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alemtuzumab

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laboratory biomarker analysis

pharmacological study

Wendy Stock

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.

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.

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

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)

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.

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.

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 (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 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.

National Cancer Institute (NCI)

See detailed description or participant flow.

Phase I - Alemtuzumab and Combination Chemotherapy

Phase II - Alemtuzumab and Combination Chemotherapy

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Wendy Stock, M.D.

Only participants who started Alemtuzumab were analyzed per study design. Specifically, one patient declined Alemtuzumab and was excluded from this analysis.

Maximum Tolerated Dose (MTD) of Alemtuzumab (Phase I)

Number of Participants Who Proceed to Course V Within 2-6 Weeks of the Last Dose of Alemtuzumab (Phase II)

Patients who reported a Complete Response (CR) during treatment and were analyzed for the presence of circulating leukemia cells.

Minimal Residual Disease (MRD) During Treatment With Alemtuzumab (Phase II)

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.

Disease-free Survival, for Only Complete Response Patients

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.

Overall Survival

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).

Three participants were deemed ineligible and excluded from this analysis.

Number of Participants Achieving Complete Remission

COURSE 1-allopurinol (ALL) orally (PO) 4x daily (QID) d1-14, cyclophosphamide (CTX) intravenously (IV) d1, daunorubicin IV d1-3, vincristine (VCR) IV d1,8,15 \& 22, dexamethasone (DEX) PO 2x daily (BID) d1-7 \& 15-21, asparaginase (APG) subcutaneously (SC) d5,8,11,15,18 \& 22, and filgrastim (FIL) SC d4-11. Ph+ pts imatinib (IMT) PO d15-28 COURSE 2-methotrexate (MTX) intrathecally (IT) d1, cytarabine IV d1-3, DEX eye drops QID d1-4, cotrimoxazole (CRT) PO BID 3x wkly d1-29 and CTX, APG \& FIL as course 1. Ph+ pts IMT PO d1-28 COURSE 3-VCR IV d1,15 \& 29, MTX IV \& IT d1,15 \& 19, MTX PO q6 hr d1-2,15-16 \& 29-30, mercaptopurine (6-MP) PO d1-35, leucovorin (LCV) IV d 2,16 \& 30, LCV PO q6 hr d3-4 \& CRT PO BID 3x wkly d1-43. Ph+ pts IMT PO d1-42 COURSE 4-alemtuzumab 10,20 or 30 mg SC 3x wkly q4 wk, acyclovir PO QID q6 mo COURSE 5-course 1 COURSE 6-course 2 COURSE 7-course 3 COURSE 8-6-MP PO, VCR IV d1, DEX PO d1-5, MTX PO d1,8,15 \& 22 and CRT PO BID 3d wkly. Ph+ pts IMT PO d1-28 q24 mo

COURSE 1-allopurinol (ALL) orally (PO) 4x daily (QID) d1-14, cyclophosphamide (CTX) intravenously (IV) d1, daunorubicin IV d1-3, vincristine (VCR) IV d 1,8,15 \& 22, dexamethasone (DEX) PO 2x daily (BID) d 1-7 \& 15-21, asparaginase (APG) subcutaneously (SC) d 5,8,11,15,18 \& 22, and filgrastim (FIL) SC d 4-11. Ph+ pts imatinib (IMT) PO d 15-28 COURSE 2-methotrexate (MTX) intrathecally (IT) d1, cytarabine IV d1-3, DEX eye drops QID d 1-4, cotrimoxazole (CRT) PO BID 3x wkly d1-29 and CTX, APG \& FIL as course 1. Ph+ pts IMT PO d1-28 COURSE 3-VCR IV d 1,15 \& 29, MTX IV \& IT d 1,15 \& 19, MTX PO q6 hr d 1-2,15-16 \& 29-30, mercaptopurine (6-MP) PO d1-35, leucovorin (LCV) IV d 2,16 \& 30, LCV PO q6 hr d 3-4 \& CRT PO BID 3x wkly d1-43. Ph+ pts IMT PO d1-42 COURSE 4-alemtuzumab 30 mg SC 3x wkly q4 wk, acyclovir PO QID q6 mo COURSE 5-course 1 COURSE 6-course 2 COURSE 7-course 3 COURSE 8-6-MP PO, VCR IV d1, DEX PO d1-5, MTX PO d 1,8,15 \& 22 and CRT PO BID 3x wkly. Ph+ pts IMT PO d1-28 q24 mo

Registration Through Course 3

Course IV: Alemtuzumab

Spots Global Cancer Trial Database for philadelphia chromosome positive childhood precursor acute lymphoblastic leukemia