Amelioration of Rigosertib Treatment Related Genitourinary (GU) Adverse Events (AEs) in
Patients with Myelodysplastic Syndromes: Implementation of Novel Dosing Regimen Derived
through Pharmacokinetic Modeling in Phase 2 Study of Oral Rigosertib in Combination with
Azacitidine
David Taft1, Chen Ren2, Tarang Vora1, Patrick Zbyszewski2, Joseph Morgan2, Michael Petrone2,
Steve Fruchtman2 and Manoj Maniar2
1
Long Island University, Brooklyn, NY
2
Onconova Therapeutics, Inc., Newtown, PA
Introduction: Rigosertib is a small molecule inhibitor of cellular signaling pathways in cancer
cells by acting as a Ras mimetic. The inhibitory effect is mediated by Rigosertib binding to the
Ras-binding domain found in many Ras effector proteins (Athuluri-Divakar SK, Cell 2016). Oral
administration of Rigosertib was initially evaluated in lower risk MDS patients. The drug,
administered as 560 mg BID (q12hr; 2/3 wks), was associated with high rates of transfusion
independence but with significant GU AEs (Raza, et al, Blood 2017 130:1689). Subsequently, a
reduction in the PM dose to 280 mg led to a decrease in GU AEs, suggesting a causal
relationship with nocturnal bladder drug concentration. Similarly, when oral administration of
Rigosertib was tested with standard dose of parenteral Azacitidine in a Phase I/II trial
(NCT01926587) at a dose of 560/280 mg (Q12hrs, 3/4 weeks), the ORR was 77%; 88% for the
HMA naïve group and 60% for the HMA relapsed/refractory group for the high risk MDS
patients. The impressive response rate, in the combination treatment, was also associated with
significant GU AEs. Hence, it is important to understand the underlying cause and devise ways
to maximize response rates with minimization of GU AEs.
Previously, it was established that GU AEs were unlikely to be related to the higher systemic
exposure of the drug (Maniar, et al ASH 2018, Abstract submitted) but attributed to the nocturnal
dwell time of drug in the bladder of patients treated with continuous oral administration (3/4
weeks). In this investigation, we developed a pharmacokinetic model to simulate the systemic
and bladder exposure of Rigosertib after repeated oral dosing. The overall aim was to identify
and implement an oral dosing regimen for Rigosertib that would maximize the systemic
exposure with minimization of bladder concentration during the sleep cycle, thereby potentially
mitigating or eliminating the GU AE’s.
Methods: A 2-compartment model with 1st order absorption and elimination (Figure 1) was
fitted to data collected from patients with solid malignancies at a 560 mg dose (n=25). Model
parameter estimates were then used to generate a virtual population of 100 patients. Each virtual
patient was randomly assigned parameter values based on the 95% confidence interval for each
parameter estimate obtained through the modeling analysis. Model simulations were then
performed to evaluate the steady state systemic and urinary exposure of Rigosertib in the virtual
population after treatment with different dosing schedules (Figure 2). Besides plasma exposure
(Cmax, AUC), the predicted rigosertib bladder concentration during the sleep-cycle was also
assessed. From this analysis, optimal dosing regimens were selected for evaluation in a Phase 2
study in HR-MDS patients in combination with Azacitidine. The model was validated by
comparing the predicted systemic exposure with observed data using these optimal dosing
regimens, and by comparing Grade 3 GU AE’s events from the pre- and post-optimization of
dosing regimen (NCT01926587).
Results: The model-predicted steady state plasma concentration-time profile of Rigosertib for
different dosing regimens is shown in Figure 3. The duration of exposure of drug above
minimum effective concentration (MEC, 0.175 ug/ml) was not changed by varying the dosing
regimen. Importantly, model simulations demonstrated that BID dosing, with the dosing interval
of 8 hours, would reduce the bladder concentration of Rigosertib by as much as 70% during
sleep without compromising systemic drug exposure (Table 1). As illustrated in Table 2, model
simulated Rigosertib exposure (Cmax, AUC) compared favorably with data from patients treated
with the novel twice daily dosing regimens (560mg/560mg and 840 mg/280mg, dosing interval
of 8 hours), thereby validating the model. Preliminary safety data from the on-going trial
demonstrates that the Grade 3 GU AEs were significantly reduced (12%) with the optimized
dosing regimen compared to the pre-optimized dosing regimen (29%) despite using a higher total
dose of drug (1120 mg vs 840 mg).
Conclusions: This study demonstrates the utility of pharmacokinetic modeling for designing a
dosing regimen directed at reducing the incidence of toxicity. The identified dose and dosing
schedules successfully reduced the risk of Grade 3 GU AEs of rigosertib without compromising
the duration of systemic exposure of Rigosertib above MEC in HR MDS patients.