Ofatumumab Plus Bendamustine in Frontline and Relapsed Chronic Lymphocytic Leukaemia (CLL)

NCT01520922 | Completed Phase 2 Results

• 2 other identifiers: 1159912011-005178-43
• Study Type: interventional
• Target: 99
• Locations: 8 countries
• Sites: 33

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. 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. 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).

Conditions

Chronic Lymphocytic Leukemia (CLL); Leukaemia, Lymphocytic, Chronic

Keywords

Relapsed or Refractory Chronic Lymphocytic Leukemia; Chronic Lymphocytic Leukemia; CLL; Cancer; Lymphoid leukemia; Lymphoblastic leukemia

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Overall Response (OR), as Assessed by the Investigator

  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.

  From the start of study treatment until 3 months after the last dose of study treatment

Secondary Outcomes (27)

• 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 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 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)

• 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 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)

Study Arms (1)

Ofatumumab plus bendamustine

EXPERIMENTAL

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).

Biological: Ofatumumab; Drug: Bendamustine

Interventions

Ofatumumab BIOLOGICAL

Ofatumumab (ARZERRA™) is an immunoglobulin G1κ (IgG1κ) human monoclonal antibody that specifically recognises a distinct epitope encompassing both large and small extracellular loops on the human CD20 molecule expressed on B cells and binds to this site with high affinity with a dissociation half-life of approximately 3 hours. Ofatumumab induces more efficient complement-dependent cytotoxicity (CDC) mediated cell lysis in vitro, compared to rituximab, especially in low CD20 density cells.

Also known as: Arzerra

Ofatumumab plus bendamustine

Bendamustine DRUG

Bendamustine is a cytostatic drug which structurally combines a purine-like benzamidazol nucleus and a bifunctional alkylating nitrogen mustard group.

Also known as: Bendamustine hydrochloride, Levact, Ribomustin, Treanda

Ofatumumab plus bendamustine

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (33)

Novartis Investigative Site

Tuscon, Arizona, 85719, United States

Location

Novartis Investigative Site

Aurora, Colorado, 80045, United States

Location

Novartis Investigative Site

Fort Myers, Florida, 33916, United States

Location

Novartis Investigative Site

St. Petersburg, Florida, 33705, United States

Location

Novartis Investigative Site

Nashville, Tennessee, 37203, United States

Location

Novartis Investigative Site

Ogden, Utah, 84403, United States

Location

Novartis Investigative Site

Brussels, 1200, Belgium

Location

Novartis Investigative Site

Ghent, 9000, Belgium

Location

Novartis Investigative Site

Leuven, 3000, Belgium

Location

Novartis Investigative Site

Brno, 625 00, Czechia

Location

Novartis Investigative Site

Hradec Králové, Czechia

Location

Novartis Investigative Site

Olomouc, 775 20, Czechia

Location

Novartis Investigative Site

Prague, 128 08, Czechia

Location

Novartis Investigative Site

Athens, 11 527, Greece

Location

Novartis Investigative Site

Thessaloniki, 564 29, Greece

Location

Novartis Investigative Site

Modena, Emilia-Romagna, 41124, Italy

Location

Novartis Investigative Site

Rome, Lazio, 00161, Italy

Location

Novartis Investigative Site

Rome, Lazio, 00168, Italy

Location

Novartis Investigative Site

Milan, Lombardy, 20122, Italy

Location

Novartis Investigative Site

Novara, Piedmont, 28100, Italy

Location

Novartis Investigative Site

Turin, Piedmont, 10126, Italy

Location

Novartis Investigative Site

Chorzów, 41-500, Poland

Location

Novartis Investigative Site

Słupsk, 76-200, Poland

Location

Novartis Investigative Site

Wroclaw, 50-367, Poland

Location

Novartis Investigative Site

Kazan', 420029, Russia

Location

Novartis Investigative Site

Moscow, 115478, Russia

Location

Novartis Investigative Site

Novosibirsk, 630087, Russia

Location

Novartis Investigative Site

Saint Petersburg, 197 089, Russia

Location

Novartis Investigative Site

St'Petersburg, 191024, Russia

Location

Novartis Investigative Site

Barcelona, 08035, Spain

Location

Novartis Investigative Site

Barcelona, 08036, Spain

Location

Novartis Investigative Site

Madrid, 28006, Spain

Location

Novartis Investigative Site

Majadahonda (Madrid), 28222, Spain

Location

Related Publications (1)

• 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.

  PMID: 27222473 DERIVED

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, B-Cell; Recurrence; Neoplasms; Leukemia, Lymphoid; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

ofatumumab; Bendamustine Hydrochloride

Condition Hierarchy (Ancestors)

Leukemia; Neoplasms by Histologic Type; 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)

Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

trialandresults.registries@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

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

Study Design

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

Study Record Dates

• First Submitted: January 19, 2012
• First Posted: January 30, 2012
• Study Start: March 1, 2012
• Primary Completion: February 1, 2013
• Study Completion: November 1, 2015
• Last Updated: January 19, 2017
• Results First Posted: December 16, 2013

Record last verified: 2016-11

Locations

BE (3); PL (3); RU (5); GR (2); IT (6); ES (4); CZ (4); US (6)