Clinical trial NCT02495922: A Phase III Trial on the Effect of Elotuzumab in VRD Induction /Consolidation and Lenalidomide Maintenance in Patients With Newly Diagnosed Myeloma
Official title: A Randomized Phase III Trial on the Effect of Elotuzumab in VRD Induction /Consolidation and Lenalidomide Maintenance in Patients With Newly Diagnosed Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Myeloma
Lead sponsor: University of Heidelberg Medical Center
Sponsor class: OTHER
First posted: 2015-07-13
Enrollment: 564
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Trial in patients with newly diagnosed myeloma to evaluate the effect of elotuzumab in induction and consolidation therapy with bortezomib/lenalidomide/dexamethasone 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:Elotuzumab, lenalidomide

Patients are randomized in one of 4 study arms (A1, A2, B1, B2). Patients randomized in arm A1 or A2 will receive 4 cycles VRD (Bortezomib (Velcade®), Lenalidomide (Revlimid®), Dexamethasone). Patients in arm B1 or B2 will additionally receive the monoclonal antibody Elotuzumab in the 4 cycles VRD. After induction therapy patients undergo intensifying therapy according to GMMG standard (usually mobilization therapy followed by stem cell collection and autologous stem cell transplantation). After intensification a consolidation therapy will be performed with two cycles VRD (A1 und B1) or VRD+ Elotuzumab (A2 und B2), followed by Lenalidomide maintenance therapy with (arm A2 and B2) or without (arm A1 and B1) additional Elotuzumab. Maintenance therapy will be performed for 2 years.

Primary objective is the determination of the best of four treatment strategies regarding progression-free survival (PFS), defined as time from randomisation to progression or death from any cause whichever occurs first.

The duration of the trial for each patients is expected to be 36-39 months (induction and intensification treatment: 7-10 months, 3 months rest between intensification and start of consolidation, consolidation 2 months, maintenance phase 24 months).

Eligibility criteria: Inclusion Criteria:

* Patients meeting all of the following criteria will be considered for admission to the trial:
* Confirmed diagnosis of untreated multiple myeloma requiring systemic therapy (diagnostic criteria (IMWG updated criteria (2014) )
* Measurable disease, defined as any quantifiable monoclonal protein value, defined by at least one of the following three measurements:

  * 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
* Age 18 - 70 years inclusive
* WHO performance status 0-3 (WHO=3 is allowed only if caused by MM and not by co-morbid conditions)
* Negative pregnancy test at inclusion (women of childbearing potential)
* For all men and women of childbearing potential: patients must be willing and capable to use adequate contraception during the complete therapy. Patients must agree on the requirements regarding the lenalidomide pregnancy prevention programme described in chapter 6.
* 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
* Ability of patient to understand character and individual consequences of the clinical trial
* Written informed consent (must be available before enrollment in the trial)

Exclusion Criteria:

* Patients presenting with any of the following criteria will not be included in the trial:
* Patient has known hypersensitivity to any drugs given in the protocol, notably bortezomib, lenalidomide, dexamethasone and elotuzumab or to any of the constituent compounds (incl. boron and mannitol).
* Systemic AL amyloidosis (except for AL amyloidosis of the skin or the bone marrow)
* Previous chemotherapy or radiotherapy during the past 5 years except local radiotherapy in case of local myeloma progression.
* Severe cardiac dysfunction (NYHA classification III-IV)
* Significant hepatic dysfunction (serum bilirubin ≥ 1,8mg/dl and/or ASAT and/or ALAT ≥ 2.5 times normal level), unless related to myeloma.
* Patients with renal insufficiency requiring hemodialysis
* HIV positivity
* Patients with active or history of hepatitis B or C
* Patients with active, uncontrolled infections
* 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 4.0)
* Patients with a history of active malignancy during the past 5 years with the exception of basal cell carcinoma of the skin or stage 0 cervical carcinoma treated with curative intent
* Patients with acute diffuse infiltrative pulmonary and/or pericardial disease
* Autoimmune hemolytic anemia with positive Coombs test or immune thrombocytopenia
* Platelet count \< 75 x 109/l, or, dependent on bone marrow infiltration by plasma cells, platelet count \< 30 x 109/l (patients with platelet count \< 75 x 109/l, but \> 30 x 109/l may be eligible if percentage of plasma cells in bone marrow is ≥ 50%), (transfusion support within 14 days before the test is not allowed)
* Haemoglobin ≤ 8.0 g/dl, unless related to myeloma
* Absolute neutrophil count (ANC) \< 1.0 x 10\^9/l (the use of colony stimulating factors within 14 days before the test is not allowed), unless related to myeloma
* Pregnancy and lactation
* 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.

No patients will be allowed to enrol in this trial more than once.

Primary outcomes:
measure: the best of four treatment strategies regarding Progression Free Survival (PFS)
timeFrame: time from randomization to progression or death from any cause whichever comes first, censored after two years of maintenance therapy (i.e. approx. after 36 months after randomisation)
Secondary outcomes:
measure: overall survival
timeFrame: time from randomisation to time of death from any cause. Patients still being alive at the time of the analysis will be censored at the date last known to be alive. (assessed up to 80 months)
measure: complete response rates after induction
timeFrame: approx. after 3 months (after induction therapy)
measure: complete response rates after consolidation
timeFrame: approx. after 9 months (after consolidation therapy)
measure: Progression Free Survival after end of trial
timeFrame: time from randomisation to progression or death from any cause whichever comes first, censored at the end date of the trial (i.e. assessed up to 80 months)
measure: best response to treatment during the study
timeFrame: response assessment after ca. 3 months, 4 months, 7 months, 9 months,11 months, 14 months, and subsequently every 3 months during maintenance treatment, up to 35 months after start of study treatment.
measure: time to progression, censored at end of the trial
timeFrame: From date of randomization until the date of first documented progression, assessed up to 80 months
measure: duration of response, censored at end of the trial
timeFrame: assessed up to 80 months
measure: toxicity during induction treatment, consolidation and maintenance treatment with respect to adverse Events of CTCAE grade 3 or higher
timeFrame: from first administration of study drug until 40 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. 3 months, 7 months, 9 months, subsequently every 6 months, up to 36 months
Other outcomes:
Locations:
city: Aschaffenburg
country: Germany
facility: Studienzentrum Aschaffenburg
city: Baden-Baden
country: Germany
facility: MVZ Onkologie gGmbH der Klinikum Mittelbaden gGmbH
city: Berlin
country: Germany
facility: HELIOS Klinikum, Klinik für Hämatologie, Onkologie und Immunologie
city: Berlin
country: Germany
facility: Onkologisches MVZ Berlin Tegel
city: Berlin
country: Germany
facility: Charité Campus Benjamin Franklin, III. Med. Abt. (Hämatologie/Onkologie)
city: Bielefeld
country: Germany
facility: Klinikum Bielefeld, Klinik für Hämatologie, Onkologie und Palliativmedizin
city: Bielefeld
country: Germany
facility: Studiengesellschaft Onkologie Bielefeld GbR
city: Bochum
country: Germany
facility: Hämatologisch-onkologische Schwerpunktpraxis
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: ZAHO, Zentrum für ambulante Hämatologie und Onkologie
city: Bottrop
country: Germany
facility: Schwerpunktpraxis für Onkologie/Hämatologie
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz GmbH, Innere Medizin III
city: Darmstadt
country: Germany
facility: Onkologisches Studienzentrum Darmstadt
city: Darmstadt
country: Germany
facility: Klinikum Darmstadt, Med. Klinik V, Hämatologie/Onkologie
city: Duisburg
country: Germany
facility: HELIOS St. Johannes Klinik, Akademisches Krankenhaus der Heinrich-Heine-Universität Düsseldorf
city: Dusseldorf
country: Germany
facility: MVZ Düsseldorf GmbH
city: Düsseldorf
country: Germany
facility: Sana Kliniken Düsseldorf GmbH
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 Klinik f. Hämatologie und 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 am Main
country: Germany
facility: Centrum für Hämatologie und Onkologie Bethanien
city: Frankfurt am Main
country: Germany
facility: Universitätsklinikum Frankfurt, Goethe-Universität Medizinische Klinik II
city: Frankfurt/Main
country: Germany
facility: Agaplesion Markus Krankenhaus
city: Friedrichshafen
country: Germany
facility: Praxis und Tagesklinik Friedrichshafen
city: Gerlingen
country: Germany
facility: Gemeinschaftspraxis Schmitt/Eulenbuch
city: Gießen
country: Germany
facility: Justus-Liebig-Universität, Medizinische Klinik IV
city: Hagen
country: Germany
facility: Kath. Krankenhaus Hagen gGmbH, Abt. Hämatologie/Onkologie
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf, II - Med. Klinik und Poliklinik
city: Hamburg
country: Germany
facility: Asklepios Klinik Hamburg Altona, II. Med. Klinik
city: Hamm
country: Germany
facility: Evangelisches Krankhaus Hamm gGmbH
city: Heidelberg
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Heidelberg
country: Germany
facility: University Hospital Heidelberg, Med. Klinik V
city: Heilbronn
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Heilbronn
country: Germany
facility: SLK Kliniken Heilbronn, Med. Klinik III
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes, Innere Medizin I
city: Kaiserslautern
country: Germany
facility: Westpfalz-Klinikum GmbH
city: Karlsruhe
country: Germany
facility: Onkologische Schwerpunktpraxis Karlsruhe
city: Kassel
country: Germany
facility: Onkologische Gemeinschaftspraxis Kassel
city: Koblenz
country: Germany
facility: Praxisklinik für Hämatologie und Onkologie
city: Köln
country: Germany
facility: Universitätsklinikum Köln, Klinik I - Innere Medizin
city: Lebach
country: Germany
facility: Onkologisches Zentrum, Gemeinschaftspraxis f. Hämatologie u. Onkologie im Caritas KH
city: Lemgo
country: Germany
facility: Klinikum Lippe GmbH, Hämatologie-Onkologie
city: Ludwigsburg
country: Germany
facility: Schwerpunktpraxis für Hämatologie und Onkologie
city: Ludwigshafen am Rhein
country: Germany
facility: Med. Klinik A, Klinikum der Stadt Ludwigshafen am Rhein gGmbH
city: Mainz
country: Germany
facility: Internistische Schwerpunktpraxis für Hämatologie und Onkologie
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: Oberhausen
country: Germany
facility: Praxis für Hämatologie und internistische Onkologie
city: Offenbach
country: Germany
facility: Internistisch, Onkologische Gemeinschaftspraxis Dres. Balló
city: Oldenburg
country: Germany
facility: Onkologische Praxis Oldenburg
city: Regensburg
country: Germany
facility: Krankenhaus Barmherzige Brüder, Klinik für Onkologie und Hämatologie
city: Reutlingen
country: Germany
facility: Klinikum am Steinenberg, Ermstalklinik, Medizinische Klinik I
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: Siegen
country: Germany
facility: Diakonie Klinikum Jung-Stilling-Krankenhaus, Medizinische Klinik
city: Singen
country: Germany
facility: Onkologische Schwerpunktpraxis für Onkologie und Gastroenterologie
city: Speyer
country: Germany
facility: Onkologische Schwerpunktpraxis Speyer
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: Villingen-Schwenningen
country: Germany
facility: Schwarzwald-Baar Klinikum, Klinik für Innere Medizin II
city: Winnenden
country: Germany
facility: Rems-Murr-Klinikum gGmbH Winnenden
Study officials:
affiliation: Med. Klinik V, University Hospital Heidelberg
name: Hartmut Goldschmidt, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Salwender H, Bertsch U, Weisel K, Duerig J, Kunz C, Benner A, Blau IW, Raab MS, Hillengass J, Hose D, Huhn S, Hundemer M, Andrulis M, Jauch A, Seidel-Glaetzer A, Lindemann HW, Hensel M, Fronhoffs S, Martens U, Hansen T, Wattad M, Graeven U, Munder M, Fenk R, Haenel M, Scheid C, Goldschmidt H. Rationale and design of the German-speaking myeloma multicenter group (GMMG) trial HD6: a randomized phase III trial on the effect of elotuzumab in VRD induction/consolidation and lenalidomide maintenance in patients with newly diagnosed myeloma. BMC Cancer. 2019 May 28;19(1):504. doi: 10.1186/s12885-019-5600-x.