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)
Overview
- Phase
- Phase 2
- Intervention
- Ofatumumab
- Conditions
- Chronic Lymphocytic Leukemia (CLL)
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 99
- Locations
- 1
- Primary Endpoint
- Number of Participants With Overall Response (OR), as Assessed by the Investigator
- Status
- Completed
- Last Updated
- 9 years ago
Overview
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:
- 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).
- 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.
Investigators
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-
- •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).\*
Arms & Interventions
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).
Intervention: Ofatumumab
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).
Intervention: Bendamustine
Outcomes
Primary Outcomes
Number of Participants With Overall Response (OR), as Assessed by the Investigator
Time Frame: From the start of study treatment until 3 months after the last dose of study treatment
OR is defined as the number of participants achieving an objective response (complete response \[CR\], CR with incomplete bone marrow recovery \[CRi\], partial response \[PR\], and nodular PR \[nPR\]), after 3 cycles, after 6 cycles, and after the last dose of ofatumumab and bendamustine treatment. CR (all the criteria at least 2 months after last treatment): no lymphadenopathy (Ly)/ hepatomegaly/ splenomegaly/ constitutional symptoms; neutrophils \>1500 per microliter (µL), platelets (PL) \>100,000/µL, hemoglobin (Hb) \>11 grams/deciliter (g/dL), lymphocytes (LC) \<4000/µL, bone marrow (BM) sample must be normocellular for age, \<30% LC, no lymphoid nodule. CRi: CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. PR: \>=50% decrease in LC, Ly, size of liver and spleen and at least one of the following results: PL \>100,000/µL or 50% improvement over Baseline (BL), Hb \>11 g/dL or 50% improvement over BL, LC \<4000/µL. nPR: persistent nodules BM.
Secondary Outcomes
- Investigator-assessed Kaplan-meier Estimates of Duration of Response(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))
- Investigator-Assessed Kaplan-Meier Estimates of Time to Progression(From the start of study treatment to disease progression (up to 3 years after the last dose of study treatment))
- Number of Participants With Overall Response (OR) With Computed Tomography (CT) Scan (CT Scan) Assessment, as Assessed by the Investigator(From the start of study treatment until 3 months after the last dose of study treatment)
- Number of Participants Who Received no Transfusion or at Least One Transfusion During the Study(From start of treatment until earliest date of disease progression or death (up to 3 years after the last dose of study treatment))
- Investigator-assessed Kaplan-meier Estimates of Time to Response(From the start of study treatment to the first response (CR, CRi, nPR, or PR) (up to 3 Month Follow-up (F/U) visit))
- 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(From the start of study treatment until 3 months after the last dose of study treatment)
- Investigator-assessed of Kaplan-meier Estimates of Progression-free Survival (PFS)(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))
- Investigator-assessed Kaplan-meier Estimates of Overall Survival(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))
- Time to Next Therapy(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))
- Number of Participants With the Indicated Constitutional or B-symptoms(Screening (SCR), Cycle 3 Day 1 (C3D1), Cycle 6 Day 1 (C6D1), 12, 24 and 36 Month Follow-up (F/U))
- Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)(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)
- Number of Participants With the Indicated Cytogenetics Testing at Baseline Who Also Had a Clinical Response After Last Dose of Study Treatment(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))
- 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(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))
- 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(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))
- Number of Participants With Autoimmune Hemolytic Anaemia (AIHA) Disease(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)
- 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(From the start of study treatment until earliest date of disease progression or death (up to 3 months following last dose of study treatment))
- Change From Baseline in the Immunoglobulin (Ig) Antibodies to End of Study Treatment(Baseline and end of study treatment (up to 30 months))
- Change From Baseline in Cluster of Differentiation (CD) CD5+CD19+ Cell Counts up to 36 Months(Baseline, 3-Month Follow-up to 36-Month Follow-up (in 3 months interval))
- Change From Baseline in Cluster of Differentiation (CD) CD5-CD19+ Cell Counts up to 36 Months(Baseline, 3-Month Follow-up to 36-Month Follow-up (in 3 months interval))
- 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(3 month follow up to the 36 Month Follow-up (in 3 month interval))
- Number of Participants With the Indicated Grade 3 or Grade 4 Myelosuppression (Anemia, Neutropenia, and Thrombocytopenia), as Assessed by the Investigator(From the first dose of study medication to 60 days after the last dose of study medication)
- Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Event of Infection(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)
- Number of Participants With Confirmed Positive Response for Human Anti-human Antibodies (HAHA) at the Indicated Time Points(Cycle 1 Day 1 (C1D1), Cycle 6 Day 1 (C6D1), 6-Month Follow-up (F/U), and any post-dose time point)
- Number of Participants With the Indicated Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)(Baseline (BL), Cycle 3 Day 1 (C3D1), Cycle 6 Day 1 (C6D1), 12, 24 and 36 month follow up (F/U))
- Maximum Decrease in Sum of the Product of the Diameter (SPD) From Baseline in Participants With Lymphadenopathy at Baseline(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)
- Number of Participants With the Indicated Reduction in Organomegaly (Spleen and Liver)(Screening (Scr), Cycle 3 Day 1 (C3D1), Cycle 6 Day 1 (C6D1), 12, 24 and 36 -Month Follow-Up (F/U))
- Number of Participants With an Adverse Event of Any Infusion Reactions (IR) or Serious Infusion Reactions (SIR)(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))