Ofatumumab With Fludarabine and Cyclophosphamide in B-CLL Patients (BIFROST)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00410163
First received: December 11, 2006
Last updated: December 19, 2013
Last verified: November 2013
  Purpose

To investigate the safety and efficacy of two dose regimes of ofatumumab in combination with chemotherapy in previously untreated patients with B-CLL


Condition Intervention Phase
Leukaemia, Lymphocytic, Chronic
Drug: Ofatumumab 500mg
Drug: Ofatumumab 1000mg
Drug: Fludarabine
Drug: Cyclophosphamide
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-labeled, Randomized, Two-dose, Parallel Group Trial of Ofatumumab, a Fully Human Monoclonal Anti-CD20 Antibody, in Combination With Fludarabine and Cyclophosphamide, in Patients With Previously Untreated B-cell CLL

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Number of Participants (Par.) With Complete Remission (CR), Measured From Start of Treatment Until 3 Months After Last Infusion [ Time Frame: Start of treatment (Day 1 of Week 0) until 3 months after start of last infusion (up to Week 32) ] [ Designated as safety issue: No ]
    Par. were evaluated for response by an Independent Endpoint Review Committee (IRC) in accordance with the National Cancer Institute-sponsored Working Group (NCI-WG) 1996 guideline. Par. with Complete Remission (CR) were classified as "complete responders". As per NCI-WG, CR requires all of the following criteria for a period of >=2 months: absence of lymphadenopathy (all lymph nodes <1.0 centimeters), no hepatomegaly/splenomegaly, absence of constitutional symptoms, lymphocytes <=4.0*10^9/liter (L), neutrophil leukocytes >=1.5*10^9/L, platelets >100*10^9/L, and hemoglobin >11 grams/deciliter.

  • Number of Participants (Par.) Who Were Classified as Responders and Non-responders [ Time Frame: From start of treatment (Day 1 of Week 0) until 3 months after start of last infusion (up to Week 32) ] [ Designated as safety issue: No ]
    Par. were evaluated by an IRC in accordance with NCI-WG 1996 guideline. Responders: CR, Nodular Partial Remission (nPR, same as CR, but persistent bone marrow nodules), and Partial Remission (PR, >=50% decrease in lymphocytes from pretreatment baseline (BL) value, >=50% reduction in lymphadenopathy, >=50% reduction of liver/spleen and neutrophils >= 1.5*10^9/L or platelets >100*10^9/L or hemoglobin >11 g/dL (or 50% improvement over BL for neutrophils, platelets, hemoglobin); non-responders: Stable Disease (SD, did not achieve CR/PR, and no PD), Progressive Disease (PD), or Not Evaluable (NE).


Secondary Outcome Measures:
  • Duration of Response [ Time Frame: From time of initial response to disease progression or death, whichever came first, assessed over 2 years ] [ Designated as safety issue: No ]
    The duration of response was defined as the time from the initial response (the first visit at which response was observed) to progression or death. For participants who were lost to follow-up, duration of response was censored at the date of the last attended visit at which the endpoint was assessed.

  • Progression-Free Survival [ Time Frame: From time of randomization to first documented evidence of disease progression or death due to any cause, whichever came first, assessed over 2 years ] [ Designated as safety issue: No ]
    Progression-free survival (PFS) was defined as the time from randomization until the first radiologically or clinically documented evidence of progression or death due to any cause, if sooner. For participants who were lost to follow-up, PFS was censored at the date of the last attended visit at which the endpoint was assessed. The Kaplan-Meier method was used to estimate PFS.

  • Time to Next Anti-chronic Lymphocytic Leukemia (CLL) Therapy or Death [ Time Frame: From time of randomization to first administration of next anti-CLL therapy other than ofatumumab or death, assessed over 5 years ] [ Designated as safety issue: No ]
    Time to next anti-CLL (anti-lymphoma) therapy was defined as the time from randomization until the time of first administration of the next anti-lymphoma therapy other than ofatumumab or death. For participants who were lost to follow-up, the time was censored at the date of the last attended visit at which the endpoint was assessed.

  • Median Percent Change in Tumor Size From Baseline (Visit 2, Wk 0) at Visits 9, 21, 25, 29, 33, 34, 35, and 37 [ Time Frame: Baseline Visit 2 (Week [Wk] 0); Visits 9 (Wk 4), 21 (Wk 12), 25 (Wk 16), 29 (Wk 20), 33 (Month [M] 1 after start of last infusion [LI]), 34 (M 3 after start of LI), 35 (M 6 after start of LI), 36 (M 9 after start of LI), and 37 (M 12 after start of L ] [ Designated as safety issue: No ]
    Tumor size was measured by physical examination of palpable abnormal lymph nodes. Percent change from Baseline (Visit 2, Week 0) = (value at indicated visits minus value at Visit 2 divided by value at Visit 2) * 100. Visits 33, 34, 35, 36, and 37 are measured in the number of months from the start of the last infusion. The start of the last infusion could have occurred up to Week 20.

  • Median Percent Change in CD5+CD19+ and CD5+CD20+ Cells in Peripheral Blood From Onset of Course 3 Throughout Follow-up (FU) Compared to Screening [ Time Frame: Baseline Visit 2 (Week [Wk] 0); Visits 15 (Wk 8), 21 (Wk 12), 25 (Wk 16), 29 (Wk 20), 33 (Month [M] 1 after start of last infusion [LI]), 34 (M 3 after start of LI) ] [ Designated as safety issue: No ]
    Malignant B cells (CD5+CD19+ and CD5+CD20+) were measured in peripheral blood samples by flow cytometry. Percent change from Screening (Visit 1, Week -2) = (value at indicated visits minus value at Visit 1 divided by value at Visit 1) * 100. Visits 33 and 34 are measured in the number of months from the start of the last infusion. The start of the last infusion could have occurred up to Week 20.

  • Number of Participants Who Experienced Any Adverse Event From First Treatment (Visit 2) to Visit 43 (Month 60) [ Time Frame: From first treatment (Visit 2) up to Visit 43 (Month 60) ] [ Designated as safety issue: Yes ]
    An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. A list of AEs experienced in the study at a frequency threshold of 5% can be found in the AE section.

  • Number of Participants With Positive Human Anti-human Anti Bodies (HAHA) at Visits 1, 21, 35, and 39 [ Time Frame: Visits 1 (Screening, Visit -2), 21 (Week 12), 35 (Month 6), and 39 (Month 18) ] [ Designated as safety issue: No ]
    HAHA are indicators of immunogenicity to ofatumumab. Blood samples were drawn from participants at Visits 1, 21, 35, and 39 for analysis of HAHA. Analysis of HAHA was done in batches.

  • Number of Participants Who Reported Myelosuppression (Anemia, Leukopenia, Neutropenia, and Thrombocytopenia) [ Time Frame: From first treatment (Visit 2) up to Visit 43 (Month 60) ] [ Designated as safety issue: No ]
    Myelosuppression is one of the expected AEs for FC treatment and is defined as the decrease in the ability of the bone marrow to produce blood cells. The number of participants with myelosuppression was assessed from laboratory measurements with Grades 3(severe)-4 (life-threatening/disabling) (1, mild; 2, moderate; 5, death) according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. The CTCAE is issued by the National Cancer Institute (NCI) and is the standard classification used for the severity grading scale for AEs in cancer therapy clinical studies.

  • Percent Change From Screening (Visit 1) in Complement (CH50) Levels at Visit 9 (Week 4) [ Time Frame: Visit 1 (Week -2) and Visit 9 (Week 4) ] [ Designated as safety issue: No ]
    Blood samples were drawn from participants at Visits 1 and 9 for analysis of complement (CH50) levels. Analysis of CH50 was done in batches, and CH50 levels were measured two hours after the end of study medication infusion. Percent change from Screening (Visit 1, Week -2) = (value at Visit 9 minus value at Visit 1 divided by value at Visit 1) * 100.

  • Number of Participants Classified as Responders Having CR Who Tested Negative for Minimal Residual Disease (MRD) [ Time Frame: From start of treatment (Day 1 of Week 0) until 3 months after start of last infusion (up to course 6 or Week 32) ] [ Designated as safety issue: No ]
    MRD refers to small number of leukemic cells that remain in the participant during treatment or after treatment when the participant has achieved CR. For all participants who achieved CR, the follow-up bone marrow sample was tested for malignant B cells (CD5+CD19+) to determine if there was any MRD.

  • Ctrough and Cmax at the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20) [ Time Frame: Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose) ] [ Designated as safety issue: No ]
    Cmax is defined as the maximum concentration of drug in plasma samples. Ctrough is defined as the trough plasma concentration (measured concentration at the end of a dosing interval [taken directly before next administration]). No drug is present before the first infusion; therefore, there are no Ctrough results for the first infusion.

  • AUC(0-inf) and AUC(0-672) After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20) [ Time Frame: Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose) ] [ Designated as safety issue: No ]
    AUC is defined as the area under the ofatumumab concentration-time curve as a measure of drug exposure. AUC(0-672) is AUC from start of infusion to 672 hours after start of infusion; AUC(0-inf) is AUC from start of infusion extrapolated to infinity.

  • t1/2 After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20) [ Time Frame: Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose) ] [ Designated as safety issue: No ]
    t1/2 is defined as terminal half-life and is the time required for the amount of drug in the body to decrease by half.

  • CL After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20) [ Time Frame: Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose) ] [ Designated as safety issue: No ]
    CL is the clearance of drug from plasma, which is defined as the volume of plasma from which the drug is cleared per unit time.

  • Vss After the First Infusion (Visit 2, Week 0) and Sixth Infusion (Visit 29, Week 20) [ Time Frame: Visit 2 (Week 0; up to 4 weeks after dose) and Visit 29 (Week 20; up to 9 months after dose) ] [ Designated as safety issue: No ]
    Vss is defined as the volume of distribution at steady state of ofatumumab.

  • Number of Participants With Progression or Death [ Time Frame: From time of randomization to first documented evidence of disease progression or death due to any cause, whichever came first, assessed over 2 years ] [ Designated as safety issue: No ]
    Disease progression is characterized by at least one of the following, per the Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic Leukemia: a >=50% increase in the sum of the products of at least two lymph nodes on two consecutive determinations 2 weeks apart (at least one node must be >=2 centimeters); or the appearance of new palpable lymph nodes; or a >=50% increase in liver and/or spleen size (measurement below the costal margin); or the appearance of palpable hepatomegaly or splenomegaly not previously present; or a >=50% increase in the numbers of circulating lymphocytes to at least 5.0 * 10^9/Liter; or transformation to a more aggressive histology (e.g., Richter's syndrome or prolymphocytic leukemia with >55% prolymphocytes). For participants who were lost to follow-up, PFS was censored at the date of the last attended visit at which the endpoint was assessed. The Kaplan-Meier method was used to estimate PFS.


Enrollment: 61
Study Start Date: January 2007
Study Completion Date: May 2013
Primary Completion Date: March 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Active Comparator 1
Each patient will receive a total of 6 infusions with ofatumumab every 4 weeks in combination with fludarabine and cyclophosphamide. The first infusion will be 300mg followed by 5 infusions of 500mg
Drug: Ofatumumab 500mg
Ofatumumab 500mg or should be diluted into 1000mL pyrogenefree saline and administered as an IV infusion.Duration of infusion will be approximately 6½ hours.Infusions should be given every 4 weeks until a total of 6 infusions has been given.
Drug: Fludarabine
Fludarabine (25 mg/m2) should be administered as an IV infusion daily, Days 2 through 4 of Course 1, and Days 1 through 3 of Courses 2 through 6, every 4 weeks for 6 courses
Drug: Cyclophosphamide
Cyclophosphamide (250 mg/m2) should be administered as an IV infusion daily, Days 2 through 4 of Course 1, and Days 1 through 3 of Courses 2 through 6, every 4 weeks for 6 courses.
Active Comparator: Active Comparator 2
Each patient will receive a total of 6 monthly infusions with ofatumumab in combination with fludarabine and cyclophosphamide. The first infusion will be 300mg followed by 5 infusions of 1000mg
Drug: Ofatumumab 1000mg
Ofatumumab 1000mg or should be diluted into 1000mL pyrogenefree saline and administered as an IV infusion.Duration of infusion will be approximately 6½ hours.Infusions should be given every 4 weeks until a total of 6 infusions has been given.
Drug: Fludarabine
Fludarabine (25 mg/m2) should be administered as an IV infusion daily, Days 2 through 4 of Course 1, and Days 1 through 3 of Courses 2 through 6, every 4 weeks for 6 courses
Drug: Cyclophosphamide
Cyclophosphamide (250 mg/m2) should be administered as an IV infusion daily, Days 2 through 4 of Course 1, and Days 1 through 3 of Courses 2 through 6, every 4 weeks for 6 courses.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with active B-CLL and with an indication for treatment
  2. Age ≥ 18 years
  3. Following receipt of verbal and written information about the study, the patient must provide signed informed consent before any study related activity is carried out

Exclusion Criteria:

  1. Any previous treatment for B-CLL or any other treatments that can be considered active against B-CLL
  2. Glucocorticoid unless given in doses ≤ 10 mg /day for other indications than B-CLL (e.g. asthma)
  3. Known transformation of B-CLL
  4. Known CNS involvement of B-CLL
  5. Past or current malignancy, except for:

    1. Cervical carcinoma Stage 1B or less
    2. Non-invasive basal cell and squamous cell skin carcinoma
    3. Malignant melanoma with a complete response of a duration of > 10 years
    4. Other cancer diagnoses with a complete response of a duration of > 5 years
  6. Chronic or current infectious disease requiring systemic treatment
  7. Clinically significant cardiac disease
  8. Significant concurrent, uncontrolled medical condition
  9. History of significant cerebrovascular disease
  10. Known HIV positive
  11. Positive serology for hepatitis B, unless due to vaccination
  12. Leukapheresis, except as a safety measure before chemotherapy
  13. ECOG Performance Status of 3 or 4
  14. Patients who at the time of inclusion are not expected to be able to complete the ofatumumab-FC regimen
  15. Patients who have received treatment with any non-marketed drug substance or experimental therapy within 4 weeks prior to Visit 1
  16. Current participation in any other interventional clinical study
  17. Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder)
  18. Breast feeding women or women with a positive pregnancy test at Visit 1
  19. Women of childbearing potential not willing to use adequate contraception for up to one year after last dose of ofatumumab. Adequate contraception is defined as hormonal birth control or intrauterine device. For patients in the USA the use of a double barrier method is also considered adequate.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00410163

Locations
United States, Texas
GSK Investigational Site
Houston, Texas, United States, 77030
United Kingdom
GSK Investigational Site
Plymouth, Devon, United Kingdom, PL68DH
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Publications:
Wierda WG, Kipps TJ, Durig J, Griskevicius L, Stilgenbauer S, Mayer J, et.al, Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood 2011 June 16; 117: 6450-6458

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00410163     History of Changes
Other Study ID Numbers: 111774, Hx-CD20-407, The BIFROST trial
Study First Received: December 11, 2006
Results First Received: July 28, 2011
Last Updated: December 19, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
B-cell
cyclophosphamide
fludarabine
Chronic Lymphocytic Leukemia
Ofatumumab

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Immune System Diseases
Immunoproliferative Disorders
Leukemia, B-Cell
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Antibodies, Monoclonal
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Vidarabine
Alkylating Agents
Anti-Infective Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Antiviral Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014