Clinical trial NCT00748189: Ofatumumab + Chlorambucil vs Chlorambucil Monotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia
Official title: A Phase III, Open Label, Randomized, Multicenter Trial of Ofatumumab Added to Chlorambucil Versus Chlorambucil Monotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Leukaemia, Lymphocytic, Chronic
Keywords: Safety
Untreated
Efficacy
Chronic Lymphocytic Leukemia
Chronic Lymphocytic Leukemia (CLL), untreated
Ofatumumab
Oncology
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2008-09-08
Enrollment: 447
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to evaluate the safety and efficacy of ofatumumab added to chlorambucil in patients with untreated Chronic Lymphocytic Leukemia.

Detailed description: Chlorambucil, is currently approved for treatment of frontline chronic lymphocytic leukemia, especially, but not limited to the ailing and elderly patient population. Several other more aggressive treatment options are available (e.g. fludarabine), however they are not suitable for all CLL patients, especially the ailing and elderly, due to greater toxicity. Ofatumumab is effective with low toxicity. The addition of ofatumumab to chlorambucil offers potentially a more effective therapy, with limited toxicity. The objective of this study was to evaluate progression-free survival (PFS), overall response and overall survival in subjects with previously untreated CLL with ofatumumab added to chlorambucil versus chlorambucil.

Eligibility criteria: Inclusion Criteria:

* confirmed CLL diagnosis and active CLL requiring treatment
* considered inappropriate for fludarabine-based therapy
* not been treated for CLL before
* fully active at a minimum or fully capable of selfcare and up and about more than 50% of waking hours
* age 18yrs or older
* signed written informed consent

Exclusion Criteria:

* prior CLL therapy
* abnormal/inadequate blood values, liver, and kidney function
* certain heart problems, active or chronic infections, serious significant diseases, active autoimmune hemolytic anemia (AIHA) requiring treatment, other current cancer or within last 5 years
* CLL transformation
* CLL central nervous system involvement
* current participation in other clinical study
* inability to comply with the protocol activities
* lactating or pregnant women or female patients of child-bearing potential (or male patients with such partners) not willing to use adequate contraception

Primary outcomes:
measure: Progression-Free Survival (PFS), as Assessed by the Independent Review Committee (IRC)
timeFrame: From randomization to the date of first documented disease progression or death due to any cause, whichever occured first, reported between day of first patient randomized up to about 49 months
Secondary outcomes:
measure: Number of Participants With the Best Overall Response (OR), as Assessed by the IRC
timeFrame: From randomization until the 259th PFS event occurred, up to about 49 months
measure: Number of Participants Who Were Negative for Minimal Residual Disease (MRD)
timeFrame: From randomization until the 259th PFS event occurred (Median follow-up approximately 28.9 months)
measure: Overall Survival
timeFrame: From randomization up to about 111 months
measure: Time to Response, as Assessed by the IRC
timeFrame: From randomization uo to about 27 months
measure: Duration of Response (DOR), as Assessed by the IRC
timeFrame: From randomization up to about 43 months
measure: Time to Progression, as Assessed by the IRC
timeFrame: From randomization up to about 49 months
measure: Time to Next Therapy
timeFrame: From randomization up to about 49 months
measure: Number of Participants With Improvement in ECOG Performance Status of 0 or 1
timeFrame: Baseline, Cycle 3 Day 1, 1 month Follow-up
measure: Number of Participants With Improvement in Constitutional Symptoms (CS)
timeFrame: Baseline, Cycle 3 Day 1, and 1 month Follow-up
measure: Number of Participants With a Human Anti-human Antibody (HAHA) Positive Result
timeFrame: Baseline, Cycle 4 Day 1, 1 Month Follow-up, and 6 Month Follow-up
measure: Cmax and Ctrough of Ofatumumab
timeFrame: Cycle 1 Day 1,Cycle 1 Day 8, Cycle 2 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, and Cycle 9 Day 1
measure: Total Plasma Clearance (CL) of Ofatumumab
timeFrame: Cycle 4 Day 1
measure: AUC(0-tau) of Ofatumumab
timeFrame: Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 4 Day 1
measure: Volume of Distribution at Steady State (Vss) of Ofatumumab
timeFrame: Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 4 Day 1
measure: Plasma Half Life (t1/2) of Ofatumumab
timeFrame: Cycle 4 Day 1
measure: Dose-normalized Cmax of Chlorambucil and Phenylacetic Acid Mustard (PAAM)
timeFrame: Cycle 3 Day 1
measure: Dose-normalized AUC(0-6) and AUC(0-inf) of Chlorambucil and Dose-normalized AUC(0-6) of Phenylacetic Acid Mustard (PAAM)
timeFrame: Cycle 3 Day 1
measure: Change From Baseline in Health Related Quality of Life (HRQOL)
timeFrame: Baseline, Cycle 4 day 1, cycle 7 day 1, 1 month follow-up, 6 month follow-up, 12 month follow-up
measure: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
timeFrame: From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy, up to approximately 111 months.
measure: Number of Participants With AEs and SAEs of Maximum Severity of Grade 3 or Higher
timeFrame: From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy, up to approximately 111 months.
measure: Number of Participants With at Least One Grade 3/Grade 4 Myelosuppression (Anemia, Neutropenia, and Thrombocytopenia)
timeFrame: From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy, up to approximately 111 months.
measure: Number of Participants With Autoimmune Hemolytic Anaemia (AIHA) Disease
timeFrame: From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy, up to approximately 111 months.
measure: Number of Participants Who Received no Transfusion or at Least One Transfusion During the Study
timeFrame: From start of treatment to the last study visit/withdrawal visit (Median follow-up approximately 28.9 months)
measure: Mean Change From Baseline in the Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM
timeFrame: From start of treatment up to 30 days after last treatment
Other outcomes:
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facility: Novartis Investigative Site
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city: Murrieta
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city: San Antonio
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city: Erlangen
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state: Hessen
city: Kassel
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facility: Novartis Investigative Site
state: Hessen
city: Hannover
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facility: Novartis Investigative Site
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city: Lehrte
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facility: Novartis Investigative Site
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city: Essen
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facility: Novartis Investigative Site
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city: Koeln
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facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Moenchengladbach-Rheydt
country: Germany
facility: Novartis Investigative Site
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city: Muenster
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city: Saarbruecken
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city: Athens,
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city: Mumbai
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city: Cork
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city: Dublin
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city: Galway
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city: James Street
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city: Waterford
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city: Potenza
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state: Basilicata
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state: Campania
city: Albano Laziale (Roma)
country: Italy
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city: Genova
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state: Liguria
city: Brescia
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state: Lombardia
city: Milano
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city: Milano
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city: Novara
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country: Russian Federation
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country: Russian Federation
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city: Barcelona
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facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Hospitalet de Llobregat (Barcelona)
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Salamanca
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
city: Lulea
country: Sweden
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Uppsala
country: Sweden
facility: Novartis Investigative Site
city: Plymouth
country: United Kingdom
facility: Novartis Investigative Site
state: Devon
city: Taunton
country: United Kingdom
facility: Novartis Investigative Site
state: Somerset
city: Sunderland
country: United Kingdom
facility: Novartis Investigative Site
state: Tyne
city: Bath
country: United Kingdom
facility: Novartis Investigative Site
city: Belfast
country: United Kingdom
facility: Novartis Investigative Site
city: Birmingham
country: United Kingdom
facility: Novartis Investigative Site
city: Bournemouth
country: United Kingdom
facility: Novartis Investigative Site
city: Bradford
country: United Kingdom
facility: Novartis Investigative Site
city: Cambridge
country: United Kingdom
facility: Novartis Investigative Site
city: Canterbury, Kent
country: United Kingdom
facility: Novartis Investigative Site
city: Carshalton
country: United Kingdom
facility: Novartis Investigative Site
city: Cornwall
country: United Kingdom
facility: Novartis Investigative Site
city: Dudley
country: United Kingdom
facility: Novartis Investigative Site
city: Exeter
country: United Kingdom
facility: Novartis Investigative Site
city: Glasgow
country: United Kingdom
facility: Novartis Investigative Site
city: Leeds
country: United Kingdom
facility: Novartis Investigative Site
city: Liverpool
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
city: Milton Keynes
country: United Kingdom
facility: Novartis Investigative Site
city: Newcastle-upon-Tyne
country: United Kingdom
facility: Novartis Investigative Site
city: Norwich
country: United Kingdom
facility: Novartis Investigative Site
city: Oxford
country: United Kingdom
facility: Novartis Investigative Site
city: Peterborough
country: United Kingdom
facility: Novartis Investigative Site
city: Rhyl, Denbighshire
country: United Kingdom
facility: Novartis Investigative Site
city: Salford
country: United Kingdom
facility: Novartis Investigative Site
city: Stoke on Trent
country: United Kingdom
facility: Novartis Investigative Site
city: Swindon
country: United Kingdom
facility: Novartis Investigative Site
city: Uxbridge
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Tausch E, Beck P, Schlenk RF, Jebaraj BJ, Dolnik A, Yosifov DY, Hillmen P, Offner F, Janssens A, Babu GK, Grosicki S, Mayer J, Panagiotidis P, McKeown A, Gupta IV, Skorupa A, Pallaud C, Bullinger L, Mertens D, Dohner H, Stilgenbauer S. Prognostic and predictive role of gene mutations in chronic lymphocytic leukemia: results from the pivotal phase III study COMPLEMENT1. Haematologica. 2020 Oct 1;105(10):2440-2447. doi: 10.3324/haematol.2019.229161.
citation: Hillmen P, Robak T, Janssens A, Babu KG, Kloczko J, Grosicki S, Doubek M, Panagiotidis P, Kimby E, Schuh A, Pettitt AR, Boyd T, Montillo M, Gupta IV, Wright O, Dixon I, Carey JL, Chang CN, Lisby S, McKeown A, Offner F; COMPLEMENT 1 Study Investigators. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015 May 9;385(9980):1873-83. doi: 10.1016/S0140-6736(15)60027-7. Epub 2015 Apr 14.
citation: Jewell RC, Laubscher K, Lewis E, Fang L, Gafoor Z, Carey J, McKeown A, West S, Wright O, Sedoti D, Dixon I, Hottenstein CS, Chan G. Assessment of the effect of ofatumumab on cardiac repolarization. J Clin Pharmacol. 2015 Jan;55(1):114-21. doi: 10.1002/jcph.376. Epub 2014 Aug 21.