Phase II Study of Eltrombopag in Subjects with Fanconi Anemia

Background. Fanconi anemia (FA) is a rare genetic disorder that often presents with progressive bone marrow failure (BMF) due to an impaired DNA damage response and chronic exposure to elevated levels of proinflammatory cytokines. To date, hematopoietic stem/progenitor cell (HSPC) transplantation remains the only curative treatment for FA-associated BMF. However, donor availability, graft failure, and FA-specific transplant toxicities remain significant hurdles. Androgens have been successfully used but side effects often prevent prolonged therapy. Attempts at genetic correction of FA are underway but clinical efficacy has not yet been demonstrated. In this clinical trial, we investigate whether eltrombopag (EPAG), an FDA-approved mimetic of thrombopoietin that promotes trilineage hematopoiesis in subjects with acquired BMF (Olnes, NEJM 2012; Townsley, NEJM 2017), may offer a novel therapeutic modality for subjects with FA. Our pre-clinical studies indicate that EPAG evades blockade of signal transduction from c-MPL induced by inflammatory cytokines (Alvarado, Blood 2019). Additionally, we found that EPAG enhances DNA repair activity in human HSPCs (Guenther, Exp Hematol 2019). Thus, EPAG may positively influence two of the main known mechanisms leading to BMF in FA.

Study Design. This is a non-randomized, phase II study of EPAG given to subjects with FA (NCT03204188). Subjects receive EPAG for 6 months at an oral daily dose adjusted for age and ethnicity. Subjects who cannot tolerate the medication or fail to respond by 6 months are taken off study drug. Subjects who respond at 6 months are invited in the extension phase for an additional 3 years. They continue on the same dose of EPAG until they reach robust count criteria (platelets > 50K/μL, hemoglobin (Hgb) > 10 g/dL in the absence of transfusions, and absolute neutrophil count (ANC) > 1K/uL for > 8 weeks) or until they reach steady state response (defined as stable counts for 6 months). Drug dose is tapered slowly to the lowest dose that maintains a stable platelet count and eventually discontinued until they meet off study criteria or the study is closed.

Eligibility Assessment. Inclusion criteria: (1) Confirmed diagnosis of FA by a biallelic mutation in a known FANC gene and/or by positive chromosome breakage analysis in lymphocytes and/or skin fibroblasts; (2) One or more of the following cytopenias: platelets ≤ 30K/μL or platelet transfusion dependence in the 8 weeks prior to study entry, ANC ≤ 500/μL, Hgb ≤ 9.0 g/dL or red blood cell (RBC) transfusion dependence in the 8 weeks prior to study entry; (3) Failed or declined treatment with androgens; 4) Age > 4 years. Exclusion criteria: (1) Evidence of MDS or AML; (2) Cytogenetic abnormalities associated with poor prognosis in FA; (3) Known biallelic mutations in BRCA2; (4) Active malignancy or likelihood of recurrence of malignancies within 12 months; (5) Treatment with androgens ≤ 4 weeks prior to initiating EPAG.

Primary Endpoints. The primary efficacy endpoint is the proportion of drug responders at 6 months. Response to EPAG is defined by one or more of the following criteria: (1) Platelets increase by 20K/μL above baseline, or platelet transfusion independence; (2) Hgb increase by > 1.5g/dL or a reduction in the units of RBC transfusions by at least 50%; (3) At least a 100% increase in ANC for subjects with a pretreatment ANC of < 0.5 x 10⁹/L, or an ANC increase > 0.5 x 10⁹/L. The primary safety endpoint is the toxicity profile assessed at 6 months using the CTCAE criteria.

Sample Size and Statistical Methods. Simon's Two-Stage Minimax Design is used, with a response probability of ≤ 20% to terminate the treatment. In the first stage, 12 subjects will be accrued. The study will be stopped if no more than 2 subjects respond to the treatment within 6 months. If 3 or more subjects respond within 6 months in the first stage, then an additional 13 subjects will be accrued, for a total of 25 subjects.

Enrollment. Two subjects have been enrolled to date. No drug-related adverse events have been observed. Subject #1 (7YO female) did not respond to 6 months of EPAG, likely due to limited HSPC reserve in the context of profound cytopenias (ANC = 100/µL, Hgb = 6g/dL, Plt = 0K/µL). In contrast, subject #2 (49YO female) showed response to EPAG at 3 months and will continue on the extension phase of the study.

Conclusion. This study will provide important clinical information on safety and efficacy of EPAG in subjects with FA.