Description:
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.
Title
- Brief Title: Ofatumumab With High Dose Methylprednisone Followed by Ofatumumab and Alemtuzumab in 17p CLL
- Official Title: A Phase II Study of Ofatumumab-High Dose Methylprednisolone Followed by Ofatumumab-Alemtuzumab in 17p Deletion CLL
Clinical Trial IDs
- ORG STUDY ID:
11-304
- SECONDARY ID:
NCCN Protocol Number: NCCN-001
- SECONDARY ID:
GSK Protocol Number: OFT115580
- NCT ID:
NCT01465334
Conditions
Interventions
Drug | Synonyms | Arms |
---|
Ofatumumab | GSK 1841157 | Relapsed/Refractory |
High-Dose Methylprednisolone | HDMP | Relapsed/Refractory |
Alemtuzumab | Campath-1H | Relapsed/Refractory |
Purpose
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
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Treatment Naive | Experimental | 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 | - Ofatumumab
- High-Dose Methylprednisolone
- Alemtuzumab
|
Relapsed/Refractory | Experimental | 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 | - Ofatumumab
- High-Dose Methylprednisolone
- Alemtuzumab
|
Eligibility Criteria
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.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Induction Overall Response Rate (ORR) |
Time Frame: | Disease was evaluated after weeks 8 and 16 of Part A and at 12, 18 and 24 weeks during part B. |
Safety Issue: | |
Description: | 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). |
Secondary Outcome Measures
Measure: | Number of Participants Achieving Induction Complete Response (CR) |
Time Frame: | Disease was evaluated after weeks 8 and 16 of Part A and at 12, 18 and 24 weeks during part B. |
Safety Issue: | |
Description: | 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. |
Measure: | Overall Objective Response Rate (ORR) |
Time Frame: | 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. |
Safety Issue: | |
Description: | 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). |
Measure: | Number of Participants With Overall CR |
Time Frame: | 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. |
Safety Issue: | |
Description: | 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. |
Measure: | Overall MRD Negative Rate |
Time Frame: | 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. |
Safety Issue: | |
Description: | 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. |
Measure: | Transplant Rate |
Time Frame: | Evaluated up to 36 cycles (approximately 2.75 years) of treatment (Parts A, B and C) |
Safety Issue: | |
Description: | Percentage of participants eligible for allogeneic hematopoietic stem cell transplantation (alloHSCT) that are able and willing to proceed to alloHSCT. |
Measure: | Number of Participants With Treatment-Related Grades 1-3 Hyperglycemia During Part A Induction |
Time Frame: | 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) |
Safety Issue: | |
Description: | 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. |
Measure: | 3-Year Progression-Free Survival (PFS) Probability |
Time Frame: | 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. |
Safety Issue: | |
Description: | 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. |
Measure: | 3-year Overall Survival (OS) Probability |
Time Frame: | Median survival follow-up was 45 months (range 31-58 months) in this study cohort. |
Safety Issue: | |
Description: | 3-year OS is the probability of participants remaining alive at 3 years from study entry estimated using Kaplan-Meier methods. |
Measure: | Number of Participants Completing Part A Treatment |
Time Frame: | Evaluated up to 4 cycles/16 weeks. |
Safety Issue: | |
Description: | Participants counted as completing Part A with either 2 or 4 cycles of treatment per protocol. |
Measure: | Number of Participants Completing Only 2 Cycles of Part A Treatment |
Time Frame: | Evaluated after 2 cycles/8 weeks of Part A therapy. |
Safety Issue: | |
Description: | Participants counted if only completed 2 cycles of Part A treatment per protocol. |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Terminated |
Lead Sponsor: | Dana-Farber Cancer Institute |
Trial Keywords
Last Updated
September 16, 2019