Clinical trial NCT01563055: A Phase I/II, Open-label Study of Ofatumumab Added to Chlorambucil in Previously Untreated Japanese Patients With Chronic Lymphocytic Leukemia
Official title: A Phase I/II, Open-label Study of Ofatumumab Added to Chlorambucil in Previously Untreated Japanese Patients With Chronic Lymphocytic Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukaemia, Lymphocytic, Chronic
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2012-03-26
Enrollment: 10
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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).

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 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).

Primary outcomes:
measure: Number of Participants Who Developed Toxicity Requiring Discontinuation From Study Treatment During Cycle 1
timeFrame: From start of treatment through Cycle 1 (Week 4)
measure: Number of Participants With Overall Response, as Assessed by the Independent Review Committee (IRC) With CT, IRC and Investigator
timeFrame: From start of treatment until disease progression or death (up to Week 62.3)
Secondary outcomes:
measure: Number of Participants With CR, as Assessed by the IRC, IRC With CT, and the Investigator
timeFrame: From start of treatment until disease progression or death (up to Week 62.3)
measure: Progression-free Survival (PFS), as Assessed by the IRC and the Investigator
timeFrame: From start of treatment until disease progression or death (up to Week 62.3)
measure: Overall Survival
timeFrame: From start of treatment until death (up to Week 62.3
measure: Time to Response, as Assessed by the IRC
timeFrame: From start of treatment until the first response (CR/CRi/nPR/PR) (up to Week 62.3)
measure: Duration of Response, as Assessed by the IRC
timeFrame: From initial response (CR/CRi/nPR/PR) until disease progression or death (up to Week 62.3)
measure: Time to Next Chronic Lymphocytic Leukemia (CLL) Therapy
timeFrame: From start of treatment until the first administration of the next CLL therapy (up to Week 62.3)
measure: Number of Participants With no B-symptoms (Constitutional Symptoms) and With at Least One B-symptom (Constitutional Symptoms) at the Indicated Time Points
timeFrame: Baseline, C2-D29, C3-D57, C4-D85, C5-D113, C6-D141, C7-D169, C8-D197, C9 -D225, FU 1-PDFU 1 (28 days post Day 1 of Last Cycle), FU 85-PDFU 85 (84 days after FU-1), and FU 169-PDFU 169 (168 days after FU-1)
measure: Number of Participants With Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
timeFrame: Baseline, C2-D29, C3-D57, C4-D85, C5-D113, C6-D141, C7-D169, C8-D197, C9 -D225, FU 1-PDFU 1 (28 days post Day 1 of Last Cycle), FU 85-PDFU 85 (84 days after FU-1), and FU 169-PDFU 169 (168 days after FU-1)
measure: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
timeFrame: From start of treatment until follow-up for survival (up to Week 62.3)
measure: Number of Participants With AEs of Maximum Severity
timeFrame: From start of treatment until follow-up for survival (up to Week 62.3)
measure: Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Events
timeFrame: From start of treatment until follow-up for survival (up to Week 62.3)
measure: Number of Participants With the Indicated Results for Human Anti-human Antibody (HAHA) at the Indicated Time Points
timeFrame: Screening, Cycle 4-Day 85, FU 1-PDFU 1 (28 days post Day 1 of Last Cycle), and FU 169-PDFU 169 (168 days after FU-1)
measure: Mean Change From Baseline in the Immunoglobulins (Ig) Antibodies IgA, IgG, and IgM at the Indicated Time Points
timeFrame: Baseline (Cycle 1-Day 1), FU 1-PDFU 1 (28 days post Day 1 of Last Cycle), and FU 169-PDFU 169 (168 days after FU-1)
measure: Number of Participants Who Were Positive or Negative for Minimal Residual Disease (MRD), as Assessed by IRC With CT
timeFrame: FU 85-PDFU 85 (84 days after FU-1)
measure: Change From Baseline in CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points
timeFrame: Baseline, C1-D15, C2-D29, C2-D43, C3-D57, C4-D85, C5-D113, C6-D141, C7-D169, C8-D197, C9-D225, FU 1-PDFU 1 (28 days post Day 1 of Last Cycle), FU 85-PDFU 85 (84 days after FU-1), and FU 169-PDFU 169 (168 days after FU-1)
measure: Beta-2 Microglobulin at Cycle 1-Day 1
timeFrame: Cycle 1-Day 1
measure: Complement (CH50) at Cycle 1-Day 1 and Cycle 4-Day 85
timeFrame: Cycle 1-Day 1 and Cycle 4-Day 85
measure: Maximum (Peak) Plasma Concentration (Cmax) of Ofatumumab
timeFrame: Cycle 1-Day 1 and Cycle 3-Day 57
measure: Cmax of Serum Chlorambucil
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: Cmax of Serum Phenyl Acetic Acid Mustard
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: Minimum Plasma Concentration (Cmin) of Ofatumumab
timeFrame: Cycle 1-Day 8, Cycle 2-Day 29, Cycle 3-Day 57, Cycle 4-Day 85, Cycle 5-Day 113, and Cycle 6-Day 141
measure: Cmin of Chlorambucil
timeFrame: Cycle 1-Day 4 and Cycle 3-Day 57
measure: Cmin of Phenyl Acetic Acid Mustard
timeFrame: Cycle 1-Day 4 and Cycle 3-Day 57
measure: Total Plasma Clearance (CL) of Ofatumumab
timeFrame: Cycle 1-Day 1
measure: Area Under the Drug Plasma Concentration-time Curve From Dosing to Time Tau (AUC[0-tau]) of Ofatumumab
timeFrame: Cycle 1-Day 1 and Cycle 3-Day 57
measure: AUC(0-tau) of Chlorambucil
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: AUC(0-tau) of Phenyl Acetic Acid Mustard
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC[0-infinity]) for Ofatumumab
timeFrame: Cycle 1-Day 1
measure: AUC(0-infinity) for Chlorambucil
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: AUC(0-infinity) for Phenyl Acetic Acid Mustard
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: Volume of Distribution at Steady State (Vss) of Ofatumumab
timeFrame: Cycle 1-Day 1
measure: Plasma Half-life (t1/2) of Ofatumumab
timeFrame: Cycle 1-Day 1 and Cycle 3-Day 57
measure: Plasma Half-life (t1/2) of Chlorambucil
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: Plasma Half-life (t1/2) of Phenyl Acetic Acid Mustard
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: Time to Maximum Concentration (Tmax) of Ofatumumab
timeFrame: Cycle 1-Day 1 and Cycle 3-Day 57
measure: Time to Maximum Concentration (Tmax) of Chlorambucil
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: Time to Maximum Concentration (Tmax) of Phenyl Acetic Acid Mustard
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: Mean Residence Time to Infinity (MRTinf) of Ofatumumab
timeFrame: Cycle 1-Day 1
measure: Mean Residence Time Inf (MRTinf) of Chlorambucil
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: Mean Residence Time Inf (MRTinf) of Phenyl Acetic Acid Mustard
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: Volume of Distribution (Vz) of Ofatumumab
timeFrame: Cycle 1-Day 1
measure: Apparent Total Clearance of the Drug From Plasma (CL/F) for Chlorambucil
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: Apparent Volume of Distribution During Terminal Phase (Vz/F) of Chlorambucil
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: %AUC_extrap of Ofatumumab
timeFrame: Cycle 1-Day 1
measure: %AUC_extrap of Chlorambucil
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: %AUC_extrap of Phenyl Acetic Acid Mustard
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: AUC (0-t) of Ofatumumab
timeFrame: Cycle 1-Day 1 and Cycle 3-Day 57
measure: AUC (0-t) of Chlorambucil
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: AUC (0-t) of Phenyl Acetic Acid Mustard
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: Dose Normalized Cmax (Cmax/D) for Chlorambucil
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: Cmax/D for Phenyl Acetic Acid Mustard
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D, and AUC (0-tau)/D of Chlorambucil
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
measure: AUC (0-6)/D, AUC(0-24)/D, AUC (0-inf)/D and AUC (0-tau)/D of Phenyl Acetic Acid Mustard
timeFrame: Cycle 1-Day 1, Cycle 1-Day 4, and Cycle 3-Day 57
Other outcomes:
Locations:
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Hokkaido
country: Japan
facility: GSK Investigational Site
city: Kanagawa
country: Japan
facility: GSK Investigational Site
city: Kyoto
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: