Alemtuzumab and Combination Chemotherapy in Treating Patients With Untreated Acute Lymphoblastic Leukemia

Official Title: “A Phase I/II Dose Escalation Study of Subcutaneous Campath-1H (NSC #715969, IND #10864) During Intensification Therapy in Adults With Untreated Acute Lymphoblastic Leukemia (ALL)”

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies such as alemtuzumab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Combining chemotherapy with monoclonal antibody therapy may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of alemtuzumab and to see how well it works when given together with combination chemotherapy in patients with previously untreated acute lymphoblastic leukemia.

OBJECTIVES: - Determine the feasibility and toxicity profiles of escalating doses of alemtuzumab during post-remission intensification therapy in patients with untreated acute lymphoblastic leukemia. - Determine the maximum tolerated dose of this drug in these patients. (Phase I portion closed to accrual as of 7/5/2005) - Determine the disease-free and overall survival of patients treated with this regimen. - Determine whether this drug can further reduce minimal residual disease states in these patients. - Correlate pretreatment characteristics (e.g., cytogenetics and molecular changes) with disease-free and overall survival in patients treated with this regimen. - Determine the feasibility of combining this regimen with imatinib mesylate in patients with Philadelphia chromosome-positive disease.

OUTLINE: This is a multicenter, dose-escalation study of alemtuzumab. All courses are 28 days in length except courses 3 and 7 which are 42 days. Treatment continues in the absence of disease progression or unacceptable toxicity. - Course 1 (induction): Patients receive daunorubicin IV over 5-60 minutes on days 1-3; cyclophosphamide IV over 15-30 minutes on day 1; vincristine IV over 1-2 minutes on days 1, 8, 15, and 22; oral dexamethasone on days 1-7 and 15-21; asparaginase subcutaneously (SC) on days 5, 8, 11, 15, 18, and 22; and filgrastim (G-CSF) SC once daily beginning on day 4 and continuing until blood counts recover.* Beginning no earlier than day 15, patients with Philadelphia chromosome (Ph)-positive disease also receive oral imatinib mesylate once daily until day 28. Patients > 60 years of age with Ph-positive disease achieving a complete remission are removed from study.

NOTE: *Patients 60 years of age and over do not receive cyclophosphamide and receive dexamethasone on days 1-7 only. - Course 2 (early intensification): After sufficient recovery from course 1, patients receive cyclophosphamide IV over 15-30 minutes on day 1; cytarabine IV over 3 hours on days 1-3; methotrexate intrathecally (IT) on day 1; asparaginase SC on days 15, 18, and 22; and G-CSF once daily beginning on day 4 and continuing until blood counts recover.

Patients with Ph-positive disease also receive oral imatinib mesylate once daily on days 1-28.Patients will receive dexamethasone eyedrops on days 1,2,3,and 4. Patients will be given cotrimoxazole PO twice a day 3 days per week until the completion of all chemotherapy or inhaled pentamidine once a month if allergic sulfonamides. - Course 3 (CNS prophylaxis): After sufficient recovery from course 2, patients receive vincristine IV over 1-2 minutes, methotrexate IV over 3 hours, and methotrexate IT on days 1, 15, and 29; oral methotrexate every 6 hours for 4 doses beginning 6 hours after the start of methotrexate IV infusion on days 1, 15, and 29; oral mercaptopurine on days 1-35; leucovorin calcium IV over 5-10 minutes on days 2, 16, and 30; and oral leucovorin calcium every 6 hours for 8 doses beginning 12 hours after IV leucovorin calcium on days 3 and 4, 17 and 18, and 31 and 32. Patients with Ph-positive disease also receive oral imatinib mesylate once daily on days 1-42.

Patients who have CD52^+ disease as determined by pretreatment immunohistochemistry, and meet all of the following criteria proceed to course 4. - M_0 or M_1 marrow with absolute neutrophil count at least 1,500/mm^3 and platelet count at least 100,000/mm^3 - AST less than 3 times upper limit of normal - Cytomegalovirus polymerase chain reaction negative - No serious infection All other patients proceed to course 5. - Course 4 (immunotherapy): - Phase I: Patients receive alemtuzumab SC 3 times per week for 4 weeks. Cohorts of at least 6 patients receive escalating doses of alemtuzumab until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 4 of 6 or 5 of 12 patients experience dose-limiting toxicity. - Phase II: Patients receive treatment as in phase I at the MTD of alemtuzumab. - Course 5 (late intensification): Beginning 2-6 weeks after the completion of course 4, patients receive treatment as in course 1 except with dexamethasone on days 1-7 only. - Course 6 (late intensification): After sufficient recovery from course 5, patients receive treatment as in course 2. - Course 7 (CNS intensification): After sufficient recovery from course 6, patients receive treatment as in course 3. - Course 8 (maintenance therapy): After completion of courses 1-7 and in the absence of disease progression, patients receive maintenance therapy. Patients receive oral mercaptopurine daily; vincristine IV over 1-2 minutes on day 1; oral methotrexate once weekly on days 1, 8, 15, and 22; and oral dexamethasone on days 1-5. Courses repeat every 28 days for up to 24 months from study entry. Patients with Ph-positive disease also receive oral imatinib mesylate once daily beginning on day 1 and continuing until completion of study therapy.

For testicular disease at study entry that persists or worsens after 4 weeks of therapy or testicular disease that develops after study therapy has begun, patients undergo testicular radiotherapy once daily 5 days a week for 13 treatments.

Patients with CNS leukemia receive methotrexate IT 1-2 times weekly for 5 weeks and leucovorin calcium IV 24 hours after each methotrexate dose. Patients also undergo cranial radiotherapy once daily 5 days a week for 12 treatments. Radiotherapy begins on day 5 of course 1 for patients with CNS leukemia at study entry or the day after diagnosis of CNS leukemia for patients who develop disease after study therapy has begun. If remission is achieved, patients continue study therapy and receive methotrexate once monthly for 12 months.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually for up to 10 years from study entry.

PROJECTED ACCRUAL: A total of 18-36 patients will be accrued for the phase I portion of the study within 5-12 months (closed to accrual as of 7/5/2005). A total of 236-282 patients will be accrued for the phase II portion of the study within 33-42 months.

Intervention(s) in this Clinical Trial

• Biological: alemtuzumab
  • 3 cohorts receive 10, 20, or 30 mg alemtuzumab sub Q injection 3 times/wk for 4 wks in Module D of Phases I and II
• Biological: filgrastim
  • Mod A, courses I & V: 5 ug/kg/day subQ inj start on D4 for at 7 days, then until abs neutrophil count is > 5000/uL Mod B, courses II & IV: 5 ug/kg/day subQ inj start on D 4, con't until abs neutrophil count is > 5000/uL
• Drug: asparaginase
  • 6000U/sq m subQ on days 5,8,15,18, 22 of Mod A, Courses I & V and days 15, 18, 22 of Mod B Courses II & VI
• Drug: cyclophosphamide
  • For pts < = 60 y/o 1200 mg/sq m IV infusion over 15-30 min on day 1 Mod A courses I & V For all pts 1000 mg/sq m IV infusion over 15-30 min day 1 of Mod B courses II & VI
• Drug: cytarabine
  • 2000 mg/sq m IV infusion over 3 hrs days 1, 2, 3 Mod B, courses II & VI
• Drug: daunorubicin hydrochloride
  • 80 mg/sq m/day slow IV infusion days 1, 2, 3 Mod A Courses I & V 60 mg/sq m/day slow IV infusion days 1, 2, 3 Mod B Courses II & VI
• Drug: dexamethasone
  • 5 mg/sq m PO bid days 1-7 and for pts < = 60y/o days 15-21 Mod A, Course I and days 1-7 for Course V 0.1% eye drops 2 drops qid & prn ea eye days 1-4 Mod B courses II & VI 6 mg/sq m PO days 1-5 of ea maintenance cycle (Course VIII)
• Drug: imatinib mesylate
  • For PH+ patients only: 400 mg PO/day d 15 or later- d 28 Mod A, Courses I & V; d 1-28 Mod B, courses II & VI, and d 1-42 Mod C courses III & VII 600 mg/day PO d 1 of month 1 maintenance until protocol tx is completed
• Drug: leucovorin calcium
  • 25 mg/sq m IV push 6 hrs post last MTX Mod C courses III & VII on days 2,16,30 10 mg PO q 6 hrs for 8 doses or until serum MTX < 0.05 uM starting 12 hrs after last IV dose
• Drug: mercaptopurine
  • 60 mg/sq m per day days 1-35 Mod C courses III & VII and during maintenance
• Drug: methotrexate
  • Intrathecal 15 mg d 1 Mod B Courses II & VI & d 1,15,29 Mod C courses III & VII IV 1000 mg/sq m d 1,15,29 Mod C courses III & VII PO 25 mg/sq m q 6 hrs 4 doses (starting 6 h post IV MTX) on days 1,2,15,16,29,30 Mod C courses III & VII; PO 20mg/sq m d 1,8,15,22 of ea maintenance cycle
• Drug: vincristine sulfate
  • 2 mg IV push d 1,8,15,22 Mod A courses I & V d 1, 15, 29 Mod C courses III & VII d 1 ea maintenance cycle
• Drug: Allopurinol
  • 300 mg PO days 1-14 Mod A Course I

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Alemtuzumab and combination chemotherapy
  • Alemtuzumab dosing is characterized in conjunction with chemotherapy for adults with untreated acute ALL

Primary Measures

• Toxicity: dose escalation (Phase 1)
  • Time Frame: 28 days
    Safety Issue?: Yes
• Feasibility (Phase 2)
  • Time Frame: 28 days
    Safety Issue?: Yes

Secondary Measures

• Disease-free survival (DFS) (Phase II)
  • Time Frame: 3 years
    Safety Issue?: No
• Overall survival (OS) (Phase II)
  • Time Frame: up to 10 yrs from study entry
    Safety Issue?: No

DISEASE CHARACTERISTICS:

• Histologically confirmed precursor B- or T-lymphoblastic leukemia, L1 or L2 acute lymphoblastic leukemia (ALL), or acute undifferentiated leukemia
• No Burkitt-type ALL
• No prior treatment for leukemia except for any of the following:
• Emergency leukapheresis
• Emergency treatment for hyperleukocytosis with hydroxyurea
• Cranial radiotherapy for CNS leukostasis (1 dose only)
• Must have a pretreatment bone marrow or peripheral blood sample submitted for central immunophenotyping
• Only patients who express CD52 at least 10% in the leukemic blast cell channel are eligible to receive alemtuzumab during module D, course IV

PATIENT CHARACTERISTICS:

• Age
• 15 and over
• Performance status
• Not specified
• Life expectancy
• Not specified
• Hematopoietic
• Not specified
• Hepatic
• Not specified
• Renal
• Not specified
• Other
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 6 months after study participation

PRIOR CONCURRENT THERAPY:

• Biologic therapy
• See Disease Characteristics
• Chemotherapy
• See Disease Characteristics
• No other concurrent chemotherapy
• Endocrine therapy
• Not specified
• Radiotherapy
• See Disease Characteristics
• No concurrent palliative radiotherapy
• Concurrent whole brain radiotherapy allowed for documented CNS disease
• Surgery
• Not specified
• Other
• No concurrent alcoholic beverages
• No concurrent over-the-counter pain relievers

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 15 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Cancer and Leukemia Group B Other

Overall Clinical Trial Officials and Contacts

Wendy Stock, MD Study Chair University of Chicago  

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00061945

Study ID Number: CDR0000302482

ClinicalTrials.gov Identifier: NCT00061945

Health Authority: United States: Food and Drug Administration

Clinical trial summary from the National Cancer Institute's PDQ® database