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The Carthadex trial.


- candidate number8252
- NTR NumberNTR2422
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR22-jul-2010
- Secondary IDs2010-029 METC Erasmus MC
- Public TitleThe Carthadex trial.
- Scientific TitleCarfilzomib in combination with Thalidomide and Dexamethasone for remission induction and consolidation of Multiple Myeloma at first presentation.
- ACRONYMThe Carthadex trial
- hypothesisReplacing 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.
- Healt Condition(s) or Problem(s) studiedMultiple myeloma
- Inclusion criteria1. Patients with a confirmed diagnosis of multiple myeloma stage I to III according to the ISS criteria;
2. Age 18-65 years inclusive;
3. WHO performance status 0-3 (WHO=3 is allowed only when caused by MM and not by co-morbid conditions);
4. Negative urine pregnancy test at inclusion if applicable;
5. Written informed consent.
- Exclusion criteria1. Known intolerance of Thalidomide;
2. Systemic AL amyloidosis;
3. Non-secretory MM;
4. Waldenstrom's macroglobulinemia or IgM MM;
5. Previous chemotherapy or radiotherapy except 2 cycles of Melphalan/Prednisone or local radiotherapy in case of local myeloma progression;
6. Severe cardiac dysfunction (NYHA classification II-IV, see appendix III);
7. Severe pulmonary dysfunction;
8. Significant hepatic dysfunction (serum bilirubin 30 mol/L or transaminases 3.0 times normal level), unless related to myeloma;
9. Creatinine clearance (measured or calculated) <15cc/min;
10. Alkaline Phosphatase >3x ULN;
11. ANC < 1,0 x109/L, platelets < 75 x109/L, Hb < 4.9 mmol/L;
12. Non-secretory MM defined as SPEP < 5 g/L and UPEP < 200 mg/24 hr;
13. Intolerance to thromboprophylaxis;
14. Patients known to be HIV-positive;
15. Patients with active, uncontrolled infections;
16. Patients with neuropathy, CTC grade 3 or higher, or grade 2 painful peripheral neuropathy;
17. Patients with a history of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma;
18. Patients (all males and all pre-menopausal women) who are not willing or capable to use adequate contraception during the therapy;
19. Lactating women;
20. WHO Performance status > 3.
- mec approval receivedyes
- multicenter trialyes
- randomisedno
- groupParallel
- TypeSingle arm
- Studytypeintervention
- planned startdate 26-jul-2010
- planned closingdate1-apr-2018
- Target number of participants145
- InterventionsInduction 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.
- Primary outcomeResponse (Complete response (CR), very good partial response (VGPR), overall response (OR)):
1. After induction prior to HDM/ASCT;
2. After HDM/ASCT prior to consolidation treatment;
3. At end of consolidation treatment.
- Secondary outcome1. Efficacy and toxicity of induction treatment;
2. Efficacy and toxicity of consolidation treatment;
3. Feasibility of good quality stem cell harvest;
4. Progression-free survival (PFS).
- Timepoints1. induction treatment cycles;
2. High-dose Melphalan and autologous stem cell transplantation;
3. Consolidation cycles;
4. 2 monthly follow up.
- Trial web siteN/A
- statusplanned
- CONTACT FOR PUBLIC QUERIESProf. Dr. P. Sonneveld
- CONTACT for SCIENTIFIC QUERIESProf. Dr. P. Sonneveld
- Sponsor/Initiator Erasmus Medical Center
- Funding
(Source(s) of Monetary or Material Support)
Onyx Pharmaceuticals
- PublicationsN/A
- Brief summaryBackground 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.
- Main changes (audit trail)30-jul-2015: INTERVENTION NEW

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.

For patient numbers 71 to 90
Induction treatment (before HDM/ASCT):
Carfilzomib 20mg/m2 for days 1,2, then 45mg/m2 days 8,9,15,16 of cycle 1, then 45mg/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 45mg/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 91 to 110
Induction treatment (before HDM/ASCT):
Carfilzomib 20mg/m2 for days 1,2, then 56mg/m2 days 8,9,15,16 of cycle 1, then 56mg/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 56mg/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 111 to 145
Induction treatment (before HDM/ASCT):
Carfilzomib 20mg/m2 for days 1,2, then 56mg/m2 days 8,9,15,16 of cycle 1, then 56mg/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. 8 cycles.
Consolidation treatment (guideline 8 weeks after HDM/ASCT):
Carfilzomib 56mg/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.


One hundred and forty five 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, at remission for required confirmation and at relapse for diagnosis of relapse. 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. Thereafter every 6 months until 5 years after registration.
- RECORD22-jul-2010 - 30-jul-2015


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