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NCT01554852 Clinical Trial

Use of Thalidomide, Lenalidomide, Carfilzomib, Bortezomib and Vorinostat in the Initial Treatment of Newly Diagnosed Multiple Myeloma Patients

Multiple Myeloma Clinical Trial

— Myeloma XI  

Official title:
Randomised Comparisons, in Myeloma Patients of All Ages, of Thalidomide, Lenalidomide, Carfilzomib and Bortezomib Induction Combinations, and of Lenalidomide and Combination Lenalidomide Vorinostat as Maintenance (Myeloma XI)

Clinical Trial Details — Status: Active, not recruiting

Administrative data
NCT number NCT01554852
Other study ID # EudraCT number: 2009-010956-93
Secondary ID
Status Active, not recruiting
Phase Phase 3
First received
Last updated
Start date May 2010
Est. completion date December 2022

Study information
Verified date June 2018
Source University of Leeds
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

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 with or without carfilzomib.

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.

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, carfilzomib 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 with or without carfilzomib.

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.

Recruitment information / eligibility
Status Active, not recruiting
Enrollment 4420
Est. completion date December 2022
Est. primary completion date December 2021
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility 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

- 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

- Patient has active or prior hepatitis C

- 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

Study Design

Related Conditions & MeSH terms

Intervention

Drug:
• Induction (intensive pathway) - cyclophosphamide, lenalidomide, & dexamethasone (CRD) regimen
Days 1 & 8 - cyclophosphamide 500 mg PO Days 1-21 - lenalidomide 25 mg daily PO Days 1-4 & 12-15 - dexamethasone 40 mg daily PO This cycle is repeated every 28 days
• Induction (intensive pathway) - cyclophosphamide, thalidomide, & dexamethasone (CTD) regimen
Days 1,8,15 (i.e. weekly) - cyclophosphamide 500 mg PO Continuously - thalidomide 50 mg hard capsules. Initially 100 mg daily PO for 3 weeks, increasing to 200 mg daily PO Days 1-4 and 12-15 - dexamethasone 40 mg daily PO The cycle is repeated every 21 days
• Induction (intensive pathway) - carfilzomib, cyclophosphamide, lenalidomide, & dexamethasone (CCRD) regimen
Days 1 & 8 - cyclophosphamide 500 mg PO Days 1 & 2, 8 & 9, 15 & 16 - carfilzomib 20*/36 mg/m2** IV (*carfilzomib 20 mg/m2 is only administered on days 1 and 2 of cycle 1; **carfilzomib will be dose capped at a body surface area of 2.2 m2) Days 1-21 - lenalidomide 25 mg daily PO Days 1-4, 8, 9 & 15, 16 - dexamethasone 40 mg daily PO This cycle is repeated every 28 days
• Induction (non-intensive pathway) - cyclophosphamide, lenalidomide, & dexamethasone attenuated (CRDa) regimen
Days 1 & 8 - cyclophosphamide 500 mg PO Days 1-21 - lenalidomide 25 mg daily PO Days 1-4 & 15-18 - dexamethasone 20 mg daily PO This cycle is repeated every 28 days
• Induction (non-intensive pathway) - cyclophosphamide, thalidomide, & dexamethasone attenuated (CTDa) regimen
Days 1, 8, 15, 22 (weekly) - cyclophosphamide 500 mg PO Continuously - thalidomide 50 mg hard capsules; initially 50 mg daily PO for 4 weeks, increasing every 4 weeks by 50 mg increments to 200 mg daily PO Days 1-4 & 15-18 - dexamethasone 20 mg daily PO This cycle is repeated every 28 days
• Consolidation (intensive & non-intensive pathways) - bortezomib, cyclophosphamide, & dexamethasone (VCD) regimen
Days 1, 4, 8 & 11 - bortezomib 1.3 mg/m2 SC or IV Days 1, 8, 15 - cyclophosphamide 500 mg PO Days 1-2, 4-5, 8-9 & 11-12 - dexamethasone 20 mg daily PO This cycle is repeated every 21 days
• Maintenance (intensive & non-intensive pathways) - lenalidomide maintenance
Days 1-21 - lenalidomide 10 mg daily PO This cycle is repeated every 28 days
• Maintenance (intensive & non-intensive pathways - protocol v5.0 only) - lenalidomide plus vorinostat maintenance
Days 1-21 - lenalidomide 10 mg daily PO Days 1-7 & 15-21 - vorinostat 300mg PO This cycle is repeated every 28 days
• High dose melphalan therapy and autologous stem cell transplant (intensive pathway only)
High dose melphalan therapy and autologous stem cell transplant to be given as per local practice

Locations
Country Name City State
United Kingdom 112 sites UK wide United Kingdom

Sponsors (4)
Lead Sponsor Collaborator
University of Leeds Amgen, Celgene, Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

United Kingdom, 

Outcome
Type Measure Description Time frame Safety issue
Primary Overall survival Overall survival 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. Time from initial randomisation to the trial death from any cause or last follow-up
Primary Progression-free survival 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 time from initial randomisation to the trial to progression or death from any cause
Secondary Response Disease progression and response rates will be determined according to the modified International uniform response criteria for multiple myeloma Response will be determined according to the modified international uniform response criteria for multiple myeloma
Secondary Toxicity Toxicity will be reported based on adverse events, as graded by CTCAE V4.0 and determined by routine clinical assessments at each centre will be based on adverse events as graded by CTCAE v4.0
See also
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Terminated NCT03399448 - NY-ESO-1-redirected CRISPR (TCRendo and PD1) Edited T Cells (NYCE T Cells) Phase 1
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Active, not recruiting NCT05024045 - Study of Oral LOXO-338 in Patients With Advanced Blood Cancers Phase 1
Active, not recruiting NCT03989414 - A Study to Determine the Recommended Dose and Regimen and to Evaluate the Safety and Preliminary Efficacy of CC-92480 in Combination With Standard Treatments in Participants With Relapsed or Refractory Multiple Myeloma (RRMM) and Newly Diagnosed Multiple Myeloma (NDMM) Phase 1/Phase 2
Active, not recruiting NCT03792763 - Denosumab for High Risk SMM and SLiM CRAB Positive, Early Myeloma Patients Phase 2
Withdrawn NCT03608501 - A Study of Ixazomib, Thalidomide and Dexamethasone in Newly Diagnosed and Treatment-naive Multiple Myeloma (MM) Participants Non-eligible for Autologous Stem-cell Transplantation Phase 2
Recruiting NCT04537442 - Clinical Study to Evaluate the Safety and Efficacy of IM21 CAR-T Cells in the Treatment of Elderly Patients With Relapsed or Refractory Multiple Myeloma Phase 1
Completed NCT02546167 - CART-BCMA Cells for Multiple Myeloma Phase 1

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