Phase I Study of Clofarabine with Standard-Dose Infusional Cytarabine (Ara-C) as Intensive Induction Therapy for Newly-Diagnosed De Novo Acute Myeloid Leukemia in Older Adults Age ≥60 Years.
Authors: Foran James , The Angelina , Dixon Pam , Devetten Marcel , Sekeres Mikkael 
Published: April 2020

Abstract
Background The median age of AML is approximately 70 years, and the survival of older adults age ≥60 years remains poor with standard therapy. Clofarabine (CLO) has significant single agent activity in AML, and in vitro studies demonstrate synergy with Ara-C. We therefore performed a phase I study to determine the maximum tolerated dose (MTD) of CLO with standard dose Ara-C (100mg/m2/day D1-7 by 24hr continuous infusion) as AML induction therapy. CLO was administered daily × 5 days beginning D2 to allow for pharmacokinetic (PK) & pharmacodynamic (PD) studies.
Methods Enrollment was restricted to newly-diagnosed de novo AML patients age ≥60 years considered candidates for intensive therapy; those with prior MDS or hypoplastic AML (&lt;20% bone marrow cellularity) were excluded. Pts were treated in cohorts of 3–6 to determine MTD of CLO with standard dose infusional Ara-C (100mg/m2 × 7). DLT was defined as grade III/IV non-hematologic toxicity occurring in &gt;1 pt per cohort. The CLO starting dose was 30mg/m2/day ×5 (dose level 1), with the intention to increase to CLO 40mg/m2 if tolerated. However, CLO dose reductions of 25% (CLO 22.5 mg/m2/day × 5, dose level -1) & 50% (CLO 15mg/m2/day ×5, dose level -2) were allowed in the event of dose-limiting toxicity (DLT). Pts achieving complete remission (CR) received 2 cycles consolidation with CLO ×5 & Ara-C 100mg/m2 × 5.
Results A total of 13 pts (median age 69 yrs, range 61–77; 10 male) have been treated. DLT was observed at dose level 1 (Table 1), and the protocol was amended to mandate additional hydration with CLO, and antibiotic/antifungal prophylaxis. At dose level -1, 1 pt died from PE on D27 after hematologic recovery, considered treatment-related per protocol, mandating dose de-escalation to dose level -2. Pt 13 is in active induction therapy, and not yet evaluable for response, although DLT has not been encountered. Febrile neutropenia occurred in 11/13 pts. The MTD in this study is CLO 15mg/m2/day × 5 with standard infusional Ara-C (dose level -2). Significant clinical activity was observed, particularly at higher CLO doses, including CR in 2 pts with complex karyotype. In contrast, only 1/5 evaluable pts at dose level-2 achieved CR. PK & PD studies are in progress.
Conclusions In contrast to prior reports using intermediate dose bolus Ara-C (1g/m2), the MTD of CLO combined with standard dose infusional Ara-C in older adults with AML is lower, and the toxicity profile appears different. Significant clinical activity was noted at higher CLO dose levels & with complex karyotype. Based on this observation an escalation to CLO 20mg/m2 is now planned.
CLO & Standard Dose Infusional Ara-C: Toxicity & Efficacy Patient CLO Dose Level Age Cytogenetics Response (CR Duration) DLT Fail - failure to achieve CR 1 1 (30mg) 66 −7 Death Infection/Renal 2 1 61 −7, complex CR (15 mths) none 3 1 69 intermediate CR (2 mths) none 4 1 77 5q-, complex Death Infection/Renal/Vasc Leak 5 −1 (22.5mg) 75 +8 Death Pneumonia 6 −1 67 diploid CR (5 mths) none 7 −1 71 9q- Death Pulm Embolism Day 27 8 −2 (15mg) 74 5q-, complex Fail none 9 −2 64 diploid Fail none 10 −2 63 diploid Fail none 11 −2 73 complex CR (5 mths) none 12 −2 72 diploid Fail none 13 −2 63 diploid - -