Back to results

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

Primary Purpose

Chronic Lymphocytic Leukemia

Status

Unknown status

Phase

Phase 1

Locations

Belgium

Study Type

Interventional

Intervention

valproic acid and 2-chlorodeoxyadenosine

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukemia focused on measuring CLL previously treated

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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
- 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

Exclusion Criteria:

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
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

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

valproic acid combined with CdA

Arm Description

valproic acid, oral daily intake, combined with 2-chlorodeoxyadenosine administered intravenously for 4 cycles

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Full Information

NCT ID

NCT01295593

First Posted

February 10, 2011

Last Updated

June 6, 2012

Sponsor

Cliniques universitaires Saint-Luc- Université Catholique de Louvain

1. Study Identification

Unique Protocol Identification Number

NCT01295593

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2012

Overall Recruitment Status

Unknown status

Study Start Date

December 2010 (undefined)

Primary Completion Date

April 2013 (Anticipated)

Study Completion Date

April 2013 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Cliniques universitaires Saint-Luc- Université Catholique de Louvain

4. Oversight

Data Monitoring Committee

5. Study Description

Brief 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. 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Lymphocytic Leukemia

Keywords

CLL previously treated

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

33 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

valproic acid combined with CdA

Arm Type

Experimental

Arm Description

valproic acid, oral daily intake, combined with 2-chlorodeoxyadenosine administered intravenously for 4 cycles

Intervention Type

Drug

Intervention Name(s)

valproic acid and 2-chlorodeoxyadenosine

Intervention Description

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

Primary Outcome Measure Information:

Title

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

Time Frame

6 months on average

Secondary Outcome Measure Information:

Title

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

Time Frame

6 months on average

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 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 Exclusion Criteria: 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 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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Eric Van Den Neste, MD, PhD

Phone

+32 27 64 18 00

eric.vandenneste@uclouvain.be

First Name & Middle Initial & Last Name or Official Title & Degree

Sabrina Costantini

Phone

+32 27 64 18 09

sabrina.costantini@uclouvain.be

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Eric Van Den Neste, MD, PhD

Organizational Affiliation

Cliniques universitaires Saint-Luc

Official's Role

Principal Investigator

Facility Information:

Facility Name

Clinique Sud Luxembourg

City

Arlon

ZIP/Postal Code

6700

Country

Belgium

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Pascal Pierre, MD

Facility Name

Institut Jules Bordet

City

Brussels

ZIP/Postal Code

1000

Country

Belgium

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Dominique Bron, MD, PhD

Facility Name

ULB Erasme

City

Brussels

ZIP/Postal Code

1070

Country

Belgium

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Alain Kentos, MD

Facility Name

Cliniques universitaires Saint Luc

City

Brussels

ZIP/Postal Code

1200

Country

Belgium

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Eric Van Den Neste, MD, PhD

Facility Name

Grand Hôpital de Charleori - Site notre Dame

City

Charleroi

ZIP/Postal Code

6000

Country

Belgium

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Marc André, MD

Facility Name

Clinique Notre-Dame de Grâce

City

Gosselies

ZIP/Postal Code

6041

Country

Belgium

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Marie Maerevoet, MD

Facility Name

Hôpital de Jolimont

City

Haine-St-Paul

ZIP/Postal Code

7100

Country

Belgium

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Valérie Delrieu, MD

Facility Name

CHU ULg

City

Liège

ZIP/Postal Code

4000

Country

Belgium

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Bernard De Prijck, MD

Facility Name

Clinique Saint Pierre

City

Ottignies

ZIP/Postal Code

1340

Country

Belgium

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Thierry Connerotte, MD, PhD

Facility Name

Heilig-Hartziekenhuis

City

Roeselaere

ZIP/Postal Code

8800

Country

Belgium

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Hilde Demuynck, MD

Facility Name

Cliniques de Mont Godinne

City

Yvoir

ZIP/Postal Code

5530

Country

Belgium

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Christian Chatelain, MD, PhD

12. IPD Sharing Statement

Learn more about this trial

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

We'll reach out to this number within 24 hrs

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

Chronic Lymphocytic Leukemia

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial