Phase 1 Trial of Cladribine, High-Dose Cytarabine, G-CSF, and Dose-Escalated Mitoxantrone (CLAG-M) Plus Gemtuzumab Ozogamicin in Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) or Other High-Grade Myeloid Neoplasm
Authors: Godwin Colin D. , Othus Megan , Percival Mary-Elizabeth M. , Scott Bart L. , Becker Pamela S. , Gardner Kelda M. , Keel Sioban B. , Dhawale Tejaswini M. , Oehler Vivian G. , Abkowitz Janis L. , Halpern Anna B. , Hendrie Paul C. , Orlowski Kaysey F. , Woo Alice , Estey Elihu H. , Walter Roland B. 
Published: November 2019

Background: We recently found that CLAG-M was safe and produced higher rates of CR/CRi and higher measurable residual disease (MRD)-negative CR (measured by multiparameter flow cytometry [MFC]) than standard "7+3" therapy in fit patients with newly-diagnosed AML or other high-grade myeloid neoplasm with ≥10% blasts (HG-MN). Since addition of the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO) to chemotherapy reduces relapse risk and improves survival in some AML patients, we conducted a phase 1 study (NCT03531918) to determine the maximum tolerated dose (MTD) of GO with CLAG-M in fit adults with newly-diagnosed AML (APL excluded) or HG-MN.
Patients and Methods: Adults ≥18 years were eligible if they were fit (treatment-related mortality [TRM] score ≤13.1, corresponding to < 13.1% risk of TRM within 1 month) and had LVEF ≥45%, creatinine ≤2.0 mg/dL, and bilirubin ≤2.5-times upper limit of normal. Patients with concomitant illness with expected survival <1 year, with uncontrolled infection, or in myeloid blast phase of chronic myeloid leukemia were excluded. Doses were escalated in cohorts of 6 patients over 2 dose levels of GO ("GO1": 3 mg/m2 on day 1; "GO3": 3 mg/m2 on days 1, 4, and 7 [doses capped 4.5 mg]); the highest dose level achieved could then enroll an additional 6 patients (12 total) if ≤2 dose-limiting toxicities (DLTs) were observed. CLAG-M consisted of cladribine 5 mg/m2/day (days 1-5), cytarabine 2 g/m2/day (days 1-5), G-CSF 300 or 480 μg/day (for weight <76 kg vs. ≥76 kg; days 0-5), and mitoxantrone (18 mg/m2/day; days 1-3). A second course of CLAG-M (without GO) was given if MRD-negative CR/CRi was not achieved. DLT was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia/infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms, if recovery to grade ≤2 within 14 days. The protocol was approved by the Fred Hutchinson Cancer Research Center Institutional Review Board.
Results: We enrolled 18 patients, median age 66 (range: 28-77) years, median TRM score 3.92 (range: 0.14-10.3) with newly-diagnosed AML (n=14) or HG-MN (n=4); 7 were "favorable", 4 "intermediate and 7 "adverse" by 2017 European LeukemiaNet criteria. The first 6 patients were treated at GO1, with 1 DLT (grade 3 left ventricular systolic dysfunction). Two subsequent cohorts of 6 were treated at GO3. Three DLTs occurred at this second dose level (grade 4 aminotransferase level increase, grade 3 posterior reversible encephalopathy syndrome, grade 3 intracranial hemorrhage). As prespecified in the protocol, with ≤4/12 DLTs the MTD was formally not reached and GO3 was declared the recommended phase 2 dose. Among 18 evaluable patients, 13 achieved CR and 2 CRi for a CR/CRi rate of 83% (95% confidence interval: 59-96%). 13/15 CR/CRi patients were negative for MRD by MFC and cytogenetics for an MRDneg CR/CRi rate of 72% (49-88%). The 3 patients without CR/CRi had marrow aplasia without MFC evidence of AML at time of study removal. Two underwent allogeneic hematopoietic cell transplantation in aplasia; the other achieved later neutrophil recovery prior to AML recurrence 2.5 months following induction without interval therapy. 5/18 did not have platelet recovery to 100,000/µL prior to the next therapy/removal from study. Median time to absolute neutrophil count of 1000/µL (achieved in 16/18 patients) and platelet count of 100,000/µL (achieved in 13/18 patients) was 35 (range: 24-48) days and 31 (range: 26-48) days, respectively. Besides infections and neutropenic fever, hypertension and left ventricular systolic dysfunction were the most common adverse events. One patient had severe, self-limited liver toxicity characterized by weight gain and elevated aminotransferases without hyperbilirubinemia and did not meet typical clinical criteria for sinusoidal obstructive syndrome. There were no deaths within 56 days of starting induction in this study cohort.
Conclusions: CLAG-M with fractionated-dose GO is feasible in patients with newly-diagnosed AML/HG-MN and appears to have high anti-tumor efficacy. CR/CRi and MRDneg CR rates were similar to what we observed with CLAG-M alone (86% and 71%, respectively). A phase 2 study based on these findings has been initiated, using event-free survival as primary efficacy endpoint.

Disclosures
Othus: Celgene: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Membership on an entity's Board of Directors or advisory committees. Percival:Nohla Therapeutics: Research Funding; Pfizer Inc.: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Scott:Agios: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Incyte: Consultancy. Becker:The France Foundation: Honoraria; Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding. Gardner:Abbvie: Speakers Bureau. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy; NCCN: Consultancy. Halpern:Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Walter:Agios: Consultancy; Amgen: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding.

OffLabel Disclosure:
Cladribine is not approved for AML, only Hairy Cell Leukemia, however it is widely used for AML with literature supporting it.