Clinical trial NCT01042704: Bendamustine in Combination With Lenalidomide and Dexamethasone in Refractory or Relapsed Multiple Myeloma
Official title: Phase I Study of Bendamustine in Combination With Lenalidomide (CC-5013) and Dexamethasone in Patients With Refractory or Relapsed Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Myeloma
Keywords: Relapsed Myeloma
Refractory Myeloma
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Cephalon
First posted: 2010-01-05
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to see if the combination of bendamustine, lenalidomide and dexamethasone will help people with multiple myeloma that has returned after standard treatment or has been resistant to other treatments.


Eligibility criteria: Inclusion Criteria:

* Patients must have histologically or cytologically confirmed symptomatic Multiple Myeloma, Salmon-Durie Stage II or III or International Staging System II or III that has been previously treated with at least one cycle of a specific therapy; after which the patient has shown progressive or refractory disease, and must meet at least one of the following parameters of measurable disease:
* Bone marrow plasmacytosis with \> 10% plasma cells, or sheets of plasma cells, or biopsy proven plasmacytoma which must be obtained within 6 weeks prior to registration.
* Measurable levels of monoclonal protein (M protein): \> 1 g/dL of IgG or IgM M-protein or \> 0.5 g/dL IgA or IgD M protein on serum protein electrophoresis OR \> 200 mg of free light chain on a 24 hour urine protein electrophoresis which must be obtained within 4 weeks prior to registration OR \> 20 mg/dL involved free light chain on serum free light chain testing with an abnormal kappa:lambda light chain ratio. Note that if both serum and urine m-components are present, both must be followed in order to evaluate response. Both SPEP and UPEP must be performed within 28 days prior to registration.
* Patients with lytic bone disease, defined as at least one lytic lesion that can be accurately measured in at least one dimension.
* Patients must have received prior chemotherapy for their myeloma, but not in the last 4 weeks. Patients may have previously received autologous peripheral blood stem cell transplantation. Prior treatment with lenalidomide is allowed.
* Patients should not have received any radiation for the preceding 4 weeks before entry onto the study. Exception: local radiation therapy for symptomatic bone lesions (eg,uncontrolled pain or high risk of pathologic fracture)
* Age \>= 18 years
* Life expectancy of greater than 6 months.
* ECOG performance status \>=2 (Karnofsky \>=60%). Patients with PS of 3 are eligible if their PS is due to pain, which would likely improve with treatment.
* Patients must have normal organ and marrow function as defined below, obtained within 4 weeks prior to registration:

  * Hgb \> 9 g/dL (which may be supported by transfusion or growth factors)
  * leukocytes \>=2,000/ml
  * absolute neutrophil count ≥1000/ ml
  * platelets \>=75,000/mcL
  * total bilirubin \>=2.5 mg/dl
  * AST(SGOT)/ALT(SGPT) \>=5 X institutional upper limit of normal
  * creatinine \<2.5 mg/dl
* Patients must not be pregnant or breast feeding. Due to the potential teratogenic properties of lenalidomide, the use of this drug in patients that are pregnant is absolutely contraindicated. Further, all women of childbearing potential and sexually active males must agree to avoid conception while participating in this study. Specifically, women of childbearing potential must either agree to refrain from sexual intercourse or employ a dual method of contraception, one of which is highly effective (IUD, birth control pills, tubal ligation or partners vasectomy), and another additional method (condom, diaphragm, or cervical cap) for 4 weeks prior to receiving lenalidomide, and for four weeks after discontinuing this therapy. Sexually active males cannot participate unless they agree to use a condom (even if they have undergone a prior vasectomy) while having intercourse with a woman of child bearing potential while taking lenalidomide and for four weeks after stopping treatment. Women of child bearing potential (those who have not had a hysterectomy or the absence of menstrual periods for at least 24 consecutive months) must have a negative pregnancy test 10-14 days prior to the initiation of therapy and a repeat negative pregnancy test 24 hours prior to the initiation of lenalidomide.
* Ability to understand and the willingness to sign a written informed consent document. Patient must be informed of the investigational nature of this study.

Exclusion Criteria:

* Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Exception: local radiation therapy for symptomatic bone lesions (eg, uncontrolled pain or high risk of pathologic fracture)
* Patients receiving any other investigational agents.
* Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
* Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to lenalidomide and/or Bendamustine or other agents used in the study.
* Patients with a second malignancy other than squamous/basal cell carcinoma of the skin or in situ carcinoma of the cervix unless the tumor was curatively treated at least two years previously.
* Inability to comply with study and/or follow-up procedures.
* If a patient is on full-dose anticoagulants, the following criteria should be met for enrollment:

  * Must not have active bleeding or pathological conditions that carry high risk of bleeding (e.g. tumor involving major vessels, known varices).
  * Must have a platelet count \>75,000.
  * Must have stable INR between 2-3.
* Patients who have not collected hematopoietic progenitors and are potential candidates for autologous transplantation .
* Patients that have a serious cardiac condition, such as myocardial infarction within 6 months or heart disease as defined by the New York Heart Association Class III or IV,
* Patients with prior allogeneic stem cell transplant.
* Non-secretory patients (i.e., patients who do not meet the minimum M-protein or light chain criteria)

Primary outcomes:
measure: To establish the dose of each drug recommended for a future Phase II protocol with the combination
timeFrame: 1 year
Secondary outcomes:
measure: To explore anti-tumor activity of the combination of Bendamustine plus Lenalidomide and dexamethasone
timeFrame: 2.5 years
measure: Toxicity, time to progression, overall survival.
timeFrame: 2.5 years
Other outcomes:
Locations:
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Steubenville
country: United States
facility: UPMC Cancer Centers - Teramana Cancer Center
state: Ohio
city: Beaver
country: United States
facility: UPMC Cancer Centers - Beaver
state: Pennsylvania
city: Clairton
country: United States
facility: UPMC Cancer Centers - Jefferson
state: Pennsylvania
city: Greensburg
country: United States
facility: UPMC Cancer Centers - Arnold Palmer at Mountain View
state: Pennsylvania
city: Greensburg
country: United States
facility: UPMC Cancer Centers - Arnold Palmer at Oakbrook
state: Pennsylvania
city: Indiana
country: United States
facility: UPMC Cancer Centers - Indiana
state: Pennsylvania
city: Johnstown
country: United States
facility: UPMC Cancer Centers - Johnstown
state: Pennsylvania
city: McKeesport
country: United States
facility: Hematology-Oncology Associates of UPCI
state: Pennsylvania
city: McKeesport
country: United States
facility: Hematology/Oncology - Private Practice
state: Pennsylvania
city: Monroeville
country: United States
facility: UPMC Cancer Centers - Monroeville
state: Pennsylvania
city: Mount Pleasant
country: United States
facility: UPMC Cancer Centers - Arnold Palmer at Mt. Pleasant
state: Pennsylvania
city: New Castle
country: United States
facility: UPMC Cancer Centers - New Castle
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Cancer Centers - St. Margaret's
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Cancer Centers - Hillman Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Cancer Centers - Passavant
state: Pennsylvania
city: Pittsburgh
country: United States
facility: VA Healthcare System - 646
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Cancer Centers - Drake
state: Pennsylvania
city: Uniontown
country: United States
facility: UPMC Cancer Centers - Uniontown
state: Pennsylvania
city: Washington
country: United States
facility: UPMC Cancer Centers - Washington
state: Pennsylvania
city: Wexford
country: United States
facility: UPMC Cancer Centers - North Hills
state: Pennsylvania
city: Windber
country: United States
facility: UPMC Cancer Centers - Windber
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh Physicians, Hematology/Oncology
name: Robert L Redner, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
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 Francais du Myelome. N Engl J Med. 1996 Jul 11;335(2):91-7. doi: 10.1056/NEJM199607113350204.
citation: Londono F. Thalidomide in the treatment of actinic prurigo. Int J Dermatol. 1973 Sep-Oct;12(5):326-8. doi: 10.1111/j.1365-4362.1973.tb00066.x. No abstract available.
citation: Vogelsang GB, Farmer ER, Hess AD, Altamonte V, Beschorner WE, Jabs DA, Corio RL, Levin LS, Colvin OM, Wingard JR, et al. Thalidomide for the treatment of chronic graft-versus-host disease. N Engl J Med. 1992 Apr 16;326(16):1055-8. doi: 10.1056/NEJM199204163261604.
citation: Hayashi T, Hideshima T, Akiyama M, Podar K, Yasui H, Raje N, Kumar S, Chauhan D, Treon SP, Richardson P, Anderson KC. Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application. Br J Haematol. 2005 Jan;128(2):192-203. doi: 10.1111/j.1365-2141.2004.05286.x.
citation: Strasser K, Ludwig H. Thalidomide treatment in multiple myeloma. Blood Rev. 2002 Dec;16(4):207-15. doi: 10.1016/s0268-960x(02)00031-0.
citation: Tohnya TM, Figg WD. Immunomodulation of multiple myeloma. Cancer Biol Ther. 2004 Nov;3(11):1060-1. doi: 10.4161/cbt.3.11.1303. Epub 2004 Nov 12.
citation: Lentzsch S, LeBlanc R, Podar K, Davies F, Lin B, Hideshima T, Catley L, Stirling DI, Anderson KC. Immunomodulatory analogs of thalidomide inhibit growth of Hs Sultan cells and angiogenesis in vivo. Leukemia. 2003 Jan;17(1):41-4. doi: 10.1038/sj.leu.2402745.
citation: Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999 Nov 18;341(21):1565-71. doi: 10.1056/NEJM199911183412102.
citation: Anagnostopoulos A, Weber D, Rankin K, Delasalle K, Alexanian R. Thalidomide and dexamethasone for resistant multiple myeloma. Br J Haematol. 2003 Jun;121(5):768-71. doi: 10.1046/j.1365-2141.2003.04345.x.
citation: Podar K, Anderson KC. The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood. 2005 Feb 15;105(4):1383-95. doi: 10.1182/blood-2004-07-2909. Epub 2004 Oct 7.
citation: Palumbo A, Bertola A, Musto P, Caravita T, Callea V, Nunzi M, Grasso M, Falco P, Cangialosi C, Boccadoro M. Oral melphalan, prednisone, and thalidomide for newly diagnosed patients with myeloma. Cancer. 2005 Oct 1;104(7):1428-33. doi: 10.1002/cncr.21342.
citation: Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, LeBlanc R, Catley LP, Doss D, Kelly K, McKenney M, Mechlowicz J, Freeman A, Deocampo R, Rich R, Ryoo JJ, Chauhan D, Balinski K, Zeldis J, Anderson KC. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002 Nov 1;100(9):3063-7. doi: 10.1182/blood-2002-03-0996.
citation: Zangari M, Tricot G, Zeldis J, Eddlemon P, Saghafifar F, Barlogie B. Results of phase I study of CC-5013 for the treatment of multiple myeloma (MM) patients who relapse after high dose chemotherapy (HDCT). Blood. 2001 :775a (A3226).
citation: Richardson P, Jagannath 5, Schlossman R, eta!. A multi-center, randomized, phase 2 study to evaluate the efficacy and safety of 2 CC-5013 dose regimens when used alone or in combination with dexamethasone (Dex) for the treatment of relapsed or refractory multiple myeloma (MM). Blood. 2003;1 02:235a.
citation: Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, Lin B, Podar K, Gupta D, Chauhan D, Treon SP, Richardson PG, Schlossman RL, Morgan GJ, Muller GW, Stirling DI, Anderson KC. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood. 2001 Jul 1;98(1):210-6. doi: 10.1182/blood.v98.1.210.
citation: Hideshima T, Chauhan D, Podar K, Schlossman RL, Richardson P, Anderson KC. Novel therapies targeting the myeloma cell and its bone marrow microenvironment. Semin Oncol. 2001 Dec;28(6):607-12. doi: 10.1016/s0093-7754(01)90033-8.
citation: Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai YT, Treon SP, Lin B, Schlossman RL, Richardson P, Muller G, Stirling DI, Anderson KC. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood. 2000 Nov 1;96(9):2943-50.
citation: Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T, Munshi NC, Treon SP, Anderson KC. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood. 2002 Jun 15;99(12):4525-30. doi: 10.1182/blood.v99.12.4525.
citation: Dimopoulos MA, Spencer A, Attal M, a!. e. Study of lenalidomide plus dexamethasone versus dexamethasone alone in relapsed or refractory multiple myeloma (MM); results of a phase 3 study (MM-01 0). Blood. 2005:106:1 06a (abstract).
citation: Weber DM, Chen D, Niesvizky R, et al. Lenalidomide plus high-dose dexamethasone provides improved overall survival compared to high-dose dexamethasone alone for relapsed or refractory multiple myeloma (MM): results of a North American phase Ill study (MM-009). Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings. 2006;24(1 8S):Abstract #7521.
citation: Schrijvers D, Vermorken JB. Phase I studies with bendamustine: an update. Semin Oncol. 2002 Aug;29(4 Suppl 13):15-8. doi: 10.1053/sonc.2002.34874.
citation: Ponisch W, Mitrou PS, Merkle K, Herold M, Assmann M, Wilhelm G, Dachselt K, Richter P, Schirmer V, Schulze A, Subert R, Harksel B, Grobe N, Stelzer E, Schulze M, Bittrich A, Freund M, Pasold R, Friedrich T, Helbig W, Niederwieser D; East German Study Group of Hematology and Oncology (OSHO). Treatment of bendamustine and prednisone in patients with newly diagnosed multiple myeloma results in superior complete response rate, prolonged time to treatment failure and improved quality of life compared to treatment with melphalan and prednisone--a randomized phase III study of the East German Study Group of Hematology and Oncology (OSHO). J Cancer Res Clin Oncol. 2006 Apr;132(4):205-12. doi: 10.1007/s00432-005-0074-4. Epub 2006 Jan 10.
citation: Ponisch W, Rozanski M, Goldschmidt H, Hoffmann FA, Boldt T, Schwarzer A, Ritter U, Rohrberg R, Schwalbe E, Uhlig J, Zehrfeld T, Schirmer V, Haas A, Kreibich U, Niederwieser D; East German Study Group of Haematology and Oncology (OSHO). Combined bendamustine, prednisolone and thalidomide for refractory or relapsed multiple myeloma after autologous stem-cell transplantation or conventional chemotherapy: results of a Phase I clinical trial. Br J Haematol. 2008 Oct;143(2):191-200. doi: 10.1111/j.1365-2141.2008.07076.x. Epub 2008 Aug 24.
citation: Balfour JA, Goa KL. Bendamustine. Drugs. 2001;61(5):631-8; discussion 639-40. doi: 10.2165/00003495-200161050-00009.
citation: Blade J, Samson D, Reece D, Apperley J, Bjorkstrand 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. doi: 10.1046/j.1365-2141.1998.00930.x. No abstract available.
citation: Hrusovsky I, Heidtmann H, (ASH Annual Meeting Abstracts) Blood 2005 106:abstract 5122
citation: Lentzsch S, O'Sullivan A, Kennedy RC, Abbas M, Dai L, Pregja SL, Burt S, Boyiadzis M, Roodman GD, Mapara MY, Agha M, Waas J, Shuai Y, Normolle D, Zonder JA. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood. 2012 May 17;119(20):4608-13. doi: 10.1182/blood-2011-12-395715. Epub 2012 Mar 26.