Clinical trial NCT01045681: Study of Bendamustine, Velcade and Dexamethasone in the Treatment of Elderly Patients With Multiple Myeloma
Official title: A Phase II Study of Bendamustine, Velcade and Dexamethasone (BVD) in the Treatment of Elderly Patients (>= 65 Years) With Multiple Myeloma in 1st Relapse or Refractory to 1st Line Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma
Elderly patients
first relapse
refractory to first line therapy
Bendamustine Velcade Dexamethasone Association
Lead sponsor: Intergroupe Francophone du Myelome
Sponsor class: NETWORK
First posted: 2010-01-11
Enrollment: 75
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The present trial is designed as a phase II study that aims at estimating the efficacy of the combination of bendamustine, bortezomib and dexamethasone in relapsed/refractory multiple myeloma (MM). The response rate, i.e. the rate of the patients achieving a Complete Response or Partial Response at cycle 4, divided by the total intent to treat patient number is chosen as primary efficacy endpoint.

The estimation of the efficacy rate is to be based on an explorative pilot study, since immediate embarking on a large-scale comparative efficacy trial would not be acceptable from the point of view of resources. Moreover, this would induce ethical objections, as it does not seem to be justifiable to expose a large number of patients to an experimental approach without sufficient exploratory indications of an improved risk-benefit ratio.

Detailed description: After relapse or after early progression on first-line treatment, the prognosis of multiple myeloma (MM) patients is unfavourable, and the search for new treatment regimens, including drugs with novel mechanisms of action is essential.

Bendamustine and bortezomib have shown high activity boch in first-line regimens and pre-treated patients. The novel mechanism of action of the proteasome inhibitor and the non-cross resistance of bendamustine to other alkylating agents established in the first-line treatment of multiple myeloma seem to recommend a combination of the two drugs for salvage therapy (second-line regimen). Finally, the promising response data in a series of relapsing MM patients treated with bendamustine, bortezomib and prednisone support this assumption, as well as the feasibility and tolerability of the combination.

In summary, there is some evidence for a favorable risk/benefit ratio for the combination of bendamustine, bortezomib and a corticoid drug, warranting the exploration in a larger, prospectively designed multicenter phase II study.

Eligibility criteria: Inclusion Criteria:

* Symptomatic multiple myeloma (MM) patient at the time of diagnosis (but not necessarily at the time of relapse), according to International Myeloma Working Group criteria.
* Patient having received conventional chemotherapy in 1st line treatment because of age 65 years or over, or younger than 65 years and ineligible to high-dose therapy plus stem cell transplantation.
* Measurable disease (≥10g/L monoclonal gammapathy and/or ≥ 200 mg/24h proteinuria or involved serum free light chain ≥ 100mg/L with abnormal FLC ratio \< 0.26 or \> 1.65)
* Patient in 1st relapse or refractory to 1st line therapy. Relapse is defined by M-component increase of ≥25% from baseline, in serum and/or urine (the absolute increase in serum must be ≥ 5 g/l - the absolute increase of BJ proteins in urine must be ≥200 mg/24 h). (It is recommended to treat only symptomatic or rapidly evolutive relapses)
* Life expectancy of at least 3 months
* ECOG performance status \<= 2 at study entry
* Laboratory test results within these ranges:
* Absolute neutrophil count \>= 1.5 x 109/L
* Platelet count \>= 100 x 109/L
* Serum creatinine \<= 250 umol/l
* AST (SGOT) and ALT (SGPT) \<= 3 x ULN
* Disease free of prior malignancies for \>= 5 years, with exception of curatively treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast
* Able to adhere to the study visit schedule and other protocol requirements
* Using effective contraceptive methods during and for 6 months after study treatment (for fertile men, women of childbearing potential).
* Provision of informed consent.
* A period of at least 15 days must be respected between the last treatment of myeloma and the beginning of the study.

Exclusion Criteria:

* Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
* Any comorbidity which places the subject at unacceptable risk if he/she were to participate in the study.
* Patients treated with high-dose therapy plus stem cell transplantation in 1st line therapy
* Any prior use of bortezomib (Velcade) or bendamustine (Ribomustin)
* Concurrent use of other anti-cancer agents or treatments other than those stated in this treatment plan
* Use of any other experimental drug or therapy within 28 days prior to the start of study treatment.
* Known hypersensitivity to the study drugs
* Positive HIV serology, positive hepatitis C serology, active infection hepatitis A, active infection hepatitis B.
* Severe cardiovascular disorders within 12 months prior to the start of study treatment (e.g. myocardial infarct, ischemic episodes, arrhythmias)
* Previous major surgery less than 30 days before start of treatment
* Active infection,
* Pregnant or lactating women.

Primary outcomes:
measure: To assess of the overall response rate (complete response (CR) + partial response (PR))
timeFrame: After four 28-day consecutives cycles
Secondary outcomes:
measure: Time to best response
timeFrame: the time from treatment start to the first detection of the best response category, calculated for all patients, which are not primarily refractory
measure: Progression-free survival
timeFrame: The time form the initial dose of chemotherapy to the time of disease progression or death, or to the date of last assessment without any such event (censored observation)
measure: Time to progression
timeFrame: The time from baseline to the development of progressive disease
measure: Overall survival
timeFrame: The time interval from initial dose to the date of death or last observation (censored)
measure: Rate of additional response
timeFrame: Following 2 consolidation cycles and following 6 maintenance cycles
measure: Toxicity/Adverse events
timeFrame: From the time a signed and dated informed consent form is obtained until 60 days following the lase dose of study medication or until the start of a new subsequent antimyeloma therapy
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHRU Hôpital Sud
city: Angers
country: France
facility: CHRU, Hôpital du Bocage
city: Avignon
country: France
facility: Centre Hospitalier H.Duffaut
city: Bayonne
country: France
facility: Centre Hospitalier de la Cote Basque
city: Besançon
country: France
facility: Hôpital Jean Minjoz / CHU BESANCON
city: Blois
country: France
facility: Centre Hospitalier
city: Bobigny
country: France
facility: Hôpital Avicenne
city: Bordeaux
country: France
facility: Polyclinique Bordeaux Nord Aquitaine
city: Brest
country: France
facility: Hôpital A.Morvan
city: Caen
country: France
facility: Centre F.Baclesse
city: Clermont Ferrand
country: France
facility: CHU Clermont Ferrand
city: Corbeil-essonnes
country: France
facility: CH Sud Francilien
city: Dijon
country: France
facility: CHU DIJON, Hôpital Le Bocage
city: Dunkerque
country: France
facility: Centre Hospitalier Général
city: Grenoble
country: France
facility: Hôpital A.Michallon
city: La Roche Sur Yon
country: France
facility: CH Départemental
city: Le Coudray
country: France
facility: Centre Hospitalier de Chartres
city: Le Mans
country: France
facility: Centre Jean Bernard
city: Lille
country: France
facility: CHRU Hôpital Claude Huriez
city: Marseille
country: France
facility: Institut Paoli Calmette
city: Meaux
country: France
facility: CH MEAUX
city: Nantes
country: France
facility: CHRU Hôtel Dieu
city: Nice
country: France
facility: Hôpital de l'Archet 1
city: Paris
country: France
facility: Intitut Curie
city: Paris
country: France
facility: CHU Hôpital St-Antoine
city: Pierre Benite
country: France
facility: Centre Hopsitalier Lyon Sud
city: Pontoise
country: France
facility: Centre Hospitalier René Dubos
city: Pringy
country: France
facility: Centre Hospitalier de la Région d'Annecy
city: Reims
country: France
facility: CHU Reims Hôpital R.Debré
city: Rennes
country: France
facility: CHRU - Hôpital sud
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint-cloud
country: France
facility: Centre René Huguenin
city: Toulouse
country: France
facility: CHRU Hopital Purpan
city: Tours
country: France
facility: CHRU Hopital Bretonneau
city: Valence
country: France
facility: Centre Hospitalier
city: Vandœuvre-lès-Nancy
country: France
facility: CHRU - Hôpitaux de Brabois
city: Vannes
country: France
facility: CH P.Chubert
Study officials:
affiliation: Unité Hématologie Biologique Institut Curie PARIS
name: Philippe RODON, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Service Hématologie Hôpitaux de Brabois VANDOEUVRE LES NANCY
name: Cyrille HULIN, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Service Hématologie CHU Nantes
name: Jean-Luc HAROUSSEAU, Professor
role: STUDY_DIRECTOR
affiliation: IFM Hématologie Biologique Institut Curie PARIS
name: Claire MATHIOT, Doctor
role: STUDY_CHAIR
affiliation: IFM Hôpital Claude Huriez Lille
name: Marie-Odile PETILLON, Doctor
role: STUDY_CHAIR
References:
citation: Rodon P, Hulin C, Pegourie B, Tiab M, Anglaret B, Benboubker L, Jardel H, Decaux O, Kolb B, Roussel M, Garderet L, Leleu X, Fitoussi O, Chaleteix C, Casassus P, Lenain P, Royer B, Banos A, Benramdane R, Cony-Makhoul P, Dib M, Fontan J, Stoppa AM, Traulle C, Vilque JP, Petillon MO, Mathiot C, Dejoie T, Avet-Loiseau H, Moreau P. Phase II study of bendamustine, bortezomib and dexamethasone as second-line treatment for elderly patients with multiple myeloma: the Intergroupe Francophone du Myelome 2009-01 trial. Haematologica. 2015 Feb;100(2):e56-9. doi: 10.3324/haematol.2014.110890. Epub 2014 Nov 14. No abstract available.