A Phase I/II, a Single Arm, Open-label Study of Ofatumumab (GSK1841157) in Patients With Previously Treated Chronic Lymphocytic Leukemia

Phase 2

Completed

Conditions: Leukaemia, Lymphocytic, Chronic

Interventions: Drug: ofatumumab 100 mg, 1000 mg / vial

Registration Number: NCT01077622

Lead Sponsor: GlaxoSmithKline

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 10

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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
2000 mg dose	ofatumumab 100 mg, 1000 mg / vial	ofatumumab , 300mg followed by 7 weekly infusions 2000 mg, followed by 4 monthly infusions 2000mg

Primary Outcome Measures

Name	Time	Method
Number of Participants With a Dose-limiting Toxicity (DLT)	Up to Week 8	A DLT was defined as the following toxicological findings, according to the Common Terminology Criteria for Adverse Events (AE) v3.0: any treatment-related Grade (G) \>=3 non-hematotoxic AE, occurrence of G3 infusion reaction (treatment-related AE) at the day of infusion in a participant who received pre-medication or appropriate management during infusion (glucocorticoid) (the severity of the AE must have remained as \>= G3 until the next day); and any of following: \>= G4 hematotoxic treatment-related AEs (neutropenia lasting 7 days or more, febrile neutropenia).
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	Up to Week 48	Par. were evaluated in accordance with the National Cancer Institute-sponsored Working Group. CR: no lymphadenopathy (Ly)/hepatomegaly/splenomegaly/constitutional symptoms; neutrophils \>=1.5\10\^9/liter (L), platelets \>100\10\^9/L, hemoglobin \>11.0 grams/deciliter, lymphocytes (LC) \<4.0\*10\^9/L, bone marrow (BM) sample must be normocellular for age, \<30% LC, no lymphoid nodule. CRi: CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to chronic lymphocytic leukemia but related to drug toxicity. PR: \>=50% decrease in LC, Ly, size of liver and spleen, etc. nPR: nodules in BM.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS) as Assessed by a SERC	Up to Week 48	PFS is defined as the time from the start of treatment to the first documented sign of progressive disease (PD) or death due to any cause (whichever occurs earlier).
Duration of Response as Assessed by a SERC	Up to Week 48	Duration of response is defined as the time from the first documented evidence of PR or better until the first documented sign of PD or death due to any reason in participants with PR or better.
Overall Survival	Up to Week 48	Overall survival is defined as the time from the first infusion of investigational drug to death due to any cause.
Time to Response as Assessed by a SERC	Up to Week 48	Time to response is defined as the time from the first infusion of investigational drug to the first response (PR or better).
Time to Next Chronic Lymphocytic Leukemia (CLL) Therapy as Assessed by a SERC	Up to Week 48	Time to next CLL therapy is defined as the time from the first infusion of investigational drug to the first administration of the next CLL treatment. CLL therapy includes anti-cancer chemotherapy, anti-cancer radiotherapy, radio-immunotherapy, and antibody therapy.
Mean Laboratory Data for Hemoglobin at the Indicated Weeks as Assessed by the Investigator	Day 1; Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48	Blood samples of the participants were collected for the assessment of hemoglobin.
Mean Laboratory Data for Lymphocytes at the Indicated Weeks as Assessed by the Investigator	Day 1; Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48	Blood samples of the participants were collected for the assessment of lymphocytes.
Mean Laboratory Data for Lymphocytes as a Percentage in the Bone Marrow at the Indicated Weeks as Assessed by the Investigator	Weeks 8, 16, 24, 36, and 48	Bone marrow (BM) aspiration was performed, and the bone marrow smears were prepared for the assessment of lymphocytes in the BM.
Mean Laboratory Data for Total Neutrophils (Total Absolute Neutrophil Count [ANC]) at the Indicated Weeks as Assessed by the Investigator	Day 1; Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48	Blood samples of the participants were collected for the assessment of total neutrophils.
Mean Laboratory Data for Platelet Count at the Indicated Weeks as Assessed by the Investigator	Day 1; Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48	Blood samples of the participants were collected for the assessment of platelets.
Percentage of Bone Marrow Infiltration at the Indicated Weeks as Assessed by a SERC	Weeks 8, 16, 24, 36, and 48	SERC assessed bone marrow infiltration with the bone marrow smears of participants provided by trial sites.
Mean Laboratory Data for Lymphocytes at the Indicated Weeks as Assessed by a SERC	Weeks 8, 16, 24, 36, and 48	SERC assessed lymphocytes based on the data provided by trial sites.
Mean Laboratory Data for Lymphocytes as a Percentage in the Bone Marrow at the Indicated Weeks as Assessed by a SERC	Weeks 8, 16, 24, 36, and 48	SERC assessed lymphocytes in the bone marrow (BM) based on the data with BM smears provided by trial sites.
Mean Laboratory Data for Total Neutrophils (Total ANC) at the Indicated Weeks as Assessed by a SERC	Weeks 8, 16, 24, 36, and 48	SERC assessed total neutrophils based on the data provided by trial sites.
Number of Peripheral Blood Cluster of Differentiation (CD) CD19+ CD20+ Cells	Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48	CD19+ CD20+ cells in the peripheral blood were counted as measures of malignant B-cells and were measured by flow cytometry. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus.
Number of Peripheral Blood CD20+ CD23+ Cells	Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48	CD20+ CD23+ cells in the peripheral blood were counted as measures of malignant B-cells and were measured by flow cytometry. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus.
Number of Peripheral Blood CD19+ CD23+ Cells	Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48	CD19+ CD23+ cells in the peripheral blood were counted as measures of malignant B-cells and were measured by flow cytometry. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus.
Number of Peripheral Blood CD19+ CD5+ Cells	Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48	CD19+ CD5+ cells in the peripheral blood were counted as measures of malignant B-cells and were measured by flow cytometry. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus.
Number of Peripheral Blood CD20+ CD5+ Cells	Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48	CD20+ CD5+ cells in the peripheral blood were counted as measures of malignant B-cells and were measured by flow cytometry. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus.
Number of Peripheral Blood CD23+ CD5+ Cells	Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48	CD23+ CD5+ cells in the peripheral blood were counted as measures of malignant B-cells and were measured by flow cytometry. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus.
Ratio of Immunoglobulin (Ig) Kappa/Ig Lambda	Day 1; Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 36, and 48	Peripheral blood Ig kappa and Ig lambda were measured using flow cytometry. Abnormality of a ratio of Ig kappa and Ig lambda indicates clonality of lymphocytes. A normal range of this parameter is between 1.0 and 3.2.
Number of Participants With the Indicated Shift From Baseline (BL) in Night Sweats at the Indicated Weeks	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48	Night sweats are one of the clinical characteristics of CLL. B symptoms are systemic symptoms of fever, night sweats, weight loss, and extreme fatigue, which can be associated with CLL. Participants who had night sweats at BL, and still had night sweats at Week 1, for example, are represented in the BL, yes; Week 1, yes category. Participants who had night sweats at BL, but did not have night sweats at Week 1 are represented in the BL, yes; Week 1, no category.
Number of Participants With the Indicated Shift From Baseline (BL) in Weight Loss at the Indicated Weeks	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48	Weight loss is one of the clinical characteristics of CLL. B symptoms are systemic symptoms of fever, night sweats, weight loss, and extreme fatigue, which can be associated with CLL. Participants who had weight loss at BL, and still had weight loss at Week 1, for example, are represented in the BL, yes; Week 1, yes category. Participants who had weight loss at BL, but did not have weight loss at Week 1 are represented in the BL, yes; Week 1, no category.
Number of Participants With the Indicated Shift From Baseline (BL) in Fever at the Indicated Weeks	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48	Fever is one of the clinical characteristics of CLL. B symptoms are systemic symptoms of fever, night sweats, weight loss, and extreme fatigue, which can be associated with CLL. Participants who had fever at BL, and still had fever at Week 1, for example, are represented in the BL, yes; Week 1, yes category. Participants who had fever at BL, but did not have fever at Week 1 are represented in the BL, yes; Week 1, no category.
Number of Participants With the Indicated Shift From Baseline (BL) in Extreme Fatigue at the Indicated Weeks	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48	Extreme fatigue is one of the clinical characteristics of CLL. B symptoms are systemic symptoms of fever, night sweats, weight loss, and extreme fatigue, which can be associated with CLL. Participants who had extreme fatigue at BL, and still had extreme fatigue at Week 1, for example, are represented in the BL, yes; Week 1, yes category. Participants who had extreme fatigue at BL, but did not have extreme fatigue at Week 1 are represented in the BL, yes; Week 1, no category.
Mean Change From Baseline in the Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM at Weeks 8, 24, and 48	Baseline and Weeks 8, 24, and 48	Immunoglobulins, or antibodies, are large proteins used by the immune system to identify and neutralize foreign particles such as bacteria and viruses. Their normal blood levels indicate proper immune status. Low levels indicate immuno-suppression. IgA, IgG, and IgM were measured in the blood samples of the participants.
Number of Participants Who Tested Positive/Negative for Human Anti-human Antibodies (HAHA) at Screening and at Weeks 24 and 48	Screening; Weeks 24 and 48	HAHA are indicators of immunogenicity to ofatumumab.
Number of Participants With a Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 28, 36, and 48	ECOG PS is used to assess how a participant's disease is progressing, to assess how the disease affects the daily living abilities of the participant, and to determine appropriate treatment and prognosis. The grades for the scale range from 0 (fully active) to 4 (completely disabled), with increasing severity.
Maximum (Peak) Plasma Concentration (Cmax) of Ofatumumab	Day 1; Weeks 7 and 24	Blood sampling on Day 1 and at Weeks 7 and 24 for pharmacokinetic (PK) evaluation was performed at the following time points: 0.5 hour (hr) before infusion; end of infusion; and 10 minutes (min), 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.
Minimum Plasma Concentration (Cmin) of Ofatumumab	Weeks 7 and 24	Blood sampling at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), 120 hr (5 days), 168 hr (7 days), and 336 hr (14 days) after infusion of ofatumumab.
Time to Reach Cmax (Tmax) Following Ofatumumab Administration	Day 1; Weeks 7 and 24	Blood sampling on Day 1 and at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.
Half-life (t1/2) of Ofatumumab	Day 1; Weeks 7 and 24	t1/2 of ofatumumab is the time required for the plasma concentration of ofatumumab to decrease by half. Blood sampling on Day 1 and at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.
Area Under the Plasma Concentration-time Curve From Time Zero to Time t (AUC[0-t]) for Ofatumumab	Day 1; Weeks 7 and 24	AUC(0-t) was evaluated from the plasma concentration versus time curve from time zero to the last measurable time point (time t). Blood sampling on Day 1 and at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.
Area Under the Plasma Concentration-time Curve From Time Zero to 168 hr (AUC[0-168]) for Ofatumumab at Week 7	Week 7	Blood sampling at Week 7 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), 120 hr (5 days), 168 hr (7 days), and 336 hr (14 days) after infusion of ofatumumab.
Area Under the Plasma Concentration-time Curve From Time Zero to 672 hr (AUC[0-672]) for Ofatumumab at Week 24	Week 24	Blood sampling at Week 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), 120 hr (5 days), 168 hr (7 days), and 336 hr (14 days) after infusion of ofatumumab.
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC[0-infinity]) for Ofatumumab	Day 1; Weeks 7 and 24	Blood sampling on Day 1 and at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.
Clearance (CL) of Ofatumumab From Plasma	Day 1; Weeks 7 and 24	CL of ofatumumab from plasma of participants was evaluated. Blood sampling on Day 1 and at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.
Volume of Distribution (Vz) During the Terminal Phase for Ofatumumab	Day 1; Weeks 7 and 24	Vz for ofatumumab was calculated as a ratio of the amount of ofatumumab in the body during the terminal phase to the plasma concentration during the terminal phase. Blood sampling on Day 1 and at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.
Volume of Distribution at Steady State (Vss) for Ofatumumab	Day 1; Weeks 7 and 24	Vss for ofatumumab was calculated as a ratio of the amount of ofatumumab in the body in equilibrium conditions to steady-state plasma concentrations. Blood sampling on Day 1 and at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.
Mean Residence Time (MRTinf) of Ofatumumab	Day 1; Weeks 7 and 24	MRTinf is the average amount of time that ofatumumab spends in the body. Blood sampling on Day 1 and at Weeks 7 and 24 for PK evaluation was performed at the following time points: 0.5 hr before infusion; end of infusion; and 10 min, 1 hr, 2 hr, 24 hr (1 day), 72 hr (3 days), and 120 hr (5 days) after infusion of ofatumumab. At Weeks 7 and 24, blood sampling was also performed 168 hr (7 days) and 336 hr (14 days) after infusion of ofatumumab.