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Phase 1: 1-3 patients will be treated in order to establish Cyclophosphamide and Clofarabine dose and to confirm reasonable safety and engraftment efficacy.

Drug - Clofarabine,Cyclophosphamide \& Alemtuzumab - Clofar (30mg/m2) D -8 to -4; Cyclo (500mg/m2) D -8 \& -7 \& Alem (20mg over 2hrs)

Phase II patients 4-9 will treat at the selected dose level of Clofarabine and Cyclophosphamide.

Drug - Clofarabine, Cyclophosphamide \& Alemtuzumab Clofar (30mg/m2) D -8 to -4; Cyclo (1000mg/m2) D -8 \& -7 \& Alem (20mg)-pts.

Hydrocortisone 100 mg IV 30 minutes prior to each dose of Clofarabine. Ondansetron 16 mg PO or IV or another comparable antiemetic should be given prior to each dose of Clofarabine. An additional similar dose should be given prior to Cyclophosphamide dose. Clofarabine 30 mg/M2 -8 through - 4 (5 doses) infusion. Alemtuzumab on day -8 only and after Clofarabine. Cyclophosphamide 500 mg/m2 Days -8 and -7 (2 doses) given over 1 hour beginning 4 hours after the beginning of Clofarabine infusion.

Clofar, Cyclophos, Alemtuzumab

Hydrocortisone 100 mg IV 30 minutes prior to each dose of Clofarabine. Ondansetron 16 mg PO or IV or another comparable antiemetic should be given prior to each dose of Clofarabine. An additional similar dose should be given prior to Cyclophosphamide dose. Clofarabine 30 mg/M2 -8 through - 4 (5 doses) infusion. Alemtuzumab on day -8 only and after Clofarabine. Cyclophosphamide 1000 mg/m2 Days -8 and -7 (2 doses) given over 1 hour beginning 4 hours after the beginning of Clofarabine infusion (patients 4-9)

Clofar, Cyclophos,Alemtuzumab(Ph II)

David F Claxton, MD

Allogeneic hematopoietic transplant is curative for many patients with hematological neoplasms but conditions to provide optimal engraftment and anti-tumor efficacy with minimal toxicity are still under way. Clofarabine is a newly licensed agent with dramatic anti-leukemic activity. Its incorporation into a regimen for pre-transplant conditioning of acute leukemia and lymphoma patients is logical, exploiting both the anti-tumor activities it is recognized to have and the immunosuppressive activity seen with drugs in its class.

Non-myeloablative conditioning allows curative allogeneic hematopoietic transplantation for patients unable to tolerate more toxic conventional conditioning regiments. These regiments continue to be refined and evolve. No standard regimen is yet agreed upon. The incorporation of the newly licenses agent Clofarabine into a non-myeloablative regimen is logical given its recognized anti-leukemic activity. This study will assess the safety and efficacy of Cyclophosphamide and Clofarabine in promoting hematopoietic engraftment after allogeneic transplant of blood stem cells. Patients eligibility will include those with advanced hematological neoplasms who might benefit from allogeneic blood cell transplant. Patients must have adequate organ function and suitable related or unrelated donors for transplant. In Phase I of the study 9-12 patients will be treated in order to establish Cyclophosphamide and Clofarabine dose, and to confirm reasonable safety and engraftment efficacy. Phase II will treat at total of 20 patients at the selected dose level of Clofarabine and Cyclophosphamide. Results will be compared to extensive Penn State Milton S. Hershey Medical Center experience using Fludarabine and Cyclophosphamide in a similar patient population. Supportive care, including graft versus host disease prophylaxis will be similar to that recently used at Hershey Medical Center. Primary endpoints will include survival and engraftment as compared to historical results at Hershey Medical Center. Disease specific outcomes for frequent diagnoses such as acute leukemia and non-hodgkin's lymphoma will be assessed as secondary endpoints.

Clofarabine and Non-Myeloablative Allogeneic Hematopoietic Transplantation

Establish the safety of Clofarabine and cyclophosphamide preceding allogeneic hematopoietic engraftment. Assess the efficacy of Clofarabine and cyclophosphamide as conditioning for promoting allogeneic hematopoietic engraftment.

Adequacy of engraftment will be assessed via assessment of chimerism (percent donor engraftment). Less than 20% engraftment by day 30 is then failure of engraftment.

Safety is defined per common toxicity criteria - Non-Hematological and non renal toxicities of ≥grade 3 or ≥grade 4 up to day 30 are scored as toxicity.

Observe disease free survivals in acute leukemia and lymphoma patients receiving allogeneic hematopoietic transplant after Clofarabine and cyclophosphamide conditioning.

Observe overall survival in leukemia and lymphoma patients receiving transplant after clofarabine and cyclophosphamide conditioning.

Milton S. Hershey Medical Center

Professor of Medicine

Phase 1: 1-3 patients will be treated in order to establish Cyclophosphamide and Clofarabine dose and to confirm reasonable safety and engraftment efficacy.

Dose Level I: Hydrocortisone 100 mg IV 30 minutes prior to each dose of Clofarabine. Ondansetron 16 mg PO or IV or another comparable antiemetic should be given prior to each dose of Clofarabine. An additional similar dose should be given prior to Cyclophosphamide dose. Clofarabine 30 mg/M2 -8 through - 4 (5 doses) infusion. Alemtuzumab on day -8 only and after Clofarabine. Cyclophosphamide 500 mg/m2 Days -8 and -7 (2 doses) given over 1 hour beginning 4 hours after the beginning of Clofarabine infusion.

Clofarabine, Cyclophosphamide & Alemtuzumab (Phase I)

Phase II patients 4-9 will treat at the selected dose level of Clofarabine and Cyclophosphamide.

Dose Level 2: Hydrocortisone 100 mg IV 30 minutes prior to each dose of Clofarabine. Ondansetron 16 mg PO or IV or another comparable antiemetic should be given prior to each dose of Clofarabine. An additional similar dose should be given prior to Cyclophosphamide dose. Clofarabine 30 mg/M2 -8 through - 4 (5 doses) infusion. Alemtuzumab on day -8 only and after Clofarabine. Cyclophosphamide 1000 mg/m2 Days -8 and -7 (2 doses) given over 1 hour beginning 4 hours after the beginning of Clofarabine infusion (patients 4-9)

Spots Global Cancer Trial Database for clofar, cyclophos, alemtuzumab