Ofatumumab Plus Bendamustine in Frontline and Relapsed Chronic Lymphocytic Leukaemia (CLL)

NCT ID: NCT01520922

Last Updated: 2017-01-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 99 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-03-31
• Study Completion Date: 2015-11-30

Brief Summary

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.

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).

The studies primary endpoint is overall response rate (ORR) as determined by Investigator evaluation. The ORR is the percentage of subjects achieving an objective response (i.e., partial response or better), using the IWCLL updated NCI-WG guidelines. Response assessments are 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.

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. Following progression, only survival status and details concerning the subject's next CLL therapy will be recorded.

Detailed Description

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.

Conditions

Chronic Lymphocytic Leukemia (CLL); Leukaemia, Lymphocytic, Chronic

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Ofatumumab plus bendamustine

In this single arm, Phase II study, each patient who is willing to participate and is found eligible according to the inclusion and exclusion criteria will enter the treatment phase. Eligible subjects will be allocated to receive the following study treatments depending upon their previous CLL treatment status: 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 intravenous infusions of bendamustine (90 mg/m2, Days 1 and 2; every 28 Days). 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 intravenous infusions of bendamustine (70 mg/m2, Days 1 and 2; every 28 Days).

Group Type: EXPERIMENTAL

Ofatumumab

Intervention Type: BIOLOGICAL

Ofatumumab (ARZERRA™) is an immunoglobulin G1κ (IgG1κ) human monoclonal antibody that specifically recognises a distinct epitope encompassing both large and small extracellular loops on the human CD20 molecule expressed on B cells and binds to this site with high affinity with a dissociation half-life of approximately 3 hours. Ofatumumab induces more efficient complement-dependent cytotoxicity (CDC) mediated cell lysis in vitro, compared to rituximab, especially in low CD20 density cells.

Bendamustine

Intervention Type: DRUG

Bendamustine is a cytostatic drug which structurally combines a purine-like benzamidazol nucleus and a bifunctional alkylating nitrogen mustard group.

Interventions

Ofatumumab

Ofatumumab (ARZERRA™) is an immunoglobulin G1κ (IgG1κ) human monoclonal antibody that specifically recognises a distinct epitope encompassing both large and small extracellular loops on the human CD20 molecule expressed on B cells and binds to this site with high affinity with a dissociation half-life of approximately 3 hours. Ofatumumab induces more efficient complement-dependent cytotoxicity (CDC) mediated cell lysis in vitro, compared to rituximab, especially in low CD20 density cells.

Intervention Type: BIOLOGICAL

Bendamustine

Bendamustine is a cytostatic drug which structurally combines a purine-like benzamidazol nucleus and a bifunctional alkylating nitrogen mustard group.

Intervention Type: DRUG

Other Intervention Names

Arzerra; Bendamustine hydrochloride; Levact; Ribomustin; Treanda

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Tuscon, Arizona, United States

Novartis Investigative Site

Aurora, Colorado, United States

Novartis Investigative Site

Fort Myers, Florida, United States

Novartis Investigative Site

St. Petersburg, Florida, United States

Novartis Investigative Site

Nashville, Tennessee, United States

Novartis Investigative Site

Ogden, Utah, United States

Novartis Investigative Site

Brussels, , Belgium

Novartis Investigative Site

Ghent, , Belgium

Novartis Investigative Site

Leuven, , Belgium

Novartis Investigative Site

Brno, , Czechia

Novartis Investigative Site

Hradec Králové, , Czechia

Novartis Investigative Site

Olomouc, , Czechia

Novartis Investigative Site

Prague, , Czechia

Novartis Investigative Site

Athens, , Greece

Novartis Investigative Site

Thessaloniki, , Greece

Novartis Investigative Site

Modena, Emilia-Romagna, Italy

Novartis Investigative Site

Rome, Lazio, Italy

Novartis Investigative Site

Rome, Lazio, Italy

Novartis Investigative Site

Milan, Lombardy, Italy

Novartis Investigative Site

Novara, Piedmont, Italy

Novartis Investigative Site

Turin, Piedmont, Italy

Novartis Investigative Site

Chorzów, , Poland

Novartis Investigative Site

Słupsk, , Poland

Novartis Investigative Site

Wroclaw, , Poland

Novartis Investigative Site

Kazan', , Russia

Novartis Investigative Site

Moscow, , Russia

Novartis Investigative Site

Novosibirsk, , Russia

Novartis Investigative Site

Saint Petersburg, , Russia

Novartis Investigative Site

St'Petersburg, , Russia

Novartis Investigative Site

Barcelona, , Spain

Novartis Investigative Site

Barcelona, , Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Majadahonda (Madrid), , Spain

Countries

United States; Belgium; Czechia; Greece; Italy; Poland; Russia; Spain

References

Flinn IW, Panayiotidis P, Afanasyev B, Janssens A, Grosicki S, Homenda W, Smolej L, Kuliczkowski K, Doubek M, Domnikova N, West SL, Chang CN, Barker AM, Gupta IV, Wright OJ, Offner F. A phase 2, multicenter study investigating ofatumumab and bendamustine combination in patients with untreated or relapsed CLL. Am J Hematol. 2016 Sep;91(9):900-6. doi: 10.1002/ajh.24430. Epub 2016 Jul 3.

Reference Type: DERIVED

PMID: 27222473 (View on PubMed)

Other Identifiers

2011-005178-43

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

115991

Identifier Type: -

Identifier Source: org_study_id