Acute Undifferentiated Leukemia, B-cell Adult Acute Lymphoblastic Leukemia, B-cell Childhood Acute Lymphoblastic Leukemia, L1 Adult Acute Lymphoblastic Leukemia, L1 Childhood Acute Lymphoblastic Leukemia, L2 Adult Acute Lymphoblastic Leukemia, L2 Childhood Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia, Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia, Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia, T-cell Adult Acute Lymphoblastic Leukemia, T-cell Childhood Acute Lymphoblastic Leukemia, Untreated Adult Acute Lymphoblastic Leukemia, Untreated Childhood Acute Lymphoblastic Leukemia
Conditions
Brief summary
This phase I/II trial studies the side effects and best dose of alemtuzumab when given together with combination chemotherapy and to see how well it works in treating patients with untreated acute lymphoblastic leukemia. Monoclonal antibodies, such as alemtuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy also work in different ways to kill cancer cells or stop them from growing. Giving alemtuzumab together with combination chemotherapy may be a better way to block cancer growth.
Detailed description
PRIMARY OBJECTIVES: I. To determine the feasibility and toxicity profiles of escalating doses of Campath-1H (alemtuzumab) given subcutaneously during post-remission intensification treatment of adults with acute lymphoblastic leukemia (ALL). II. To determine the disease-free survival (DFS) and overall survival (OS) when Campath-1H is used during post-remission intensification treatment of adults with ALL. III. To determine whether antibody treatment with Campath-1H can further reduce minimal residual disease states in adult ALL. IV. To obtain preliminary descriptive data on serum levels of Campath-1H during course IV, module D using limited pharmacokinetic sampling during the phase I and II components of the study. V. To obtain feasibility data on the addition of imatinib to Cancer and Leukemia Group B (CALGB) induction and postremission combination chemotherapy for patients with Philadelphia chromosome positive (Ph+) ALL. OUTLINE: This is a dose-escalation study of alemtuzumab. COURSE 1 (module A): Patients receive allopurinol orally (PO) 4 times daily (QID) on days 1-14, cyclophosphamide\* intravenously (IV) over 15-30 minutes on day 1, daunorubicin hydrochloride IV on days 1-3, vincristine sulfate IV on days 1, 8, 15, and 22, dexamethasone PO twice daily (BID) on days 1-7 and 15-21, asparaginase subcutaneously (SC) on days 5, 8, 11, 15, 18, and 22, and filgrastim SC on days 4-11. Patients who are Ph+ also receive imatinib mesylate PO on days 15-28. \*Note: Patients who are = 60 years old do not receive cyclophosphamide. COURSE 2 (module B): Patients receive methotrexate intrathecally (IT) on day 1, cytarabine IV over 3 hours on days 1-3, dexamethasone as eye drops QID on days 1-4, trimethoprim-sulfamethoxazole PO BID 3 times weekly on days 1-29, and cyclophosphamide, asparaginase and filgrastim as in course 1. Patients who are Ph+ also receive imatinib mesylate PO on days 1-28. COURSE 3 (module C): Patients receive vincristine sulfate IV on days 1, 15, and 29, methotrexate IV over 3 hours and IT on days 1, 15, and 19, methotrexate PO every 6 hours on days 1-2, 15-16, and 29-30, mercaptopurine PO on days 1-35, leucovorin calcium IV on days 2, 16, and 30, leucovorin calcium PO every 6 hours on days 3-4, and trimethoprim-sulfamethoxazole PO BID 3 times weekly on days 1-43. Patients who are Ph+ also receive imatinib mesylate PO on days 1-42. COURSE 4 (module D): Patients receive alemtuzumab SC 3 times weekly for 4 weeks and begin acyclovir PO QID for 6 months (continuing through course 8). * Phase I Cohort 1: 10 mg * Phase I Cohort 2: 20 mg * Phase I Cohort 3/Phase II MTD: 30 mg COURSE 5 (module A): Patients repeat course 1, minus allopurinol. COURSE 6 (module B): Patients repeat course 2. COURSE 7 (module C): Patients repeat course 3. COURSE 8: Patients receive mercaptopurine PO, vincristine sulfate IV on day 1, dexamethasone PO on days 1-5, methotrexate PO on days 1, 8, 15, and 22, and trimethoprim-sulfamethoxazole PO BID 3 days weekly. Patients who are Ph+ also receive imatinib mesylate PO on days 1-28. Courses repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months for 10 years.
Interventions
DRUGleucovorin calcium
Given IV and PO
BIOLOGICALalemtuzumab
Given SC
DRUGacyclovir
Given PO
OTHERlaboratory biomarker analysis
Correlative studies
DRUGimatinib mesylate
Given PO
DRUGmethotrexate
Given IT, IV, and PO
DRUGcytarabine
Given IV
DRUGtrimethoprim-sulfamethoxazole
Given PO
DRUGmercaptopurine
Given PO
DRUGallopurinol
Given PO
DRUGcyclophosphamide
Given IV
DRUGdaunorubicin hydrochloride
Given IV
DRUGvincristine sulfate
Given IV
DRUGdexamethasone
Given PO and as eye drops
DRUGasparaginase
Given SC
BIOLOGICALfilgrastim
Given SC
OTHERpharmacological study
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
15 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Unequivocal histologic diagnosis of precursor B or precursor T lymphoblastic leukemia (World Health Organization \[WHO\] classification), L1 or L2 ALL or acute undifferentiated leukemia (AUL) (French-American-British Cooperative group \[FAB\] Classification); Burkitt-type ALL (FAB L3, surface immunoglobulin \[SIg\]+) are excluded * No prior treatment for leukemia with three permissible exceptions: * Emergency leukapheresis II. Emergency treatment for hyperleukocytosis with hydroxyurea III. Cranial radiation therapy (RT) for central nervous system (CNS) leukostasis (one dose only) * All patients must have a pre-treatment bone marrow or peripheral blood sample submitted for central immunophenotyping; only those patients who express CD52 \>= 10% in the leukemia blast cell channel will be eligible to receive Campath-1H during module D, course IV
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Alemtuzumab (Phase I) | 6 weeks | The maximum tolerated dose is defined as the highest alemtuzumab dose at which less than 40% of patients develop the dose limiting toxicity (DLT), where DLT is defined as the inability to proceed (due to medical complications) with the protocol treatment within six weeks of receiving the last dose of alemtuzumab. Groups of six patients will be enrolled into each cohort at the time of re-registration prior to starting Course IV. After a cohort has accrued 6 patients and at least 3 have completed the 2-6 week post alemtuzumab observation period without DLT, the incoming patients will be assigned to the next cohort in the table while the DLT and other toxicities continue to be assessed for the newly closed cohort. If less than 3 out of 6 enrolled patients in a cohort have completed the 2-6 week post alemtuzumab observation period without DLT, additional patients may continue to enroll in that same cohort, i.e., accrual will not be suspended while waiting for patient follow-up data. |
| Number of Participants Who Proceed to Course V Within 2-6 Weeks of the Last Dose of Alemtuzumab (Phase II) | 8 months | The primary endpoint is the number of participants who are able to proceed to course V within two - six weeks of completion of course IV. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Minimal Residual Disease (MRD) During Treatment With Alemtuzumab (Phase II) | 9 years 4 months | Minimal Residual Disease measures the presence of of circulating leukemia cells in the body. Patients that report a Complete Response (CR) during treatment are further tested to determine the presence of small amounts of circulating leukemia cells. Here we report the number of patients who were MRD negative. |
| Disease-free Survival, for Only Complete Response Patients | 9 years 4 months | Disease Free Survival (DFS) is defined as the time from a Complete Response (CR) until death or relapse. The date of last clinical assesment will be used as the censor date for patients with no death or relapse. The DFS will be estimated using the Kaplan-Meier method with confidence intervals presented. |
| Overall Survival | 9 years 4 months | Overall Survival is defines as the time from registration to death due to any cause. It is estimated using the Kaplan-Meier method with confidence intervals presented. |
Countries
United States
Participant flow
Recruitment details
From June 2003 to May 2007, a total of 302 participants were recruited.
Pre-assignment details
Two (2) participants cancelled prior to receiving any treatment and were removed from all analyses.
Participants by arm
| Arm | Count |
|---|---|
| Phase I - Alemtuzumab and Combination Chemotherapy See detailed description or participant flow. | 119 |
| Phase II - Alemtuzumab and Combination Chemotherapy See detailed description or participant flow. | 181 |
| Total | 300 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Course IV: Alemtuzumab | Declined Alemtuzumab | 1 | 1 |
| Course IV: Alemtuzumab | Early exits | 6 | 15 |
| Registration Through Course 3 | Early discontinuation during course I-IV | 76 | 90 |
| Registration Through Course 3 | Not Alemtuzumab Eligible | 18 | 25 |
Baseline characteristics
| Characteristic | Phase I - Alemtuzumab and Combination Chemotherapy | Total | Phase II - Alemtuzumab and Combination Chemotherapy |
|---|---|---|---|
| Age, Continuous | 48.3 years | 46.8 years | 46.5 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 9 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 28 Participants | 17 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 11 Participants | 9 Participants |
| Race (NIH/OMB) White | 101 Participants | 251 Participants | 150 Participants |
| Region of Enrollment United States | 119 participants | 300 participants | 181 participants |
| Sex: Female, Male Female | 55 Participants | 128 Participants | 73 Participants |
| Sex: Female, Male Male | 64 Participants | 172 Participants | 108 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 99 / 119 | 152 / 181 |
| serious Total, serious adverse events | 60 / 119 | 98 / 181 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Alemtuzumab (Phase I)
The maximum tolerated dose is defined as the highest alemtuzumab dose at which less than 40% of patients develop the dose limiting toxicity (DLT), where DLT is defined as the inability to proceed (due to medical complications) with the protocol treatment within six weeks of receiving the last dose of alemtuzumab. Groups of six patients will be enrolled into each cohort at the time of re-registration prior to starting Course IV. After a cohort has accrued 6 patients and at least 3 have completed the 2-6 week post alemtuzumab observation period without DLT, the incoming patients will be assigned to the next cohort in the table while the DLT and other toxicities continue to be assessed for the newly closed cohort. If less than 3 out of 6 enrolled patients in a cohort have completed the 2-6 week post alemtuzumab observation period without DLT, additional patients may continue to enroll in that same cohort, i.e., accrual will not be suspended while waiting for patient follow-up data.
Time frame: 6 weeks
Population: Only participants who started Alemtuzumab were analyzed per study design. Specifically, one patient declined Alemtuzumab and was excluded from this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Alemtuzumab and Combination Chemotherapy | Maximum Tolerated Dose (MTD) of Alemtuzumab (Phase I) | 30 mg |
Primary
Number of Participants Who Proceed to Course V Within 2-6 Weeks of the Last Dose of Alemtuzumab (Phase II)
The primary endpoint is the number of participants who are able to proceed to course V within two - six weeks of completion of course IV.
Time frame: 8 months
Population: Only participants who started Alemtuzumab were analyzed per study design. Specifically, one patient declined Alemtuzumab and was excluded from this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Alemtuzumab and Combination Chemotherapy | Number of Participants Who Proceed to Course V Within 2-6 Weeks of the Last Dose of Alemtuzumab (Phase II) | 30 participants |
Secondary
Disease-free Survival, for Only Complete Response Patients
Disease Free Survival (DFS) is defined as the time from a Complete Response (CR) until death or relapse. The date of last clinical assesment will be used as the censor date for patients with no death or relapse. The DFS will be estimated using the Kaplan-Meier method with confidence intervals presented.
Time frame: 9 years 4 months
Population: All patients who received protocol treatment and had a complete response (CR) during treatment were included in this analysis. Phase I patients, who achieved complete response, were included with the phase II patients, who achieved complete response, for this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Alemtuzumab and Combination Chemotherapy | Disease-free Survival, for Only Complete Response Patients | 58.6 months |
| Phase II - Alemtuzumab and Combination Chemotherapy | Disease-free Survival, for Only Complete Response Patients | 19.8 months |
Secondary
Minimal Residual Disease (MRD) During Treatment With Alemtuzumab (Phase II)
Minimal Residual Disease measures the presence of of circulating leukemia cells in the body. Patients that report a Complete Response (CR) during treatment are further tested to determine the presence of small amounts of circulating leukemia cells. Here we report the number of patients who were MRD negative.
Time frame: 9 years 4 months
Population: Patients who reported a Complete Response (CR) during treatment and were analyzed for the presence of circulating leukemia cells.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I - Alemtuzumab and Combination Chemotherapy | Minimal Residual Disease (MRD) During Treatment With Alemtuzumab (Phase II) | 16 Participants |
Secondary
Overall Survival
Overall Survival is defines as the time from registration to death due to any cause. It is estimated using the Kaplan-Meier method with confidence intervals presented.
Time frame: 9 years 4 months
Population: All patients who registered, received protocol treatment, and were eligible were evaluated for this endpoint. Phase I patients were included with the phase II patients for this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Alemtuzumab and Combination Chemotherapy | Overall Survival | 33.6 months |
| Phase II - Alemtuzumab and Combination Chemotherapy | Overall Survival | 23.1 months |
Post Hoc
Number of Participants Achieving Complete Remission
A complete remission (CR) requires the following: an absolute neutrophil count (segs and bands) \> 1500/μl, no circulating blasts, platelets \> 100,000/μl; bone marrow cellularity \> 20% with trilineage hematopoiesis, and \< 5% marrow blast cells, none of which appear neoplastic. All previous extramedullary manifestations of disease must be absent (e.g., lymphadenopathy, splenomegaly, skin or gum infiltration, testicular masses, or CNS involvement).
Time frame: 9 years
Population: Three participants were deemed ineligible and excluded from this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Alemtuzumab and Combination Chemotherapy | Number of Participants Achieving Complete Remission | 92 participants |
| Phase II - Alemtuzumab and Combination Chemotherapy | Number of Participants Achieving Complete Remission | 145 participants |