Clinical trial NCT01077622: A Phase I/II, a Single Arm, Open-label Study of Ofatumumab (GSK1841157) in Patients With Previously Treated Chronic Lymphocytic Leukemia
Official title: A Phase I/II, a Single Arm, Open-label Study of Ofatumumab (GSK1841157) in Patients With Previously Treated Chronic Lymphocytic Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukaemia, Lymphocytic, Chronic
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2010-03-01
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: Ofatumumab is an IgG1κ fully human monoclonal antibody (mAb) that specifically recognizes an epitope on the human differentiation antigen CD20 molecule. In vitro and in vivo studies demonstrated that ofatumumab depletes CD20 positive (CD20+) B cells through complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC), which results in the antitumour effect.

This is an open-label study to evaluate safety, tolerability, efficacy and PK profile of ofatumumab monotherapy in chronic lymphocytic leukemia (CLL) patients. Ofatumumab will be administered intravenously at the first dose of 300mg followed by 7 weekly infusions of 2000mg, followed by 4 infusions of 2000mg at every 4 weeks.

Primary objective of the study (Part A) is to evaluate tolerability, and the study (Part B) is to assess overall response rate in CLL population.

10 subjects will be enrolled into this study. Subjects will be followed for 48 weeks.

Detailed description: Ofatumumab is an IgG1κ fully human monoclonal antibody (mAb) that specifically recognizes an epitope on the human differentiation antigen CD20 molecule. In vitro and in vivo studies demonstrated that ofatumumab depletes CD20 positive (CD20+) B cells through complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC), which results in the antitumour effect.

This is an open-label study to evaluate safety, tolerability, efficacy and PK profile of ofatumumab monotherapy in chronic lymphocytic leukemia (CLL) patients. Ofatumumab will be administered intravenously at the first dose of 300mg followed by 7 weekly infusions of 2000mg, followed by 4 infusions of 2000mg at every 4 weeks.

Primary objective of the study (Part A) is to evaluate tolerability, and the study (Part B) is to assess overall response rate in CLL population.

10 subjects will be enrolled into this study. Subjects will be followed for 48 weeks.

Eligibility criteria: Inclusion Criteria:

Subjects eligible for enrolment in the study must meet all of the following criteria at the time of screening:

* Patients who gave consent to this study participation and signed into informed consent form.
* Previously treated(Patients who received at least one prior CLL therapy and have either relapsed or have refractory disease, both requiring therapy.) CLL with at least 5 x 109 B lymphocytes/ L (5000/μL). The diagnosis of CLL requires CD5, CD19, CD20 and CD23 positivity, according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines \[Hallek, 2008\].
* Laboratory test values meet the following criteria which indicate that patients have sufficient physiological functions;

Neutrophils:1≥ 500 /mm3 ALT ≤ 2.5 times upper local normal limit Creatinine ≤ 1.5 times upper local normal limit Total bilirubin≤ 1.5 times upper local normal limit

1:Patients should not receive any hematopoietic cytokine such as G-CSF preparations within 1 week before screening laboratory test for neutrophil counting.

- Patients who passed the following periods from the last anti-cancer treatments at the time of screening: At least 4 weeks after anti-cancer chemotherapy. At least 4 weeks after anti-cancer radiotherapy. At least 4 weeks after glucocorticoids treatment for CLL unless ≤ 10 mg of prednisolone /day.

At least 12 weeks after radio-immunotherapy and/or antibody therapy.

* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1, or 2.
* Life expectancy more than 24 weeks after screening test.
* Aged ≥ 20 (at the time of signing informed consent).
* 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:

A subject will not be eligible for inclusion in this study if any of the following criteria is met:

* Active malignancy which needs therapy with anti-cancer drug, except for CLL.
* Known Richter's transformation.
* Previous autologous stem cell transplantation, within 24 weeks prior to screening.
* Previous allogenic stem cell transplantation.
* Known CNS involvement.
* History of significant cerebrovascular disease.
* Current cardiac disease requiring medical treatment (e.g. atrial flutter treated with acetylsalicylic acid and beta blocking agents).
* Chronic or active infectious disease requiring systemic (intravenous or oral) treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis and tuberculosis.
* Suspected/known immediate or delayed hypersensitivity to components of ofatumumab.
* Patients previously treated with ofatumumab.
* Positive serology test for any of HBsAg, anti-HBcAb or anti-HCVAb. If only anti-HBcAb results is positive, HBV-DNA test will be performed. If HBV-DNA results in negative, the patient is eligible.
* HIV positivity.
* Pregnant or lactating women.
* Women of childbearing potential not willing to use adequate contraception during the study and one year after the last dose of ofatumumab, and male patients not willing to use adequate contraception during the study. Adequate contraception is defined as follows but not limited to; Abstinence. Oral Contraceptive (exclude oral progesterone alone). Intrauterine device (IUD) or intrauterine system (IUS). Male partner sterilization. Double barrier method: condom or occlusive cap (diaphragm or cervical / vault caps) plus spermicidal agent (gel / film) etc.
* Use of an investigational drug within 4 weeks prior to screening.
* Current participation in any other clinical study.
* Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease.
* Patients who an investigator (or sub investigator) judges ineligible to this study.

Note; Child-bearing potential: a woman with functioning ovaries and uterine, or no documented sterility (i.e., a woman with functioning ovaries who have a current documented tubal ligation, women who have had a hysterectomy, women who are post-menopausal, or women who have had both ovaries surgically removed).

Primary outcomes:
measure: Number of Participants With a Dose-limiting Toxicity (DLT)
timeFrame: Up to Week 8
measure: Percentage of Participants (Par.) With Objective Response (OR), Defined as Complete Remission (CR), CR Incomplete (CRi), Partial Remission (PR), and Nodular PR (nPR) as Assessed by a Safety and Evaluation Review Committee (SERC) and the Investigator
timeFrame: Up to Week 48
Secondary outcomes:
measure: Progression-free Survival (PFS) as Assessed by a SERC
timeFrame: Up to Week 48
measure: Duration of Response as Assessed by a SERC
timeFrame: Up to Week 48
measure: Overall Survival
timeFrame: Up to Week 48
measure: Time to Response as Assessed by a SERC
timeFrame: Up to Week 48
measure: Time to Next Chronic Lymphocytic Leukemia (CLL) Therapy as Assessed by a SERC
timeFrame: Up to Week 48
measure: Mean Laboratory Data for Hemoglobin at the Indicated Weeks as Assessed by the Investigator
timeFrame: Day 1; Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
measure: Mean Laboratory Data for Lymphocytes at the Indicated Weeks as Assessed by the Investigator
timeFrame: Day 1; Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
measure: Mean Laboratory Data for Lymphocytes as a Percentage in the Bone Marrow at the Indicated Weeks as Assessed by the Investigator
timeFrame: Weeks 8, 16, 24, 36, and 48
measure: Mean Laboratory Data for Total Neutrophils (Total Absolute Neutrophil Count [ANC]) at the Indicated Weeks as Assessed by the Investigator
timeFrame: Day 1; Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
measure: Mean Laboratory Data for Platelet Count at the Indicated Weeks as Assessed by the Investigator
timeFrame: Day 1; Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
measure: Percentage of Bone Marrow Infiltration at the Indicated Weeks as Assessed by a SERC
timeFrame: Weeks 8, 16, 24, 36, and 48
measure: Mean Laboratory Data for Lymphocytes at the Indicated Weeks as Assessed by a SERC
timeFrame: Weeks 8, 16, 24, 36, and 48
measure: Mean Laboratory Data for Lymphocytes as a Percentage in the Bone Marrow at the Indicated Weeks as Assessed by a SERC
timeFrame: Weeks 8, 16, 24, 36, and 48
measure: Mean Laboratory Data for Total Neutrophils (Total ANC) at the Indicated Weeks as Assessed by a SERC
timeFrame: Weeks 8, 16, 24, 36, and 48
measure: Number of Peripheral Blood Cluster of Differentiation (CD) CD19+ CD20+ Cells
timeFrame: Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48
measure: Number of Peripheral Blood CD20+ CD23+ Cells
timeFrame: Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48
measure: Number of Peripheral Blood CD19+ CD23+ Cells
timeFrame: Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48
measure: Number of Peripheral Blood CD19+ CD5+ Cells
timeFrame: Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48
measure: Number of Peripheral Blood CD20+ CD5+ Cells
timeFrame: Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48
measure: Number of Peripheral Blood CD23+ CD5+ Cells
timeFrame: Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48
measure: Ratio of Immunoglobulin (Ig) Kappa/Ig Lambda
timeFrame: Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48
measure: Number of Participants With the Indicated Shift From Baseline (BL) in Night Sweats at the Indicated Weeks
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
measure: Number of Participants With the Indicated Shift From Baseline (BL) in Weight Loss at the Indicated Weeks
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
measure: Number of Participants With the Indicated Shift From Baseline (BL) in Fever at the Indicated Weeks
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
measure: Number of Participants With the Indicated Shift From Baseline (BL) in Extreme Fatigue at the Indicated Weeks
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
measure: Mean Change From Baseline in the Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM at Weeks 8, 24, and 48
timeFrame: Baseline and Weeks 8, 24, and 48
measure: Number of Participants Who Tested Positive/Negative for Human Anti-human Antibodies (HAHA) at Screening and at Weeks 24 and 48
timeFrame: Screening; Weeks 24 and 48
measure: Number of Participants With a Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48
measure: Maximum (Peak) Plasma Concentration (Cmax) of Ofatumumab
timeFrame: Day 1; Weeks 7 and 24
measure: Minimum Plasma Concentration (Cmin) of Ofatumumab
timeFrame: Weeks 7 and 24
measure: Time to Reach Cmax (Tmax) Following Ofatumumab Administration
timeFrame: Day 1; Weeks 7 and 24
measure: Half-life (t1/2) of Ofatumumab
timeFrame: Day 1; Weeks 7 and 24
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Time t (AUC[0-t]) for Ofatumumab
timeFrame: Day 1; Weeks 7 and 24
measure: Area Under the Plasma Concentration-time Curve From Time Zero to 168 hr (AUC[0-168]) for Ofatumumab at Week 7
timeFrame: Week 7
measure: Area Under the Plasma Concentration-time Curve From Time Zero to 672 hr (AUC[0-672]) for Ofatumumab at Week 24
timeFrame: Week 24
measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC[0-infinity]) for Ofatumumab
timeFrame: Day 1; Weeks 7 and 24
measure: Clearance (CL) of Ofatumumab From Plasma
timeFrame: Day 1; Weeks 7 and 24
measure: Volume of Distribution (Vz) During the Terminal Phase for Ofatumumab
timeFrame: Day 1; Weeks 7 and 24
measure: Volume of Distribution at Steady State (Vss) for Ofatumumab
timeFrame: Day 1; Weeks 7 and 24
measure: Mean Residence Time (MRTinf) of Ofatumumab
timeFrame: Day 1; Weeks 7 and 24
Other outcomes:
measure: Serum Hemolytic Complement Titer at Weeks 36 and 48: CH50
timeFrame: Weeks 36 and 48
Locations:
city: Aichi
country: Japan
facility: GSK Investigational Site
city: Kanagawa
country: Japan
facility: GSK Investigational Site
city: Nagasaki
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: