Ofatumumab With High Dose Methylprednisone Followed by Ofatumumab and Alemtuzumab in 17p CLL

Study Overview
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Brief Summary
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The main purpose of this study is to examine how two separate groups of 17p deletion Chronic lymphocytic leukemia (CLL) participants respond to sequential treatment with this particular combination of drugs. The two groups are those participants who have previously received treatment for their CLL and those who have not yet received any treatment. The combination of drugs is Ofatumumab and High-Dose Methylprednisolone (HDMP) first followed by Ofatumumab and Alemtuzumab. All three drugs are FDA approved and have known activity in treating 17p CLL. We hope that by combining these drugs together in this study, they will have more benefit than each one alone and that the subjects' CLL will be significantly impacted.

Detailed Description
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Participants were assigned to 1 of 2 groups based on prior treatment status. Both groups received the same therapy. Part A: Ofatumumab + HDMP 2-4 cycles Part B: Ofatumumab + Alemtuzumab 1-6 cycles Part C: Maintenance with Ofatumumab + Alemtuzumab up to 2 years Between days 15-22 of Cycle 2 of Part A, participants are restaged. Participants who achieve nodal complete response discontinue Part A therapy and undergo minimal residual disease (MRD) assessment to guide the decision whether to go to Part B or Part C. The participants with persistent disease after 2 cycles of Part A therapy receive 2 more cycles of Part A therapy and then undergo another restaging as well as MRD assessment. At restaging, participants with minimal disease are eligible for Part C or allogeneic stem cell transplant (SCT) off protocol. The remaining participants receive Part B therapy. On Part B, restaging occurs at weeks 12 and 18. If MRD negative complete response (CR) status is achieved then therapy is discontinued and the primary endpoint evaluation occurs 2 months later. Otherwise with persistent disease Part B therapy continues up to 24 weeks and the primary endpoint evaluation occurs after Part B therapy is completed. Participants who achieve clinical complete response may receive Part C therapy or be observed while waiting SCT.

Official Title
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A Phase II Study of Ofatumumab-High Dose Methylprednisolone Followed by Ofatumumab-Alemtuzumab in 17p Deletion CLL

Conditions
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CLL, SLL

Intervention / Treatment
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* Drug: Ofatumumab
* Drug: High-Dose Methylprednisolone
* Drug: Alemtuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented CLL/SLL 17p deletion by FISH in 20% or more nuclei on peripheral blood, bone marrow or lymph node Normal organ function Exclusion Criteria: Pregnant or breast feeding Current active hepatic or biliary disease Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, tuberculosis and active Hepatitis C History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae Other past or current malignancy. Participants who have been free of malignancy for at least 2 years, or who have a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Known HIV positive Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months prior to study entry, congestive heart failure, and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities. Significant concurrent uncontrolled medical conditions including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the subject. Positive serology for Hepatitis B or C History of allergic reactions attributed to ofatumumab.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Naive<br>Participants were assigned to 1 of 2 groups based on prior treatment status. Both groups received the same therapy as follows (cycle duration=28 days): Induction Part A: Ofatumumab + HDMP 2-4 cycles Ofatumumab: cycle 1 - 300 mg intravenously (IV) Day 1 then 1000 mg IV Days 8, 15, 22; cycles 2-4 - 1000 mg IV Days 1, 8, 15, 22 High-Dose Methylprednisolone (HDMP): 1000 mg/m2 IV Days 1-3 Participants with nodal complete response at cycle 2 re-staging then discontinued Part A therapy. Induction Part B: Ofatumumab + Alemtuzumab 1-6 cycles Ofatumumab: 1000 mg IV Day 1 Alemtuzumab: 30 mg subcutaneously Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24 and 26 Participants with at least stable disease could continue continue to Part C or, if eligible, proceed to allogeneic stem cell transplant (SCT) off study. Maintenance Part C: Ofatumumab + Alemtuzumab up to 26 cycles Ofatumumab: 1000 mg IV Day 1 every other cycle Alemtuzumab: 30 mg subcutaneously Days 14, 28 | Drug: Ofatumumab<br> <br> * Other names: GSK 1841157;Drug: High-Dose Methylprednisolone<br> <br> * Other names: HDMP;Drug: Alemtuzumab<br> <br> * Other names: Campath-1H;|
| Experimental: Relapsed/Refractory<br>Participants were assigned to 1 of 2 groups based on prior treatment status. Both groups received the same therapy as follows (cycle duration=28 days): Induction Part A: Ofatumumab + HDMP 2-4 cycles Ofatumumab: cycle 1 - 300 mg intravenously (IV) Day 1 then 1000 mg IV Days 8, 15, 22; cycles 2-4 - 1000 mg IV Days 1, 8, 15, 22 High-Dose Methylprednisolone (HDMP): 1000 mg/m2 IV Days 1-3 Participants with nodal complete response at cycle 2 re-staging then discontinued Part A therapy. Induction Part B: Ofatumumab + Alemtuzumab 1-6 cycles Ofatumumab: 1000 mg IV Day 1 Alemtuzumab: 30 mg subcutaneously Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24 and 26 Participants with at least stable disease could continue continue to Part C or, if eligible, proceed to allogeneic stem cell transplant (SCT) off study. Maintenance Part C: Ofatumumab + Alemtuzumab up to 26 cycles Ofatumumab: 1000 mg IV Day 1 every other cycle Alemtuzumab: 30 mg subcutaneously Days 14, 28 | Drug: Ofatumumab<br> <br> * Other names: GSK 1841157;Drug: High-Dose Methylprednisolone<br> <br> * Other names: HDMP;Drug: Alemtuzumab<br> <br> * Other names: Campath-1H;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction Overall Response Rate (ORR) | Induction ORR is the percentage of participants achieving a minimum of partial response (PR) over induction treatment based on International Workshop on Chronic Lymphocytic Leukemia (IW-CLL) criteria (Hallek, et al 2008). There are numerous diagnostic tests used for response evaluation including potentially CBC and differential count, marrow aspirate and biopsy, ultrasound of the abdomen, CT scans (chest, pelvis, abdomen) and physical examination. PR is a 50% or greater decrease of measured size of lymphadenopathy, hepatomegaly, splenomegaly as well as blood lymphocytes (over baseline), marrow infiltrate or B-lymphoid nodules and a 50% or greater increase from baseline in platelet count (or level >100,000/micro liter), hemoglobin (or level >11 grams/deciliter), neutrophils (or level >1500/microliter). | Disease was evaluated after weeks 8 and 16 of Part A and at 12, 18 and 24 weeks during part B. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving Induction Complete Response (CR) | CR over induction treatment was based on International Workshop on Chronic Lymphocytic Leukemia (IW-CLL) criteria (Hallek, et al 2008). There are numerous diagnostic tests used for response evaluation including potentially CBC and differential count, marrow aspirate and biopsy, ultrasound of the abdomen, CT scans (chest, pelvis, abdomen) and physical examination. CR is absence of significant lymphadenopathy (nodes<1.5 centimeters in long axis diameter), hepatomegaly, splenomegaly as well as blood lymphocytes<4000/microliter, normocellular for age marrow with <30% lymphocytes, no B-lymphoid nodules and platelet>100,000/micro liter, hemoglobin>11 grams/deciliter, neutrophils>1500/microliter. | Disease was evaluated after weeks 8 and 16 of Part A and at 12, 18 and 24 weeks during part B. | 
| Overall Objective Response Rate (ORR) | Overall ORR is the percentage of participants achieving a minimum of partial response (PR) over induction and maintenance treatment based on International Workshop on Chronic Lymphocytic Leukemia (IW-CLL) criteria (Hallek, et al 2008). There are numerous diagnostic tests used for response evaluation including potentially CBC and differential count, marrow aspirate and biopsy, ultrasound of the abdomen, CT scans (chest, pelvis, abdomen) and physical examination. PR is a 50% or greater decrease of measured size of lymphadenopathy, hepatomegaly, splenomegaly as well as blood lymphocytes (over baseline), marrow infiltrate or B-lymphoid nodules and a 50% or greater increase from baseline in platelet count (or level >100,000/micro liter), hemoglobin (or level >11 grams/deciliter), neutrophils (or level >1500/microliter). | Disease was evaluated after weeks 8 and 16 of Part A, at 12, 18 and 24 weeks during part B and every 6 months on Part C. | 
| Number of Participants With Overall CR | CR overall (induction and maintenance treatment) was based on International Workshop on Chronic Lymphocytic Leukemia (IW-CLL) criteria (Hallek, et al 2008). There are numerous diagnostic tests used for response evaluation including potentially CBC and differential count, marrow aspirate and biopsy, ultrasound of the abdomen, CT scans (chest, pelvis, abdomen) and physical examination. CR is absence of significant lymphadenopathy (nodes<1.5 centimeters in long axis diameter), hepatomegaly, splenomegaly as well as blood lymphocytes<4000/microliter, normocellular for age marrow with <30% lymphocytes, no B-lymphoid nodules and platelet>100,000/micro liter, hemoglobin>11 grams/deciliter, neutrophils>1500/microliter. | Disease was evaluated after weeks 8 and 16 of Part A, at 12, 18 and 24 weeks during part B and every 6 months on Part C. | 
| Overall MRD Negative Rate | Overall MRD negative rate is the percentage of participants classified as MRD negative by four color flow cytometry. The assay has a sensitivity of 1 in 10,000 leukocytes. | MRD was assessed after weeks 8 and 16 of Part A, at 12, 18 and 24 weeks during part B and every 6 months on Part C. | 
| Transplant Rate | Percentage of participants eligible for allogeneic hematopoietic stem cell transplantation (alloHSCT) that are able and willing to proceed to alloHSCT. | Evaluated up to 36 cycles (approximately 2.75 years) of treatment (Parts A, B and C) | 
| Number of Participants With Treatment-Related Grades 1-3 Hyperglycemia During Part A Induction | Participants ever experiencing a grade 1-3 hyperglycemia event based on CTCAEv4 with treatment attribution of possible, probably or definite as reported on case report forms were counted. | Adverse Events (AEs) were collected weekly during cycle 1 Part A and then every other week for the duration of Part A (up to 16 weeks) | 
| 3-Year Progression-Free Survival (PFS) Probability | 3-year PFS is the probability of participants remaining alive and progression-free at 3 years from study entry estimated using Kaplan-Meier methods. Disease progression (PD) per International Workshop on Chronic Lymphocytic Leukemia (IW-CLL) criteria (Hallek, et al 2008) is: the appearance of any new lesion (enlarged lymph node minimum >1.5 centimeters); an increase by 50% in greatest determined diameter of any previous site; an increase in the previously noted enlargement of the liver or spleen by 50% or more or the de novo appearance of hepatomegaly, splenomegaly; a 50% increase of blood lymphocytes (over baseline with level at least 5,000/microliter); occurrence of cytopenia secondary to CLL at least 3 months post treatment including a 50% or greater decrease from baseline in platelet count (or level <100,000/microliter) or a hemoglobin decrease of >2 grams/deciliter (or level <10 grams/deciliter); and transformation to a more aggressive histology. | Disease was evaluated on treatment after weeks 8 and 16 of Part A, at 12, 18 and 24 weeks during part B and every 6 months on Part C as well as off-treatment every 3 months up to 5 years. | 
| 3-year Overall Survival (OS) Probability | 3-year OS is the probability of participants remaining alive at 3 years from study entry estimated using Kaplan-Meier methods. | Median survival follow-up was 45 months (range 31-58 months) in this study cohort. | 
| Number of Participants Completing Part A Treatment | Participants counted as completing Part A with either 2 or 4 cycles of treatment per protocol. | Evaluated up to 4 cycles/16 weeks. | 
| Number of Participants Completing Only 2 Cycles of Part A Treatment | Participants counted if only completed 2 cycles of Part A treatment per protocol. | Evaluated after 2 cycles/8 weeks of Part A therapy. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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17p Deletion CLL