A Phase I/II, Open-label Study of Ofatumumab Added to Chlorambucil in Previously Untreated Japanese Patients With Chronic Lymphocytic Leukemia
Information source: GlaxoSmithKline
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Leukaemia, Lymphocytic, Chronic
Intervention: chlorambucil, tablets (Drug); ofatumumab (GSK1841157) infusion (Drug)
Phase: Phase 2
Status: Completed
Sponsored by: GlaxoSmithKline Official(s) and/or principal investigator(s): GSK Clinical Trials, Study Director, Affiliation: GlaxoSmithKline
Summary
This is an open-label study to evaluate tolerability, safety, efficacy and pharmacokinetic
profile of ofatumumab in combination with chlorambucil in Japanese patients with previously
untreated Chronic Lymphocytic Leukemia (CLL).
Clinical Details
Official title: A Phase I/II, Open-label Study of Ofatumumab Added to Chlorambucil in Previously Untreated Japanese Patients With Chronic Lymphocytic Leukemia
Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Number of Participants Who Developed Toxicity Requiring Discontinuation From Study Treatment During Cycle 1Number of Participants With Overall Response, as Assessed by the Independent Review Committee (IRC) With CT, IRC and Investigator
Secondary outcome: Number of Participants With CR, as Assessed by the IRC, IRC With CT, and the InvestigatorProgression-free Survival (PFS), as Assessed by the IRC and the Investigator Overall Survival Time to Response, as Assessed by the IRC Duration of Response, as Assessed by the IRC Time to Next Chronic Lymphocytic Leukemia (CLL) Therapy Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) Number of Participants With AEs of Maximum Severity Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Events Number of Participants With the Indicated Results for Human Anti-human Antibody (HAHA) at the Indicated Time Points Mean Change From Baseline in the Immunoglobulins (Ig) Antibodies IgA, IgG, and IgM at the Indicated Time Points Number of Participants Who Were Positive or Negative for Minimal Residual Disease (MRD), as Assessed by IRC With CT Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points Beta-2 Microglobulin at Cycle 1-Day 1 Complement (CH50) at Cycle 1-Day 1 and Cycle 4-Day 85 Maximum (Peak) Plasma Concentration (Cmax) of Ofatumumab Cmax of Serum Chlorambucil Cmax of Serum Phenyl Acetic Acid Mustard Minimum Plasma Concentration (Cmin) of Ofatumumab Cmin of Chlorambucil Cmin of Phenyl Acetic Acid Mustard Total Plasma Clearance (CL) of Ofatumumab Area Under the Drug Plasma Concentration-time Curve From Dosing to Time Tau (AUC[0-tau]) of Ofatumumab AUC(0-tau) of Chlorambucil AUC(0-tau) of Phenyl Acetic Acid Mustard Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC[0-infinity]) for Ofatumumab AUC(0-infinity) for Chlorambucil AUC(0-infinity) for Phenyl Acetic Acid Mustard Volume of Distribution at Steady State (Vss) of Ofatumumab Plasma Half-life (t1/2) of Ofatumumab Plasma Half-life (t1/2) of Chlorambucil Plasma Half-life (t1/2) of Phenyl Acetic Acid Mustard Time to Maximum Concentration (Tmax) of Ofatumumab Time to Maximum Concentration (Tmax) of Chlorambucil Time to Maximum Concentration (Tmax) of Phenyl Acetic Acid Mustard Mean Residence Time to Infinity (MRTinf) of Ofatumumab Mean Residence Time Inf (MRTinf) of Chlorambucil Mean Residence Time Inf (MRTinf) of Phenyl Acetic Acid Mustard Volume of Distribution (Vz) of Ofatumumab Apparent Total Clearance of the Drug From Plasma (CL/F) for Chlorambucil Apparent Volume of Distribution During Terminal Phase (Vz/F) of Chlorambucil %AUC_extrap of Ofatumumab %AUC_extrap of Chlorambucil %AUC_extrap of Phenyl Acetic Acid Mustard AUC (0-t) of Ofatumumab AUC (0-t) of Chlorambucil AUC (0-t) of Phenyl Acetic Acid Mustard Dose Normalized Cmax (Cmax/D) for Chlorambucil Cmax/D for Phenyl Acetic Acid Mustard AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D, and AUC (0-tau)/D of Chlorambucil AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D and AUC (0-tau)/D of Phenyl Acetic Acid Mustard
Detailed description:
This is an open-label study to evaluate tolerability, safety, efficacy and pharmacokinetic
profile of ofatumumab in combination with chlorambucil in Japanese patients with previously
untreated Chronic Lymphocytic Leukemia (CLL). Ofatumumab will be infused intravenously at
Day 1 (300 mg) and Day 8 (1000 mg) in the first 28-day cycle, followed by infusions of 1000
mg at the first day of each 28-day cycle. Chlorambucil will be given 10 mg/m2 at Day 1-7 in
each 28-day cycle.
The primary objectives are to evaluate tolerability and overall response rate (ORR) of
ofatumumab with chlorambucil for previously untreated (frontline) CLL.
Secondary objectives include to evaluate complete remission (CR) rate, progression free
survival (PFS), overall survival (OS), time to response, duration of response, time to next
therapy, incidence and severity of adverse events and serious adverse events, incidences of
grade 3 and 4 infections and myelosuppression (anemia, neutropenia, thrombocytopenia), and
pharmacokinetics of ofatumumab and chlorambucil.
Eligibility
Minimum age: 20 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Diagnosis of CLL defined by : Circulating B lymphocytes ≥5,000 /μL AND Flow cytometry
confirmation of immunophenotype with CD5, CD19, CD20, and CD23 prior to Visit 2.
- Considered inappropriate for fludarabine-based therapy
- Active disease and indication for treatment based on modified NCI-WG guidelines
defined by presenting at least any one of the following conditions :
Evidence of progressive marrow failure as manifested by development or worsening of anemia
and/or thrombocytopenia.
Massive (i. e. at least 6 cm below the left costal margin) or progressive or symptomatic
splenomegaly.
Massive nodes (i. e. at least 10 cm in longest diameter) or progressive or symptomatic
lymphadenopathy.
Progressive lymphocytosis with an increase of more than 50% over a two month period or an
lymphocyte doubling time of less than 6 months.
A minimum of any one of the following disease-related symptoms must be present : a)
Unintentional Weight loss ≥ 10% within the previous six months ; b) Fevers >38. 0 degree C
for ≥ 2 weeks without evidence of infection ; or c) Night sweats for more than 1 month
without evidence of infection.
- Not been previously treated for CLL (prior autoimmune hemolytic anemia treatment
permitted).
- ECOG Performance Status of 0-2.
- Life expectancy of at least 6 months, in the opinion of the investigator.
- Age ≥ 20 years.
- Signed written informed consent prior to performing any study-specific procedures.
- Patients possible to stay at the trial site for at least two days (the day of the
first infusion and a subsequent day).
Exclusion Criteria:
- Prior immuno- or chemotherapy for CLL or small lymphocytic lymphoma (SLL) with any
agent except corticosteroids used to treat autoimmune hemolytic anemia.
- Previous autologous or allogeneic stem cell transplantation.
- Active autoimmune hemolytic anemia (AIHA) requiring corticosteroid therapy > 100
mg/day equivalent to hydrocortisone, or chemotherapy.
- Known transformation of CLL (e. g. Richter).
- Known CNS involvement of CLL.
- Chronic or current active infectious disease requiring systemic antibiotics,
antifungal, or antiviral treatment such as, but not limited to, chronic renal
infection, chronic chest infection with bronchiectasis, tuberculosis and active
Hepatitis C.
- Other past or current malignancy. Subjects who have been free of malignancy for at
least 5 years, or have a history of completely resected non-melanoma skin cancer, or
successfully treated in situ carcinoma are eligible.
- Clinically significant cardiac disease including unstable angina, acute myocardial
infarction within 6 months prior to screening (Visit 1), congestive heart failure,
and arrhythmia requiring therapy, with the exception of extra systoles or minor
conduction abnormalities.
- History of significant cerebrovascular disease or event with significant symptoms or
sequelae*.
- Glucocorticoid use, unless given in doses ≤ 100 mg/day hydrocortisone (or equivalent
dose of other glucocorticoid) for <7 days for exacerbations other than CLL (e. g.
asthma).
- Known HIV positive.
- Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In
addition, if negative for HBsAg but HBcAb and/or HBsAb positive, an HBV DNA test will
be performed and if positive the subject will be excluded.
- Screening laboratory values :
Creatinine > 2. 0 times upper normal limit (unless normal creatinine clearance). Total
bilirubin > 2. 0 times upper normal limit (unless due to Gilbert's syndrome).
Alanine transaminase (ALT) > 3. 0 times upper normal limit.
- Previous treatment or known or suspected hypersensitivity to ofatumumab that in the
opinion of the investigator or medical monitor is a contraindication to their
participation in the present study.
- Treatment with any known non-marketed drug substance or experimental therapy within 5
terminal half lives or 4 weeks prior to Visit 1, whichever is longer, treatment with
any anti-CD20 monoclonal antibody within 3 months of Visit 1, or participation in any
other interventional clinical study. Note: Participation in any other interventional
clinical study after disease progression during post PD-follow-up is permitted.
- Known or suspected inability to comply with study protocol.
- Lactating women, women with a positive pregnancy test at Visit 1 or women (of
childbearing potential) as well as men with partners of childbearing potential, who
are not willing to use adequate contraception from study start through one year
following last treatment dose. Adequate contraception is defined as oral hormonal
birth control, intrauterine device, male partner sterilization (if male partner is
sole partner for that subject) and the double barrier method (condom or occlusive cap
plus spermicidal agent).
Locations and Contacts
GSK Investigational Site, Aichi 466-8650, Japan
GSK Investigational Site, Hokkaido 060-8543, Japan
GSK Investigational Site, Kanagawa 259-1143, Japan
GSK Investigational Site, Kyoto 602-8566, Japan
GSK Investigational Site, Tokyo 104-0045, Japan
GSK Investigational Site, Tokyo 135-8550, Japan
Additional Information
Starting date: April 2012
Last updated: July 16, 2015
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