Phase I Study Results of Gimatecan In the Treatment of Myelodysplastic Syndrome (MDS)
Authors: Pemmaraju Naveen , Kantarjian Hagop , Garcia-Manero Guillermo , Faderl Stefan , Ferrajoli Alessandra , Borthakur Gautam , Kadia Tapan , Cortes Jorge E. 
Published: October 2019

Abstract
Abstract 1883

Background:
Hypomethylating agents (decitabine and 5-azacytadine) are standard therapy for patients (pts) with MDS. Responses are frequently characterized by hematologic improvement with CR rates usually <10%, and responses generally have a median duration of less than 12 months. No standard therapy is available for patients who fail therapy with hypomethylating agents. Topotecan, a topoisomerase I (topo I) inhibitor has previously shown some clinical activity in MDS, although with significant toxicity. We hypothesized that Gimatecan, an oral topo I inhibitor, would be better tolerated, more convenient for patients, and have less toxicity than intravenous topo I inhibitors in treatment of MDS.

Objectives:
To define the maximum tolerated dose (MTD), dose limiting toxicity (DLT), and efficacy of treatment with gimatecan in pts with MDS.

Methods:
This was a Phase I trial conducted in relapsed/refractory pts failing at least one prior treatment. Inclusion criteria: MDS pts with greater than or equal to 5% blasts or IPSS risk group intermediate (1 or 2) or high (i.e., IPSS 0.5 and higher), age 18 years and older, ECOG PS 0–2, and adequate liver and renal function. Exclusion criteria: Pts who have received only supportive care or transfusions for MDS, pts with prior chemotherapy within 4 weeks of starting study, uncontrolled ongoing systemic illness including congestive heart failure, and women who or pregnant or breast-feeding. Hydroxyurea usage was allowed up to 48 hours prior to start of therapy. Gimatecan was administered orally once daily for 5 days every 28 days. Dose levels explored were 0.6mg, 1.0mg, 1.5mg, and 1.75mg based on a modified Fibonacci schedule. DLTs were monitored as events occurring within first 4 weeks of treatment (1st cycle) and were defined as any non-hematologic grade 3 or 4 toxicity or as grade 33 neutropenia and/or thrombocytopenia with a hypocellular bone marrow and no marrow blasts lasting for 6 weeks or more after the start of a course. All toxicities graded by NCI Common Terminology Criteria 3.0.

Results:
A total of 16 pts were included. Median age was 62.5 years (range, 37–83). Patients had received a median of 1.5 prior therapies (range,1-5). Cytogenetic analysis revealed: 4 diploid, 4 complex abnormalities, 3 monosomy 7, and 5 with other abnormalities. Median baseline bone marrow blasts prior to enrollment was 5%, with 4 pts having >10%. Baseline neutrophil count was <1×109/L in 8 pts (50%) and platelets <100×109/L in14 pts (88%). IPSS was INT-1 in 7, INT-2 in 6, and High in 3. Six pts had prior malignancies. Only one patient had grade 3 toxicity (mucositis) at a dose of 1.5 mg daily dosing that was considered related to the study drug. No other DLT were observed and an MTD was not defined. The study was ended prematurely because of drug availability. Other toxicities possibly related to gimatecan (all grade 1–2) were: nausea (4), vomiting (2), alopecia, (2) and one each diarrhea, dyspnea, mucositis, peripheral neuropathy, joint pain, and skin rash. Three patients had transient responses, all of them hematologic improvement only: one patient had improvement in hemoglobin and platelets, one in neutrophils and platelets, and one in neutrophils only. There were no pts with CR, CRp/CRn, or PR. Three patients died on study or within one week of discontinuation from study.

Conclusions:
Gimatecan is well tolerated in patients with MDS but shows minimal clinical benefit for patients with MDS at the doses used.

Disclosures:
Off Label Use: gimatecan in MDS. Faderl:Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes:Pfizer: Consultancy, Research Funding; BMS: Research Funding; Novartis: Research Funding.