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

Information source: Gruppo Italiano Malattie EMatologiche dell'Adulto
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Chronic Lymphocytic Leukemia

Intervention: Lenalidomide; Chlorambucil (Drug)

Phase: Phase 1/Phase 2

Status: Completed

Sponsored by: Gruppo Italiano Malattie EMatologiche dell'Adulto

Official(s) and/or principal investigator(s):
Roberto Foà, Principal Investigator, Affiliation: Umberto I - Dipartimento di Biotecnologie Cellulari ed Ematologia Cellulari
Francesca Romana Mauro, Co-Coordinator, Principal Investigator, Affiliation: Umberto I - Dipartimento di Biotecnologie Cellulari ed Ematologia


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.

Clinical Details

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

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label

Primary outcome:

PhI: MTD of Lenalidomide given in combination with Chlorambucil.

PhII: To evaluate the overall response rate of an induction therapy consisting of Lenalidomide given at the MTD in combination with Chlorambucil.

Secondary outcome:

Lenalidomide and chlorambucil induction therapy in terms of safety;

Post-remissional phase with Lenalidomide in terms of safety

Lenalidomide maintenance efficacy in terms of CR rate.

Progression free survival estimation according to the post-remissional approach. lenalidomide maintenance therapy or clinical observation.

Association between the response and the baseline biologic factors (IgVH, p53, FISH, ZAP-70, CD38)

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 to a new CLL treatment or death estimation.

Overall survival estimation

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.


Minimum age: 60 Years. Maximum age: 65 Years. Gender(s): Both.


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.

Locations and Contacts

Azienda Spedali Civili, Brescia 25100, Italy

Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto", Catania, Italy

Azienda Ospedaliera Pugliese Ciaccio, Catanzaro 88100, Italy

Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia, Catanzaro, Italy

Clinica Ematologica - Università degli Studi, Genova, Italy

UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico, Milano, Italy

U.O. Ematologia Clinica - Azienda USL di Pescara, Pescara, Italy

Umberto I di Roma - Dipartimento di Biotecnologie Cellulari ed Ematologia, Roma 00161, Italy

U.O. Ematologia, Azienda Ospedaliera Universitaria Senese, Siena 53100, Italy

SS.C. di Oncoematologia - Dipartimento di Medicina Clinica e Sperimentale - Azienda Ospedaliera - S. Maria Di Terni, Terni, Italy

Additional Information

GIMEMA Foundation Webpage

Starting date: November 2011
Last updated: January 27, 2015

Page last updated: August 23, 2015

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