Ofatumumab vs Physician's Choice in Subjects With Bulky Fludarabine-Refractory Chronic Lymphocytic Leukemia

Leukaemia Clinical Trial

Official title:

An Open Label, Multicenter Study Investigating the Safety and Efficacy of Ofatumumab Therapy Versus Physicians' Choice in Patients With Bulky Fludarabine-Refractory Chronic Lymphocytic Leukaemia (CLL)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01313689
• Other study ID #: 114242
• Status: Completed
• Phase: Phase 3
• Start date: April 14, 2011
• Est. completion date: April 24, 2017

Study information

• Verified date: October 2018
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study was to confirm the clinical benefit observed in the pivotal registration study, Hx-CD20-406. The Committee for Medicinal Products for Human Use (CHMP) required that a randomized study be conducted in CLL patients with bulky fludarabine-refractory disease as a specific obligation for grant of conditional approval for ARZERRA™ in the European Union (EU). This study compared ofatumumab with the physicians' choice of therapy.

Description:

Patients with CLL that is refractory to fludarabine have few treatment options and a poor prognosis. There is a continued need for new therapies for these CLL patients, as demonstrated by the limited responses and substantial toxicities with existing therapies. This is supported by the lack of a consensus around standard of care treatment for CLL patients with bulky fludarabine-refractory disease. The objective of this study was to confirm the response rate and disease control in the refractory setting through a controlled trial comparing ofatumumab with the physicians' choice of therapy in fludarabine-refractory, bulky lymphadenopathy patients. After 24 weeks of treatment with ofatumumab, patients were further randomized to either extended ofatumumab treatment or observation. Patients on the physicians' choice arm had the option of receiving ofatumumab if they experience progressive disease.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 122
• Est. completion date: April 24, 2017
• Est. primary completion date: March 18, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adults with documented diagnosis of active CLL requiring treatment

• Bulky lymphadenopathy, defined as at least 1 lymph node >5 cm

• Must be refractory to fludarabine treatment

• Age 18 yrs or older

• At least 2 prior therapies for CLL

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

• Signed written informed consent

Exclusion Criteria:

• Prior allogeneic stem cell transplant at any time, or autologous stem cell transplant within 6 months

• Treatment with any unapproved drug substance or experimental therapy within 4 weeks, or currently participating in another interventional clinical study

• CLL transformation, prolymphocytic leukemia, or central nervous system (CNS) involvement of CLL

• Active autoimmune hemolytic anemia (AIHA) requiring treatment except if associated with progressive disease requiring anti-CLL treatment

• Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment

• Human immunodeficiency virus (HIV) positive

• Significant concurrent, uncontrolled medical condition

• 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 tumor was successfully treated with curative intent at least 2 years prior to trial entry

• Non-protocol corticosteroid usage except a maintenance dose corresponding to less than or equal to 10 mg prednisone

• Abnormal lab values: Creatinine > 2.0 times upper normal limit (unless normal creatinine clearance), or total bilirubin > 2.0 times upper normal limit (unless due to liver involvement of CLL or due to Gilbert's syndrome), or alanine transaminase (ALT) > 2.5 times upper normal limit (unless due to liver involvement of CLL)

• Known or suspected hypersensitivity to ofatumumab

• Lactating or pregnant women or female patients of child-bearing potential (or male patients with such partners) not willing to use adequate contraception

Related Conditions & MeSH terms

• Leukaemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

Drug:
• Ofatumumab
Ofatumumab IV, initial dose 300 mg, followed 1 week later with 2000 mg once weekly for 7 weeks, followed 4 weeks later by one infusion of 2000 mg every 4 weeks for 4 infusions, for a total of 12 infusions over 24 weeks. After 24 weeks of ofatumumab treatment, patients who have achieved at least stable disease or better, and whom the investigator would deem appropriate for the therapy to continue, would undergo a second randomisation (2:1) to either 1) an additional ofatumumab dose regimen of 2000 mg once every 4 weeks for up to an additional 24 weeks, or 2) no further therapy (i.e. observation only).
• Physicians' Choice
Non-ofatumumab containing regimen as per physicians' choice for up to 6 months. Permitted therapies include treatments approved for CLL, and well established standards of care for CLL.

Locations

Country	Name	City	State
Austria	Novartis Investigative Site	Graz
Austria	Novartis Investigative Site	Innsbruck
Austria	Novartis Investigative Site	Linz
Austria	Novartis Investigative Site	Salzburg
Austria	Novartis Investigative Site	Wien
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Leuven
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
Czechia	Novartis Investigative Site	Hradec Kralove
Czechia	Novartis Investigative Site	Olomouc
Czechia	Novartis Investigative Site	Praha 2
France	Novartis Investigative Site	Bobigny cedex
France	Novartis Investigative Site	Brest cedex
France	Novartis Investigative Site	Clermont-Ferrand Cedex 1
France	Novartis Investigative Site	Creteil cedex
France	Novartis Investigative Site	Lille cedex
France	Novartis Investigative Site	Rennes cedex 9
France	Novartis Investigative Site	Toulouse cedex 9
France	Novartis Investigative Site	Tours cedex 9
Germany	Novartis Investigative Site	Chemnitz	Sachsen
Germany	Novartis Investigative Site	Dresden	Sachsen
Germany	Novartis Investigative Site	Essen	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Frankfurt	Hessen
Germany	Novartis Investigative Site	Frankfurt/Oder	Brandenburg
Germany	Novartis Investigative Site	Koblenz	Rheinland-Pfalz
Germany	Novartis Investigative Site	Koeln	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Kronach	Bayern
Germany	Novartis Investigative Site	Magdeburg	Sachsen-Anhalt
Germany	Novartis Investigative Site	Regensburg	Bayern
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Pecs
Hungary	Novartis Investigative Site	Szombathely
Ireland	Novartis Investigative Site	Dublin
Ireland	Novartis Investigative Site	Galway
Ireland	Novartis Investigative Site	James Street
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Ramat Gan
Italy	Novartis Investigative Site	Brescia	Lombardia
Italy	Novartis Investigative Site	Messina	Sicilia
Italy	Novartis Investigative Site	Milano	Lombardia
Italy	Novartis Investigative Site	Milano	Lombardia
Italy	Novartis Investigative Site	Modena	Emilia-Romagna
Italy	Novartis Investigative Site	Torino	Piemonte
Poland	Novartis Investigative Site	Chorzow
Poland	Novartis Investigative Site	Lodz
Poland	Novartis Investigative Site	Wroclaw
Russian Federation	Novartis Investigative Site	Chelyabinsk
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	St'Petersburg
Russian Federation	Novartis Investigative Site	St. Petersburg
Singapore	Novartis Investigative Site	Singapore
Slovakia	Novartis Investigative Site	Bratislava
Slovakia	Novartis Investigative Site	Bratislava
Slovakia	Novartis Investigative Site	Kosice
Slovakia	Novartis Investigative Site	Martin
Sweden	Novartis Investigative Site	Goteborg
Sweden	Novartis Investigative Site	Linkoping
Sweden	Novartis Investigative Site	Lulea
Sweden	Novartis Investigative Site	Orebro
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Umea
Sweden	Novartis Investigative Site	Uppsala
Ukraine	Novartis Investigative Site	Cherkasy
Ukraine	Novartis Investigative Site	Dnipropetrovsk
Ukraine	Novartis Investigative Site	Donetsk
Ukraine	Novartis Investigative Site	Kharkiv
Ukraine	Novartis Investigative Site	Khmelnytskyi
Ukraine	Novartis Investigative Site	Kyiv
Ukraine	Novartis Investigative Site	Kyiv
Ukraine	Novartis Investigative Site	Lviv
Ukraine	Novartis Investigative Site	Makiivka
Ukraine	Novartis Investigative Site	Simferopil
Ukraine	Novartis Investigative Site	Vinnitsa
Ukraine	Novartis Investigative Site	Zhytomyr
United Kingdom	Novartis Investigative Site	Bournemouth
United Kingdom	Novartis Investigative Site	Manchester
United Kingdom	Novartis Investigative Site	Oxford

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Austria,  Belgium,  Bulgaria,  Czechia,  France,  Germany,  Hungary,  Ireland,  Israel,  Italy,  Poland,  Russian Federation,  Singapore,  Slovakia,  Sweden,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS) as Assessed by Independent Review Committee (IRC)	PFS is the interval of time between the date of first randomization to the date of disease progression (PD) or death due to any reason, whichever occurred first. The date of PD was defined as the first occurrence of any criteria of progression. PD criteria requires at least one of the following: progression of lymphadenopathy, >=50% increase in liver or spleen size, >=50% increase in number of lymphocytes per microliter, more aggressive histology, occurence of cytopenia after treatment attributable to CLL. Disease progression was determined according to the 2008 International Workshop for Chronic Lymphocytic Leukaemia (IWCLL) update of the National Cancer Institute-sponsored Working Group CLL Guidelines for Response (NCI-WG). PFS was censored at the time of the last follow up for participants who have neither progressed or died.	From the randomization date up to 60 months post the randomization date.
Secondary	Progression-free Survival (PFS) as Assessed by Investigator	PFS is the interval of time between the date of first randomization to the date of disease progression (PD) or death due to any reason, whichever occurred first. The date of PD was defined as the first occurrence of any criteria of progression. PD criteria requires at least one of the following: progression of lymphadenopathy, >=50% increase in liver or spleen size, >=50% increase in number of lymphocytes per microliter, more aggressive histology, occurence of cytopenia after treatment attributable to CLL. Disease progression was determined according to the 2008 International Workshop for Chronic Lymphocytic Leukaemia (IWCLL) update of the National Cancer Institute-sponsored Working Group CLL Guidelines for Response (NCI-WG). PFS was censored at the time of the last follow up for participants who have neither progressed or died.	From the randomization date up to 60 months post the randomization date.
Secondary	Overall Response Rate (ORR) as Assessed by the IRC	ORR is defined as the number of participants achieving either complete response (CR) or partial response (PR). ORR was measured using the IWCLL updated NCI-WG guidelines 2008. CR requires all of the following criteria: 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 and no lymphoid nodules. PR requires the following criteria for at least 2 months: >=50% decrease in LC, reduction in Ly (i.e., >=50% decrease in lymph node size or no increase or new lymph nodes), >=50% decrease in the 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, neutrophils>1500/µL. Nodular PR (nPR) indicates persistent nodules in the BM.	From the randomization date up to 60 months post the randomization date.
Secondary	Overall Response Rate (ORR) as Assessed by the Investigator	ORR is defined as the number of participants achieving either complete response (CR) or partial response (PR). Overall response was measured using the IWCLL updated NCI-WG guidelines 2008. CR requires all of the following criteria: 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 and no lymphoid nodules. PR requires the following criteria for at least 2 months: >=50% decrease in LC, reduction in Ly (i.e., >=50% decrease in lymph node size or no increase or new lymph nodes), >=50% decrease in the 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, neutrophils>1500/µL. Nodular PR (nPR) indicates persistent nodules in the BM.	From the randomization date up to 60 months post the randomization date.
Secondary	Overall Survival	Overall survival (OS) is defined as the time from randomization to death due to any cause. Kaplan-Meier plots were used to estimate the reported median OS time.	From the randomization date up to 60 months post the randomization date.
Secondary	Time to Progression as Assessed by IRC	Time to progression is defined as the time from the date of randomization to disease progression (PD). PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlarged lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia. Participants who were alive and had not progressed at the time of analysis or if a progression event occurred after extensive lost-to-follow-up time were censored at the date of the last visit with adequate assessment.	From the randomization date up to 60 months post the randomization date.
Secondary	Time to Next Anti-cancer Therapy by Investigator	Time to next therapy is defined as the time from randomization until the start of the next line of treatment.	From the randomization date up to 60 months post the randomization date.
Secondary	Time to Response as Assessed by the IRC	Time to response is defined as the time from randomization to the first response (Complete Remission[CR], Complete Remission with incomplete bone marrow recovery[CRi], partial response[PR], or nodular PR[nPR]). CR(all the criteria at least 2 months after last treatment): no lymphadenopathy(Ly) > 1.5 cm/ 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. nPR: persistent nodules BM. Participants with unknown or missing responses were considered as non-responders.	From the randomization date up to 60 months post the randomization date.
Secondary	Duration of Response as Assessed by the IRC	DOR is defined as the time from the initial response (CR, CRi, nPR, or PR) to the first documented sign of PD or death due to any cause. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlarged lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia. Par. who were alive and had not progressed at the time of analysis or if a progression event occurred after extensive lost-to-follow-up time (>= 12 weeks) were censored at the date of the last visit with adequate assessment. Par. with unknown or missing responses were considered as non-responders.	From the randomization date up to 60 months post the randomization date.
Secondary	Number of Participants With Any Adverse Event (AE), Any Serious Adverse Event (SAE), Any Fatal Serious Adverse Event (FSAE), or Deaths	An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability or incapacity, is a congenital anomaly or birth defect.	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
Secondary	Number of Participants With Any Adverse Event (AE) of Special Interest	AEs of special interest included cytopenias (neutropenia [decreased neutrophil count], anaemia [decreased hemoglobin], and thrombocytopenia [decreased platelet count]), autoimmune haematologic complications (autoimmune haemolytic anaemia and haemolytic anaemia), infusion reactions, infections, mucocutaneous reactions, Tumour Lysis Syndrome (TLS), cardiovascular events, and small bowel obstruction.	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
Secondary	Mean Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM Over Time	Immunoglobulins or antibodies are large proteins used by the immune system to identify and neutralize foreign particles such as bacteria and viruses. Their normal blood levels indicate proper immune status. Low levels indicate immuno-suppression. IgA, IgG, and IgM were measured in the blood samples of the participants. Immunoglobulin testing was performed at Screening (SCR), Cycle 3 Week 4 (C3W4), Cycle 7 Week 4 (C3W4) ,Cycle 9 Week 4 (C3W4), 6 Month Follow-up Visit (6M FU), 9 Month Follow-up (9M FU), 12 Month Follow-up (12M FU), 18 Month Follow-up (18M FU), 24 Month Follow-up (24M FU), 30 Month Follow-up (30M FU), 36 Month Follow-up (36M FU), 42 Month Follow-up (42M FU). A cycle is defined as the time between one round of treatment until the start of the next round.	Screening and every 3 months during treatment, every 6 months after last treatment until PD or until 42 Month Follow-up Visit
Secondary	Number of Participants Who Were Positive or Negative for Human Anti-Human Antibodies (HAHA) Post-OFA Therapy	The presence of HAHA in human serum was determined using a validated electrochemiluminescent assay in a multi-tier assay format. All samples were first assessed in a screening (SCR) assay, and the potential positive (Pos) samples were further tested in the confirmation (CNF) assays. Confirmed positives were reported as HAHA positive and titer was determined for each positive sample. The drug tolerance of the HAHA assay is 200 microgram/milliliter (µg/mL); thus, samples that tested negative in the assay and had ofatumumab concentrations no more than 200 µg/mL were considered as conclusive negative (Neg) results.	From the randomization date up to 60 months post the randomization date.
Secondary	Changes From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, Chronic Lymphocytic Leukaemia 16 Item Module (EORTC QLQ-CLL 16)	The EORTC QLQ-CLL16 is comprised of 16 questions that address 5 domains of health-related quality of life (HRQoL) important in CLL. There are 4 multi-item scales - fatigue (2 items), treatment side effects ([TSE], 4 items), disease symptoms (disease effects scale [DES], 4 items), and infection (4 items) - and single item scales (social activities [Social Problems (SP) Scale] and future health worries[Future Health (FH) Scale].). These are measured on a four point scale where 1 = not at all and 4 = very much. These scores are transformed to give a rating from 0 - 100, where 0 =no symptoms or problems and 100 = a severe symptoms or problems. EORTC QLQ-CLL16 was assessed at Screening; Week (W) 12 (W4 of Cycle[C] 3), W24 (W4C6), W36 (W4C9), W48 (W4C13); during Follow-up which was every month for Months (M) 1-6, every 8 weeks for M7-12 and every 3 months up to M60; and then at PD.	From the randomization date up to 60 months post the randomization date.
Secondary	Mean Health Change Questionnaire (HCQ) Score	The HCQ consists of a single question in which the participant is asked if he/she has experienced any change in his/her health overall since beginning the study. For HCQ, values from 1 to 9 were assigned to the 9 responses in the HCQ questionnaire, ranging from 1 for 'my health is a great deal better' to 9 for 'my health is a great deal worse' since the beginning of the study. A score of 3 or less indicates improvement from Baseline. HCQ was assessed at Screening; Week (W) 12 (W4 of Cycle[C] 3), W24 (W4C6), W36 (W4C9), W48 (W4C13); during follow-up which was every month for Months 1-6, every 8 weeks for M7-12 and every 3 months up to M60; and then at PD..	From the randomization date up to 60 months post the randomization date.