Trial Studying Maintenance Treatment With Lenalidomide and Dexamethasone Versus Lenalidomide, Dexamethasone and MLN9708 After Autologous Hematopoietic Stem Cell Transplantation in Patients With Newly-diagnosed Symptomatic Multiple Myeloma

Sponsor

PETHEMA Foundation (Other)

Overall Status

Completed

CT.gov ID

NCT02406144

Collaborator

Celgene (Industry), Millennium Pharmaceuticals, Inc. (Industry)

316

Enrollment

Locations

Arms

Actual Duration (Months)

4.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This protocol is a randomized, open-label, national, multicenter trial studying maintenance treatment with lenalidomide and dexamethasone versus lenalidomide, dexamethasone and MLN9708 after autologous hematopoietic stem cell transplantation in patients with newly-diagnosed symptomatic multiple myeloma.

A total of 316 patients, from the study GEM2012MENOS65, will be enrolled in the study.

The pre-treatment period includes the screening visit in which participants provide informed consent in writing in order to take part in the study. The patient is then assessed to determine his/her eligibility. The selection process will begin 21 days before the first dose of medication is administered (days -21 to 0). All procedures during the pre-treatment period will be carried out after completion of the two cycles of post-transplant consolidation with VRD which coincide with the end-of-study visit of clinical trial GEM2012MENOS65.

During the treatment period, eligible patients will be included in the study and receive maintenance treatment with lenalidomide/dexamethasone versus lenalidomide/dexamethasone/MLN9708. Each cycle will last 28 days. Treatment arm A will consist of oral administration of 15 mg/day of oral lenalidomide on days 1-21, and 20 mg/day of dexamethasone administered orally on days 1-4 and 9-12 for a period of two years. Arm B of the maintenance treatment will be the same as arm A, with the addition of MLN9708 during the two year maintenance period, at a dose of 4 mg/day on days 1, 8 and 15 of the cycle.

At two years, patients with negative MRD will finish maintenance treatment. Patients with positive MRD will continue treatment with lenalidomide/dexamethasone until they have completed five years of maintenance treatment. In this case, 20 mg/day of dexamethasone will only be administered on days 1-4 of the cycle. The dose of lenalidomide will not be adjusted. (unless necessary to treat adverse events)

Once this phase of active treatment is complete, patients will begin the long-term follow-up phase, during which they will be visited every three months to evaluate progression and survival.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: MLN9708 Drug: Lenalidomide Drug: Dexamethasone	Phase 3

Detailed Description

The primary trial objectives are:

• Impact on progression-free survival (PFS) when adding MLN9708 to post-transplant maintenance treatment with lenalidomide/dexamethasone in patients with multiple myeloma.

The secondary trial objectives are:

Evaluate development and clinical significance of minimal residual disease (MRD) from the time maintenance treatment is initiated, yearly over five years.
Overall survival (OS).
Evaluate the safety and tolerability of the maintenance treatment.

Study Design

Study Type:

Interventional

Actual Enrollment :

316 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Actual Study Start Date :

Nov 1, 2014

Actual Primary Completion Date :

Sep 1, 2017

Actual Study Completion Date :

Nov 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Lenalidomide Oral administration of 15 mg/day of oral lenalidomide on days 1-21, and 20 mg/day of dexamethasone administered orally on days 1-4 and 9-12 for a period of two years	Drug: Lenalidomide Drug: Dexamethasone
Experimental: MLN9708 plus Lenalidomide MLN9708 during the two year maintenance period, at a dose of 4 mg/day on days 1, 8 and 15 of the cycle.	Drug: MLN9708 Drug: Lenalidomide Drug: Dexamethasone

Arm

Intervention/Treatment

Active Comparator: Lenalidomide

Oral administration of 15 mg/day of oral lenalidomide on days 1-21, and 20 mg/day of dexamethasone administered orally on days 1-4 and 9-12 for a period of two years

Drug: Lenalidomide

Drug: Dexamethasone

Experimental: MLN9708 plus Lenalidomide

MLN9708 during the two year maintenance period, at a dose of 4 mg/day on days 1, 8 and 15 of the cycle.

Drug: MLN9708

Drug: Lenalidomide

Drug: Dexamethasone

Outcome Measures

Primary Outcome Measures

Progression-free survival [5 years]
Months to progression disease

Secondary Outcome Measures

Minimal Residual Disease (MRD) [5 years]
Number of patient with MRD and evaluation of its clinical significance
Overall survival [6 years]
Months of survival

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 67 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

The patient must, in the opinion of the investigator, be capable of complying with all requirements of the trial.
Have signed the informed consent form
Be between 18 and 67 years of age
Have an ECOG Performance Status <= 2 (or 3 if the ECOG is due to myeloma, e.g. pathological fracture)
Multiple myeloma patient who was included in the GEM2012MENOS65 trial, and who is found to have, at a minimum, minimal response after consolidation
Life expectancy > 3 months
The patient must have the following laboratory values in the 21 days prior to initiation of treatment (day 1, cycle 1):

Platelet count ≥ 100 x 109/L and absolute neutrophil count of ≥ 1.0 x 109/L. - Platelet transfusions to help patients meet eligibility criteria are not allowed.
Corrected serum calcium < 14 mg/dL.
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x the upper limit of normal (ULN)
Total bilirubin within normal range
Calculated creatinine clearance > 30 mL/min

Female patients who:

Are postmenopausal for at least 1 year before the screening visit, OR
Are surgically sterile, OR
If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, AND
Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)

Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following:

Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR 30 Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)

Exclusion Criteria:

Patients not included in clinical trial GEM2012MENOS65
Patients included in GEM2012MENOS65 who are not found to have a least minimal response after consolidation
Patients included in GEM2012MENOS65 who were discontinued prematurely due to toxicity or disease progression
Female patients who are lactating or have a positive serum pregnancy test during the screening period.
Central nervous system involvement
Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment.
Systemic treatment, within 14 days before the first dose of MLN9708, with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.
Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 including difficulty swallowing.
Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
Peripheral neuropathy ≥ grade 2 in the 21 days prior to inclusion.
Known hypersensitivity to lenalidomide or to MLN9708, their analogues, or excipients in the various formulations of any agent.
Patients who have had a myocardial infarction in the six months prior to inclusion in the clinical trial, or who are class III or IV according to the New York Heart Association (NYHA), heart failure unstable angina, uncontrolled ventricular arrhythmias or acute ischemia detected by electrocardiogram, or conduction disorders.
Patients who are currently participating in another clinical trial or receiving any other investigational product.
Seropositive for HVB, HVC or HIV.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Complejo Hospitalario Universitario de Santiago	A Coruña	Spain
2	Hospital Txagorritxu	Alava	Spain
3	Hospital General de Albacete	Albacete	Spain
4	Hospital Del Vinalopo	Alicante	Spain
5	Hospital General Universitario de Alicante	Alicante	Spain
6	Hospital de Cabueñes	Asturias	Spain
7	Hospital Universitario Central de Asturias	Asturias	Spain
8	Hospital Clinic	Barcelona	Spain	08036
9	H.Universitari Germans Trias I Pujol de Badalona	Barcelona	Spain
10	Hospital de La Santa Creu I Sant Pau	Barcelona	Spain
11	Hospital de Sabadell (Parc Taulí)	Barcelona	Spain
12	Hospital de Sant Joan de Déu	Barcelona	Spain
13	Hospital Del Mar	Barcelona	Spain
14	Hospital Universitari Mútua de Terrasa	Barcelona	Spain
15	Hospital Vall D'Hebron	Barcelona	Spain
16	Ico L'Hospitalet	Barcelona	Spain
17	Hospital Universitario de Burgos	Burgos	Spain
18	Hospital Universitario Marqués de Valdecilla	Cantabria	Spain
19	Hospital General de Castellón	Castello	Spain
20	Hospital General de Ciudad Real	Ciudad Real	Spain
21	Complejo Hospitalario de Cáceres	Cáceres	Spain
22	Hospital de Especialidades de Jerez de La Frontera	Cádiz	Spain
23	Hospital Universitari Dr. Josep Trueta de Girona	Girona	Spain
24	Hospital de Gran Canaria Doctor Negrín	GRAN Canaria	Spain
25	Hospital Universitario Virgen de Las Nieves	Granada	Spain
26	Hospital Universitario Guadalajara	Guadalajara	Spain
27	Hospital Universitario Donostia	Guipúzcoa	Spain
28	Hospital Son Llatzer	Illes Balears	Spain
29	Hospital Universitari Son Espases	Illes Balears	Spain
30	Hospital San Pedro	La Rioja	Spain
31	Hospital de León	León	Spain
32	Hospital Universitari Arnau de Vilanova de Lleida	Lleida	Spain
33	Centro Oncológico Md Anderson International España	Madrid	Spain
34	Fundación Jiménez Díaz-Ute	Madrid	Spain
35	Hm Universitario San Chinarro	Madrid	Spain
36	Hospital Clínico San Carlos	Madrid	Spain
37	Hospital de Fuenlabrada	Madrid	Spain
38	Hospital Del Tajo	Madrid	Spain
39	Hospital General Universitario Gregorio Marañón	Madrid	Spain
40	Hospital Infanta Leonor	Madrid	Spain
41	Hospital Infanta Sofía	Madrid	Spain
42	Hospital Ramón Y Cajal	Madrid	Spain
43	Hospital Severo Ochoa	Madrid	Spain
44	Hospital Universitario 12 de Octubre	Madrid	Spain
45	Hospital Universitario de La Princesa	Madrid	Spain
46	Hospital Universitario Fundación Alcorcón	Madrid	Spain
47	Hospital Universitario Infanta Cristina	Madrid	Spain
48	Hospital Universitario La Paz	Madrid	Spain
49	Hospital Universitario Puerta de Hierro Majadahonda	Madrid	Spain
50	Complejo Hospital Costa Del Sol (Ivcs)	Malaga	Spain
51	Hospital General Universitario Santa Lucia	Murcia	Spain
52	Hospital J.M. Morales Meseguer	Murcia	Spain
53	Hospital Universitario Virgen de La Arrixaca	Murcia	Spain
54	Clinica Universidad de Navarra	Navarra	Spain
55	Complejo Hospitalario de Navarra	Navarra	Spain
56	Complejo Hospitalario de Ourense	Ourense	Spain
57	Complejo Hospitalario de Pontevedra	Pontevedra	Spain
58	Hospital Universitario de Salamanca	Salamanca	Spain
59	Hospital Universitario de Canarias	Santa Cruz de Tenerife	Spain
60	Hospital General de Segovia	Segovia	Spain
61	Hospital Nuestra Señora de Valme	Sevilla	Spain
62	Hospital Virgen del Rocío	Sevilla	Spain
63	Hospital Santa Bárbara	Soria	Spain
64	Hospital Universitari Joan Xxiii de Tarragona	Tarragona	Spain
65	Complejo Hospitalario de Toledo	Toledo	Spain
66	Hospital Nuestra Señora Del Prado	Toledo	Spain
67	Hospital Clínico Universitario Valencia	Valencia	Spain
68	Hospital Universitario Dr. Peset	Valencia	Spain
69	Hospital Universitario La Fe	Valencia	Spain
70	HOSPITAL CLíNICO UNIVERSITARIO DE VALLADOLID	Valladolid	Spain
71	Hospital Universitario Del Rio Hortega	Valladolid	Spain
72	Hospital de Cruces	Vizcaya	Spain
73	Hospital Clínico Universitario Lozano Blesa	Zaragoza	Spain
74	Hospital Universitario Miguel Servet	Zaragoza	Spain