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Chronic Lymphocytic LeukemiaPhase 1/2NCT01295593

Low Dose CdA Combined With Valproic Acid (VPA) in Previously Treated B-cell Chronic Lymphocytic Leukemia(B-CLL)

A Phase 1/2 study testing valproic acid and 2-chlorodeoxyadenosine in people with Chronic Lymphocytic Leukemia, run by Cliniques universitaires Saint-Luc- Université Catholique de Louvain at 11 sites in Belgium.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

Rationale New chemotherapeutic agents are needed in relapsing B-Cell Chronic Lymphocytic Leukemia (B-CLL) to overcome resistance of CLL cells. Valproic acid (VPA) is an inhibitor of histone deacetylase (HDAC) used as an anticonvulsant and mood-stabilizing drug for decades. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Chronic Lymphocytic Leukemia
What is being tested?
valproic acid and 2-chlorodeoxyadenosine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
33 participants
Where
11 sitesBelgium
Study dates
Dec 2010to Apr 2013
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • B-cell Chronic Lymphocytic Leukemia (CLL)
  • Patients must have intermediate or high-risk categories of the modified 3-stage Rai and Binet staging
  • Patient MUST have progressive or symptomatic disease as defined by any of the following conditions:
  • Progressive lymphocytosis with a lymphocyte count increased > 50% over the last 2 months period or an anticipation of the doubling time in less than 6 months
  • Progressive or symptomatic splenomegaly or hepatomegaly
  • Progressive or symptomatic lymphadenopathy
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  • Evidence of progressive marrow failure as manifested by development or worsening of anemia and/or thrombocytopenia
  • Presence of any B-symptoms: weight loss ≥ 10% within the previous 6 months, fever > 38.0°C for ≥ 2 weeks without evidence of infection, or night sweats without evidence of infection
  • Patient must have received one or more prior therapies for Chronic Lymphocytic Leukemia. Patients may have received any of the following prior treatment regimens: fludarabine-containing combinations, alemtuzumab single agent or combination, rituximab combinations, chlorambucil, cyclophosphamide +/- prednisone, or other forms of immunotherapy…
  • Patients must have adequate organ function:
  • Neutrophils > 500/mm³
  • Platelets > 50.000/mm³
  • Creatinine clearance (measured or calculated) > 40 ml/min
  • Age > 18 years
  • Patient's ECOG performance status must be 0-2
  • Patient's written informed consent
  • Life expectancy > 6 months

Who cannot join

  • Patients having received Valproic Acid (VPA) within 3 months
  • Previous, suspected or known hypersensitivity to VPA, or any of its derivatives
  • Liver porphyria
  • Epilepsy due to mitochondrial diseases
  • Ongoing treatment with VPA-interacting drugs
  • Cumulative Illness rating Scale (CIRS) > 6
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  • Prior allogenic or autologous bone marrow transplantation less than 12 months
  • Patient having received any anticancer agents (chemotherapy, immunotherapy or targeted agents) within 4 weeks
  • Central Nervous System involvement
  • Concomitant disease requiring prolonged use of corticosteroids (> 1 month)
  • Transformation into an aggressive B-cell malignancy (e.g. diffuse large cell lymphoma, Hodgkin lymphoma)
  • Creatinine clearance < 40 ml/min calculated according to the formula of Cockcroft and Gault. Patients with a calculated creatinine clearance below 40 ml/min may be eligible if (1) a measured creatinine clearance (based on 24 hours urine collection or other reliable method) is > 40 ml/min, or (2) a new calculation conducted after adequate hydration is > 40 ml/min.
  • Any coexisting medical or psychological condition that would preclude participation to the required study procedures
  • Patient with mental deficiency preventing proper understanding of the requirements of treatment
  • Pregnancy, lactating woman, females of childbearing potential or male patient who are unwilling to use adequate contraception
  • Clinically significant auto-immune cytopenia, Coombs-positive hemolytic anemia as judged by the treating physician
  • Patients with a history of another malignancy in complete remission less than 2 years, except basal cell skin cancer, stage 0 (in situ) cervical carcinoma or tumor treated curatively by surgery
  • Any severe co-morbidities such as New York Heart Association Class III or IV heart failure, myocardial infarction within 6 months, unstable angina, ventricular tachyarrhythmias requiring ongoing treatment, or severe uncontrolled myocardiopathy, uncontrolled hypertension, severe chronic obstructive pulmonary disease with hypoxemia or uncontrolled diabetes mellitus
  • Active bacterial, viral or fungal infection
  • Seropositivity for: Human Immunodeficiency Virus, hepatitis C or hepatitis B (unless clearly due to vaccination)
  • Liver insufficiency
  • Total bilirubin > 2 x the upper limit of normal (ULN)
  • Prior history of severe hepatic or pancreatic disorder
  • Alkaline phosphatases and aminotransferases (AST, ALT) > 2 x ULN

Trial locations and contacts

11 sites in 1 country.

Eric Van Den Neste, MD, PhD contact

+32 27 64 18 00

eric.vandenneste@uclouvain.be

Sabrina Costantini contact

+32 27 64 18 09

sabrina.costantini@uclouvain.be

11 sites in 1 country

Belgium11 sites, 11 recruiting

  • Clinique Sud Luxembourg

    Arlon, 6700

    Pascal Pierre, MD

    Recruiting

  • Institut Jules Bordet

    Brussels, 1000

    Dominique Bron, MD, PhD

    Recruiting

  • ULB Erasme

    Brussels, 1070

    Alain Kentos, MD

    Recruiting

  • Cliniques universitaires Saint Luc

    Brussels, 1200

    Eric Van Den Neste, MD, PhD

    Recruiting

  • Grand Hôpital de Charleori - Site notre Dame

    Charleroi, 6000

    Marc André, MD

    Recruiting

  • Clinique Notre-Dame de Grâce

    Gosselies, 6041

    Marie Maerevoet, MD

    Recruiting

  • Hôpital de Jolimont

    Haine-St-Paul, 7100

    Valérie Delrieu, MD

    Recruiting

  • CHU ULg

    Liège, 4000

    Bernard De Prijck, MD

    Recruiting

  • Clinique Saint Pierre

    Ottignies, 1340

    Thierry Connerotte, MD, PhD

    Recruiting

  • Heilig-Hartziekenhuis

    Roeselaere, 8800

    Hilde Demuynck, MD

    Recruiting

  • Cliniques de Mont Godinne

    Yvoir, 5530

    Christian Chatelain, MD, PhD

    Recruiting

Other trials in Belgium

About this study

Official title: Phase I-II Study of Low Dose CdA Combined With Valproic Acid (VPA) in Previously Treated B-cell Chronic Lymphocytic Leukemia (CLL) Patients

Rationale New chemotherapeutic agents are needed in relapsing B-Cell Chronic Lymphocytic Leukemia (B-CLL) to overcome resistance of CLL cells. Valproic acid (VPA) is an inhibitor of histone deacetylase (HDAC) used as an anticonvulsant and mood-stabilizing drug for decades. VPA mediates apoptosis in CLL cells through caspase activation. VPA shows toxicity toward CLL cells displaying alterations in the p53 pathway. The combination of VPA with fludarabine or 2-Chlorodeoxyadenosine (CdA, Cladribine) results in synergistic loss of B-CLL cell viability, and significant increase in apoptosis. The highest index of synergism is observed between VPA and CdA, a purine nucleoside analog active in B-CLL.

Study design Overall, the study will be proposed to previously treated patients with advanced B-CLL, who are not eligible for aggressive approaches, and who exhibit progressive disease. A total of 33 patients will be included. Estimated enrolment time is 2 years.

  • First part: It is planned to start therapy with single VPA during 2 months, targeting plasma levels that have been reported to be active in vitro toward CLL cells (but that do not exceed therapeutic levels in seizure prevention), and in parallel, to verify whether cellular targets of VPA have been actually inhibited in leukemic B-lymphocytes.
  • Second part: After the VPA preloading period (2 months), patients will be evaluated to receive CdA. CdA will be given at 5.6 mg/m²/day intravenously during 3 days, a reduced-dose schedule which is less toxic - at no obvious cost of loss of efficacy - as compared to the standard dosage of 5 days. CdA was chosen because it displays the highest level of in vitro synergism with VPA. Four monthly courses of CdA will be given. Patients will then be evaluated. VPA will be stopped at the time of response evaluation (scheduled 28 days after the last course of CdA).
Being tested
valproic acid and 2-chlorodeoxyadenosine
Keywords
CLL previously treated
Medical subject headings
Leukemia, Lymphocytic, Chronic, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • valproic acid and 2-chlorodeoxyadenosineDrug

    VPA : daily, oral, starting dose 10mg/kg/day total dose, taken in 2 separate administrations of around 5 mg/kg/day each, for a maximum of 6 months CdA : 5.6 mg/m²/day IV during 3 days, every 28 days, for a maximum of 4 cycles

Study groups in NCT01295593
Study groupRoleWhat they receive
valproic acid combined with CdAExperimentalvalproic acid, oral daily intake, combined with 2-chlorodeoxyadenosine administered intravenously for 4 cycles
Receives: Drug: valproic acid and 2-chlorodeoxyadenosine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. To determine the tolerability of VPA in combination with low dose CdA in patients with advanced B-CLL

    Measured: 6 months on average

Secondary outcomes (1)

  1. minimal dose of VPA able to achieve adequate plasma levels of VPA and effective inhibition of VPA cellular targets, therapeutic response and survival , VPA pharmacokinetics

    Measured: 6 months on average

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Feb 2011 (estimated)
  2. Study startDec 2010
  3. Primary completionApr 2013 (estimated)
  4. Study completionApr 2013 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
33 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01295593
Sponsor's protocol ID
VPA-CdA
Status last verified
Jun 2012
First submitted
10 Feb 2011
Last updated
7 Jun 2012
Results posted
No
Data monitoring committee
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing valproic acid and 2-chlorodeoxyadenosine in people with Chronic Lymphocytic Leukemia, run by Cliniques universitaires Saint-Luc- Université Catholique de Louvain at 11 sites in Belgium.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 7 Jun 2012. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 sites in Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Eric Van Den Neste, MD, PhD (+32 27 64 18 00, eric.vandenneste@uclouvain.be), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

To determine the tolerability of VPA in combination with low dose CdA in patients with advanced B-CLL (time frame: 6 months on average). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01295593.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Jun 2012.

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