous

Carfilzomib

Intervention Type: DRUG

Intravenous

Lenalidomide

Intervention Type: DRUG

Capsel

Dexamethasone

Intervention Type: DRUG

Capsel

Arm A Transplantation

Patients ≤ 70 years of age and eligible for stem cell transplantation will enter study arm A They will undergo 6 cycles of Induction Treatment : Carfilzomib, Lenalidomid, Isatuximab (I-KRd), after intensification another 4 cycles of I-KRd as consolidation will be followed by IKR maintenance until PD or Toxicity

Group Type: EXPERIMENTAL

Isatuximab

Intervention Type: DRUG

Antibody Intravenous

Carfilzomib

Intervention Type: DRUG

Intravenous

Lenalidomide

Intervention Type: DRUG

Capsel

Dexamethasone

Intervention Type: DRUG

Capsel

Interventions

Isatuximab

Antibody Intravenous

Intervention Type: DRUG

Carfilzomib

Intravenous

Intervention Type: DRUG

Lenalidomide

Capsel

Intervention Type: DRUG

Dexamethasone

Capsel

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Subjects must have newly diagnosed, untreated, symptomatic (according to the revised CRAB criteria 2014), documented myeloma and have measurable disease (serum M-protein ≥ 1 g/dL (for IgA ≥ 0.5 g/dL) or urine M-protein ≥ 200 mg/24 hours) or in case of oligosecretory myeloma: involved FLC level ≥ 10 mg/dl, provided sFLC ratio is abnormal or in case of asecretory myeloma: > 1 focal lesions measurable by MRI

Subjects must have high-risk myeloma defined as followed:

• Presence of one or more of the following cytogenetic abnormalities (determined by FISH):

• Del(17p) in ≥ 10% of purified cells
• t(4;14)
• ≥ 3 copies +1q21
• t(14;16)
• ISS Stage II or III (all patients)
• FISH analysis of external laboratories other than Heidelberg is accepted, a list of laboratories will be filed in the study central.

2. Must be ≥ 18 years at the time of signing the informed consent form.

3. Must be able to adhere to the study visit schedule and other protocol requirements in the investigators opinion.

4. WHO performance status 0-3 (WHO=3 is allowed only if caused by MM and not by co-morbid conditions)

5. Females of childbearing potential (FCBP) (1) must agree to refrain from becoming pregnant for 28 days prior to initiation of study drug, while on study drug and for 150 days* after discontinuation from the study drug by using 2 reliable methods of contraception and must agree to regular pregnancy testing during this timeframe.

• A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., who has had menses at any time in the preceding 24 consecutive months) 3) has achieved menarche at some point.

6. Females must agree to abstain from breastfeeding during study participation and 30 days* after study drug discontinuation.

7. Males must agree to use a latex condom during any sexual contact with FCBP while participating in the study and for 150 days* following discontinuation from this study, even if he has undergone a successful vasectomy.

8. Males must also agree to refrain from donating semen or sperm while on treatment with any study drug and for 150 days* after discontinuation from this study treatment.

9. All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment.

10. All subjects must agree not to share medication.

11. All participating subjects have to follow the requirements of the Lenalidomide Pregnancy Prevention Plan

Exclusion Criteria

1. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize Carfilzomib), mannitol, sucrose, histidine (as base and hydrochloride salt) and polysorbate 80 or any of the components of study therapy that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents.

2. Patients with known systemic amyloidosis (except for AL amyloidosis of the skin or the bone marrow)

3. Administration of systemic chemotherapy, biological, immunotherapy or any investigational agent (therapeutic or diagnostic) for multiple myeloma except bisphosphonate therapy. Emergency treatment with dexamethasone is allowed when the cumulative dexamethasone dose is less or equal 160 mg. It is allowed to include patients in the trial after 1 cycle (4 weeks) of any anti-myeloma first-line treatment.

4. Any of the following laboratory abnormalities:

• Absolute neutrophil count (ANC) < 1,000/μL, unless related to myeloma
• Platelet count < 30,000/ μL (in case of platelets < 50.000 /µl and ≥ 30.000 /µl myeloma bone marrow infiltration should be ≥ 50%)
• Corrected serum calcium > 14 mg/dL (> 3.5 mmol/L); or free ionized calcium > 6.5 mg/dL (> 1.6 mmol/L)
• Serum GOT/AST or SGPT/ALT > 3.0 x upper limit of normal (ULN) or serum total bilirubin > 2.0 mg/dL if not due to hereditary abnormalities as Gilbert's disease or hereditary hemolysis (Note: if the mentioned limits for bilirubin or ASAT/ALAT are exceeded, but there is no significant hepatic dysfunction at investigator's discretion, the study office has to be consulted prior to inclusion)
• Patients with severe renal impairment (eGFR < 30 ml/min/1.73 m², MDRD formula or CDK-EPI or Creatinine Clearance < 30 ml/min)

5. Active congestive heart failure (NYHA Class III to IV), symptomatic cardiac ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within four months prior study entry.

6. Known HIV seropositive, hepatitis C infection, and/or hepatitis B (except for patients with hepatitis B sAg and core antibody receiving and responding to antiviral therapy directed at hepatitis B: these patients are allowed).

7. Acute active, uncontrolled infection

8. Significant neuropathy (Grades 3 to 4, or Grade 2 with pain according CTC V4.03)

9. Second malignancy within the past 5 years except:

• adequately treated basal cell or squamous cell skin cancer
• carcinoma in situ of the cervix
• prostate cancer Gleason Score ≤ 6 with stable PSA over the past 12 months
• breast carcinoma in situ with full surgical resection
• treated medullary or papillary thyroid cancer

10. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to study entry.

11. Major surgery within 4 weeks prior to cycle 1 day 1 (kyphoplasty is not considered major surgery); subjects should have been fully recovered from any surgical related toxicities.

12. Female patients who are pregnant or lactating

13. Any other clinically significant medical disease or psychiatric condition that, in the Investigator's opinion, may interfere with protocol adherence or a patient's ability to give informed consent.

14. Participation in any other clinical trial (with the exclusion of observational, non-interventional studies))

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Universitätsklinikum Hamburg-Eppendorf

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Katja Weisel, Prof

Role: PRINCIPAL_INVESTIGATOR

Universitätsklinikum Hamburg-Eppendorf

Locations

Vivantes Am Urban

Berlin, , Germany

Campus Benjamin Franklin Charite Berlin

Berlin, , Germany

Vivantes Klinikum Neukölln

Berlin, , Germany

Städt. Kliniken Bielefeld Klinikum Mitte

Bielefeld, , Germany

Johanniter-Krankenhaus Bonn

Bonn, , Germany

Uniklinikum Chemnitz

Chemnitz, , Germany

Uniklinik Köln

Cologne, , Germany

St. Antonius Hospital

Eschweiler, , Germany

Universitätsklinikum Essen

Essen, , Germany

Asklepios Altona

Hamburg, , Germany

University Hospital Hamburg Eppendorf

Hamburg, , Germany

University Hospital Heidelberg

Heidelberg, , Germany

Universitätsmedizin der Johannes Gutenberg-Universität Mainz

Mainz, , Germany

Philipps-Universität Marburg

Marburg, , Germany

Kliniken Maria Hilf GmbH, Klinik für Hämatologie, Onkologie und Gastroenterologie

Mönchengladbach, , Germany

Klinikum Osnabrück

Osnabrück, , Germany

Universitätsklinikum Tuebingen

Tübingen, , Germany

Countries

Germany

References

Leypoldt LB, Besemer B, Asemissen AM, Hanel M, Blau IW, Gorner M, Ko YD, Reinhardt HC, Staib P, Mann C, Lutz R, Munder M, Graeven U, Peceny R, Salwender H, Jauch A, Zago M, Benner A, Tichy D, Bokemeyer C, Goldschmidt H, Weisel KC. Isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in front-line treatment of high-risk multiple myeloma: interim analysis of the GMMG-CONCEPT trial. Leukemia. 2022 Mar;36(3):885-888. doi: 10.1038/s41375-021-01431-x. Epub 2021 Nov 3. No abstract available.

Reference Type: RESULT

PMID: 34732857 (View on PubMed)

Leypoldt LB, Tichy D, Besemer B, Hanel M, Raab MS, Mann C, Munder M, Reinhardt HC, Nogai A, Gorner M, Ko YD, de Wit M, Salwender H, Scheid C, Graeven U, Peceny R, Staib P, Dieing A, Einsele H, Jauch A, Hundemer M, Zago M, Pozek E, Benner A, Bokemeyer C, Goldschmidt H, Weisel KC. Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone for the Treatment of High-Risk Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2024 Jan 1;42(1):26-37. doi: 10.1200/JCO.23.01696. Epub 2023 Sep 27.

Reference Type: RESULT

PMID: 37753960 (View on PubMed)

Leypoldt LB, Tichy D, Besemer B, Hanel M, Raab MS, Mann C, Munder M, Reinhardt HC, Nogai A, Gorner M, Ko YD, de Wit M, Salwender H, Scheid C, Graeven U, Peceny R, Staib P, Dieing A, Einsele H, Jauch A, Hundemer M, Zago M, Pozek E, Benner A, Bokemeyer C, Goldschmidt H, Weisel KC. Plain language summary of isatuximab plus carfilzomib, lenalidomide, and dexamethasone for the treatment of people with high-risk newly diagnosed multiple myeloma. Future Oncol. 2024 Dec;20(39):3193-3207. doi: 10.1080/14796694.2024.2402639. Epub 2024 Sep 30.

Reference Type: DERIVED

PMID: 39345094 (View on PubMed)

Oliva S, Kaiser MF. Is it time to tailor treatment on the basis of minimal residual disease in multiple myeloma? Lancet Haematol. 2021 Dec;8(12):e876-e877. doi: 10.1016/S2352-3026(21)00341-0. No abstract available.

Reference Type: DERIVED

PMID: 34826409 (View on PubMed)

Pawlyn C. High-risk myeloma: a challenge to define and to determine the optimal treatment. Lancet Haematol. 2021 Jan;8(1):e4-e6. doi: 10.1016/S2352-3026(20)30361-6. Epub 2020 Dec 22. No abstract available.

Reference Type: DERIVED

PMID: 33357481 (View on PubMed)

Other Identifiers

GMMG-CONCEPT

Identifier Type: -

Identifier Source: org_study_id