Ofatumumab With Fludarabine and Cyclophosphamide in B-CLL Patients

NCT00410163 | Completed Phase 2 Results DMC

• 3 other identifiers: 111774Hx-CD20-407The BIFROST trial
• Study Type: interventional
• Target: 61
• Locations: 2 countries
• Sites: 2

Brief Summary

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

Conditions

Leukaemia, Lymphocytic, Chronic

Keywords

B-cell; cyclophosphamide; fludarabine; Chronic Lymphocytic Leukemia; Ofatumumab

Outcome Measures

Primary Outcomes (2)

• Number of Participants (Par.) With Complete Remission (CR), Measured From Start of Treatment Until 3 Months After Last Infusion

  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.

  Start of treatment (Day 1 of Week 0) until 3 months after start of last infusion (up to Week 32)

• Number of Participants (Par.) Who Were Classified as Responders and Non-responders

  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).

  From start of treatment (Day 1 of Week 0) until 3 months after start of last infusion (up to Week 32)

Secondary Outcomes (16)

• Duration of Response

  From time of initial response to disease progression or death, whichever came first, assessed over 2 years

• Progression-Free Survival

  From time of randomization to first documented evidence of disease progression or death due to any cause, whichever came first, assessed over 2 years

• Time to Next Anti-chronic Lymphocytic Leukemia (CLL) Therapy or Death

  From time of randomization to first administration of next anti-CLL therapy other than ofatumumab or death, assessed over 5 years

• Median Percent Change in Tumor Size From Baseline (Visit 2, Wk 0) at Visits 9, 21, 25, 29, 33, 34, 35, and 37

  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

• 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

  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)

Study Arms (2)

Active Comparator 1

ACTIVE COMPARATOR

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; Drug: Fludarabine; Drug: Cyclophosphamide

Active Comparator 2

ACTIVE COMPARATOR

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; Drug: Fludarabine; Drug: Cyclophosphamide

Interventions

Ofatumumab 500mg DRUG

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.

Active Comparator 1

Ofatumumab 1000mg DRUG

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.

Active Comparator 2

Fludarabine DRUG

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

Active Comparator 1; Active Comparator 2

Cyclophosphamide DRUG

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 1; Active Comparator 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with active B-CLL and with an indication for treatment
• Age ≥ 18 years
• 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

You may not qualify if:

• Any previous treatment for B-CLL or any other treatments that can be considered active against B-CLL
• Glucocorticoid unless given in doses ≤ 10 mg /day for other indications than B-CLL (e.g. asthma)
• Known transformation of B-CLL
• Known CNS involvement of B-CLL
• Past or current malignancy, except for:
• Cervical carcinoma Stage 1B or less
• Non-invasive basal cell and squamous cell skin carcinoma
• Malignant melanoma with a complete response of a duration of \> 10 years
• Other cancer diagnoses with a complete response of a duration of \> 5 years
• Chronic or current infectious disease requiring systemic treatment
• Clinically significant cardiac disease
• Significant concurrent, uncontrolled medical condition
• History of significant cerebrovascular disease
• Known HIV positive
• Positive serology for hepatitis B, unless due to vaccination

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (2)

GSK Investigational Site

Houston, Texas, 77030, United States

Location

GSK Investigational Site

Plymouth, Devon, PL68DH, United Kingdom

Location

Related Publications (3)

• Wierda WG, Kipps TJ, Durig J, Griskevicius L, Stilgenbauer S, Mayer J, Smolej L, Hess G, Griniute R, Hernandez-Ilizaliturri FJ, Padmanabhan S, Gorczyca M, Chang CN, Chan G, Gupta I, Nielsen TG, Russell CA; 407 Study Investigators. Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood. 2011 Jun 16;117(24):6450-8. doi: 10.1182/blood-2010-12-323980. Epub 2011 Apr 15.

  PMID: 21498674 BACKGROUND

• Wierda WG, Kipps TJ, Dürig J, Griskevicius L, Stilgenbauer S, Mayer J et al.. Chemoimmunotherapy with Ofatumumab, Fludarabine and Cyclophosphamide (O-FC) in Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL). [Blood]. 2010;E pub ahead of print:

  BACKGROUND

• Jewell RC, Kipps TJ, Durig J, Griskevicius L, Stilgenbauer S, Smolej L, Mayer J, Hess G, Hernandez-Ilizaliturri FJ, Padmanabhan-Iyer S, Fang L, Goldstein N, Gorczyca M, Gupta I, Lisby S, Wierda WG; Hx-CD20-407 Study Investigators. Associations of ofatumumab exposure and treatment outcomes in patients with untreated CLL receiving chemoimmunotherapy. Leuk Lymphoma. 2017 Feb;58(2):348-356. doi: 10.1080/10428194.2016.1195497. Epub 2016 Jul 7.

  PMID: 27389174 DERIVED

MeSH Terms

Conditions

Leukemia, B-Cell; Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

ofatumumab; fludarabine; Cyclophosphamide

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 11, 2006
• First Posted: December 12, 2006
• Study Start: January 1, 2007
• Primary Completion: March 1, 2009
• Study Completion: May 1, 2013
• Last Updated: February 10, 2014
• Results First Posted: October 17, 2011

Record last verified: 2013-11

Locations

US (1); GB (1)