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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

Phase 1/Phase 2
60 Years
65 Years
Open (Enrolling)
Chronic Lymphocytic Leukemia

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Trial Information

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

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.

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

- 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

- 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

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.

Type of Study:


Study Design:

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

Outcome Measure:

PhI: MTD of Lenalidomide given in combination with Chlorambucil.

Outcome Description:

PhI: MTD will be identified according to all adverse events and DLTs tabulated for each dose level.

Outcome Time Frame:

At maximum 8 months from induction therapy start

Safety Issue:


Principal Investigator

Roberto Foà

Investigator Role:

Principal Investigator

Investigator Affiliation:

Umberto I - Dipartimento di Biotecnologie Cellulari ed Ematologia Cellulari


Italy: National Institute of Health

Study ID:




Start Date:

November 2011

Completion Date:

January 2014

Related Keywords:

  • Chronic Lymphocytic Leukemia
  • CLL
  • Lenalidomide
  • Chlorambucil
  • No previous treatment
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid