The Carthadex trial.

Background of the study:

Thalidomide and bortezomib combined with dexamethasone and a third agent (alkylating agent or anthracycline) are now recognized as the most active drugs for remission induction in transplant candidates. In elderly patients they are combined with Melphalan/Prednisone (MP) in first line treatment. Both drugs share the disadvantage of inducing peripheral polyneuropathy which is dose limiting in 50% of patients and leads to premature termination of treatment in 25%.
Replacing bortezomib by carfilzomib would associate effective proteasome inhibition with lack of neuropathy, thereby improving the proportion of patients who are able to complete the planned treatment and reducing the rate of serious adverse events, in particular polyneuropathy. In view of the recently reported high response rates with Bortezomib containing regimens (VD, VRD, VCD, VTD, PAD) prior and after high-dose therapy, a regimen with Carfilzomib combining less polyneuropathy with similar efficacy would be a likely candidate for standard induction in the future. Equally, such
regimen could be used for short consolidation treatment after high-dose therapy



Objective of the study:

To assess the feasibility and efficacy of Carfilzomib in combination with Thalidomide and Dexamethasone in a phase II trial.



Study design:

This trial will establish the feasibility and efficacy of Carfilzomib, in combination with Thalidomide and Dexamethasone as an induction therapy prior to therapy with High Dose Melphalan (HDM) and Autologous Stem Cell Transplantation (ASCT) in previously untreated patients with Multiple Myeloma. Stem cell harvest will be performed using high-dose Cyclophosphamide and standard G-CSF. In addition, the efficacy of a short (4 cycles) post-transplant consolidation schedule of Carfilzomib, in combination with lower dose Thalidomide and Dexamethasone will be investigated. The study will be conducted as a Phase II trial. Fifty patients will be included in the study cohort. Molecular (FISH) characterization and gene expression profiling of the myeloma tumor cells will be performed at inclusion. All patients will be followed closely for toxicities and response assessment, as indicated. After completion of treatment, all patients will be followed two-monthly until relapse or progression.



Study population:

Patients with Multiple Myeloma, ISS stage II/III age 18-65 yrs (must be transplant candidates) at first presentation; 50 patients.



Intervention:

The treatment is composed of the standard therapy for patient with Multiple Myeloma at first presentation. Instead of giving, in the consolidation & induction phase, Thalidomide, Dexamethason and a third agent (i.e. Bortezomib), Carfilzomib will be administered in combination with Thalidomide and Dexamethasone.



Primary study parameters/outcome of the study:

To establish the response, in patients with Multiple Myeloma at first presentation, to carfilzomib in combination with thalidomide and dexamethasone.



Secundary study parameters/outcome of the study:

To investigate the clinical efficacy and toxicity of carfilzomib in combination with thalidomide and dexamethasone in remission induction of Multiple Myeloma at first presentation.

To investigate the clinical efficacy and toxicity of carfilzomib in combination with thalidomide and dexamethasone in consolidation treatment of Multiple Myeloma at first presentation.

To assess the stem cell harvest following carfilzomib in combination with thalidomide and dexamethasone. To assess Progression-free survival (PFS).



Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

Carfilzomib has been given as monotherapy and also in combination with Lenalidomide and dexamethsone but not with this peticular antimyeloma standard chemotherapy regimen. So unexpected toxicites are possible.
A “first-dose” effect has been seen, which is notable for fever, chills, rigors, and/or dyspnea occurring during the evening following the first day of infusion and an increase in creatinine on Day 2, which may be the clinical sequelae of rapid tumor lysis and/or cytokine release.
At time of the normal bone marrow punctions a limited amount of extra bone marrow will be collected via the same needle.

Replacing bortezomib by carfilzomib would associate effective proteasome inhibition with lack of neuropathy, thereby improving the proportion of patients who are able to complete the planned treatment and reducing the rate of serious adverse events, in particular polyneuropathy.

1. induction treatment cycles;

2. High-dose Melphalan and autologous stem cell transplantation;

3. Consolidation cycles;

4. 2 monthly follow up.

Induction cycles:

1. Carfilzomib 20/27mg/m2 days 1,2,8,9,15,16 of a 28 day cycle;

2. Thalidomide 200 mg days 1-28 of a 28 day cycle;

3. Dexamethasone 20 mg days 1,2,8,9,15,16 of a 28 day cycle.
4. 4 cycles.



Stem Cell Harvest.

HDM 200mg/m2 ASCT.



Consolidation cycles:

1. Carfilzomib 27mg/m2 days 1,2,8,9,15,16 of a 28 day cycle;

2. Thalidomide 50 mg days 1-28 of a 28 day cycle;

3. Dexamethasone 20 mg days 1,2,8,9,15,16 of a 28 day cycle;

4. 4 cycles.



Fifty patients will be included in the study cohort. Extensive molecular (FISH) characterization and gene expression profiling of the myeloma tumor cells will be performed at inclusion. All patients will be followed closely for toxicities and response assessment, as indicated. After completion of treatment, all patients will be followed two-monthly until relapse or progression.

For patient numbers 1 to 50

Induction treatment (before HDM/ASCT):

Carfilzomib 20mg/m2 for days 1,2, then 45mg/m2 days 8,9,15,16 of cycle 1, then 27mg/m2 throughout next cycles.

Thalidomide 200 mg days 1-28 of a 28 day cycle.

Dexamethasone 20 mg days 1,2,8,9,15,16 of a 28 day cycle.

4 cycles.

Consolidation treatment (guideline 8 weeks after HDM/ASCT):

Carfilzomib 27mg/m2 days 1,2,8,9,15,16 of a 28 day cycle.

Thalidomide 50 mg days 1-28 of a 28 day cycle.

Dexamethasone 20 mg days 1,2,8,9,15,16 of a 28 day cycle.
4 cycles.



For patient numbers 51 to 70

Induction treatment (before HDM/ASCT):

Carfilzomib 20mg/m2 for days 1,2, then 45mg/m2 days 8,9,15,16 of cycle 1, then 36mg/m2 throughout next cycles.

Thalidomide 200 mg days 1-28 of a 28 day cycle.

Dexamethasone 20 mg days 1,2,8,9,15,16 of a 28 day cycle.
4 cycles.

Consolidation treatment (guideline 8 weeks after HDM/ASCT):

Carfilzomib 36mg/m2 days 1,2,8,9,15,16 of a 28 day cycle.

Thalidomide 50 mg days 1-28 of a 28 day cycle.

Dexamethasone 20 mg days 1,2,8,9,15,16 of a 28 day cycle.
4 cycles.