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

Phase 3

Completed

Conditions: Leukaemia

Interventions: Drug: Physicians' Choice
Drug: Ofatumumab

Registration Number: NCT01313689

Lead Sponsor: Novartis Pharmaceuticals

Brief 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.

Detailed 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 & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 122

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Physicians' Choice	Physicians' Choice	Physicians' choice of treatment
Ofatumumab	Ofatumumab	Biological

Primary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS) as Assessed by Independent Review Committee (IRC)	From the randomization date up to 60 months post the randomization date.	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.

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR) as Assessed by the Investigator	From the randomization date up to 60 months post the randomization date.	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.
Time to Progression as Assessed by IRC	From the randomization date up to 60 months post the randomization date.	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.
Time to Next Anti-cancer Therapy by Investigator	From the randomization date up to 60 months post the randomization date.	Time to next therapy is defined as the time from randomization until the start of the next line of treatment.
Number of Participants Who Were Positive or Negative for Human Anti-Human Antibodies (HAHA) Post-OFA Therapy	From the randomization date up to 60 months post the randomization date.	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.
Mean Health Change Questionnaire (HCQ) Score	From the randomization date up to 60 months post the randomization date.	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..
Mean Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM Over Time	Screening and every 3 months during treatment, every 6 months after last treatment until PD or until 42 Month Follow-up Visit	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.
Progression-free Survival (PFS) as Assessed by Investigator	From the randomization date up to 60 months post the randomization date.	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.
Overall Survival	From the randomization date up to 60 months post the randomization date.	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.
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)	From the randomization date up to 60 months post the randomization date.	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.
Duration of Response as Assessed by the IRC	From the randomization date up to 60 months post the randomization date.	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.
Number of Participants With Any Adverse Event (AE), Any Serious Adverse Event (SAE), Any Fatal Serious Adverse Event (FSAE), or Deaths	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	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.
Overall Response Rate (ORR) as Assessed by the IRC	From the randomization date up to 60 months post the randomization date.	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.
Time to Response as Assessed by the IRC	From the randomization date up to 60 months post the randomization date.	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.
Number of Participants With Any Adverse Event (AE) of Special Interest	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	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.