CLL, SLL
Conditions
Keywords
17p Deletion CLL
Brief summary
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.
Interventions
Sponsors
National Comprehensive Cancer Network
GlaxoSmithKline
Dana-Farber Cancer Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Induction Overall Response Rate (ORR) | Disease was evaluated after weeks 8 and 16 of Part A and at 12, 18 and 24 weeks during part B. | 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
| Measure | Time frame | Description |
|---|---|---|
| Overall Objective Response Rate (ORR) | 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 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). |
| Number of Participants With Overall CR | 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. | 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. |
| Overall MRD Negative Rate | 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. | 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. |
| Transplant Rate | Evaluated up to 36 cycles (approximately 2.75 years) of treatment (Parts A, B and C) | Percentage of participants eligible for allogeneic hematopoietic stem cell transplantation (alloHSCT) that are able and willing to proceed to alloHSCT. |
| Number of Participants Achieving Induction Complete Response (CR) | Disease was evaluated after weeks 8 and 16 of Part A and at 12, 18 and 24 weeks during part B. | 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. |
| 3-Year Progression-Free Survival (PFS) Probability | 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 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. |
| 3-year Overall Survival (OS) Probability | Median survival follow-up was 45 months (range 31-58 months) in this study cohort. | 3-year OS is the probability of participants remaining alive at 3 years from study entry estimated using Kaplan-Meier methods. |
| Number of Participants Completing Part A Treatment | Evaluated up to 4 cycles/16 weeks. | Participants counted as completing Part A with either 2 or 4 cycles of treatment per protocol. |
| Number of Participants Completing Only 2 Cycles of Part A Treatment | Evaluated after 2 cycles/8 weeks of Part A therapy. | Participants counted if only completed 2 cycles of Part A treatment per protocol. |
| Number of Participants With Treatment-Related Grades 1-3 Hyperglycemia During Part A Induction | 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) | 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. |
Countries
United States
Participant flow
Recruitment details
Participants enrolled between December 2011 and November 2014.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Naive 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 | 15 |
| Relapsed/Refractory 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 | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Disease Progression | 1 | 0 |
| Overall Study | Refractory Disease | 0 | 3 |
| Overall Study | Richter's transformation | 0 | 3 |
Baseline characteristics
| Characteristic | Treatment Naive | Relapsed/Refractory | Total |
|---|---|---|---|
| Age, Continuous | 64 years | 65 years | 65 years |
| Number of Prior Therapies 0 | 15 Participants | 0 Participants | 15 Participants |
| Number of Prior Therapies 1 | 0 Participants | 6 Participants | 6 Participants |
| Number of Prior Therapies 2 | 0 Participants | 4 Participants | 4 Participants |
| Number of Prior Therapies 3 | 0 Participants | 2 Participants | 2 Participants |
| Number of Prior Therapies 4 | 0 Participants | 3 Participants | 3 Participants |
| Region of Enrollment United States | 15 Participants | 15 Participants | 30 Participants |
| Sex: Female, Male Female | 7 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Male | 8 Participants | 12 Participants | 20 Participants |
| Time from Diagnosis to First Therapy | 6.9 months | 23 months | 12.4 months |
| Time from Diagnosis to Start on Trial | 6.8 months | 59.4 months | 27.6 months |
| Whole Exome Sequencing-Copy Number Alterations | 12.5 Events | 14 Events | 14 Events |
| Whole Exome Sequencing-Mutations | 22 mutations | 20 mutations | 21 mutations |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 7 / 15 | 6 / 15 |
| other Total, other adverse events | 15 / 15 | 14 / 15 |
| serious Total, serious adverse events | 11 / 15 | 9 / 15 |
Outcome results
Primary
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).
Time frame: Disease was evaluated after weeks 8 and 16 of Part A and at 12, 18 and 24 weeks during part B.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Naive | Induction Overall Response Rate (ORR) | 73 percentage of participants |
| Relapsed/Refractory | Induction Overall Response Rate (ORR) | 60 percentage of participants |
Secondary
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.
Time frame: Median survival follow-up was 45 months (range 31-58 months) in this study cohort.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Naive | 3-year Overall Survival (OS) Probability | 66 percentage probability |
| Relapsed/Refractory | 3-year Overall Survival (OS) Probability | 53 percentage probability |
Secondary
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.
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Naive | 3-Year Progression-Free Survival (PFS) Probability | 53 percentage probability |
| Relapsed/Refractory | 3-Year Progression-Free Survival (PFS) Probability | 25 percentage probability |
Secondary
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.
Time frame: Disease was evaluated after weeks 8 and 16 of Part A and at 12, 18 and 24 weeks during part B.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Naive | Number of Participants Achieving Induction Complete Response (CR) | 0 participants |
| Relapsed/Refractory | Number of Participants Achieving Induction Complete Response (CR) | 0 participants |
Secondary
Number of Participants Completing Only 2 Cycles of Part A Treatment
Participants counted if only completed 2 cycles of Part A treatment per protocol.
Time frame: Evaluated after 2 cycles/8 weeks of Part A therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Naive | Number of Participants Completing Only 2 Cycles of Part A Treatment | 0 participants |
| Relapsed/Refractory | Number of Participants Completing Only 2 Cycles of Part A Treatment | 0 participants |
Secondary
Number of Participants Completing Part A Treatment
Participants counted as completing Part A with either 2 or 4 cycles of treatment per protocol.
Time frame: Evaluated up to 4 cycles/16 weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Naive | Number of Participants Completing Part A Treatment | 12 participants |
| Relapsed/Refractory | Number of Participants Completing Part A Treatment | 15 participants |
Secondary
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.
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Naive | Number of Participants With Overall CR | 2 participants |
| Relapsed/Refractory | Number of Participants With Overall CR | 0 participants |
Secondary
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.
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)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Naive | Number of Participants With Treatment-Related Grades 1-3 Hyperglycemia During Part A Induction | 5 participants |
| Relapsed/Refractory | Number of Participants With Treatment-Related Grades 1-3 Hyperglycemia During Part A Induction | 6 participants |
Secondary
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.
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Naive | Overall MRD Negative Rate | 80 percentage of participants |
| Relapsed/Refractory | Overall MRD Negative Rate | 53 percentage of participants |
Secondary
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).
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Naive | Overall Objective Response Rate (ORR) | 80 percentage of participants |
| Relapsed/Refractory | Overall Objective Response Rate (ORR) | 67 percentage of participants |
Secondary
Transplant Rate
Percentage of participants eligible for allogeneic hematopoietic stem cell transplantation (alloHSCT) that are able and willing to proceed to alloHSCT.
Time frame: Evaluated up to 36 cycles (approximately 2.75 years) of treatment (Parts A, B and C)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Naive | Transplant Rate | 43 percentage of participants |
| Relapsed/Refractory | Transplant Rate | 43 percentage of participants |