A Phase II, Multi-centre Study Investigating the Safety and Efficacy of Ofatumumab and Bendamustine Combination in Patients With Untreated or Relapsed Chronic Lymphocytic Leukaemia (CLL)
18 Years
N/A
Both
Leukaemia, Lymphocytic, Chronic
Trial Information
A Phase II, Multi-centre Study Investigating the Safety and Efficacy of Ofatumumab and Bendamustine Combination in Patients With Untreated or Relapsed Chronic Lymphocytic Leukaemia (CLL)
This is a Phase II, open label, single arm, multi-centre study investigating the safety and
efficacy of ofatumumab plus bendamustine in subjects with untreated or relapsed CLL.
The primary objective of this study is to evaluate the investigator assessed overall
response rate (ORR), using the International Workshop for Chronic Lymphocytic Leukaemia
(IWCLL) updated National Cancer Institute-sponsored Working Group (NCIWG) guidelines, in two
populations i.e., subjects with previously untreated CLL and subjects with relapsed CLL
administered ofatumumab plus bendamustine.
Secondary objectives are to evaluate the overall response rate with computed tomography scan
(CT scan) assessment, complete response rate with and without CT scan assessment,
progression free survival, overall survival, duration of response, safety and tolerability,
disease, prognostic and biological marker correlation with clinical response in the two
populations i.e., subjects with previously untreated CLL and subjects with relapsed CLL
administered ofatumumab plus bendamustine.
Exploratory objectives are to investigate the relationship between genetic variants in host
DNA and the efficacy, safety and/or tolerability of ofatumumab.
Each subject from the screening phase who is willing to participate in the study and is
found eligible according to the inclusion and exclusion criteria will enter the treatment
phase and will receive a maximum of 6 Cycles of study treatment (ofatumumab plus
bendamustine). All subjects will receive 3 Cycles of study treatment (Cycles 1, 2 and 3).
Eligibility to receive study treatment for Cycles 4, 5 and 6 will be assessed following the
3rd Cycle. Subjects who have achieved at least stable disease with acceptable toxicity
following 3 Cycles of treatment will be eligible to continue to receive study treatments for
a maximum of 3 further Cycles. In case of progressive disease, at, or at any time after the
start of Cycle 4, subjects must discontinue further study treatment and move into the
study's follow-up period.
During the treatment phase, all eligible subjects will be allocated to receive the following
study treatments:
1. Subjects with Untreated CLL: Up to 6 monthly intravenous infusions of ofatumumab (Cycle
1: 300 mg Day 1 and 1000 mg Day 8; subsequent Cycles: 1000 mg at Day 1 every 28 Days)
in combination with up to 6 Cycles of intravenously infused bendamustine (90 mg/m2,
Days 1 and 2, every 28 Days).
2. Subjects with Relapsed CLL: Up to 6 monthly intravenous infusions of ofatumumab (Cycle
1: 300 mg Day 1 and 1000 mg Day 8; subsequent Cycles: 1000 mg at Day 1 every 28 Days)
in combination with up to 6 Cycles of intravenously infused bendamustine (70 mg/m2,
Days 1 and 2, every 28 Days).
Prior to each treatment Cycle, subjects must have an absolute neutrophil count > 1.0 x
109/L, a platelet count > 75 x 109/L, and must have recovered to Grade 1 or baseline from
all clinically significant non-hematologic toxicities, other than nausea, vomiting or
alopecia. If these retreatment criteria are not met, a treatment delay of up to 28 Days is
permitted; thereafter, study treatment with bendamustine and ofatumumab must be
discontinued. In cases of delays up to 14 Days, bendamustine treatment should be continued
at the same dosage, but in case of a delay between 15-28 Days, the dosage of bendamustine
must be reduced to 60 mg/m2 for all subsequent treatment Cycles for subjects recruited to
the study with previously untreated CLL and 50 mg/m2 for all subsequent treatment Cycles for
subjects recruited to the study with relapsed CLL.
Additionally, if within any Cycle, a subject develops a clinically significant Grade 3/4
non-hematologic toxicity, other than nausea, vomiting or alopecia, an absolute neutrophil
count < 1.0 x 109/L, or a platelet count < 50% of the pre-treatment value, the bendamustine
dose will also be reduced as stated above for all subsequent treatment Cycles.
Blood samples, lymph node examination, spleen and liver measurements, and constitutional
symptom evaluations are performed monthly throughout the treatment phase. A bone marrow
examination is required to confirm complete response (CR) at least two months after the
final study treatment and when a subject fulfils the IWCLL updated NCI-WG requirements for
CR. CT-Scans will also be performed, at least two months after the final study treatment,
for subjects achieving a CR or partial response (PR) according to the IWCLL updated NCI-WG
requirements. Follow-up assessments will be performed every 3 months following the last
study treatment. The follow-up period will last for a maximum of 3 years. Response
evaluation assessments to determine subject response or progression will be performed during
the follow-up period, according to the IWCLL updated NCI-WG guidelines [Hallek, 2008].
Following progression, only survival status and details concerning the subject's next CLL
therapy will be recorded.
Inclusion Criteria:
- A diagnosis of CLL defined by a circulating B-lymphocyte count of greater than or
equal to 5,000/uL at study entry or at any time in the past and flow cytometry
confirmation of immunophenotype with CD5, CD19, CD20, CD23, CD79b, and surface Ig
prior to first dose of study treatment.
- Active disease and indication for treatment based on the IWCLL updated NCI-WG
guidelines, defined by presence of at least any one of the following conditions:
Evidence of progressive marrow failure as manifested by development or worsening of
anaemia 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 a
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 greater than or equal to 10% within the previous six
months; b. Fevers greater than 100.5°F (38.0°C) for greater than or equal to 2 Weeks
without evidence of infection; Or c. Night sweats for more than 1 month without
evidence of infection.
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
- Age greater than or equal to 18 years.
- Signed written informed consent from either the subject, or their legally acceptable
representative if the subject is incapable of giving their own consent, prior to
performing any study-specific tests or procedures.
- Subjects enrolled into the previously untreated subject cohort must also meet all of
the following criteria: No prior treatment for CLL (prior corticosteroid
immunosuppression treatment for autoimmune hemolytic anaemia and idiopathic
thrombocytopenic purpura (ITP) is permitted); Be considered inappropriate for
fludarabine-based therapy for reasons that include, but are not limited to, advanced
age or presence of co-morbidities.
- Subjects enrolled into the relapsed subject cohort must also meet the following
criteria: Relapsed CLL: defined as a subject who has received at least one prior CLL
therapy and previously achieved a complete or partial remission/response lasting at
least 6 months.
Exclusion Criteria:
- Refractory CLL: defined as treatment failure (failure to achieve a CR or PR) or
disease progression within 6 months of the last anti-CLL therapy.
- Previous autologous or allogeneic stem cell transplantation.
- Active autoimmune hemolytic anaemia (AIHA) and idiopathic thrombocytopenic purpura
(ITP) requiring corticosteroid therapy greater than 25 mg prednisone (or equivalent)
or chemotherapy.
- Known transformation of CLL (e.g. Richter's).
- Known central nervous system involvement by CLL. Screening laboratory values:
Platelets less than 100 x 109/L (unless due to CLL involvement of the bone marrow).
Neutrophils less than 1.5 x 109/L (unless due to CLL involvement of the bone marrow).
Serum creatinine greater than 1.5 times the upper limit of normal (ULN); subjects
with a serum creatinine greater than 1.5 x ULN will be eligible if the calculated
creatinine clearance [Cockcroft, 1976] is greater than or equal to 30 mL/min. Total
bilirubin greater than 1.5 times ULN (unless due to liver involvement by CLL or
Gilbert's disease). Transaminases greater than 2.5 times ULN.
- 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, active
Hepatitis C, and known Human Immunodeficiency Virus (HIV) disease. All HIV-positive
subjects are excluded from this study, regardless of whether they have an Acquired
Immunodeficiency Syndrome (AIDS) defining disease and/or are on antiviral therapy.
- Other past or current malignancy (with the exception of basal cell carcinoma of the
skin or in situ carcinoma of the cervix or breast) unless the tumour was successfully
treated with curative intent at least 2 years prior to trial entry.*
- Clinically significant cardiac disease including unstable angina, acute myocardial
infarction within 6 months prior to first study treatment, 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 less than or equal to 25mg/Day prednisone
(or equivalent) for less than 7 Days for exacerbations other than CLL (e.g. asthma).*
- Positive serology for Hepatitis B (HB) defined as a positive test for Hepatitis B
surface antigen (HBsAg). In addition, if negative for HBsAg but Hepatitis B core
antibody (HBcAb) positive, a Hepatitis B Virus (HBV) DNA test will be performed and
if positive the subject will be excluded.
- Known or suspected hypersensitivity to ofatumumab or bendamustine that in the opinion
of the investigator 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 first study treatment dose, whichever is
longer, or participation in any other interventional clinical study.
- Known or suspected inability to comply with the 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 ofatumumab dose. Adequate contraception is defined as abstinence, oral
hormonal birth control, implants of levonorgestrel, estrogenic vaginal ring,
percutaneous contraceptive patches, intrauterine device, and male partner
sterilisation if male partner is sole partner for that subject. For females in the
USA, the use of a double barrier method is also considered adequate (condom or
occlusive cap plus spermicidal agent).
- Subjects can participate in the study if in the opinion of the investigator it
is thought not to affect the subject's safety, the conduct of the study or the
interpretation of the data.
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Overall response rate (ORR)
Outcome Description:
Overall Response Rate (ORR) with CT-scan assessment as determined by Investigator evaluation, is the percentage of subjects achieving an objective response (i.e., partial response or better), using the IWCLL updated NCI-WG guidelines. Response assessment is planned at the following time-points: After 3 Cycles of ofatumumab plus bendamustine treatment, after 6 Cycles of ofatumumab plus bendamustine treatment and after the last dose, if not after 6 cycles, of ofatumumab plus bendamustine treatment.
Outcome Time Frame:
Approximately 19 Months
Safety Issue:
No
Principal Investigator
GSK Clinical Trials
Investigator Role:
Study Director
Investigator Affiliation:
GlaxoSmithKline
Authority:
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Study ID:
115991
NCT ID:
NCT01520922
Start Date:
March 2012
Completion Date:
May 2016
Related Keywords:
- Leukaemia, Lymphocytic, Chronic
- Leukemia
- Leukemia, Lymphocytic, Chronic, B-Cell
- Leukemia, Lymphoid
Name | Location |
|---|---|
| GSK Investigational Site | Phoenix, Arizona 85013 - 4496 |
| GSK Investigational Site | Gainesville, Florida 32610 |
| GSK Investigational Site | Germantown, Tennessee 38138 |
| GSK Investigational Site | Aurora, Colorado 80012 |
| GSK Investigational Site | Salt Lake City, Utah 84107 |
