Clinical trial NCT02112175: Lenalidomide vs Placebo Maintenance Therapy Following Melphalan Prednisone Velcade® Induction Therapy in NDMM
Official title: Phase 3B, Randomized Trail of Revlimid® (Lenalidomide) Versus Placebo Maintenance Therapy Following Melphalan Prednisone Velcade (Bortezomib) Induction Therapy In Newly Diagnosed Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma
Lenalidomide
Revlimid
MPV
Melphalan
Prednisone
Velcade
Placebo
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2014-04-11
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare the safety and efficacy of Lenalidomide versus Placebo maintenance following melphalan, prednisone and velcade induction therapy in newly diagnosed multiple myeloma.

After the study is unblinded, subjects in treatment Arm A (Len 10 mg) will remain on study therapy at the Investigator's discretion and subjects in treatment Arm B (placebo), will be discontinued from study treatment. Subjects who discontinued from study treatment for any reason will enter the LTFU Phase.

Detailed description: The planned total number of evaluable subjects for PFS was approximately 351 (234 in the lenalidomide treatment arm; 117 in the placebo treatment arm) and the study will be conducted in European countries. However, due to the significant enrollment challenges and the changes in the NDMM treatment practices in subjects who are not eligible for transplant, such as the recent approval of Revlimid in NDMM setting, the DMC recommended to close study enrollment. Study enrollment was closed on 12 October 2015.

Eligibility criteria: Inclusion Criteria:

* Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:

Related to initial diagnosis and prior Melphalan Prednisone Velcade (MPV) induction therapy

1. Previously untreated and symptomatic multiple myeloma.
2. All 3 criteria (Durie, 2003) and at least one of the Creatinine Renal insufficiency Anemia lytic Bone lesions or osteoporosis criteria must be met.
3. Measurable disease by protein electrophoresis analyses.
4. All subjects must be treated with a minimum of 6 and a maximum of 9 cycles of MPV induction regimen, and must have achieved at least Partial Response as best overall response and maintained at Melphalan Prednisone Velcade discontinuation. If a subject achieves Complete Response prior to at least 6 cycles, the subject will be eligible, but a minimum of 6 cycles must be administered otherwise.
5. Subjects must not have received any prior anti-myeloma chemotherapy or any investigational agent except 6-9 cycles of induction therapy with Melphalan Prednisone Velcade.
6. Subjects must have cytogenetic (17 p deletion, and 4;14 translocation), β-2 microglobulin and serum albumin (International Staging System) results from their initial diagnosis available at the time of screening.

   Related to the subject
7. Must understand and voluntarily sign the informed consent document prior to the conduct of any study related assessments/procedures,
8. Age ≥ 65 years: if \< 65 years of age, the subject must be non eligible for stem cell transplantation,
9. Eastern Cooperative Oncology Group performance status score ≤ 2,
10. Able to adhere to the study visit schedules and other protocol requirements,
11. Females of Childbearing Potential must:

    1. Have two negative pregnancy tests as verified by the study doctor prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after the end of study therapy. This applies even if the subject practices true abstinence2 from heterosexual contact.
    2. Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting Investigational Product, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy.
12. Male Subjects must:

    1. Practice true abstinence or agree to use a condom during sexual contact with a pregnant female or a female or childbearing potential while participating in the study, during dose interruptions and for at least 28 days following Investigational Product discontinuation, even if he has undergone a successful vasectomy.
    2. Agree to not donate semen during Investigational Product therapy and for 28 days after end of study therapy.
13. All subjects must:

    1. Have an understanding that the study medication could have a potential teratogenic risk.
    2. Agree to abstain from donating blood while taking Investigational Product therapy and following discontinuation of Investigational Product therapy.
    3. Agree not to share study medication with another person.
    4. All female of childbearing potential and male subjects must be counseled about pregnancy precautions and risks of fetal exposure.

Exclusion Criteria:

* The presence of any of the following will exclude the subject from the study enrollment:

  1. Previous treatment with anti-myeloma therapy other than the required 6-9 cycles of Melphalan Prednisone Velcade induction therapy (does not include local radiotherapy, bisphosphonates, or a single short course of steroid \[ie, less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days; such a short course of steroid treatment must not have been given within 14 days of randomization\]).
  2. Subjects who didn't achieve Partial Response or better after getting at least 6 cycles of Melphalan Prednisone Velcade and at the end of Melphalan Prednisone Velcade whatever the overall response are not eligible.
  3. Prior therapy with immunomodulating or immunosuppressive agents, or epigenetic or desoxyribonucleic acid modulating agents. Subjects who received investigational agents are also excluded.
  4. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
  5. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
  6. Pregnant or lactating females.
  7. Any of the following laboratory abnormalities:

     Absolute neutrophil count \< 1,000/L (1.0 x 10\*9/L) Untransfused platelet count \< 50,000 cells/L (50 x 10\*9/L) Serum glutamic oxaloacetic transaminase/alanine aminotransferase or serum glutamic pyruvic transaminase/alanine aminotransferase \> 3.0 x upper limit of normal Serum bilirubin levels \> 1.5 x upper limit of normal
  8. Renal insufficiency (creatinine clearance \< 30 mL/min by Cockcroft-Gault method) or actual creatinine clearance result, or renal failure requiring hemodialysis or peritoneal dialysis.
  9. Prior history of malignancies including skin cancer, other than multiple myeloma.
  10. Prior history of deep venous thrombosis or pulmonary embolus within 3 years of randomization.
  11. Subjects who are unable or unwilling to undergo anti-thrombotic therapy.
  12. Peripheral neuropathy of \> Grade 2 severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.
  13. Known Human Immunodeficiency Virus positivity or active infectious hepatitis, type A, B, or C.
  14. Primary amyloidosis (immunoglobulin light chain) and myeloma complicated by amyloidosis.
  15. Prior allogeneic or autologous stem cell transplantation.
  16. Significant active cardiac disease within the previous 6 months including:

      New York Heart Association class II-IV congestive heart failure Unstable angina or angina requiring surgical or medical intervention Myocardial infarction
  17. Any condition that confounds the ability to interpret data from the study.

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: Approximately 6 years
Secondary outcomes:
measure: Safety; Adverse Events (AE) [type, frequency, and severity of AEs, and relationship of AEs to investigational product (IP) SAEs, laboratory abnormalities, hospitalizations, and SPMs
timeFrame: Approximately 6 years
Other outcomes:
Locations:
city: Baudour
country: Belgium
facility: Centre Hospitalier EpiCURA - Clinique Louis Caty de Baudour
city: Brussels
country: Belgium
facility: AZ-VUB
city: Charleroi
country: Belgium
facility: Grand Hopital de Charleroi
city: Edegem
country: Belgium
facility: Universitair Ziehenhuis Antwerpen
city: La Louvière-(Haine St-Paul)
country: Belgium
facility: Centre Hospitalier de Jolimont-Lobbes
city: Sint-Niklaas
country: Belgium
facility: AZ Nikolaas
city: Yvoir
country: Belgium
facility: Cliniques Universitaires UCL de Mont-Godine
city: Argenteuil
country: France
facility: CH Argenteuil Victor DupouyHematologie
city: Bayonne
country: France
facility: Centre Hospitalier de la cote basque
city: Besancon
country: France
facility: Hopital Jean Minjoz Hematologie
city: Blois Cedex
country: France
facility: Centre Hospitalier de Blois
city: Bordeaux
country: France
facility: Polyclinique Bordeaux Nord Aquitaine
city: Bourg en Bresse cedex
country: France
facility: Hopital de Fleyriat
city: Brest cedex
country: France
facility: Hopital A. MorvanHematologie
city: Caen
country: France
facility: CHU de la cote de Nacre
city: Clemont-Ferrand Cedex
country: France
facility: CHRU - Hotel Dieu
city: Clermont Ferrand
country: France
facility: Chu Estaing
city: Corbeil Essonnes
country: France
facility: Centre Hospitalier Sud Francilien - Site Gilles de Corbeil
city: Creteil
country: France
facility: Hopital Henri Mondor
city: Dunkerque
country: France
facility: Centre Hospitalier
city: La Roche Sur Yon
country: France
facility: CHD Vendee
city: Le Chesnay Cedex
country: France
facility: CH Hematologie
city: Le Kremlin bicetre CDX
country: France
facility: Kremlin Bicetre
city: Le Mans cedex
country: France
facility: Centre Hospitalier Medecine interne
city: Le Mans
country: France
facility: Centre Jean BernardOnco-Hematologie
city: Lile Cedax
country: France
facility: CHRU Hopital Claude Huriez
city: Limoges Cedex 1
country: France
facility: CH - Hôpital Dupuytren
city: Metz Cedex 03
country: France
facility: Centre Hospitalier Regional Metz-Thionville Hopital de Mercy
city: Nimes Cedex 9
country: France
facility: CHU de Nimes
city: Orleans
country: France
facility: CH La Source Onco-Hèmatologie
city: Paris
country: France
facility: Hopital Saint Louis
city: Paris
country: France
facility: Groupe Hospitalier Pitié- Salpétrière
city: Perpignan
country: France
facility: CH Perpignan - Hopital Saint-Jean
city: Pierre Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Pringy
country: France
facility: Centre Hospitalier de la Region d'Annecy
city: Rennes cedex 02
country: France
facility: CHRU Hopital sud Medecine Interne
city: St-Brieuc cedex 1
country: France
facility: Centre Hospitalier Yves Le Foll
city: Strasbourg
country: France
facility: Hopital civil
city: Strasbourg
country: France
facility: CHRU Hôpital de Hautepierre
city: Toulouse Cedex
country: France
facility: Institut Universitaire du Cancer IUCT - Oncopole
city: Tours cedex
country: France
facility: CHRU Hopital BretonneauOnco-hematologie
city: Vandoeuvre
country: France
facility: CHRU Hôpitaux de Brabois
city: Athens
country: Greece
facility: Laiko General Hospital of Athens
city: Athens
country: Greece
facility: Alexandra General Hospital of Athens
city: Patras
country: Greece
facility: University of Patras
city: Thessaloniki
country: Greece
facility: Theagenio Anticancer Hospital of Thessaloniki
city: Bologna
country: Italy
facility: Policlinico Sant'Orsola-Malpighi
city: Brescia
country: Italy
facility: Spedali Civili Brescia
city: Catania
country: Italy
facility: Ospedale Ferrarotto
city: Genova
country: Italy
facility: Clinica Ematologica, A.O.U. San Martino di Genova
city: Lecce
country: Italy
facility: Ematologia ed Immunologia, Azienda Ospedaliera Vito Fazzi di Lecce
city: Matera
country: Italy
facility: Unità Operativa di Oncoematologia, Ospedale di Matera
city: Milano
country: Italy
facility: U.O. di Ematologia e Trapianto di Midollo Osseo
city: Napoli, Campania
country: Italy
facility: Istituto Nazionale Per Lo Studio E La Cura Dei Tumori Fondazione Giovanni Pascale
city: Pavia 2
country: Italy
facility: Policlinico San Matteo Universita Di Pavia
city: Piacenza
country: Italy
facility: Ospedale Civile di Piacenza
city: Reggio Emilia
country: Italy
facility: Arcispedale Santa Maria Nuova
city: Roma
country: Italy
facility: Policlinico Umberto I
city: Rome
country: Italy
facility: Ospedale Sant'Eugenio
city: San Giovanni Rotondo
country: Italy
facility: IRCCS Casa Sollievo della Sofferenza
city: Torino
country: Italy
facility: Dipartimento Medicina ed Oncologia Sperimentale - Divisione Universitaria di Ematologia Azienda Ospe
city: Torrette Di Ancona
country: Italy
facility: Ospedale Umberto I
city: Varese
country: Italy
facility: A.O. Universitaria Fondazione Macchi
city: Barcelona
country: Spain
facility: Hospital Sant Pau
city: Barcelona
country: Spain
facility: Hospital Clinic Provincial de Barcelona
city: El Palmar (murcia)
country: Spain
facility: Hospital virgen de la Arrixaca
city: Granada
country: Spain
facility: Hospital Virgenes de las Nieves
city: Madrid
country: Spain
facility: Hospital La Princesa
city: Marbella
country: Spain
facility: Hospital Costa del Sol
city: Oviedo
country: Spain
facility: Hospital Central de Asturias
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Santiago de Compostela
country: Spain
facility: Complejo Hospitalario de Santiago
Study officials:
affiliation: Celgene Corporation
name: Amine Bensmaine, MD
role: STUDY_DIRECTOR
References:
citation: Ailawadhi S, Jacobus S, Sexton R, Stewart AK, Dispenzieri A, Hussein MA, Zonder JA, Crowley J, Hoering A, Barlogie B, Orlowski RZ, Rajkumar SV. Disease and outcome disparities in multiple myeloma: exploring the role of race/ethnicity in the Cooperative Group clinical trials. Blood Cancer J. 2018 Jul 6;8(7):67. doi: 10.1038/s41408-018-0102-7.
citation: Dumontet C, Hulin C, Dimopoulos MA, Belch A, Dispenzieri A, Ludwig H, Rodon P, Van Droogenbroeck J, Qiu L, Cavo M, Van de Velde A, Lahuerta JJ, Allangba O, Lee JH, Boyle E, Perrot A, Moreau P, Manier S, Attal M, Roussel M, Mohty M, Mary JY, Civet A, Costa B, Tinel A, Gaston-Mathe Y, Facon T. A predictive model for risk of early grade >/= 3 infection in patients with multiple myeloma not eligible for transplant: analysis of the FIRST trial. Leukemia. 2018 Jun;32(6):1404-1413. doi: 10.1038/s41375-018-0133-x. Epub 2018 Apr 26.
citation: Jain T, Sonbol MB, Firwana B, Kolla KR, Almader-Douglas D, Palmer J, Fonseca R. High-Dose Chemotherapy with Early Autologous Stem Cell Transplantation Compared to Standard Dose Chemotherapy or Delayed Transplantation in Patients with Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis. Biol Blood Marrow Transplant. 2019 Feb;25(2):239-247. doi: 10.1016/j.bbmt.2018.09.021. Epub 2018 Sep 20.
citation: Gambella M, Omede P, Spada S, Muccio VE, Gilestro M, Saraci E, Grammatico S, Larocca A, Conticello C, Bernardini A, Gamberi B, Troia R, Liberati AM, Offidani M, Rocci A, Palumbo A, Cavo M, Sonneveld P, Boccadoro M, Oliva S. Minimal residual disease by flow cytometry and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction in patients with myeloma receiving lenalidomide maintenance: A pooled analysis. Cancer. 2019 Mar 1;125(5):750-760. doi: 10.1002/cncr.31854. Epub 2018 Dec 18.
citation: Pegourie B, Karlin L, Benboubker L, Orsini-Piocelle F, Tiab M, Auger-Quittet S, Rodon P, Royer B, Leleu X, Bareau B, Cliquennois M, Fuzibet JG, Voog E, Belhadj-Merzoug K, Decaux O, Rey P, Slama B, Leyronnas C, Zarnitsky C, Boyle E, Bosson JL, Pernod G; IFM Group. Apixaban for the prevention of thromboembolism in immunomodulatory-treated myeloma patients: Myelaxat, a phase 2 pilot study. Am J Hematol. 2019 Jun;94(6):635-640. doi: 10.1002/ajh.25459. Epub 2019 Apr 1.