Clinical trial NCT01520922: Ofatumumab Plus Bendamustine in Frontline and Relapsed Chronic Lymphocytic Leukaemia (CLL)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia (CLL)
Leukaemia, Lymphocytic, Chronic
Keywords: Relapsed or Refractory Chronic Lymphocytic Leukemia
Chronic Lymphocytic Leukemia
CLL
Cancer
Lymphoid leukemia
Lymphoblastic leukemia
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-01-30
Enrollment: 99
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Number of Participants With Overall Response (OR), as Assessed by the Investigator
timeFrame: From the start of study treatment until 3 months after the last dose of study treatment
Secondary outcomes:
measure: Number of Participants With Overall Response (OR) With Computed Tomography (CT) Scan (CT Scan) Assessment, as Assessed by the Investigator
timeFrame: From the start of study treatment until 3 months after the last dose of study treatment
measure: Number of Participants With Complete Response (CR) With and Without a CT Scan Assessment After the Last Dose of Study Treatment, as Assessed by the Investigator
timeFrame: From the start of study treatment until 3 months after the last dose of study treatment
measure: Investigator-assessed Kaplan-meier Estimates of Time to Response
timeFrame: From the start of study treatment to the first response (CR, CRi, nPR, or PR) (up to 3 Month Follow-up (F/U) visit)
measure: Investigator-assessed Kaplan-meier Estimates of Duration of Response
timeFrame: From time of initial response (CR, CRi, nPR, or PR) to disease progression or death, whichever came first (up to 3 years after the last doseof study treatment)
measure: Investigator-assessed of Kaplan-meier Estimates of Progression-free Survival (PFS)
timeFrame: From the start of study treatment until earliest date of disease progression or death (up to 3 years after the last dose of study treatment)
measure: Investigator-assessed Kaplan-meier Estimates of Overall Survival
timeFrame: From the start of study treatment to the date of death due to any cause (up to 3 years after the last dose of study treatment)
measure: Investigator-Assessed Kaplan-Meier Estimates of Time to Progression
timeFrame: From the start of study treatment to disease progression (up to 3 years after the last dose of study treatment)
measure: Time to Next Therapy
timeFrame: From the start of study treatment until the start of the next anti-CLL therapy (up to 3 years after the last dose of study treatment)
measure: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
timeFrame: From first dose of study medication to 60 days after the last dose of study medication (if the event is considered as an AE), or up to 3 years after the last dose of study treatment or until the time of the next anti-CLL therapy, if considered a SAE
measure: Change From Baseline in the Immunoglobulin (Ig) Antibodies to End of Study Treatment
timeFrame: Baseline and end of study treatment (up to 30 months)
measure: Change From Baseline in Cluster of Differentiation (CD) CD5+CD19+ Cell Counts up to 36 Months
timeFrame: Baseline, 3-Month Follow-up to 36-Month Follow-up (in 3 months interval)
measure: Change From Baseline in Cluster of Differentiation (CD) CD5-CD19+ Cell Counts up to 36 Months
timeFrame: Baseline, 3-Month Follow-up to 36-Month Follow-up (in 3 months interval)
measure: Number of Participants Who Were Negative or Positive for Minimal Residual Disease (MRD) and Achieved a Bone Marrow Biopsy Confirmed Complete Response (CR) up to 36-Month Follow-up
timeFrame: 3 month follow up to the 36 Month Follow-up (in 3 month interval)
measure: Number of Participants Who Received no Transfusion or at Least One Transfusion During the Study
timeFrame: From start of treatment until earliest date of disease progression or death (up to 3 years after the last dose of study treatment)
measure: Number of Participants With Autoimmune Hemolytic Anaemia (AIHA) Disease
timeFrame: From first dose of study medication to 60 days after the last dose of study medication (if the event is considered as an AE), or up to 3 years after the last dose of study treatment or until the time of the next anti-CLL therapy, if considered a SAE
measure: Number of Participants With the Indicated Grade 3 or Grade 4 Myelosuppression (Anemia, Neutropenia, and Thrombocytopenia), as Assessed by the Investigator
timeFrame: From the first dose of study medication to 60 days after the last dose of study medication
measure: Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Event of Infection
timeFrame: From first dose of study medication to 60 days after the last dose of study medication (if the event is considered as an AE), or up to 3 years after the last dose of study treatment or until the time of the next anti-CLL therapy, if considered a SAE
measure: Number of Participants With the Indicated Constitutional or B-symptoms
timeFrame: Screening (SCR), Cycle 3 Day 1 (C3D1), Cycle 6 Day 1 (C6D1), 12, 24 and 36 Month Follow-up (F/U)
measure: Number of Participants With the Indicated Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
timeFrame: Baseline (BL), Cycle 3 Day 1 (C3D1), Cycle 6 Day 1 (C6D1), 12, 24 and 36 month follow up (F/U)
measure: Number of Participants With Confirmed Positive Response for Human Anti-human Antibodies (HAHA) at the Indicated Time Points
timeFrame: Cycle 1 Day 1 (C1D1), Cycle 6 Day 1 (C6D1), 6-Month Follow-up (F/U), and any post-dose time point
measure: Maximum Decrease in Sum of the Product of the Diameter (SPD) From Baseline in Participants With Lymphadenopathy at Baseline
timeFrame: Baseline, Cycle 2 Day 1 (C2D1), Cycle 3 Day 1 (C3D1), Cycle 4 Day 1 (C4D1), Cycle 5 Day 1 (C5D1), Cycle 6 Day 1 (C6D1), 3-Month Follow-Up (F/U), 6-Month F/U and 9-Month F/U
measure: Number of Participants With the Indicated Reduction in Organomegaly (Spleen and Liver)
timeFrame: Screening (Scr), Cycle 3 Day 1 (C3D1), Cycle 6 Day 1 (C6D1), 12, 24 and 36 -Month Follow-Up (F/U)
measure: Number of Participants With the Indicated Cytogenetics Testing at Baseline Who Also Had a Clinical Response After Last Dose of Study Treatment
timeFrame: From the start of study treatment until earliest date of disease progression or death (up to up to 3 months following last dose of study treatment)
measure: Number of Participants With the Indicated Beta 2 Microglobulin (B2M) at Baseline Who Also Had a Clinical Response After the Last Dose of Study Treatment
timeFrame: From the start of study treatment until earliest date of disease progression or death (up to up to 3 months following last dose of study treatment)
measure: Number of Participants With the Indicated Immunoglobulin Heavy Chain Variable Region (IgVH) Testing at Baseline Who Also Had a Clinical Response After Last Dose of Study Treatment
timeFrame: From the start of study treatment until earliest date of disease progression or death (up to up to 3 months following last dose of study treatment)
measure: Number of Participants With Zeta-chain-associated Protein Kinase (ZAP) 70 Testing at Baseline Who Also Had a Clinical Response After Last Dose of Study Treatment
timeFrame: From the start of study treatment until earliest date of disease progression or death (up to 3 months following last dose of study treatment)
measure: Number of Participants With an Adverse Event of Any Infusion Reactions (IR) or Serious Infusion Reactions (SIR)
timeFrame: From the first dose of study medication to 60 days after the last dose of study medication (up to 24 hours after last dose of study treatment)
Other outcomes:
Locations:
city: Tuscon
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Aurora
country: United States
facility: Novartis Investigative Site
state: Colorado
city: Fort Myers
country: United States
facility: Novartis Investigative Site
state: Florida
city: St. Petersburg
country: United States
facility: Novartis Investigative Site
state: Florida
city: Nashville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Ogden
country: United States
facility: Novartis Investigative Site
state: Utah
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Brno
country: Czech Republic
facility: Novartis Investigative Site
city: Hradec Kralove
country: Czech Republic
facility: Novartis Investigative Site
city: Olomouc
country: Czech Republic
facility: Novartis Investigative Site
city: Praha 2
country: Czech Republic
facility: Novartis Investigative Site
city: Athens,
country: Greece
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
city: Modena
country: Italy
facility: Novartis Investigative Site
state: Emilia-Romagna
city: Roma
country: Italy
facility: Novartis Investigative Site
state: Lazio
city: Roma
country: Italy
facility: Novartis Investigative Site
state: Lazio
city: Milano
country: Italy
facility: Novartis Investigative Site
state: Lombardia
city: Novara
country: Italy
facility: Novartis Investigative Site
state: Piemonte
city: Torino
country: Italy
facility: Novartis Investigative Site
state: Piemonte
city: Chorzow
country: Poland
facility: Novartis Investigative Site
city: Slupsk
country: Poland
facility: Novartis Investigative Site
city: Wroclaw
country: Poland
facility: Novartis Investigative Site
city: Kazan
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Novosibirsk
country: Russian Federation
facility: Novartis Investigative Site
city: St'Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: St. Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Majadahonda (Madrid)
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.