Use of Thalidomide, Lenalidomide, Bortezomib and Vorinostat in the Initial Treatment of Newly Diagnosed Multiple Myeloma Patients (Myeloma XI)
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Purpose
The purpose of this study is to compare a standard chemotherapy regimen of cyclophosphamide, dexamethasone plus thalidomide with a newer regimen of cyclophosphamide, dexamethasone plus lenalidomide.
Patients who do not have the best response to their initial treatment may then also be given a combination of cyclophosphamide, dexamethasone plus bortezomib.
Patients who are relatively fit may, on their doctor's advice, go on to receive more intensive chemotherapy, supported with a transplant of their own blood cells. This is standard treatment which patients may be offered anyway even if they didn't take part in this study.
After maximal response has been achieved with the treatment described above, and as long as the myeloma has not got worse, patients will be treated with either long-term lenalidomide, lenalidomide with vorinostat, or receive no further treatment, with close observation.
| Condition | Intervention | Phase |
|---|---|---|
|
Multiple Myeloma |
Drug: lenalidomide, cyclophosphamide, dexamethasone Drug: thalidomide, cyclophosphamide, dexamethasone Drug: bortezomib, cyclophosphamide, dexamethasone Drug: lenalidomide maintenance Drug: lenalidomide plus vorinostat maintenance |
Phase 3 |
| Study Type: | Interventional |
| Official Title: | Randomised Comparisons, in Myeloma Patients of All Ages, of Thalidomide, Lenalidomide and Bortezomib Induction Combinations, and of Lenalidomide and Combination Lenalidomide Vorinostat as Maintenance |
- Overall survival [ Designated as safety issue: Yes ]Overall survial for induction chemotherapy comparisons is defined as the time from initial randomisation to the trial to death from any cause or last follow-up. Overall survival for maintenance therapy comparisons is defined from the time of maintenance randomisation.
- Progression-free survival [ Designated as safety issue: Yes ]Progression-free survival for induction chemotherapy comparisons is defined as the time from initial randomisation to the trial to progression or death from any cause. Patients who do not progress will be censored at the last date they were known to be alive and progression-free. Progression-free survival for maintenance therapy comparisons is defined from the time of maintenance randomisation
- Response [ Designated as safety issue: Yes ]Disease progression and response rates will be determined according to the modified International uniform response criteria for multiple myeloma
- Toxicity [ Designated as safety issue: Yes ]Toxicity will be reported based on adverse events, as graded by CTCAE V4.0 and determined by routine clinical assessments at each centre
| Estimated Enrollment: | 1970 |
| Study Start Date: | May 2010 |
| Estimated Primary Completion Date: | September 2017 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: Intensive
The Intensive Pathway is aimed at younger and fitter patients who will receive the standard dose of chemotherapy. The initial treatments will be followed by high-dose chemotherapy with a stem cell transplant which is generally standard practice.
|
Drug: lenalidomide, cyclophosphamide, dexamethasone
Days 1 and 8 cyclophosphamide 500 mg orally Days 1-21 lenalidomide 25 mg daily orally Days 1-4 and 12-15 dexamethasone 40 mg daily orally The cycle is repeated every 28 days. Other Name: Revlimid
Drug: thalidomide, cyclophosphamide, dexamethasone
Continuously thalidomide 50 mg hard capsules - initially 100 mg daily orally for 3 weeks, increasing to 200 mg daily orally Days 1,8,15 (weekly) cyclophosphamide 500 mg orally Days 1-4 and 12-15 dexamethasone 40 mg daily orally The cycle is repeated every 21 days Days 1, 4, 8 and 11 bortezomib 1.3 mg/m2 rapid intravenous push Days 1, 8, 15 cyclophosphamide 500 mg orally Days 1-2, 4-5, 8-9 and 11-12 dexamethasone 20 mg daily orally The cycle is repeated every 21 days Other Name: Velcade
Drug: lenalidomide maintenance
Days 1-21 lenalidomide 10 mg daily orally The cycle is repeated every 28 days Other Name: Revlimid
Drug: lenalidomide plus vorinostat maintenance
Days 1-21 lenalidomide 10 mg daily orally Days 1-7 and 15-21 vorinostat 300 mg orally The cycle is repeated every 28 days Other Names:
|
|
Active Comparator: Non-intensive
Participants who are not deemed suitable for the stem cell transplant will enter the non-intensive arm of the trial, and will receive lower doses of some of the drugs.
|
Drug: lenalidomide, cyclophosphamide, dexamethasone
Days 1 and 8 cyclophosphamide 500 mg orally Days 1-21 lenalidomide 25 mg daily orally Days 1-4 and 15-18 dexamethasone 20 mg daily orally The cycle is repeated every 28 days. Other Name: Revlimid
Drug: thalidomide, cyclophosphamide, dexamethasone
Continuously thalidomide 50 mg hard capsules; initially 50 mg daily orally for 4 weeks, increasing every 4 weeks by 50 mg increments to 200 mg daily orally Days 1, 8, 15, 22 (weekly) cyclophosphamide 500 mg orally Days 1-4 and 15-18 dexamethasone 20 mg daily orally The cycle is repeated every 28 days. Days 1, 4, 8 and 11 bortezomib 1.3 mg/m2 rapid intravenous push Days 1, 8, 15 cyclophosphamide 500 mg orally Days 1-2, 4-5, 8-9 and 11-12 dexamethasone 20 mg daily orally The cycle is repeated every 21 days Other Name: Velcade
Drug: lenalidomide maintenance
Days 1-21 lenalidomide 10 mg daily orally The cycle is repeated every 28 days Other Name: Revlimid
Drug: lenalidomide plus vorinostat maintenance
Days 1-21 lenalidomide 10 mg daily orally Days 1-7 and 15-21 vorinostat 300 mg orally The cycle is repeated every 28 days Other Names:
|
Detailed Description:
The last ten years has seen the introduction of a number of effective new anti-myeloma agents into the clinical arena. These agents have been shown to be highly effective in the relapse setting and now are being introduced as treatment earlier in the disease course.
This study aims to address in the randomised setting some of the key questions concerning the use of thalidomide, bortezomib, lenalidomide and vorinostat in the initial treatment of multiple myeloma patients.
Newly diagnosed patients of all ages with symptomatic myeloma requiring treatment are eligible.
For initial treatment, thalidomide in combination with cyclophosphamide and dexamethasone, the UK gold standard, will be compared with the newer combination of lenalidomide, cyclophosphamide and dexamethasone.
For patients with a sub-optimal response to initial therapy, the response to the proteasome inhibitor bortezomib will be assessed, as previous studies have demonstrated that it is able to induce responses and improve progression-free and overall survival in patients resistant to standard chemotherapy. Patients young and fit enough to tolerate an autologous transplant will then proceed to high dose melphalan with peripheral blood stem cell rescue and then on to maintenance randomisation. Older or less fit patients will go directly to a maintenance randomisation.
The value of lenalidomide and lenalidomide combined with vorinostat maintenance will then be assessed by randomising eligible patients to receive either lenalidomide, lenalidomide combined with vorinostat maintenance therapy, or close observation.
The primary end points of the study are overall and progression-free survival (OS and PFS). Secondary end points include response and toxicity.
A number of laboratory based studies will also be performed in order to determine patient specific factors predicting overall and progression-free survival and response to treatment.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Aged 18 years or greater
- Newly diagnosed as having symptomatic multiple myeloma or non-secretory multiple myeloma
- Provide written informed consent
- Women of childbearing potential and male patients whose partner is a woman of child bearing potential must be prepared to use contraception in accordance with (and consent to) the Celgene-approved process for thalidomide and lenalidomide Risk Management and Pregnancy Prevention, or commit to absolute and continuous abstinence
- Women of child bearing potential must have a negative pregnancy test performed by a healthcare professional in accordance with the Celgene-approved process for thalidomide and lenalidomide Risk Management and Pregnancy Prevention
Exclusion Criteria:
- Asymptomatic myeloma
- Solitary plasmacytoma of bone. (Patients with previous solitary plasmacytoma now progressed to symptomatic or non-secretory myeloma are eligible)
- Extramedullary plasmacytoma (without evidence of myeloma)
- Previous (<5 years since diagnosis) or concurrent active malignancies, except surgically-removed basal or squamous cell carcinoma of the skin, treated carcinoma in situ of the breast or cervix, or incidental histologic finding of prostate cancer (TMN stage of T1a or 1b). Patients with remote histories (>5 years) of other cured malignancies may be entered.
- Documented diagnosis of Myelodysplastic Syndrome (MDS) that meets International Prognostic Scoring System (IPSS) criteria for high-risk disease
- Previous treatment for myeloma, except the following:
local radiotherapy to relieve bone pain or spinal cord compression or prior bisphosphonate treatment or corticosteroids within the last 3 months
- Known history of allergy contributable to compounds containing boron or mannitol
- Grade 2 or greater (NCI criteria) peripheral neuropathy
- Caution is advised in patients with a past history of ischaemic heart disease, pericardial disease, acute diffuse infiltrative pulmonary disease or psychiatric disorders, evidence of impaired marrow function or elevated liver function tests, but exclusion is essentially to be at the discretion of the treating clinician
- Acute renal failure (unresponsive to up to 72 hours of rehydration, characterised by creatinine >500µmol/L or urine output <400 mL/day or requirement for dialysis)
- Lactating or breastfeeding
Contacts and Locations| Contact: Jacqueline Ouzman | 0113 343 4330 | j.ouzman@leeds.ac.uk |
| United Kingdom | |
| 135 sites UK wide | Recruiting |
| United Kingdom, United Kingdom | |
More Information
Additional Information:
No publications provided
| ClinicalTrials.gov Identifier: | NCT01554852 History of Changes |
| Other Study ID Numbers: | EudraCT number: 2009-010956-93 |
| Study First Received: | February 21, 2012 |
| Last Updated: | March 19, 2012 |
| Health Authority: | United Kingdom: Medicines and Healthcare Products Regulatory Agency |
Keywords provided by University of Leeds:
|
myeloma lenalidomide Revlimid cyclophosphamide dexamethasone |
bortezomib Velcade vorinostat Zolinza stem cell |
Additional relevant MeSH terms:
|
Multiple Myeloma Neoplasms, Plasma Cell Neoplasms by Histologic Type Neoplasms Hemostatic Disorders Vascular Diseases Cardiovascular Diseases Paraproteinemias Blood Protein Disorders Hematologic Diseases Hemorrhagic Disorders Lymphoproliferative Disorders Immunoproliferative Disorders Immune System Diseases Cyclophosphamide |
Thalidomide Vorinostat Bortezomib Lenalidomide Dexamethasone Dexamethasone acetate Dexamethasone 21-phosphate BB 1101 Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Pharmacologic Actions Antirheumatic Agents Therapeutic Uses Antineoplastic Agents, Alkylating |
ClinicalTrials.gov processed this record on May 22, 2013