A Phase I Study of Carfilzomib for Relapsed or Refractory Acute Myeloid and Acute Lymphoblastic Leukemia
Authors: Wartman Lukas D. , Fiala Mark A. , Hawkins Emily , Fletcher Theresa , Allen Melissa , Cashen Amanda F. , DiPersio John F. , Jacoby Meagan , Stockerl-Goldstein Keith E. , Pusic Iskra , Uy Geoffrey L. , Westervelt Peter , Vij Ravi 
Published: October 2019

Abstract
Background: The outcome for patients with relapsed or refractory acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) remains extremely poor; new chemotherapy agents with activity against these leukemias are urgently needed. Proteasome inhibition is a promising therapeutic target in acute leukemias with established efficacy in several other hematologic malignancies. Several published studies have demonstrated the potent in vitro anti-leukemic activity of the selective proteasome inhibitor carfilzomib (CFZ) in leukemia cell lines as well as in primary human AML and ALL blasts. Given the favorable toxicity profile of CFZ, there was a strong rationale to begin the clinical study of this agent in the treatment of acute leukemias. We performed a phase I, single arm, single center, open label study of CFZ in adult patients with relapsed or refractory AML and ALL.
Objectives: The primary objective was to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of CFZ in adult patients with relapsed/refractory AML and ALL. Secondary objectives included: determination of disease response, time to response, remission duration, progression-free survival, event-free survival, and overall survival. The study was designed to determine the safety and tolerability of carfilzomib in this patient population.
Patients/Methods: Patients with relapsed or refractory AML or ALL after ³ 1 line of therapy, with good performance status and organ function were eligible. CFZ was given on days 1, 2, 8, 9, 15, 16, 22, and 23 in a 28-day cycle at escalating doses of 36, 45, and 56mg/m2. All dose levels included lead-in doses on days 1, 2, 8 and 9. Up to 6 cycles of treatment were allowed.
Dose escalation was performed using a 3+3 design; MTD was defined as the highest dose level where DLT occurred in less than 1 of 3 or 2 of 6 patients. Disease response was determined using International Working Group (IWG) criteria for AML.
Results: 18 patients were enrolled from Dec 2010-July 2014. Eight patients discontinued prior to completion of cycle 1 for reasons other than study-related toxicity and were replaced.The median age was 70 years (range 32-78). 12 of the 18 patients were male. 17 patients had AML while 1 patient had ALL. The median number of prior therapies was 2 (range 1-4). 2 patients had undergone prior allogeneic stem cell transplantation. The median time from diagnosis to start of protocol was 9.7 months (range 1.4-102.0).
Median white blood cell (WBC) count at study start was 3.2x109/L (range 0.6-42.2), with median peripheral blood blasts of 18% (range 0-62), and bone marrow blasts 45.5% (range 11-92). 7 of the 17 patients with AML had complex cytogenetics.
10 of the 18 patients were evaluable for disease response. Of the 10 evaluable patients, 2 patients achieved a partial response (PR), and 4 additional patients had stable disease (SD). The median duration on study was 21.5 days (range 1-64), with median overall survival (OS) of 1.9 months.
CFZ was generally well tolerated; no DLTs were observed in any cohort. The most common grade 3/4 non-hematologic toxicities regardless of attribution were: dyspnea (17%), activated partial thromboplastin time prolongation (17%), intracranial hemorrhage or hematoma (11%), infection (11%), CHF exacerbation (11%), and hypophosphatemia (11%).
Conclusions: Administration of CFZ was well tolerated, and a MTD was not established. The recommended dosage for further studies is 56mg/m2. In this limited phase 1 study of heavily pre-treated patients, we observed modest anti-leukemic activity. However, additional clinical trials incorporating CFZ in combination with other chemotherapeutic agents are now needed to assess the potential efficacy of CFZ in the treatment of AML and ALL.
Abstract 5292. Table 1 ID Dose Level Diagnosis # of Prior Lines of Therapy Prior SCT # of Cycles Best Response 1 1 (36mg/m2) AML 1 N 3 SD 2 1 (36mg/m2) AML 3 Y <1 NA 3 1 (36mg/m2) AML 2 N 2 PR 4 1 (36mg/m2) AML 2 N 2 SD 5 2 (45mg/m2) AML 2 N 1 PD 6 2 (45mg/m2) AML 2 N <1 NA 7 2 (45mg/m2) AML 3 N <1 NA 8 2 (45mg/m2) AML 2 N <1 NA 9 2 (45mg/m2) AML 2 N 2 SD 10 2 (45mg/m2) AML 3 N <1 NA 11 2 (45mg/m2) AML 2 N 2 SD 12 2 (45mg/m2) AML 2 N 1 PD 13 3 (56mg/m2) AML 3 N 1 PD 14 3 (56mg/m2) AML 4 Y 2 PR 15 3 (56mg/m2) AML 1 N 1 PD 16 3 (56mg/m2) AML 3 N <1 NA 17 3 (56mg/m2) ALL 1 N <1 NA 18 3 (56mg/m2) AML 2 N <1 NA
Abbreviations: NA- Not Applicable; SD- Stable Disease; PR- Partial Response; PD- Progressive Disease

Disclosures
Off Label Use: We performed a phase I, single arm, single center, open label study of the selective proteasome inhibitor carfilzomib (CFZ) in adult patients with relapsed or refractory AML and ALL. CFZ is approved for the treatment of patients with multiple myeloma who have already received at least two other treatments including bortezomib and an immunomodulatory agent (lenalidomide and/or thalidomide), and whose disease has progressed (got worse) on their last therapy or within 60 days of their last therapy.. Vij:Onyx Pharmaceuticals, Inc.: Honoraria, Research Funding.