B-Cell Chronic Lymphocytic Leukemia (B-CLL)
Conditions
Keywords
CAMPATH, Alemtuzumab, Leukemia, MabCampath, Chronic, Subcutaneous, CLL, C-CLL, Relapsed, Refractory, Chronic Lymphocytic Leukemia
Brief summary
This is a Phase II, open-label, prospective, multicenter study to evaluate the efficacy and safety of subcutaneously administered alemtuzumab (CAMPATH, MabCampath) as therapy for patients with relapsed or refractory B-CLL who have been previously treated.
Interventions
BIOLOGICALAlemtuzumab
Alemtuzumab is administered using escalating doses and alternating injection sites. The dose is escalated as tolerated using 3mg, 10mg, and 30mg administered subcutaneously (SC) (if tolerated). When escalation to 30 mg is tolerated, all subsequent doses are administered at 30 mg SC 3 times per week at alternating injection sites for up to 18 weeks. Part 1 of the study: The first 20 patients will be randomized to either Arm 1 (dose escalation) or Arm 2 (no escalation). Part 1 of the study has been completed; no additional patients will be enrolled in Part 1. An assigned review panel has reviewed the safety data from Part 1 and determined that all patients will be enrolled and treated under a no escalation schedule for Part 2 of the study.
Sponsors
Bayer Healthcare Pharmaceuticals, Inc./Bayer Schering Pharma
Genzyme, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A diagnosis of B-cell chronic lymphocytic leukemia (B-CLL); according to the National Cancer Institute Working Group (NCI WG) Criteria. * World Health Organization (WHO) performance status of 0, 1, or 2. * Life expectancy ≥ 12 weeks. * Previous therapy with at least one but no more than 5 regimens (single agent or combination regimen). One therapy regimen is defined as consecutive, contiguous cycles of the same drug(s) with no treatment interruptions lasting \> 3 months. * Patient requires treatment for CLL per the following criteria: -Rai stage III or IV; -Rai stage 0-II with at least one of the following - evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia; Massive (i.e. greater than 6 cm below the left costal margin) or progressive splenomegaly; Progressive lymphocytosis with an increase of greater than 50% over a 2-month period or an anticipated doubling time of less than 6 months; Lymphocyte count \> 100\*10\^9/L; B symptoms. * More than 3 weeks since prior chemotherapy. Patient must have recovered from the acute side effects incurred as a result of previous therapy. * More than 3 weeks since using investigational agents. Patient must have recovered from the acute side effects incurred as a result of previous therapy. * Serum creatinine and conjugated (direct) bilirubin less than or equal to 2 times the institutional upper limit of normal (ULN) unless secondary to direct infiltration of the liver with CLL. * Female patients with childbearing potential must have a negative pregnancy test (serum or urine) within 2 weeks of first dose of study drug(s). All patients must agree to use an effective contraceptive method while on study treatment, if appropriate, and for a minimum of 6 months following study therapy. * Signed, written informed consent (in the US, includes The Health Insurance Portability and Accountability Act of 1996 (HIPAA) authorization)
Exclusion criteria
* Positive Coombs test and evidence of active hemolysis. * Platelet count less than 50\*10\^9/L without splenomegaly. * History of anaphylaxis following exposure to rat or mouse derived CDR-grafted humanized monoclonal antibodies. * Previously treated with CAMPATH. * Previous bone marrow transplant. * Known central nervous system (CNS) involvement with B-CLL * Active infection, including human immunodeficiency virus (HIV) positive. * Active second malignancy. * Recent documented history (within 2 years) of active tuberculosis (TB), current active TB infection, currently receiving anti-tuberculous medication (e.g., INH, rifampin, streptomycin, pyrazinamide, or others). * Active hepatitis or a history of prior viral hepatitis B or hepatitis C, or positive hepatitis B serologies. Patients with a positive hepatitis B surface antibody (HBsAb) test with a documented history of prior hepatitis B immunization are eligible as long as other criteria are met (i.e. negative tests for: hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) and hepatitis C virus antibody (HCVAb)). * Other severe, concurrent diseases (e.g., cardiac or pulmonary disease), mental disorders, or major organ malfunction (liver, kidney) that could interfere with the patient ability to participate in the study. * Pregnant or nursing women. * Cytomegalovirus (CMV) positive by polymerase chain reaction (PCR) (above the level of detection). A patient that is PCR positive will require treatment to reduce the viral load to a non-detectable level; but such a patient may be considered for study entry once the infection has been treated. * Medical condition requiring chronic use of oral corticosteroids at a dose higher than physiologic replacement.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Best Disease Response as Determined by the Independent Response Review Panel (IRRP) | up to 44 weeks | Participants were evaluated by the IRRP according to National Cancer Institute (NCI) 1996 response criteria. The best response observed during the study is summarized. Response categories include Complete Response (CR) with normal physical exam, marrow cells and blood values, Partial Response (PR) with a \>= 50% decrease from baseline in lymphocytes, lymphadenopathy and liver or spleen exam, Stable Disease (SD) without significant progression from baseline, or Progressive Disease (PD) with increased size/number of nodes, size of liver or spleen, increase in lymphocytes, aggressive histology. |
| Percentage of Participants Who Had an Overall Response (OR) as Determined by the Independent Response Review Panel (IRRP) | up to 44 weeks | Participants were evaluated by the IRRP according to National Cancer Institute (NCI) 1996 response criteria. The percentage of participants whose best response observed during the study was either a Complete Response (CR) or a Partial Response (PR). Overall Response (OR) = CR + PR. A Complete Response (CR) exhibits a normal physical exam, marrow cells and blood values. A Partial Response (PR) has a \>= 50% decrease from baseline in lymphocytes, lymphadenopathy and liver or spleen exam. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kaplan-Meier Estimates of Overall Survival | up to 5 years | Overall survival was defined as the time in days from the date of first treatment to the date of death due to any cause for all participants. Results are stated in months. |
| Kaplan-Meier Estimates of Progression Free Survival as Determined by the Independent Response Review Panel (IRRP) | up to 5 years | Progression-free survival was defined as the number of days from the date of first treatment to the date of first objective documentation of progressive disease (PD) as determined by the IRRP, or death due to any cause. Results are expressed in months. Progressive Disease (PD) was defined as an increase in size/number of nodes, size of liver or spleen, increase in lymphocytes, or aggressive histology. |
| Participants With Treatment-Emergent Adverse Events (TEAE) | up to 18 weeks of treatment plus 45 days | Number of participants with treatment-emergent adverse events (TEAEs). AEs were graded by the investigator using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and were assessed for relatedness to study treatment (5 point scale from 'not related' to 'definitely related') and severity (5 point scale with grade 5 being most severe). Categories reported include participant counts for treatment-emergent AEs, injection site reactions, AEs for infections, serious AEs, AEs causing discontinuation of study drug(s), deaths and severity. |
| Participants With a Minimal Residual Disease (MRD) Status of Negative | 44 weeks | MRD negativity represents a very positive response outcome. MRD negativity in this report was defined by the absence of tumor cells in bone marrow, using 4-color flow cytometry. All patients are evaluated for treatment response based on National Cancer Institute Working Group (NCIWG) criteria. Of patients who have achieved a clinical complete response (CR) or partial response (PR) that met National Cancer Institute Working Group (NCIWG) criteria of CR except blood recovery, a bone marrow sample was taken for flow cytometry measure of MRD negativity. |
| Kaplan-Meier Estimates of Duration of Response as Determined by the Independent Response Review Panel (IRRP) | up to 5 years | Duration of response was analyzed for participants who achieved a complete response (CR) or partial response (PR) and was defined as the number of days from the first date of documented response to the date of progressive disease (PD) as determined by IRRP or death due to any cause. Results are stated in months. Progressive Disease (PD) was defined as an increase in size/number of nodes, size of liver or spleen, increase in lymphocytes, or aggressive histology. |
Countries
Belgium, Czechia, France, Serbia, United Kingdom, United States
Participant flow
Pre-assignment details
109 patients screened and 86 enrolled and treated.
Participants by arm
| Arm | Count |
|---|---|
| Alemtuzumab 30mg Participants received a target dose of alemtuzumab 30mg by subcutaneous injection three times a week for up to 18 weeks. Some participants started in the Escalation subpopulation and started at a lower dose and escalated from 3mg to 10 mg to the target 30 mg dose in the first 1-2 weeks. | 86 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Follow-up | Death | 31 |
| Follow-up | Lost to Follow-up | 4 |
| Treatment | Adverse Event | 21 |
| Treatment | Confirmed complete response, MRD - | 3 |
| Treatment | Death | 1 |
| Treatment | Evidence of disease progression | 2 |
| Treatment | Non-compliance | 1 |
| Treatment | Physician Decision | 5 |
| Treatment | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Alemtuzumab 30mg |
|---|---|
| Age, Continuous | 65.32 years STANDARD_DEVIATION 9.035 |
| Current Binet Stage Stage A | 20 participants |
| Current Binet Stage Stage B | 22 participants |
| Current Binet Stage Stage C | 44 participants |
| Current Rai Stage Rai Stage 0 | 7 participants |
| Current Rai Stage Rai Stage I | 10 participants |
| Current Rai Stage Rai Stage II | 22 participants |
| Current Rai Stage Rai Stage III | 7 participants |
| Current Rai Stage Rai Stage IV | 40 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants |
| Race/Ethnicity, Customized Asian | 1 participants |
| Race/Ethnicity, Customized Black or African American | 2 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants |
| Race/Ethnicity, Customized Other | 1 participants |
| Race/Ethnicity, Customized White | 82 participants |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 57 Participants |
| World Health Organization (WHO) Performance 0 | 55 participants |
| World Health Organization (WHO) Performance 1 | 28 participants |
| World Health Organization (WHO) Performance 2 | 3 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 81 / 86 |
| serious Total, serious adverse events | 46 / 86 |
Outcome results
Primary
Number of Participants With Best Disease Response as Determined by the Independent Response Review Panel (IRRP)
Participants were evaluated by the IRRP according to National Cancer Institute (NCI) 1996 response criteria. The best response observed during the study is summarized. Response categories include Complete Response (CR) with normal physical exam, marrow cells and blood values, Partial Response (PR) with a \>= 50% decrease from baseline in lymphocytes, lymphadenopathy and liver or spleen exam, Stable Disease (SD) without significant progression from baseline, or Progressive Disease (PD) with increased size/number of nodes, size of liver or spleen, increase in lymphocytes, aggressive histology.
Time frame: up to 44 weeks
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alemtuzumab 30mg | Number of Participants With Best Disease Response as Determined by the Independent Response Review Panel (IRRP) | Overall response (CR+PR) | 37 participants |
| Alemtuzumab 30mg | Number of Participants With Best Disease Response as Determined by the Independent Response Review Panel (IRRP) | Complete response (CR) | 5 participants |
| Alemtuzumab 30mg | Number of Participants With Best Disease Response as Determined by the Independent Response Review Panel (IRRP) | Partial response (PR) | 32 participants |
| Alemtuzumab 30mg | Number of Participants With Best Disease Response as Determined by the Independent Response Review Panel (IRRP) | Stable disease (SD) | 24 participants |
| Alemtuzumab 30mg | Number of Participants With Best Disease Response as Determined by the Independent Response Review Panel (IRRP) | Progressive disease (PD) | 4 participants |
| Alemtuzumab 30mg | Number of Participants With Best Disease Response as Determined by the Independent Response Review Panel (IRRP) | Not Evaluable (NE) | 21 participants |
Primary
Percentage of Participants Who Had an Overall Response (OR) as Determined by the Independent Response Review Panel (IRRP)
Participants were evaluated by the IRRP according to National Cancer Institute (NCI) 1996 response criteria. The percentage of participants whose best response observed during the study was either a Complete Response (CR) or a Partial Response (PR). Overall Response (OR) = CR + PR. A Complete Response (CR) exhibits a normal physical exam, marrow cells and blood values. A Partial Response (PR) has a \>= 50% decrease from baseline in lymphocytes, lymphadenopathy and liver or spleen exam.
Time frame: up to 44 weeks
Population: Full analysis set. 95% confidence interval calculated using exact binomial method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alemtuzumab 30mg | Percentage of Participants Who Had an Overall Response (OR) as Determined by the Independent Response Review Panel (IRRP) | 43.0 percentage of participants |
Secondary
Kaplan-Meier Estimates of Duration of Response as Determined by the Independent Response Review Panel (IRRP)
Duration of response was analyzed for participants who achieved a complete response (CR) or partial response (PR) and was defined as the number of days from the first date of documented response to the date of progressive disease (PD) as determined by IRRP or death due to any cause. Results are stated in months. Progressive Disease (PD) was defined as an increase in size/number of nodes, size of liver or spleen, increase in lymphocytes, or aggressive histology.
Time frame: up to 5 years
Population: Participants who had a complete response or a partial response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alemtuzumab 30mg | Kaplan-Meier Estimates of Duration of Response as Determined by the Independent Response Review Panel (IRRP) | 11.09 months |
Secondary
Kaplan-Meier Estimates of Overall Survival
Overall survival was defined as the time in days from the date of first treatment to the date of death due to any cause for all participants. Results are stated in months.
Time frame: up to 5 years
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alemtuzumab 30mg | Kaplan-Meier Estimates of Overall Survival | 38.29 months |
Secondary
Kaplan-Meier Estimates of Progression Free Survival as Determined by the Independent Response Review Panel (IRRP)
Progression-free survival was defined as the number of days from the date of first treatment to the date of first objective documentation of progressive disease (PD) as determined by the IRRP, or death due to any cause. Results are expressed in months. Progressive Disease (PD) was defined as an increase in size/number of nodes, size of liver or spleen, increase in lymphocytes, or aggressive histology.
Time frame: up to 5 years
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alemtuzumab 30mg | Kaplan-Meier Estimates of Progression Free Survival as Determined by the Independent Response Review Panel (IRRP) | 12.43 months |
Secondary
Participants With a Minimal Residual Disease (MRD) Status of Negative
MRD negativity represents a very positive response outcome. MRD negativity in this report was defined by the absence of tumor cells in bone marrow, using 4-color flow cytometry. All patients are evaluated for treatment response based on National Cancer Institute Working Group (NCIWG) criteria. Of patients who have achieved a clinical complete response (CR) or partial response (PR) that met National Cancer Institute Working Group (NCIWG) criteria of CR except blood recovery, a bone marrow sample was taken for flow cytometry measure of MRD negativity.
Time frame: 44 weeks
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alemtuzumab 30mg | Participants With a Minimal Residual Disease (MRD) Status of Negative | 4 participants |
Secondary
Participants With Treatment-Emergent Adverse Events (TEAE)
Number of participants with treatment-emergent adverse events (TEAEs). AEs were graded by the investigator using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and were assessed for relatedness to study treatment (5 point scale from 'not related' to 'definitely related') and severity (5 point scale with grade 5 being most severe). Categories reported include participant counts for treatment-emergent AEs, injection site reactions, AEs for infections, serious AEs, AEs causing discontinuation of study drug(s), deaths and severity.
Time frame: up to 18 weeks of treatment plus 45 days
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alemtuzumab 30mg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE | 82 participants |
| Alemtuzumab 30mg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 TEAE related to drug | 80 participants |
| Alemtuzumab 30mg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 injection site reaction | 49 participants |
| Alemtuzumab 30mg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 injection site reaction related to drug | 48 participants |
| Alemtuzumab 30mg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 infection | 49 participants |
| Alemtuzumab 30mg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 infection related to drug | 35 participants |
| Alemtuzumab 30mg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 serious AE | 46 participants |
| Alemtuzumab 30mg | Participants With Treatment-Emergent Adverse Events (TEAE) | >=1 serious AE related to drug | 39 participants |
| Alemtuzumab 30mg | Participants With Treatment-Emergent Adverse Events (TEAE) | Discontinued study drug due to AE | 21 participants |
| Alemtuzumab 30mg | Participants With Treatment-Emergent Adverse Events (TEAE) | Discontinued study drug due to related AE | 20 participants |
| Alemtuzumab 30mg | Participants With Treatment-Emergent Adverse Events (TEAE) | Deaths | 12 participants |
| Alemtuzumab 30mg | Participants With Treatment-Emergent Adverse Events (TEAE) | Deaths within 30 days of last dose | 3 participants |
| Alemtuzumab 30mg | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE with worst severity grade 1 | 3 participants |
| Alemtuzumab 30mg | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE with worst severity grade 2 | 8 participants |
| Alemtuzumab 30mg | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE with worst severity grade 3 | 18 participants |
| Alemtuzumab 30mg | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE with worst severity grade 4 | 45 participants |
| Alemtuzumab 30mg | Participants With Treatment-Emergent Adverse Events (TEAE) | TEAE with worst severity grade 5 | 8 participants |