Phase 2
Completed N=97
Ofatumumab Plus Bendamustine in Frontline and Relapsed Chronic Lymphocytic Leukaemia (CLL)
Source: ClinicalTrials.gov NCT01520922 ↗Enrolled (actual)
97
Serious AEs
46.4%
Results posted
Dec 2013
Primary outcomePrimary: Number of Participants With Overall Response (OR), as Assessed by the Investigator — 19; 6; 2; 2 Participants
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants With Overall Response (OR), as Assessed by the Investigator |
19; 6; 2; 2; 4; 8 | — |
| SECONDARY Number of Participants With Overall Response (OR) With Computed Tomography (CT) Scan (CT Scan) Assessment, as Assessed by the Investigator |
12; 5; 1; 2; 2; 6 | — |
| SECONDARY 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 |
19; 6; 12; 5 | — |
| SECONDARY Investigator-assessed Kaplan-meier Estimates of Time to Response |
0.95; 1.08 | — |
| SECONDARY Investigator-assessed Kaplan-meier Estimates of Duration of Response |
35.15; 21.75 | — |
| SECONDARY Investigator-assessed of Kaplan-meier Estimates of Progression-free Survival (PFS) |
36.07; 22.54 | — |
| SECONDARY Investigator-assessed Kaplan-meier Estimates of Overall Survival |
NA; NA | — |
| SECONDARY Investigator-Assessed Kaplan-Meier Estimates of Time to Progression |
36.0; 22.67 | — |
| SECONDARY Time to Next Therapy |
31.18; 16.82 | — |
| SECONDARY Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) |
43; 50; 20; 25 | — |
| SECONDARY Change From Baseline in the Immunoglobulin (Ig) Antibodies to End of Study Treatment |
0.0768; 0.0540; -0.714; -1.246; -0.0490; -0.0463 | — |
| SECONDARY Change From Baseline in Cluster of Differentiation (CD) CD5+CD19+ Cell Counts up to 36 Months |
-72622.5; -40644.2; -61258.2; -45630.4; -76688.7; -49527.3 | — |
| SECONDARY Change From Baseline in Cluster of Differentiation (CD) CD5-CD19+ Cell Counts up to 36 Months |
-5800.8; -2052.4; -3921.1; -3822.8; -5969.7; -2288.4 | — |
| SECONDARY 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 |
7; 4; 9; 0; 1; 1 | — |
| SECONDARY Number of Participants Who Received no Transfusion or at Least One Transfusion During the Study |
38; 33; 6; 20 | — |
| SECONDARY Number of Participants With Autoimmune Hemolytic Anaemia (AIHA) Disease |
0; 1 | — |
| SECONDARY Number of Participants With the Indicated Grade 3 or Grade 4 Myelosuppression (Anemia, Neutropenia, and Thrombocytopenia), as Assessed by the Investigator |
8; 27; 9; 16; 1; 2 | — |
| SECONDARY Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Event of Infection |
5; 10 | — |
| SECONDARY Number of Participants With the Indicated Constitutional or B-symptoms |
19; 22; 4; 5; 1; 2 | — |
| SECONDARY Number of Participants With the Indicated Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) |
16; 23; 28; 29; 0; 1 | — |
| SECONDARY Number of Participants With Confirmed Positive Response for Human Anti-human Antibodies (HAHA) at the Indicated Time Points |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Maximum Decrease in Sum of the Product of the Diameter (SPD) From Baseline in Participants With Lymphadenopathy at Baseline |
-83.5; -77.3; -92.1; -90.9; -99.1; -94.6 | — |
| SECONDARY Number of Participants With the Indicated Reduction in Organomegaly (Spleen and Liver) |
23; 31; 21; 19; 0; 0 | — |
| SECONDARY Number of Participants With the Indicated Cytogenetics Testing at Baseline Who Also Had a Clinical Response After Last Dose of Study Treatment |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY 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 |
9; 3; 3; 2; 4; 6 | — |
| SECONDARY 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 |
6; 4; 2; 0; 0; 4 | — |
| SECONDARY 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 |
1; 1; 0; 0; 0; 0 | — |
| SECONDARY Number of Participants With an Adverse Event of Any Infusion Reactions (IR) or Serious Infusion Reactions (SIR) |
30; 34; 3; 4; 30; 35 | — |
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 s
Data sourced from ClinicalTrials.gov (NCT01520922). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.