Chlorambucil + Lenalidomide and Lenalidomide Maintenance in Untreated Elderly With Chronic Lymphocytic Leukemia (CLL)

This study is currently recruiting participants.
Verified November 2013 by Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor:
Information provided by (Responsible Party):
Gruppo Italiano Malattie EMatologiche dell'Adulto
ClinicalTrials.gov Identifier:
NCT01403246
First received: January 13, 2011
Last updated: November 26, 2013
Last verified: November 2013
  Purpose

This is a phase I-II multicenter, open label study in previously untreated and elderly patients (> 60 years) with CLL ,which includes 2 sections:

Induction phase with Chlorambucil and Lenalidomide (CL):

  • Phase 1: a non-comparative phase aimed at defining the MTD of lenalidomide given in combination with chlorambucil and the efficacy and safety of the lenalidomide and chlorambucil combination;
  • Phase 2: a non-comparative phase aimed at defining the overall response rate of lenalidomide given at the MTD in combination with chlorambucil.

Maintenance versus clinical observation:

-A comparative phase including lenalidomide or clinical observation aimed at defining the benefit of lenalidomide given as maintenance therapy.


Condition Intervention Phase
Chronic Lymphocytic Leukemia
Drug: Lenalidomide; Chlorambucil
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Official Title: Phase I-II Multicenter Study to Assess the Efficacy and Safety of the Chlorambucil + Lenalidomide Combination and Lenalidomide Maintenance Therapy in Untreated Elderly Pts With CLL. EudraCT Number 2009-013415-35

Resource links provided by NLM:


Further study details as provided by Gruppo Italiano Malattie EMatologiche dell'Adulto:

Primary Outcome Measures:
  • PhI: MTD of Lenalidomide given in combination with Chlorambucil. [ Time Frame: At maximum 8 months from induction therapy start ] [ Designated as safety issue: Yes ]
    PhI: MTD will be identified according to all adverse events and DLTs tabulated for each dose level.

  • PhII: To evaluate the overall response rate of an induction therapy consisting of Lenalidomide given at the MTD in combination with Chlorambucil. [ Time Frame: At the end of the study. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Lenalidomide and chlorambucil induction therapy in terms of safety; [ Time Frame: After 20 months therapy and 18-60 months follow-up ] [ Designated as safety issue: Yes ]
    Induction phase with chlorambucil and Lenalidomide in terms of safety [type, frequency, and severity of adverse events (AEs)].

  • Post-remissional phase with Lenalidomide in terms of safety [ Time Frame: After 20 months therapy and 18-60 months follow-up ] [ Designated as safety issue: Yes ]
    type, frequency, and severity of adverse events (AEs)

  • Lenalidomide maintenance efficacy in terms of CR rate. [ Time Frame: After 20 months therapy and 18-60 months follow-up ] [ Designated as safety issue: No ]
  • Progression free survival estimation according to the post-remissional approach. lenalidomide maintenance therapy or clinical observation. [ Time Frame: After 20 months therapy and 18-60 months follow-up starting from date of randomization in the maintenance therapy. ] [ Designated as safety issue: No ]
  • Association between the response and the baseline biologic factors (IgVH, p53, FISH, ZAP-70, CD38) [ Time Frame: After 20 months therapy and 18-60 months follow-up ] [ Designated as safety issue: No ]
  • Progression free survival estimation according to the baseline biologic factors starting from the date of first dose of study drug in the induction phase. [ Time Frame: After 20 months therapy and 18-60 months follow-up ] [ Designated as safety issue: No ]
  • Time to a new CLL treatment or death estimation. [ Time Frame: an estimation of 40 months. ] [ Designated as safety issue: No ]
  • Overall survival estimation [ Time Frame: an estimation of 40 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 89
Study Start Date: November 2011
Estimated Study Completion Date: January 2014
Estimated Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Lenalidomide; Chlorambucil
    MTD of lenalidomide given in combination with chlorambucil
Detailed Description:

All patients will receive six monthly courses of the chlorambucil (C) and lenalidomide (L) schedule consisting of 8 days of C (d1-d8) combined with L given daily until response assessment which will take place 12 weeks from the start (d+1) of course VI, while patients continue their treatment with lenalidomide daily.

In the first phase of the induction phase of the study the dose of L given with C will be gradually escalated to reach the MTD. In the second phase of the induction phase, C will be given in combination with the Maximum Tolerated Dose of L (either the MTD or the maximum planned dose of 10mg).

Patients who will achieve a response after 6 courses of CL induction phase -PR, CRi, CR and MRD negative CR- will be eligible for the post-induction phase of the study. Patients will be randomized (1:1), stratifying according to the quality of response (PR vs CR, CRi, MRD-CR) and the genetic profile (11q, 17p-, p53mut vs other), to receive L daily, (L arm) or no further therapy (Clinical observation arm) until day 364 or until PD or unacceptable toxicity develops, whichever occurs first. During maintenance (L arm), L will be given at the dose tolerated by the patient during the period interval from d+28 of the 6th course of CL and the day of evaluation of the response (d+84 from the start of 6th course of CL). At screening, blood samples will be drawn and a physical examination, a CT scan or a thorax radiography and an abdomen ultrasound, a bone marrow biopsy and aspirate will be performed. A clinical examination will be carried out and blood samples will be harvested weekly during CL treatment. Twelve weeks from the start (d+1) of 6th CL course (d+84), clinical response will be assessed. During the post-remissional phase, a monthly clinical examination will be performed in all patients. Patients randomized to receive L as maintenance therapy will have an additional blood examination during treatment. Eight weeks after the completion of the post-remissional phase (d+420), a new response assessment will be performed (physical examination and blood samples, a CT scan or a thorax radiography and an abdomen ultrasound, a bone marrow biopsy and aspirate). Thereafter, patients will be monitored for response duration at least over the following 18 months.

  Eligibility

Ages Eligible for Study:   60 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • CLL diagnosis according to the 2008 revised NCI criteria.
  • Age > 65 years or between 60 and 65 years if not suitable for fludarabine-based regimens according to the investigator's judgment.
  • ECOG performance status of ≤2 at study entry.
  • No previous treatment.
  • Advanced stage or progressive CLL according to the 2008 revised NCI criteria.
  • Disease-free of prior malignancies other than CLL for ≥3 years, with the exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast.
  • Able to take low molecular weight heparin or in alternative, low-fixed-dose warfarin or, in alternative, low-dose aspirin.
  • Able to adhere to the study visit schedule and other protocol requirements.
  • Female subjects of childbearing potential(FCBP) must:

    • Understands the potential teratogenic risk to the unborn child and the need for effective contraception;
    • Be capable of complying with effective contraceptive measures.
    • Be informed and understand the potential consequences of pregnancy and the need to notify her study doctor immediately if there is a risk of pregnancy.
    • Understand the need to commence the study treatment as soon as study drug is dispensed following a negative pregnancy test.
    • Uderstand the need and accepts to undergo pregnancy testing based on the frequency outlined in this protocol.
    • Contraception.
    • Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual contact during the following time periods related to this study: 1) for at least 28 days before starting study drug; 2) while participating in the study; 3) dose interruptions; and 4) for at least 28 days after study treatment discontinuation.
    • The two methods of reliable contraception must include one highly effective method and one additional effective (barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if needed. The following are examples of highly effective and additional effective methods of contraception:
    • Highly effective methods:

      1. Intrauterine device (IUD)
      2. Hormonal (birth control pills, injections, implants)
      3. Tubal ligation
      4. Partner's vasectomy
    • Additional effective methods:

      1. Male condom
      2. Diaphragm
      3. Cervical Cap
  • Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are not recommended. If a patient is currently using combined oral contraception the patient should switch to one of the effective method listed above. The risk of venous thromboembolism continues for 4 to 6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive steroids may be reduced during co-treatment with dexamethasone.
  • Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered particularly in patients with neutropenia.
  • Pregnancy testing.
  • FCBP must have two negative pregnancy tests prior to starting study drug. The first pregnancy test must be performed within 10 to 14 days prior to the start of study drug and the second pregnancy test must be performed within 24 hours prior to the start of study drug.
  • FCBP must agree to have a medically supervised pregnancy test every 4 weeks including 4 weeks after the end of study treatment, except in the case of confirmed tubal sterilization. This requirement also applies to women of childbearing potential who practice complete and continued abstinence.
  • Females must agree to abstain from breastfeeding during study participation and for at least 28 days after study drug discontinuation.
  • Male patients must:

    • Understand the potential teratogenic risk if engaged in sexual activity with a pregnant female or a female of childbearing potential.
    • Must practice complete abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 28 days following study drug discontinuation, even if he has undergone a successful vasectomy.
    • If pregnancy or a positive pregnancy test does occur in the partner of a male study patient during study participation, the investigator must be notified immediately.
  • Female and male patients:

    • should be instructed never to give this medicinal product to another person and to return any unused capsules to the study doctor at the end of treatment.
    • Should not donate blood during therapy and for at least 28 days following discontinuation of study drug.
    • Male patients should not donate blood, semen or sperm during therapy or for at least 28 days following discontinuation of study drug.
  • Laboratory test results within these ranges:

    • Serum creatinine ≤1.5 mg/dL and creatinine clearance ≥ 60mL/min
    • Total bilirubin ≤1.5 mg/dL
  • AST (SGOT) and ALT (SGPT) ≤1.5 x ULN.
  • All patients must be able to understand and voluntarily sign the informed consent form.

Exclusion criteria:

  • Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
  • A CIRS score > 6.
  • Pregnant or Lactating Females.
  • Known positive serology for HIV or active hepatitis B or C.
  • Active infection requiring systemic anti-viral, antibiotic or anti-fungal therapy.
  • History of tuberculosis within the last five years or recent exposure to tuberculosis equal to or less than 6 months.
  • History of renal failure requiring dialysis.
  • Known presence of alcohol and/or drug abuse.
  • History of thrombosis, thromboembolism within one year.
  • Hearth failure, arrhythmia.
  • ≥ grade 2 neuropathy.
  • Uncontrolled hyperthyroidism or hypothyroidism.
  • Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.
  • One or more laboratory abnormalities:
  • calculated creatinine clearance (Cockroft-Gault) <60mL/min;
  • electrolyte abnormalities according to the Cairo Bishop definition of laboratory TLS.
  • GOT, GPT, γGT > 1.5 x upper limit of normal value;
  • serum bilirubin >1.5 mg/dL.
  • Lactose Intolerance.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01403246

Contacts
Contact: Antonella Graziosi +39 0670390517 a.graziosi@gimema.it

Locations
Italy
Azienda Spedali Civili Not yet recruiting
Brescia, Italy, 25100
Contact: Marina MOTTA, Dr.         
Principal Investigator: Marina Motta, Dr.         
Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto" Not yet recruiting
Catania, Italy
Contact: Francesco DI RAIMONDO, Pr.         
Principal Investigator: Francesco DI RAIMONDO, Pr.         
Sub-Investigator: Paolo FIUMARA, Pr.         
Azienda Ospedaliera Pugliese Ciaccio Recruiting
Catanzaro, Italy, 88100
Contact: Rosanna MIRABELLI, Dr.         
Principal Investigator: Rosanna MIRABELLI, Dr.         
Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia Recruiting
Catanzaro, Italy
Contact: Stefano Molica, Dr.         
Principal Investigator: Stefano Molica, Dr.         
Sub-Investigator: Luciano Levato, Dr.         
Clinica Ematologica - Università degli Studi Recruiting
Genova, Italy
Contact: Angelo Michele CARELLA, Dr         
Principal Investigator: Angelo Michele CARELLA, Pr.         
Sub-Investigator: Tiziana Piazza, Dr.         
UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico Recruiting
Milano, Italy
Contact: Agostino CORTELEZZI, Pr.         
Principal Investigator: Agostino CORTELEZZI, Pr.         
U.O. Ematologia Clinica - Azienda USL di Pescara Not yet recruiting
Pescara, Italy
Contact: Francesco ANGRILLI, Dr.         
Principal Investigator: Francesco ANGRILLI, Dr.         
Sub-Investigator: Simona FALORIO, Dr.         
Umberto I di Roma - Dipartimento di Biotecnologie Cellulari ed Ematologia Recruiting
Roma, Italy, 00161
Contact: Roberto Foà         
Contact: Francesca Romana Mauro         
Principal Investigator: Roberto Foà         
Sub-Investigator: Francesca Romana Mauro         
U.O. Ematologia, Azienda Ospedaliera Universitaria Senese Not yet recruiting
Siena, Italy, 53100
Contact: Francesco Forconi         
Principal Investigator: Francesco FORCONI, Pr.         
SS.C. di Oncoematologia - Dipartimento di Medicina Clinica e Sperimentale - Azienda Ospedaliera - S. Maria Di Terni Recruiting
Terni, Italy
Contact: Anna Marina LIBERATI, Dr.         
Principal Investigator: Anna Marina LIBERATI, Dr.         
Sub-Investigator: Viviana APPOLLONI, Dr.         
Sponsors and Collaborators
Gruppo Italiano Malattie EMatologiche dell'Adulto
Investigators
Principal Investigator: Roberto Foà Umberto I - Dipartimento di Biotecnologie Cellulari ed Ematologia Cellulari
Principal Investigator: Francesca Romana Mauro, Co-Coordinator Umberto I - Dipartimento di Biotecnologie Cellulari ed Ematologia
  More Information

Additional Information:
No publications provided

Responsible Party: Gruppo Italiano Malattie EMatologiche dell'Adulto
ClinicalTrials.gov Identifier: NCT01403246     History of Changes
Other Study ID Numbers: CLL0709
Study First Received: January 13, 2011
Last Updated: November 26, 2013
Health Authority: Italy: National Institute of Health

Keywords provided by Gruppo Italiano Malattie EMatologiche dell'Adulto:
CLL
Lenalidomide
Chlorambucil
No previous treatment

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Chlorambucil
Lenalidomide
Thalidomide
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Leprostatic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on April 20, 2014