Clinical trial NCT03617731: Trial on the Effect of Isatuximab to Lenalidomide/Bortezomib/Dexamethasone (RVd) Induction and Lenalidomide Maintenance in Patients With Newly Diagnosed Myeloma (GMMG HD7)
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Multiple Myeloma
Lead sponsor: University of Heidelberg Medical Center
Sponsor class: OTHER
First posted: 2018-08-06
Enrollment: 662
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 2 x 2 arms, 1. randomization before induction therapy (arm IA and IB), 2. randomization before maintenance therapy (arm IIA and IIB)
Primary purpose: TREATMENT

Brief 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

Detailed 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).

Eligibility criteria: 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.

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Primary outcomes:
measure: MRD negativity after induction Treatment (comparison of arms IA and IB)
timeFrame: 18 weeks after start of study treatment
measure: Progression Free Survival (PFS) after second randomization (arms IIA and IIB)
timeFrame: time from 2. randomization to progression or death from any cause whichever comes first, censored after three years of maintenance therapy
Secondary outcomes:
measure: to compare the four treatment arms (IA-IIA, IA-IIB, IB-IIA, IB-IIB) regarding Progression free survival (PFS)
timeFrame: time from 1. randomization (study inclusion) to progression or death whichever comes first (assessed up to 79 months)
measure: to compare all 4 treatment arms (IA-IIA, IA-IIB, IB-IIA, IB-IIB) regarding overall survival (OS) from time of 1.randomization
timeFrame: time from randomisation to time of death from any cause (assessed up to 79 months)
measure: Overall survival from second randomization
timeFrame: time from 2. randomization to time of death from any cause (assessed up to 75 months)
measure: Complete Response (CR) rates after induction therapy
timeFrame: After induction treatment (18 weeks after start of treatment)
measure: Complete Response (CR) after high dose therapy
timeFrame: After high dose therapy (9 or 12 months after start of therapy)
measure: Complete Response (CR) during/after maintenance therapy
timeFrame: During/after maintenance therapy (6 months after start of therapy up to 36 months of maintenance therapy)
measure: MRD negativity after high dose therapy
timeFrame: After high dose therapy (9 or 12 months after start of therapy)
measure: MRD negativity during and after maintenance therapy
timeFrame: up to 36 months after start of maintenance therapy
measure: Best response to treatment during the trial
timeFrame: 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
measure: PFS 2 (PFS after next line of therapy) from 2. randomization
timeFrame: time from 2. randomization to time of overall end of trial (up to 75 months)
measure: 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
timeFrame: : 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
measure: Quality of Life Assessment
timeFrame: 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)
measure: Pharmakokinetic analyses of Isatuximab in induction treatment of patients in Arm IB (selected sites only)
timeFrame: 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
measure: Pharmakokinetic analyses of Isatuximab in maintenance treatment of patients in Arm IIB (selected sites only)
timeFrame: 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
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen, Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltransplantation
city: Bad Saarow
country: Germany
facility: Helios Klinikum Bad Saarow, Klinik für Hämatologie, Onkologie und Palliativmedizin
city: Berlin
country: Germany
facility: Charité, Campus Benjamin Franklin , III. Medizinische Abteilung (Hämatologie/Onkologie)
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukölln, Klinik für Hämatologie und Onkologie
city: Berlin
country: Germany
facility: HELIOS Klinikum, Klinik für Hämatologie, Onkologie und Immunologie
city: Bielefeld
country: Germany
facility: Studiengesellschaft Onkologie Bielefeld GbR
city: Bielefeld
country: Germany
facility: Klinikum Bielefeld, Klinik für Hämatologie, Onkologie und Palliativmedizin
city: Bochum
country: Germany
facility: Medizinische Universitätsklinik, Knappschaftskrankenhaus
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn, Medizinische Klinik und Poliklinik III, Schwerpunkt Onkologie, Hämatologie und Rheumatologie
city: Bonn
country: Germany
facility: Johanniter Krankenhaus Bonn
city: Bonn
country: Germany
facility: Zentrum für ambulante Hämatologie und Onkologie (ZAHO)
city: Braunschweig
country: Germany
facility: Städtisches Klinikum Braunschweig, Med. Klinik III, Hämatologie und Onkologie
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz GmbH, Innere Medizin III
city: Cottbus
country: Germany
facility: Carl-Thiem-Klinikum Cottbus gGmbH, II. Medizinische Klinik
city: Darmstadt
country: Germany
facility: Onkologisches Studienzentrum Darmstadt
city: Darmstadt
country: Germany
facility: Klinikum Darmstadt, Med. Klinik V, Hämatologie/Onkologie
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus Dresden, an der Technischen Universität Dresden, Medizinische Klinik und Poliklinik I
city: Duisburg
country: Germany
facility: HELIOS St. Johannes Klinik, Akademisches Krankenhaus der Heinrich-Heine-Universität Düsseldorf
city: Düsseldorf
country: Germany
facility: Marien Hospital Düsseldorf GmbH, Klinik für Onkologie, Hämatologie und Palliativmedizin
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf, Klinik für Hämatologie,Onkologie und Klin. Immunologie
city: Erlangen
country: Germany
facility: Universitätsklinik Erlangen
city: Eschweiler
country: Germany
facility: St. Antonius-Hospital Eschweiler, Klinik für Hämatologie / Onkologie
city: Essen
country: Germany
facility: Universitätsklinikum Essen, Klinik für Hämatologie
city: Essen
country: Germany
facility: Ev. Krankenhaus Essen-Werden gGmbH, Zentrum für Innere Medizin, Klinik für Hämatologie, Onkologie und Stammzelltransplantation
city: Frankfurt (Oder)
country: Germany
facility: Gemeinschaftspraxis Prof. Dr. Michael Kiehl und Dipl. Med. Wolfgang Stein
city: Frankfurt (Oder)
country: Germany
facility: Klinikum Frankfurt (Oder) GmbH
city: Frankfurt am Main
country: Germany
facility: Centrum für Hämatologie und Onkologie Bethanien
city: Frankfurt am Main
country: Germany
facility: Agaplesion Markus Krankenhaus, Med. Klinik I
city: Frankfurt am Main
country: Germany
facility: Krankenhaus Nordwest, Institut für Klinisch-Onkologische Forschung
city: Frankfurt am Main
country: Germany
facility: Universitätsklinikum Frankfurt, Goethe-Universität Medizinische Klinik II
city: Fulda
country: Germany
facility: Klinikum Fulda, Klinisches Studienzentrum GmbH
city: Gießen
country: Germany
facility: Universitätsklinik der Justus-Liebig-Universität, Medizinische Klinik IV
city: Goch
country: Germany
facility: Katholisches Karl-Leisner-Klinikum gGmbH, Wilhelm-Anton-Hospital Goch, Klinik für Hämatologie - Onkologie
city: Hagen
country: Germany
facility: Kath. Krankenhaus Hagen gGmbH, Abt. Hämatologie/Onkologie
city: Hamburg
country: Germany
facility: Asklepios Klinik Hamburg St. Georg
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg Eppendorf, Zentrum für Onkologie, Studienzentrale der II. Medizinischen Klinik
city: Hamburg
country: Germany
facility: Asklepios Klinik Hamburg Altona, II. Med. Klinik
city: Hannover
country: Germany
facility: Immunologisch-onkologisches MVZ am Siloah Krankenhaus
city: Hannover
country: Germany
facility: KRH Klinikum Siloah, Klinik für Hämatologie und Onkologie
city: Heidelberg
country: Germany
facility: Onkologische Schwerpunktpraxis Heidelberg
city: Heidelberg
country: Germany
facility: Krankenhaus St. Vincentius der evangelischen Stadtmission Heidelberg, Abt. Hämatologie, Onkologie, Rheumatologie
city: Heidelberg
country: Germany
facility: University Hospital Heidelberg, Med. Klinik V
city: Heilbronn
country: Germany
facility: SLK Kliniken Heilbronn, Med. Klinik III
city: Herne
country: Germany
facility: Marien Hospital Herne
city: Homburg (Saar)
country: Germany
facility: Universitätsklinikum des Saarlandes, Innere Medizin I
city: Kaiserslautern
country: Germany
facility: Westpfalz-Klinikum GmbH, Klinik für Innere Medizin I
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe
city: Koblenz
country: Germany
facility: Praxisklinik für Hämatologie und Onkologie
city: Köln
country: Germany
facility: Uniklinik Köln, Klinik I für Innere Medizin
city: Lebach
country: Germany
facility: Gemeinschaftspraxis für Hämatologie und Onkologie am Caritas Krankenhaus
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig AöR, Medizinische Klinik und Poliklinik I-Hämatologie und Zelltherapie, Internistische Onkologie, Hämostaseologie
city: Ludwigshafen am Rhein
country: Germany
facility: Med. Klinik A, Klinikum der Stadt Ludwigshafen am Rhein gGmbH
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz, III. Med. Klinik
city: Mannheim
country: Germany
facility: III. Medizinische Klinik Hämatologie und Internistische Onkologie
city: Mannheim
country: Germany
facility: Mannheimer Onkologie Praxis
city: Marburg
country: Germany
facility: Philipps-Universität Marburg, Hämatologie/Onkologie/Immunologie
city: Minden
country: Germany
facility: Mühlenkreiskliniken (AöR) Johannes Wesling Klinikum Minden, Hämatologie/Onkologie, Hämostaseologie und Palliativmedizin
city: Mönchengladbach
country: Germany
facility: Krankenhaus Maria Hilf GmbH, Franziskuskrankenhaus, Med. Klinik I
city: Münster
country: Germany
facility: Universitätsklinikum Münster, Med. Klinik A
city: Osnabrück
country: Germany
facility: Klinikum Osnabrück GmbH
city: Paderborn
country: Germany
facility: Brüderkrankenhaus St. Josef Paderborn, Klinik für Hämatologie und Onkologie
city: Regensburg
country: Germany
facility: Krankenhaus Barmherzige Brüder, Klinik für Onkologie und Hämatologie
city: Saarlouis
country: Germany
facility: Gemeinschaftspraxis für Hämatologie und Onkologie, Onkologisches Zentrum
city: Schwäbisch Hall
country: Germany
facility: Diakonie-Klinikum Schwäbisch Hall gGmbH, Innere Medizin III
city: Siegburg
country: Germany
facility: ZAHO-Zentrum für ambulante Hämatologie und Onkologie, Standort Siegburg
city: Speyer
country: Germany
facility: Onkologische Schwerpunktpraxis Speyer
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart, Stuttgart Cancer Center, Tumorzentrum Eva Mayr-Stihl
city: Trier
country: Germany
facility: Klinikum Mutterhaus der Borromäerinnen gGmbH
city: Tübingen
country: Germany
facility: University Hospital Tübingen, Med. Klinik und Poliklinik, Abt. II
city: Ulm
country: Germany
facility: Bundeswehrkrankenhaus Ulm, Abteilung Innere Medizin - Hämatologie und internistische Onkologie
city: Villingen-Schwenningen
country: Germany
facility: Schwarzwald-Baar Klinikum, Innere Medizin II
city: Winnenden
country: Germany
facility: Rems-Murr-Kliniken gGmbH
Study officials:
affiliation: Med. Klinik V, University Hospital Heidelberg
name: Hartmut Goldschmidt, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Goldschmidt H, Mai EK, Bertsch U, Fenk R, Nievergall E, Tichy D, Besemer B, Durig J, Schroers R, von Metzler I, Hanel M, Mann C, Asemissen AM, Heilmeier B, Weinhold N, Huhn S, Kriegsmann K, Luntz SP, Holderried TAW, Trautmann-Grill K, Gezer D, Klaiber-Hakimi M, Muller M, Khandanpour C, Knauf W, Scheid C, Munder M, Geer T, Riesenberg H, Thomalla J, Hoffmann M, Raab MS, Salwender HJ, Weisel KC; German-Speaking Myeloma Multicenter Group (GMMG) HD7 investigators. Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone as induction therapy for newly diagnosed, transplantation-eligible patients with multiple myeloma (GMMG-HD7): part 1 of an open-label, multicentre, randomised, active-controlled, phase 3 trial. Lancet Haematol. 2022 Nov;9(11):e810-e821. doi: 10.1016/S2352-3026(22)00263-0.