Trial on the Effect of Isatuximab to Lenalidomide/Bortezomib/Dexamethasone (RVd) Induction and Lenalidomide Maintenance in Patients With Newly Diagnosed Myeloma (GMMG HD7)

Multiple Myeloma Clinical Trial

Official title:

A Randomized Phase III Trial Assessing the Benefit of the Addition of Isatuximab to Lenalidomide / Bortezomib / Dexamethasone (RVd) Induction and Lenalidomide Maintenance in Patients With Newly Diagnosed Multiple Myeloma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03617731
• Other study ID #: GMMG HD7
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: October 18, 2018
• Est. completion date: December 2025

Study information

• Verified date: May 2023
• Source: University of Heidelberg Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Trial in patients with newly diagnosed myeloma to evaluate the effect of isatuximab in induction therapy with lenalidomide/bortezomib/dexamethasone (RVd) and in lenalidomide maintenance treatment

Description:

Prospective, multicentre, randomised, parallel group, open, phase III clinical trial, for patients with confirmed diagnosis of untreated multiple myeloma requiring systemic therapy. Investigational Medicinal Products: Isatuximab, Lenalidomide 1. Randomization: Patients are randomized in one of 2 study arms (IA or IB) before induction therapy. Patients randomized in arm IA will receive 3 cycles RVd (Bortezomib (Velcade®), Lenalidomide (Revlimid®, each cycle is 42 days), Dexamethasone). Patients in arm IB will additionally receive the monoclonal antibody Isatuximab in the 3 cycles RVd. After induction therapy patients undergo intensifying therapy according to GMMG standard (usually mobilization therapy followed by stem cell collection and autologous stem cell transplantation). 2. Randomization: Before maintenance treatment patients are randomized in one of 2 study arms (IIA and IIB): Patients in arm IIA receive Lenalidomide maintenance therapy for three years, patients in arm IIB receive additional Isatuximab. There are two primary objectives: 1. to compare the induction regimen (IA vs IB) regarding minimal residual disease (MRD) negativity after induction (assessed by flow cytometry; sensitivity at least 1e-5) 2. to compare the maintenance strategies (arms IIA vs IIB) regarding progression-free survival (PFS), defined as time from 2nd randomization (prior to maintenance therapy) to progression or death from any cause whichever occurs first. The duration of the trial for each patients is expected to be 45-48 months (induction and intensification treatment: 6-9 months, 3 months rest between intensification and start of maintenance phase 36 months).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 662
• Est. completion date: December 2025
• Est. primary completion date: May 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

1. Confirmed diagnosis of untreated multiple myeloma requiring systemic therapy (diagnostic criteria (IMWG updated criteria (2014)1) see appendix IA. For some patients systemic therapy may be required though these diagnostic criteria are not fulfilled. In this case the GMMG study office has to be consulted prior to inclusion.)

2. Patient is eligible for high dose therapy and autologous stem cell transplantation.

3. Measurable disease, defined as any quantifiable monoclonal protein value, defined by at least one of the following three measurements:2

• Serum M-protein = 10g/l (for IgA = 5g/l)
• Urine light-chain (M-protein) of = 200 mg/24 hours
• Serum FLC assay: involved FLC level = 10 mg/dl provided sFLC ratio is abnormal

4. Age 18 - 70 years inclusive

5. WHO performance status 0-2

6. Negative pregnancy test at inclusion (females of childbearing potential)

7. All patients must agree on the requirements regarding the lenalidomide pregnancy prevention plan described in section 6. For all men and females of childbearing potential: patients must be willing and capable to use adequate contraception during the complete therapy.

8. All patients must

• agree to abstain from donating blood while taking lenalidomide and for 28 days following discontinuation of lenalidomide therapy
• agree not to share study drug lenalidomide with another person and to return all unused study drug to the investigator or pharmacist

9. Ability of patient to understand character and individual consequences of the clinical trial

10. Provide written informed consent (must be available before enrolment in the trial) Exclusion Criteria

1. Patient has known hypersensitivity (or contraindication) to dexamethasone, sucrose histidine (as base and hydrochloride salt), boron, mannitol, and polysorbate 80 or any of the components of study therapy that are not amenable to premedication with steroids or H2 blockers that would prohibit further treatment with these agents.

2. Systemic AL amyloidosis (except for AL amyloidosis of the skin or the bone marrow)

3. Plasma cell leukemia

4. Previous chemotherapy or radiotherapy during the past 5 years except local radiotherapy in case of local myeloma progression. (Note: patients may have received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency therapy.) Previous therapy due to smouldering myeloma may be acceptable. In this case the GMMG study office has to be consulted prior to inclusion

5. Severe cardiac dysfunction (NYHA classification III-IV), ejection fraction < 40%

6. Significant hepatic dysfunction (ASAT and/or ALAT = 3 times normal level and/or serum bilirubin = 1.5 times normal level if not due to hereditary abnormalities as Gilbert's disease), unless related to myeloma.

7. Patients with active or history of hepatitis B or C

8. HIV positivity

9. Patients with active, uncontrolled infections

10. Patients with severe renal insufficiency (Creatinine Clearance < 30ml/min)

11. Patients with peripheral neuropathy or neuropathic pain, CTC grade 2 or higher (as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0)

12. Patients with a history of active malignancy during the past 5 years with the exception of following malignancies after curative therapy: basal cell carcinoma of the skin, squamous cell skin carcinoma, stage 0 cervical carcinoma or any in situ malignancy

13. Patients with acute diffuse infiltrative pulmonary and/or pericardial disease

14. Autoimmune hemolytic anemia with positive Coombs test or immune thrombocytopenia

15. Platelet count < 75 x 109/l

16. Haemoglobin < 8.0 g/dl, unless related to myeloma

17. Absolute neutrophil count (ANC) < 1.0 x 109/l (the use of colony stimulating factors within 14 days before the test is not allowed)

18. Corrected serum calcium > 14 mg/dl (> 3.5 mmol/l)

19. Unable or unwilling to undergo thromboprophylaxis

20. Pregnancy and lactation

21. Participation in other clinical trials. This does not include long-term follow-up periods without active drug treatment of previous studies during the last 6 months.

22. Prisoners or subjects who are legally institutionalized, or those unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions. No patients will be allowed to enrol in this trial more than once. -

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Lenalidomide
25 mg per os on day 1-14 and d22-35 in induction cycle 1-3 (Arms IA and IB) 10 mg p.o. on day 1-28 in maintenance cycle 1-3, 15 mg p.o. on day 1-28 in maintenance cycle 4-39 (Arms IIA and IIB)
• Bortezomib
all arms: 1,3 mg/m^2 subcutaneous on day 1, 4, 8, 11, 22, 25, 29 32 in 3 induction cycles
• Dexamethasone
20 mg per os on day 1,2 and 4,5 and 8,9 and 11,12 and 15 and 22,23 and 25,26 and 29,30 and 32,33 in induction cycles 1-3 (Arms IA and IB). Maintenance cycle 1 on day 1, 8, 15, 22 Dexamethasone 20 mg/d per os (Arm IIA). In Arm IIB Dexamethasone 20 mg i.v. on days of Isatuximab infusion in the first maintenance cycle (d 1, 8, 15, 22), dexamethasone will be administered intravenously as part of the premedication. If an isatuximab dose is skipped or discontinued dexamethasone should be administered orally.
• Isatuximab
10 mg/kg in the vein( i.v) on day 1,8,15, 22, 29 in induction cycle 1 on day 1, 15 and 29 in induction cycle 2 and 3 (Arm IB). 10 mg/kg i.v. on day 1,8, 15 and 22 in maintenance cycle 1, 10 mg/kg i.v. on day 1 and 15 in maintenance cycle 2 and 3, 10 mg/kg i.v. on day 1 in maintenance cycle 4 - 39 (Arm IIB)

Locations

Country	Name	City	State
Germany	Uniklinik RWTH Aachen, Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltransplantation	Aachen
Germany	Studienzentrum Aschaffenburg	Aschaffenburg
Germany	Helios Klinikum Bad Saarow, Klinik für Hämatologie, Onkologie und Palliativmedizin	Bad Saarow
Germany	Charité, Campus Benjamin Franklin , III. Medizinische Abteilung (Hämatologie/Onkologie)	Berlin
Germany	HELIOS Klinikum, Klinik für Hämatologie, Onkologie und Immunologie	Berlin
Germany	Vivantes Klinikum Neukölln, Klinik für Hämatologie und Onkologie	Berlin
Germany	Klinikum Bielefeld, Klinik für Hämatologie, Onkologie und Palliativmedizin	Bielefeld
Germany	Studiengesellschaft Onkologie Bielefeld GbR	Bielefeld
Germany	Medizinische Universitätsklinik, Knappschaftskrankenhaus	Bochum
Germany	Johanniter Krankenhaus Bonn	Bonn
Germany	Universitätsklinikum Bonn, Medizinische Klinik und Poliklinik III, Schwerpunkt Onkologie, Hämatologie und Rheumatologie	Bonn
Germany	Zentrum für ambulante Hämatologie und Onkologie (ZAHO)	Bonn
Germany	Städtisches Klinikum Braunschweig, Med. Klinik III, Hämatologie und Onkologie	Braunschweig
Germany	Klinikum Chemnitz GmbH, Innere Medizin III	Chemnitz
Germany	Carl-Thiem-Klinikum Cottbus gGmbH, II. Medizinische Klinik	Cottbus
Germany	Klinikum Darmstadt, Med. Klinik V, Hämatologie/Onkologie	Darmstadt
Germany	Onkologisches Studienzentrum Darmstadt	Darmstadt
Germany	Universitätsklinikum Carl Gustav Carus Dresden, an der Technischen Universität Dresden, Medizinische Klinik und Poliklinik I	Dresden
Germany	HELIOS St. Johannes Klinik, Akademisches Krankenhaus der Heinrich-Heine-Universität Düsseldorf	Duisburg
Germany	Marien Hospital Düsseldorf GmbH, Klinik für Onkologie, Hämatologie und Palliativmedizin	Düsseldorf
Germany	Universitätsklinikum Düsseldorf, Klinik für Hämatologie,Onkologie und Klin. Immunologie	Düsseldorf
Germany	Universitätsklinik Erlangen	Erlangen
Germany	St. Antonius-Hospital Eschweiler, Klinik für Hämatologie / Onkologie	Eschweiler
Germany	Ev. Krankenhaus Essen-Werden gGmbH, Zentrum für Innere Medizin, Klinik für Hämatologie, Onkologie und Stammzelltransplantation	Essen
Germany	Universitätsklinikum Essen, Klinik für Hämatologie	Essen
Germany	Gemeinschaftspraxis Prof. Dr. Michael Kiehl und Dipl. Med. Wolfgang Stein	Frankfurt (Oder)
Germany	Klinikum Frankfurt (Oder) GmbH	Frankfurt (Oder)
Germany	Agaplesion Markus Krankenhaus, Med. Klinik I	Frankfurt am Main
Germany	Centrum für Hämatologie und Onkologie Bethanien	Frankfurt am Main
Germany	Krankenhaus Nordwest, Institut für Klinisch-Onkologische Forschung	Frankfurt am Main
Germany	Universitätsklinikum Frankfurt, Goethe-Universität Medizinische Klinik II	Frankfurt am Main
Germany	Klinikum Fulda, Klinisches Studienzentrum GmbH	Fulda
Germany	Universitätsklinik der Justus-Liebig-Universität, Medizinische Klinik IV	Gießen
Germany	Katholisches Karl-Leisner-Klinikum gGmbH, Wilhelm-Anton-Hospital Goch, Klinik für Hämatologie - Onkologie	Goch
Germany	Kath. Krankenhaus Hagen gGmbH, Abt. Hämatologie/Onkologie	Hagen
Germany	Asklepios Klinik Hamburg Altona, II. Med. Klinik	Hamburg
Germany	Asklepios Klinik Hamburg St. Georg	Hamburg
Germany	Universitätsklinikum Hamburg Eppendorf, Zentrum für Onkologie, Studienzentrale der II. Medizinischen Klinik	Hamburg
Germany	Immunologisch-onkologisches MVZ am Siloah Krankenhaus	Hannover
Germany	KRH Klinikum Siloah, Klinik für Hämatologie und Onkologie	Hannover
Germany	Krankenhaus St. Vincentius der evangelischen Stadtmission Heidelberg, Abt. Hämatologie, Onkologie, Rheumatologie	Heidelberg
Germany	Onkologische Schwerpunktpraxis Heidelberg	Heidelberg
Germany	University Hospital Heidelberg, Med. Klinik V	Heidelberg
Germany	SLK Kliniken Heilbronn, Med. Klinik III	Heilbronn
Germany	Marien Hospital Herne	Herne
Germany	Universitätsklinikum des Saarlandes, Innere Medizin I	Homburg (Saar)
Germany	Westpfalz-Klinikum GmbH, Klinik für Innere Medizin I	Kaiserslautern
Germany	Städtisches Klinikum Karlsruhe	Karlsruhe
Germany	Praxisklinik für Hämatologie und Onkologie	Koblenz
Germany	Uniklinik Köln, Klinik I für Innere Medizin	Köln
Germany	Gemeinschaftspraxis für Hämatologie und Onkologie am Caritas Krankenhaus	Lebach
Germany	Universitätsklinikum Leipzig AöR, Medizinische Klinik und Poliklinik I-Hämatologie und Zelltherapie, Internistische Onkologie, Hämostaseologie	Leipzig
Germany	Med. Klinik A, Klinikum der Stadt Ludwigshafen am Rhein gGmbH	Ludwigshafen am Rhein
Germany	Universitätsmedizin der Johannes Gutenberg-Universität Mainz, III. Med. Klinik	Mainz
Germany	III. Medizinische Klinik Hämatologie und Internistische Onkologie	Mannheim
Germany	Mannheimer Onkologie Praxis	Mannheim
Germany	Philipps-Universität Marburg, Hämatologie/Onkologie/Immunologie	Marburg
Germany	Mühlenkreiskliniken (AöR) Johannes Wesling Klinikum Minden, Hämatologie/Onkologie, Hämostaseologie und Palliativmedizin	Minden
Germany	Krankenhaus Maria Hilf GmbH, Franziskuskrankenhaus, Med. Klinik I	Mönchengladbach
Germany	Universitätsklinikum Münster, Med. Klinik A	Münster
Germany	Klinikum Osnabrück GmbH	Osnabrück
Germany	Brüderkrankenhaus St. Josef Paderborn, Klinik für Hämatologie und Onkologie	Paderborn
Germany	Krankenhaus Barmherzige Brüder, Klinik für Onkologie und Hämatologie	Regensburg
Germany	Gemeinschaftspraxis für Hämatologie und Onkologie, Onkologisches Zentrum	Saarlouis
Germany	Diakonie-Klinikum Schwäbisch Hall gGmbH, Innere Medizin III	Schwäbisch Hall
Germany	ZAHO-Zentrum für ambulante Hämatologie und Onkologie, Standort Siegburg	Siegburg
Germany	Onkologische Schwerpunktpraxis Speyer	Speyer
Germany	Klinikum Stuttgart, Stuttgart Cancer Center, Tumorzentrum Eva Mayr-Stihl	Stuttgart
Germany	Klinikum Mutterhaus der Borromäerinnen gGmbH	Trier
Germany	University Hospital Tübingen, Med. Klinik und Poliklinik, Abt. II	Tübingen
Germany	Bundeswehrkrankenhaus Ulm, Abteilung Innere Medizin - Hämatologie und internistische Onkologie	Ulm
Germany	Schwarzwald-Baar Klinikum, Innere Medizin II	Villingen-Schwenningen
Germany	Rems-Murr-Kliniken gGmbH	Winnenden

Sponsors (1)

Lead Sponsor	Collaborator
University of Heidelberg Medical Center

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MRD negativity after induction Treatment (comparison of arms IA and IB)	Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5)	18 weeks after start of study treatment
Primary	Progression Free Survival (PFS) after second randomization (arms IIA and IIB)	Response Evaluation by IMWG criteria	time from 2. randomization to progression or death from any cause whichever comes first, censored after three years of maintenance therapy
Secondary	to compare the four treatment arms (IA-IIA, IA-IIB, IB-IIA, IB-IIB) regarding Progression free survival (PFS)	Response evaluation by IMWG criteria	time from 1. randomization (study inclusion) to progression or death whichever comes first (assessed up to 79 months)
Secondary	to compare all 4 treatment arms (IA-IIA, IA-IIB, IB-IIA, IB-IIB) regarding overall survival (OS) from time of 1.randomization	survival status	time from randomisation to time of death from any cause (assessed up to 79 months)
Secondary	Overall survival from second randomization	survival status	time from 2. randomization to time of death from any cause (assessed up to 75 months)
Secondary	Complete Response (CR) rates after induction therapy	Response Evaluation by IMWG criteria	After induction treatment (18 weeks after start of treatment)
Secondary	Complete Response (CR) after high dose therapy	Response Evaluation by IMWG criteria	After high dose therapy (9 or 12 months after start of therapy)
Secondary	Complete Response (CR) during/after maintenance therapy	Response Evaluation by IMWG criteria	During/after maintenance therapy (6 months after start of therapy up to 36 months of maintenance therapy)
Secondary	MRD negativity after high dose therapy	Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5)	After high dose therapy (9 or 12 months after start of therapy)
Secondary	MRD negativity during and after maintenance therapy	Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5)	up to 36 months after start of maintenance therapy
Secondary	Best response to treatment during the trial	Response evaluation by IMWG criteria	response assessment after 3 months, 4,5 months, 5,5 months, 9 months (if applicable: 3 months later after 2. high dose therapy) subsequently every 3 months during maintenance treatment, up to 48 months after start of study treatment
Secondary	PFS 2 (PFS after next line of therapy) from 2. randomization	Response evaluation by IMWG criteria	time from 2. randomization to time of overall end of trial (up to 75 months)
Secondary	Toxicity during induction and maintenance with respect to adverse events of CTC grade >3 (and specific adverse events of CTC grade > 2 as defined in the protocol and serious adverse events	toxicity according CTCAE Version v5.0	: from first administration of study drug until 30 days after last administration of study drug or any drug of the study treatment or upon start of a new subsequent chemotherapy, whichever occurs first
Secondary	Quality of Life Assessment	EORTC (European Organization of Research and Treatment of Cancer) -QLQC30 Questionnaire to assess the quality of life of cancer patients. Impairment of daily life is asked in 4 scales from "not at all" (best) to "very much" (worst scale), EORTC-QLQMY20 questionnaire to assess health-related quality of life in patients with multiple myeloma with 4 scales from "not at all (best scale) to "very much" (worst scale); EQ(EuroQol Group)-5D-5L Health questionnaire comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. Additionally a visual analogue scale from 100 (best) to 0 (worst scale) is used to assess the quality of health questionnaires.	assessed at baseline, after ca. 4.5 months, 9 months, (additionally after 12 months,if a second high dose therapy is administered) after 12 months of maintenance and at end of study (up to 50 months)
Secondary	Pharmakokinetic analyses of Isatuximab in induction treatment of patients in Arm IB (selected sites only)	Determination of serum concentration of isatuximab at different timepoints before, during and after isatuximab infusion	Up to 18 weeks in induction treatment (C1: D1, before infusion, at end of infusion, 1 h after infusion, C1 D8,15,22,29 before infusion; C2 and 3:D1 before infusion
Secondary	Pharmakokinetic analyses of Isatuximab in maintenance treatment of patients in Arm IIB (selected sites only)	Determination of serum concentration of isatuximab at different timepoints	Up to 9 months (C1: D1, before infusion, at end of infusion, 1 h after infusion, C1 D8,15,22 before infusion, C2 -9, D1: before infusion