Myeloablative Fractionated Busulfan Conditioning Regimen with Sorafenib in Patients with AML: Results of Phase I Clinical Trial

Background: Myeloablative conditioning can be given safely to older patients by administering busulfan over a longer period (fractionated busulfan regimen) than the standard four-day regimen. (Popat, et al Lancet Haematology 2018). This longer conditioning regimen duration allows the addition of oral targeted agents like sorafenib, which may be synergistic with conditioning chemotherapy and thus further improve disease control. Therefore, we added sorafenib to fludarabine and fractionated busulfan regimen (f-bu) in a phase 1 dose-finding trial studying 4 different doses of sorafenib with f-bu (NCT03247088). Here we report the results of this trial.

Methods: Between 3/2018 and 6/2021, 24 patients with AML aged 18 to 70 years with adequate organ function and 8/8-HLA matched related or unrelated donors were enrolled prospectively. The dose of sorafenib was varied among the four values 200, 400, 600, and 800 mg administered from day -24 to -5. Dose-limiting toxicity (DLT) was defined as grade 3 or higher regimen-related non-hematologic, non-infectious, non-GVHD toxicity occurring between day -24 and day 3. The Bayesian Model Averaging Continual Reassessment Method (BMA-CRM) with target DLT probability 0.30 was used to choose doses for successive cohorts of 3 patients. The first cohort was treated at the lowest sorafenib dose 200, with all successive cohorts' doses chosen adaptively by the BMA-CRM. The doses and schedules of busulfan and fludarabine were fixed, with f-Bu dose targeting an area under the concentration vs time curve (AUC) of 20,000 ± 12% μmol.min given over 3 weeks. The first two doses of busulfan (80 mg/m2 IV each) were administered on days -20 and -13 on an outpatient basis. The last four Bu doses were calculated to give a total course AUC of 20,000 ± 12% μmol.min and were given as inpatient following each dose of Flu 40 mg/m2 on days -6 through -3. GVHD prophylaxis was post-transplant cyclophosphamide (PTCy) 50mg/kg on days 3 and 4 and tacrolimus. Recipients of unrelated donor grafts also received MMF. All patients were eligible to receive post-transplant maintenance sorafenib after engraftment.

Results: The median age was 52 years (range, 30-70). Disease status was CR in 16 (66.6%) patients, CRi in 5 (20.8%), and advanced in 3 (12.5%). Adverse risk karyotype was present in 10 (41.7%) patients. MRD was present in 13 (54.2%). 9 (38%) had mutated flt3. The donor was unrelated in 14 (58%), and peripheral blood stem cells were the graft source in 21(87.5%). Due to the absence of DLTs, the BMA-CRM assigned 200mg, 400mg, 600mg, and 800mg of sorafenib, respectively, to the first 4 cohorts, and the next 4 cohorts were given 800mg. Only 2 dose-limiting skin toxicities were seen, one in cohort 3 with 600mg of sorafenib and the second in cohort 6 with 800mg of sorafenib. 800mg was the final recommended phase 2 dose.

The median follow-up in 20 surviving patients was 7.6 months and 1-year progression free survival was 89% (95% CI 75-100%). Other outcomes are summarized in Table 1.

Conclusion: Sorafenib can be safely added to the fractionated busulfan regimen. Early data on efficacy appear promising, with an 89% PFS at 1 year of follow up.

Figure 1

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Figure 1

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