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

• ClinicalTrials.gov Identifier: NCT03104842
• Recruitment Status: Active, not recruiting
• First Posted: April 7, 2017
• Last Update Posted: January 25, 2023
• Sponsor: Universitätsklinikum Hamburg-Eppendorf
• Information provided by (Responsible Party): Universitätsklinikum Hamburg-Eppendorf

Tracking Information

• First Submitted Date: March 29, 2017
• First Posted Date: April 7, 2017
• Last Update Posted Date: January 25, 2023
• Actual Study Start Date: August 15, 2017
• Estimated Primary Completion Date: February 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 3, 2017)

MRD negativity [ Time Frame: after consolidation , an average of 1 year from first dosis ]

MRD negativity (8-color flow, Euro-Flow plus Black Swan Panel)

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluation iNduction, Consolidation and Maintenance Treatment With Isatuximab , Carfilzomib, LEnalidomide and Dexamethasone
• Official Title: Clinical Phase II, Multicenter, Open-label Study Evaluating iNduction, Consolidation and Maintenance With Isatuximab (SAR650984), Carfilzomib, LEnalidomide and Dexamethasone (I-KRd) in Primary Diagnosed High-risk Multiple Myeloma paTients
• 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
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma

Intervention

• Drug: Isatuximab
  Antibody Intravenous
• Drug: Carfilzomib
  Intravenous
• Drug: Lenalidomide
  Capsel
• Drug: Dexamethasone
  Capsel

Study Arms

• Experimental: 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
  Interventions:

  • Drug: Isatuximab
  • Drug: Carfilzomib
  • Drug: Lenalidomide
  • Drug: Dexamethasone
• Experimental: 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
  Interventions:

  • Drug: Isatuximab
  • Drug: Carfilzomib
  • Drug: Lenalidomide
  • Drug: Dexamethasone

Publications *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 1, 2022): 246
• Original Estimated Enrollment (submitted: April 3, 2017): 153
• Estimated Study Completion Date: September 2026
• Estimated Primary Completion Date: February 2025 (Final data collection date for primary outcome measure)

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))

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT03104842
• Other Study ID Numbers: GMMG-CONCEPT
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Universitätsklinikum Hamburg-Eppendorf
• Original Responsible Party: University Hospital Tuebingen
• Current Study Sponsor: Universitätsklinikum Hamburg-Eppendorf
• Original Study Sponsor: University Hospital Tuebingen
• Collaborators: Not Provided

Investigators

• Principal Investigator: Katja Weisel, Prof; Universitätsklinikum Hamburg-Eppendorf

• PRS Account: Universitätsklinikum Hamburg-Eppendorf
• Verification Date: January 2023