Study of Bendamustine, Lenalidomide and Low-dose Dexamethasone, for the Treatment of Patients With Relapsed Myeloma

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2013 by Gruppo Italiano Studio Linfomi
Sponsor:
Information provided by (Responsible Party):
Gruppo Italiano Studio Linfomi
ClinicalTrials.gov Identifier:
NCT01686386
First received: July 31, 2012
Last updated: April 4, 2013
Last verified: April 2013
  Purpose

This is an open Label, Phase I/II, multicenter study. In the first phase it defines the maximum tolerated dose (MTD) of Bendamustine (B) given in combination with Lenalidomide (L) and low-dose Dexamethasone (d) and in the second phase it evaluates the antitumour activity of Bendamustine, Lenalidomide and Low-dose Dexamethasone (BdL) given in combination, in relapsed multiple myeloma patients.


Condition Intervention Phase
Multiple Myeloma
Drug: Bendamustine
Drug: Lenalidomide
Drug: Dexamethasone
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Bendamustine, Lenalidomide and Low-dose Dexamethasone, (BdL) for the Treatment of Patients With Relapsed Myeloma.

Resource links provided by NLM:


Further study details as provided by Gruppo Italiano Studio Linfomi:

Primary Outcome Measures:
  • Phase I:Determination of Maximum Tolerated Dose [ Time Frame: up to 28 days during first cycle ] [ Designated as safety issue: Yes ]
    In the first phase of the study, the dose of Bendamustine and Lenalidomide given with will be gradually escalated to reach the Maximum Tolerated Dose. The Maximum Tolerated Dose of Bendamustine and Lenalidomide will be evaluated during the first course (cycle 1) of Bendamustine Dexamethasone Lenalidomide (BdL) administered

  • Phase I:Determination of occurrence rate of AE/SAEs [ Time Frame: up to 28 day (during the first cycle 1of BdL administered) ] [ Designated as safety issue: Yes ]
    To assess the Safety and Toxicity of the Bendamustine,Dexamethasone and Lenalidomide (BdL) regimen

  • Phase II: Overall Response Rate (ORR) [ Time Frame: An avarage of 6 months (after 6 cycles of therapy) ] [ Designated as safety issue: No ]
    To assess the antitumour activity of the BdL regimen, in term of Complete response, Partial response and Stable disease, according to the best schedule identified during Phase I.


Secondary Outcome Measures:
  • Phase I: Assessment of the preliminary antineoplastic properties of the BdL [ Time Frame: after an avarage of 6 months ] [ Designated as safety issue: No ]
    To explore the preliminary antitumor activity of drug combination in patients with relapsed MM

  • Phase II: AE/SAEs [ Time Frame: Every 28 days (during all cycles) ] [ Designated as safety issue: Yes ]
    To define the safety profile of the treatment assessing the occurrence rate and the severity

  • Phase II:Determination of the response rates [ Time Frame: Assessed after 6 months ] [ Designated as safety issue: No ]
    To assess Partial Response and Complete Response rates

  • Phase II:Time to Event parameters [ Time Frame: avarage 6 months ] [ Designated as safety issue: No ]
    To evaluate the efficacy of the BdL regimen in patients with relapsed MM, in terms of Progression-Free Survival, Time to Progression, Time to Response, Duration of Response ,Overall Survival(PFS, TTP, TTR, DR, OS)


Estimated Enrollment: 60
Study Start Date: February 2010
Estimated Study Completion Date: October 2013
Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dose escalation benda lena dexa

Phase I: Participants will be treated in groups (cohorts) of three to six subjects per cohort, according to a modified Fibonacci design. The dose of Bendamustine and Lenalidomide (from 0 to 5) will be increased from one cohort to the next. Regardless of the treatment cohort, participants will receive treatment in cycles lasting 28 days. In the first phase of the study, the dose of B and L given with will be gradually escalated to reach the MTD.

Phase II: Dexamethasone will be given in combination with the MTD of Bendamustine and Lenalidomide in cycles lasting 28 days.

Drug: Bendamustine
Phase I: dose escalation of Bendamustine Phase II: Dexamethasone will be given in combination with the MTD of Bendamustine and Lenalidomide in cycles lasting 28 days.
Drug: Lenalidomide
Phase I: dose escalation of Lenalidomide Phase II: Dexamethasone will be given in combination with the Maximum Tolerated Dose (MTD) of Bendamustine and Lenalidomide in cycles lasting 28 days.
Drug: Dexamethasone
Phase I and Phase II Dexamethasone fixed dose 40 mg/die

Detailed Description:

Multiple myeloma is a B-cell malignancy resulting from the monoclonal proliferation of plasma cells within the bone marrow. According to the American Cancer Society, 14,600 new cases of multiple myeloma will be diagnosed in 2002, and these will account for approximately 1% of all new cancer cases. Multiple myeloma will contribute to 2% of all cancer deaths this year; an estimated 10,800 deaths will occur overall. The disease is more prevalent in men and is twice as common in African-Americans as in Caucasians. Multiple myeloma is commonly thought of as a disease of older patients; the median age at diagnosis is 68 years, and the incidence increases more than 4%/year in those older than 85 years. The median survival with standard treatment is only 3 years.

Therapeutic options for patients with multiple myeloma (MM) are rapidly changing. The emergence of two highly active novel agents, bortezomib and lenalidomide, have dramatically changed the landscape of treatment options and have improved outcomes for many patients. Combinations of conventional agents with novel agents have also demonstrated significant efficacy for patients with newly diagnosed and relapsed myeloma. Among the conventional agents that are being explored is the bifunctional alkylator agent bendamustine, which has demonstrated single-agent activity and activity with novel agents.

Lenalidomide is a new immunomodulating agent effective in multiple myeloma, especially when associated with dexamethasone or melphalan and prednisone. The role of lenalidomide in the treatment of relapsed/refractory patients with MM has been established and current research is focused on the combination of lenalidomide with chemotherapy to further improve results.

Bendamustine is a bi-functional alkylating agent with a purine- like benzimidazole ring that has been administered successfully to patients with MM. In vitro studies showed that bendamustine possesses a unique profile of activity, which was clearly divergent from other common nitrogen mustard drugs. Bendamustine and prednisone in newly diagnosed MM patients results in superior complete response rate, prolonged time to treatment failure and improved quality of life compared to treatment with melphalan and prednisone. The role of bendamustine, thalidomide and prednisolone (BPT) in patients with relapsed or refractory diseases stage II/III has been investigated by the East German Study group of Hematology and Oncology (OSHO). The response rate was higher than 80%.

Despite the impressive efficacy of the lenalidomide/dexamethasone in relapsed MM, treated patients will eventually relapse (median Time to Progression (TTP) is expected to be nearly a year according the results of the two phase III randomized studies). Combination with an effective novel agent as bendamustine could further increase both the response rate and the TTP of lenalidomide/dexamethasone and induce durable responses in relapsed or refractory MM patients. The identification of an appropriate lenalidomide dose to be adopted in combination with bendamustine and dexamethasone and the generation of exploratory data on the efficacy of this novel combination appears to be important in terms of future development of even more effective treatments of MM.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Voluntary written informed consent
  • Men and women age ≥ 18 years
  • Female subjects are either post-menopausal or surgically sterilized or willing to use 2 simultaneous methods of contraception
  • Male patients must agree to use a latex condom during sexual contact with females of childbearing potential throughout the study and for at least 28 days following discontinuation of lenalidomide;
  • Confirmed diagnosis of Multiple Myeloma with measurable disease .Patients with evidence of relapsed disease after more than 1 and equal but not more than 3 prior lines of therapy.
  • ECOG Performance Status 0 - 2
  • Required baseline haematology and chemistry parameters

Exclusion Criteria:

  • Myocardial infarction within 6 months prior to enrollment or has NYHA class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
  • Female subjects either pregnant or breast-feeding (negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result)
  • Patients have received other investigational drugs with 14 days before enrollment.
  • Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
  • Any of the following laboratory abnormalities:

Absolute neutrophil count (ANC) <1,000 /μl (1x109 /L) Untransfused platelet count < 50,0000cell/μl (50x109 /L) Serum SGOT/AST or SGPT/ALT > 2.0 upper limit of normal (ULN) Total bilirubin > 2.0 mg/dL Renal insufficiently (serum creatinine level > 2.5 mg/dl or Creatinine clearance < 30 mL/min calculated by Cockcroft-Gault estimation)

  • Patients with active infections are ineligible.
  • Patients who are HIV positive are ineligible.
  • Patients with active leptomeningeal involvement are ineligible.
  • Patients with a history of previous CSF tumor involvement without symptoms or signs are eligible provided the CSF is now free of disease on lumbar puncture, and MRI of the brain shows no tumor involvement.
  • History of other malignancies within 3 years prior to study entry except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer or breast, low grade, early stage localized prostate cancer treated surgically with curative intent (TNM stage of T1a or T1b),
  • Patients with uncontrolled insulin-dependent diabetes mellitus or uncompensated major thyroid or adrenal dysfunction are ineligible.
  • Patients with an ECOG performance status of > 2 are ineligible.
  • Malabsorption syndrome or uncontrolled gastrointestinal toxicities
  • Clinically significant pleural effusion in the previous 12 months or current ascitis
  • Clinically-significant coagulation or platelet function disorder
  • Intolerance to bendamustine and/or lenalidomide
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01686386

Contacts
Contact: Fortunato Morabito, MD +390984681329 fortunato_morabito@tin.it
Contact: Fortunato Morabito, MD +390984681539 fortunato_morabito@tin.it

Locations
Italy
U. O. C. Ematologia - Azienda Ospedaliera Cosenza Recruiting
Cosenza, Italy, 87100
Contact: Fortunato Morabito, MD    +390984681329    fortunato_morabito@tin.it   
Sponsors and Collaborators
Gruppo Italiano Studio Linfomi
Investigators
Study Chair: Fortunato Morabito, MD Unità Operativa Complessa di Ematologia- Stabilimento Ospedaliero Annunziata - Azienda Ospedaliera di Cosenza
  More Information

Publications:
Rummel MJ, von Gruenhagen U, Niederle N, et al: Bendamustine plus rituximab versus CHOP plus rituximab in the first-line treatment of patients with indolent and mantle-cell lymphomas: The first interim results of a randomized phase III study ofthe StiL (Study Group Indolent Lymphomas, Germany). Blood 110:120a, 2007 (abstr 385).

Responsible Party: Gruppo Italiano Studio Linfomi
ClinicalTrials.gov Identifier: NCT01686386     History of Changes
Other Study ID Numbers: RV-MM-GIMEMA/GISL430, 2010-018336-40
Study First Received: July 31, 2012
Last Updated: April 4, 2013
Health Authority: Italy: National Institute of Health
Italy: Ethics Committee

Keywords provided by Gruppo Italiano Studio Linfomi:
Relapsed
Multiple Myeloma
Lenalidomide
Bendamustine

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
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
Bendamustine
Lenalidomide
Nitrogen Mustard Compounds
Thalidomide
BB 1101
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents

ClinicalTrials.gov processed this record on July 23, 2014