Sequential Trial on Reduced Intensity Conditioning (RIC) Allogeneic Transplantation

NCT01460420 | Completed Phase 1 DMC

• 1 other identifier: EMN-alloRIC2010
• Study Type: interventional
• Target: 49
• Locations: 4 countries
• Sites: 10

Brief Summary

The aim of the current study is to improve the outcome of patients with hematologic malignancies (in a phase I trial) and more specifically multiple myeloma (in a phase II trial) by 2 interventions: reduce the risk of graft-versus-host disease (GVHD) and improve the efficacy of the procedure decreasing the risk of relapses after transplant. Currently, the standard approach used in most centers to prevent graft-versus-host disease after allogeneic transplantation is based on the combination of a calcineurin inhibitor (cyclosporine or tacrolimus) plus a short course of methotrexate. Unfortunately, this strategy is far from ideal, since the risk of acute GVHD is in the range of 30-40% among patients receiving a matched related donor transplantation and even higher among patients receiving transplantation from an unrelated donor while the incidence of chronic GVHD is 60-70% among patients receiving peripheral blood progenitor cells from either a related or unrelated donor. As far as the patients with multiple myeloma (MM) is concerned, although the development of new drugs has markedly changed the outcome and management of these patients, allogeneic transplantation so far appears to be the only curative option, especially among those patients relapsing after first line treatment. Nevertheless, still new strategies within the allogeneic transplant setting are needed to improve its results. Relapses may occur either extramedullary (very common in this setting) or systemic. In order to reduce the risk of systemic relapses the investigators will use maintenance therapy with Lenalidomide (Len) which, together with bortezomib (Bz) should contribute to eradicate minimal residual disease (MRD). In case the patient do not obtain complete remission or near complete remission after transplant, in addition to the maintenance therapy, the investigators will use four intensification cycles with VRD (Bz-Len-Dexamethasone). In summary, the goal is to optimize the efficacy of allogeneic transplantation by two interventions: one focused on reducing the risk of relapse and the other on reducing the incidence of GVHD.

Conditions

Hematologic Malignancies; Multiple Myeloma

Keywords

Allogeneic transplantation; Hematologic malignancies; Multiple myeloma; RIC (Reduced Intensity Conditioning)

Outcome Measures

Primary Outcomes (1)

• Phase I trial: Safety of Len + Bz in patients with hematologic malignancies Phase II trial: Safety and efficacy of an optimized strategy of allogeneic transplantation in multiple myeloma undergoing allogeneic transplantation.

  For phase I trial: safety of Len + Bz. The phase I trial safety criteria will be evaluated in terms of (1) engraftment defined as \> 500 granulocytes / microL and \> 20.000 platelets / microL x 3 consecutive days will be required for 9/10 patients, (2) incidence of neuropathy grades 3-4 attributed to Bz \> 20% (3) incidence of gastrointestinal toxicity attributed to Bz \> 20%. For phase II trial: safety evaluated through adverse events and toxicity and efficacy evaluated as reduction of relapse rate as defined by the EBMT criteria.

  Up to one year after transplant

Secondary Outcomes (5)

• Incidence of GVHD with this combination (phase I and II)

  Up to one year after transplant

• Phase II: response and relapse rate of this approach

  Up to one year after transplant

• Phase II: safety of the procedure

  Up to one year after transplant

• Evaluate the efficacy on survival

  Up to one year after transplant

• Efficacy of positron emission tomography (PET scan)and local radiotherapy

  Up to one year after transplant

Study Arms (1)

Bortezomib + Lenalidomide

EXPERIMENTAL

After conditioning treatment and graft versus host disease prophylaxis with Bz 1.3 mg/m2 on days +1, +4 and +7 plus sirolimus/rapamycin at a dose of 6 mg po on day -5 and then 4 mg per day in order to maintain serum levels in the range of 6-12 ng /mL, a maintenance therapy with Bz 1.3 mg/m2 on days 1, 8 and 15 in cycles of 56 days up to 6 cycles post-transplant and on day +180 Len will be started at a dose of 5 mg and will be maintained until relapse.

Drug: Bz (Bortezomib); Drug: Len (lenalidomide)

Interventions

Bz (Bortezomib) DRUG

Bz 1.3 mg/m2 on days +1, +4 and +7. Maintenance therapy and dose reduction pre-specified.

Also known as: Codenamed PS-341, Marketed as Velcade

Bortezomib + Lenalidomide

Len (lenalidomide) DRUG

Len at a dose of 6 mg po on day -5 and then 4 mg per day in order to maintain serum levels in the range of 6-12 ng /mL. Maintenance therapy and dose reduction pre-specified.

Also known as: Rapamycin, CC-5013, Marketed as Revlimid

Bortezomib + Lenalidomide

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Phase I: For the first 10 patients:
• Patients with any haematological malignancy in \> CR1 (first complete remission)
• Suitable related donor human leukocyte antigen (HLA)identical
• Age \> 18 and \< 70 years
• For the 10 subsequent patients:
• Patients with any haematological malignancy candidates to receive an allogeneic transplant
• Suitable related or unrelated donor (a maximum of 1 mismatched is allowed)
• Age \> 18 and \< 70 years phase II trial:
• High-risk multiple myeloma patients at first relapse / second complete remission candidates to receive an allogeneic transplantation
• Age:\> 18 \< 70 years.
• Suitable donor, related or unrelated (a maximum of 1 mismatched is allowed)
• Measurable disease
• High risk first relapse is defined as:
• First early relapse after Autologous Stem Cell Transplant (ASCT)\< 24 months
• First late relapses in case the patient does not achieve CR after second ASCT

You may not qualify if:

• Any of the following:
• Prior severe comorbidity such as:
• Heart failure or previous infarction
• Uncontrolled Hypertension
• Arrhythmia
• Cirrhosis
• Psychiatric disease
• Prior history of other neoplasia except for carcinoma in situ in the last 10 years
• Hypersensitivity to Bz, Boric acid mannitol.
• Patients unable to use appropriate contraceptive methods
• Positive human immunodeficiency virus (HIV) or active viral hepatitis
• Patients with pericardial disease
• Patients with acute diffuse infiltrative pulmonary disease
• Patients not willing to comply with the Lenalidomide Pregnancy Prevention Risk Management Plan
• Patients not willing to receive thromboprophylaxis during the consolidation phase will not be eligible.

Sponsors & Collaborators

• European Myeloma Network B.V.: lead

Study Sites (10)

Medizinische Klinik and Poliklinik II, University Hospital

Würzburg, Germany

Location

S Giovanni Battista Hospital

Torino, Italy

Location

Azienda Ospedaliera Universitaria di Udine

Udine, Italy

Location

Hospital Clinic i Provincial,

Barcelona, Spain

Location

Hospital Santa Creu I Sant Pau,

Barcelona, Spain

Location

Hospital Universitario Ramón y Cajal

Madrid, 28034, Spain

Location

Hospital Gregorio Marañón,

Madrid, Spain

Location

Hospital Clinico Universitario Salamanca,

Salamanca, Spain

Location

Hospital Universitario Virgen del Rocío,

Seville, Spain

Location

Karolinska University Hospital, Huddinge

Stockholm, Sweden

Location

MeSH Terms

Conditions

Hematologic Neoplasms; Multiple Myeloma

Interventions

Bortezomib; Lenalidomide; Sirolimus

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Piperidones; Piperidines; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Macrolides; Lactones

Study Officials

• Jose-Antonio Perez-Simon, MD-PhD

  University Hospital Virgen del Rocio

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 22, 2011
• First Posted: October 26, 2011
• Study Start: November 1, 2011
• Primary Completion: June 1, 2017
• Study Completion: June 29, 2017
• Last Updated: July 6, 2017

Record last verified: 2017-07

Locations

DE (1); SE (1); ES (6); IT (2)