Velcade-Melphalan-Prednisone in Older Untreated Multiple Myeloma Patients.

Multiple Myeloma Clinical Trial

Official title:

A National, Multi-Center, Open-Label Study of Velcade in Combination With Melphalan and Prednisone (V-MP) in Older Untreated Multiple Myeloma Patients.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00388635
• Other study ID #: PET-VEL-2004-01
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: October 16, 2006
• Last updated: January 8, 2011
• Start date: April 2004
• Est. completion date: December 2008

Study information

• Verified date: January 2011
• Source: PETHEMA Foundation
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

This protocol is planned as a multicentric, national, open-label trial designed to evaluate, first, optimal dose of Velcade® (Bortezomib) in combination with melphalan and prednisone. After optimal dose is known, the second aim is evaluate safety and tolerance of V-MP plan, in respond terms, in a cohort of 60 patients. Finally, the entire results will be compared with those obtained from a series of 100 patients, all of them over 70 years old, diagnosed of Multiple Myeloma belonging to the GEM protocol finished in May 2003

Description:

Multiple Myeloma is a neoplastic disorder of the last maturation stage of B cell, called plasmatic cell. It represents the second most common haematological neoplasia, after Non Hodgkin Lymphoma. The annual incidence is over 4 cases per 100.000. Multiple Myeloma is an invariably mortal disease. When illness advances, the reduction of infections resistance, the intense bones destruction (with bone pain, pathological fractures and hypercalcemia), anaemia, renal failure and, in a less frequency, neurological complications and hyperviscosity provoke severe morbidity and mortality. Five-year survival rate in patients with Multiple Myeloma treated with conventional chemotherapy is 29%. There is an urgent need of new therapeutic agents for the treatment of this disease

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: December 2008
• Est. primary completion date: January 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 65 Years and older

Eligibility

Inclusion Criteria:

• Patient is, in the investigator's opinion, willing and able to comply with the protocol requirements.

• Patient has given voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.

• Age over 65 years.

• Patient recently diagnosed with symptomatic Multiple Myeloma based on standard criteria and that has not received any previous chemotherapy treatment for Multiple Myeloma.

• Patient has measurable disease, defined as follows:

For secretory multiple myeloma, measurable disease is defined as any quantifiable serum monoclonal protein value and, where applicable, urine light-chain excretion of = 200 mg/24 hours.

For oligo or non-secretory multiple myeloma, measurable disease is defined by the presence of soft tissue (not bone) plasmacytomas as determined by clinical examination or applicable radiographs (i.e. MRI, CT-Scan). In patients with oligo-secretory multiple myeloma, the serum and/or urine M-protein measurements are very low and difficult to follow for response assessment. In patients with non-secretory multiple myeloma, there is no M-protein in serum or urine.

• Patient has a Karnofsky performance status higher 60%.

• Patient has a life-expectancy >3 months.

• Patient has the following laboratory values within 14 days before Baseline visit (Day 1 of Cycle 1, before study drug administration:

Platelet count = 100x109/L, hemoglobin = 8 g/dl and absolute neutrophil count (ANC) = 1.0x109/L.

Corrected serum calcium < 14mg/dl. Aspartate transaminase (AST): = 2.5 x the upper limit of normal. Alanine transaminase (ALT): ): = 2.5 x the upper limit of normal. Total bilirubin: =1.5 x the upper limit of normal. Serum creatinine value = 2mg/dl.

Exclusion Criteria:

• Patient previously received treatment with Velcade.

• Patient previously received treatment for Multiple Myeloma.

• Patient had major surgery within 4 weeks before enrollment.

• Patient has a platelet count < 100 x 109/L within 14 days before enrollment.

• Patient has an absolute neutrophil count < 1.0 x 109/L within 14 days before.

• Patient has < Grade 2 peripheral neuropathy within 14 days before enrollment.

• Patient has hypersensitivity to bortezomib, boron or mannitol.

• Patient has received other investigational drugs within 14 days before enrollment.

• Patient is known to be seropositive for the human immunodeficiency virus (HIV), Hepatitis B surface antigen-positive or active hepatitis C infection.

• Patient had a myocardial infarction within 6 months of enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.

Patient is enrolled in another clinical research study and/or is receiving an investigational agent for any reason.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Velcade
Phase I: Velcade, 1.0mg/m2-1.3mg/m2 in escalating doses every 6 weeks for 4 cycles Pase II: Velcade at optimal doses, twice a week (days 1, 4, 8, 11, 22, 25, 28 and 32) follow a rest period for 10 days (days 33 to 42)
• Melphalan
Melfalán 9mg/m2 days 1 to 4, V.O, follow by a rest period of 38 days in phse I and II
• Prednisone
Prednisone 60mg/m2 v.o days 1 to 4 follows by a rest period of 38 days (phase I and II)

Locations

Country	Name	City	State
Spain	Hospital Clínic	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Germans Trias i Pujol	Barcelona
Spain	Hospital Virgen Blanca de León	Leon
Spain	Hospital Clínico San Carlos de Madrid	Madrid
Spain	Hospital Doce de Octubre	Madrid
Spain	Hospital Ramón y Cajal	Madrid
Spain	Hospital Universitario de la Princesa	Madrid
Spain	Hospital Morales Messeguer	Murcia
Spain	Hospital Central de Asturias	Oviedo	Asturias
Spain	Hospital Son Llatzer	Palma de Mallorca	Mallorca
Spain	Clínica Universitaria de Navarra	Pamplona	Navarra
Spain	Hospital Clínico Universitario de Salamanca	Salamanca
Spain	Hospital General de Segovia	Segovia
Spain	Hospital Universitario de Canarias	Tenerife	Islas Canarias
Spain	Hospital Clínic	Valencia
Spain	Hospital La Fe	Valencia
Spain	Hospital Universitario Dr. Peset	Valencia
Spain	Hospital Clínico Lozano Blesa	Zaragoza

Sponsors (3)

Lead Sponsor	Collaborator
PETHEMA Foundation	Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Millennium Pharmaceuticals, Inc.

Country where clinical trial is conducted

Spain, 

References & Publications (32)

2. Longo D. Plasma cell disorders. In : Fauce A, et al. Ed. Harrison's Principles of Internal Medicine. 14th Ed. New York, New York: Mc Graw-Hill; 1998: 712-718

26. McConkey DJ, Pettaway C, Elliott P, et al. The proteasome as a new drug target in metastatic prostate cancer. ATMDACC 7th Annual Genitourinary Oncology Conference, 1998

28. Millenium Pharmaceuticals, Inc. (PS-341) Investigator's Brochure, Version 5.0, 2001

Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S, Elliott PJ. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 1999 Jun 1;59(11):2615-22. — View Citation

Alexanian R, Barlogie B, Tucker S. VAD-based regimens as primary treatment for multiple myeloma. Am J Hematol. 1990 Feb;33(2):86-9. — View Citation

Alexanian R, Dimopoulos M. The treatment of multiple myeloma. N Engl J Med. 1994 Feb 17;330(7):484-9. Review. — View Citation

Alexanian R, Dimopoulos MA, Delasalle K, Barlogie B. Primary dexamethasone treatment of multiple myeloma. Blood. 1992 Aug 15;80(4):887-90. — View Citation

Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med. 1996 Jul 11;335(2):91-7. — View Citation

Baldwin AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest. 2001 Feb;107(3):241-6. Review. — View Citation

Bataille R, Harousseau JL. Multiple myeloma. N Engl J Med. 1997 Jun 5;336(23):1657-64. Review. — View Citation

Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science. 1996 Nov 1;274(5288):782-4. — View Citation

Bladé J, Samson D, Reece D, Apperley J, Björkstrand B, Gahrton G, Gertz M, Giralt S, Jagannath S, Vesole D. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998 Sep;102(5):1115-23. — View Citation

Case DC Jr, Lee DJ 3rd, Clarkson BD. Improved survival times in multiple myeloma treated with melphalan, prednisone, cyclophosphamide, vincristine and BCNU: M-2 protocol. Am J Med. 1977 Dec;63(6):897-903. — View Citation

Driscoll J. The role of the proteasome in cellular protein degradation. Histol Histopathol. 1994 Jan;9(1):197-202. Review. — View Citation

Goldberg AL, Stein R, Adams J. New insights into proteasome function: from archaebacteria to drug development. Chem Biol. 1995 Aug;2(8):503-8. Review. — View Citation

Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin. 2000 Jan-Feb;50(1):7-33. — View Citation

Gregory WM, Richards MA, Malpas JS. Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: an overview of published trials. J Clin Oncol. 1992 Feb;10(2):334-42. — View Citation

Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, Anderson KC. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 2001 Apr 1;61(7):3071-6. — View Citation

Huang YW, Hamilton A, Arnuk OJ, Chaftari P, Chemaly R. Current drug therapy for multiple myeloma. Drugs. 1999 Apr;57(4):485-506. Review. — View Citation

Koepp DM, Harper JW, Elledge SJ. How the cyclin became a cyclin: regulated proteolysis in the cell cycle. Cell. 1999 May 14;97(4):431-4. Review. — View Citation

Mileshkin L, Biagi JJ, Mitchell P, Underhill C, Grigg A, Bell R, McKendrick J, Briggs P, Seymour JF, Lillie K, Smith JG, Zeldis JB, Prince HM. Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age. Blood. 2003 Jul 1;102(1):69-77. Epub 2003 Mar 13. — View Citation

Oken MM. Management of Myeloma: Current and Future Approaches. Cancer Control. 1998 May;5(3):218-225. — View Citation

Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994 Sep 9;78(5):773-85. — View Citation

Raje N, Anderson K. Thalidomide--a revival story. N Engl J Med. 1999 Nov 18;341(21):1606-9. — View Citation

Read MA, Neish AS, Luscinskas FW, Palombella VJ, Maniatis T, Collins T. The proteasome pathway is required for cytokine-induced endothelial-leukocyte adhesion molecule expression. Immunity. 1995 May;2(5):493-506. — View Citation

Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003 Jun 26;348(26):2609-17. — View Citation

Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006 Nov 15;108(10):3458-64. Epub 2006 Jul 13. — View Citation

Richter-Ruoff B, Wolf DH. Proteasome and cell cycle. Evidence for a regulatory role of the protease on mitotic cyclins in yeast. FEBS Lett. 1993 Dec 20;336(1):34-6. — View Citation

Sherr CJ. Cancer cell cycles. Science. 1996 Dec 6;274(5293):1672-7. Review. — View Citation

Smith ML, Newland AC. Treatment of myeloma. QJM. 1999 Jan;92(1):11-4. Review. — View Citation

Westin J. Conventional chemotherapy in multiple myeloma. Pathol Biol (Paris). 1999 Feb;47(2):169-71. — View Citation

Zetter BR. Adhesion molecules in tumor metastasis. Semin Cancer Biol. 1993 Aug;4(4):219-29. Review. — View Citation

* Note: There are 32 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Determinate the efficacy of combination velcade, melphalan, prednisone		1 year	No
Secondary	Assess safety and tolerability		1 year	Yes
Secondary	Assess potential superiority of this regimen versus historical controls with melphalan and prednisone alone		2 years	No
Secondary	Evaluate efficacy in terms of progression-free survival and overall survival		5 years	No

External Links

•   Pethema Foundation web
•   Spanish association of Haematology