Contributions
Abstract: PB1919
Type: Publication Only
Background
Rigosertib, a novel phosphoinositide 3/polo-like kinase pathway inhibitor, selectively induces the apoptosis of cancer cells and is safe and well tolerated in pts with recurrent/relapsed or refractory MDS.
Aims
We conducted a multicenter, open-label, Phase I study of intravenous rigosertib to evaluate its safety, efficacy, and pharmacokinetics and to determine the recommended dose (RD) for Japanese pts.
Methods
The key eligibility criteria were as follows: recurrent/relapsed or refractory MDS; age: 20 or older; FAB classification (RA, RARS, RAEB, RABE-t, and CMML), excepting patients at IPSS low- or Int-1 risk with respect to RA; ECOG PS of 0 to 2; no major organ dysfunction; and written informed consent. Rigosertib (1,200 and 1,800 mg daily) was administered intravenously for 72 h, followed by 11-day monitoring in one 14-day cycle. The primary endpoint was dose-limiting toxicity (DLT). The secondary endpoints were 1) safety as assessed with adverse events (AEs) and laboratory results; 2) efficacy as assessed with the International Working Group 2006 criteria; and 3) pharmacokinetics.
Results
Between June 2012 and February 2015, 7 male and 2 female pts (median age: 70; range: 63-84) were enrolled, and 3 and 6 pts were eventually assigned to the 1,200 and 1,800 mg arms, respectively. According to the FAB classification, 6, 2, and 1 pts were categorized to RAEB, RAEB-t, and RA, respectively. There were 3 pts each in the IPSS Int-1, Int-2, and high-risk groups, with 1 and 2 pts in each risk group in the 1,200 and 1,800 mg arms, respectively. The median numbers of delivered cycles in the 1,200 and 1,800 mg arms were 4 (2 to 4) and 2 (1 to 8), respectively. DLT occurred not in the 1,200 mg arm but in the 1,800 mg arm: 5 episodes of ≥grade 3 nonhematologic toxicities in 2 pts. One pt developed 2 episodes of sepsis and meningitis, and the other 3 episodes of hypochloremia, pustular rash, and hyponatremia. Thus, 2 among 6 pts in the 1,800 mg arm developed DLT, which led us to conclude that 1,800 mg/day is the RD for Japanese pts. No deaths occurred during the study period. However, 5 pts died during follow-up, 4 of whom died from primary disease progression. Furthermore, 1 pt died of grade 5 bacterial pneumonitis that was rated to “Unrelated”. In the 1,200 mg arm, 2 cases each of grade 3/4 thrombocytopenia, grade 4 neutropenia, and grade 3/4 leukopenia, as well as 1 case of grade 3 lymphopenia developed. In the 1,800 mg arm, 3 cases of grade 3/4 leukopenia, 2 cases each of grade 3 CD4 lymphopenia, grade 4 thrombocytopenia, and grade 3/4 neutropenia, as well as 1 case each of grade 4 lymphopenia, increased C-reactive protein, erythropenia, and hypochloremia developed. Three cases of SAEs, including grade 4 meningitis, grade 4 sepsis, and grade 3 catheter-related infection, developed in the 1,800 mg arm. Stable disease was obtained in 2 pts in the 1,800 mg arm. Hematological remission, hematological improvement, and cytogenetic response were not obtained in the two arms. The Cmax values in the 1,200 and 1,800 mg arms were 5.99±1.50 and 6.74±2.39 μg/mL, respectively. The AUC0-∞ values were 314.6±142.7 and 324.8±83.9 μg × hr/mL, respectively.
Conclusion
This Phase I study showed that intravenous rigosertib (1,800 mg daily) for consecutive 72 h was well tolerated, indicating that this is the RD for Japanese pts with MDS similar to a Phase III study in the U.S. Based on these clinical outcomes, Japanese pts with MDS are participating in a global randomized Phase III study to compare rigosertib with physicians’ choice of treatment.
Session topic: 10. Myelodysplastic syndromes - Clinical
Keyword(s): Phase I, Pharmacokinetic, MDS, Clinical Trial
Abstract: PB1919
Type: Publication Only
Background
Rigosertib, a novel phosphoinositide 3/polo-like kinase pathway inhibitor, selectively induces the apoptosis of cancer cells and is safe and well tolerated in pts with recurrent/relapsed or refractory MDS.
Aims
We conducted a multicenter, open-label, Phase I study of intravenous rigosertib to evaluate its safety, efficacy, and pharmacokinetics and to determine the recommended dose (RD) for Japanese pts.
Methods
The key eligibility criteria were as follows: recurrent/relapsed or refractory MDS; age: 20 or older; FAB classification (RA, RARS, RAEB, RABE-t, and CMML), excepting patients at IPSS low- or Int-1 risk with respect to RA; ECOG PS of 0 to 2; no major organ dysfunction; and written informed consent. Rigosertib (1,200 and 1,800 mg daily) was administered intravenously for 72 h, followed by 11-day monitoring in one 14-day cycle. The primary endpoint was dose-limiting toxicity (DLT). The secondary endpoints were 1) safety as assessed with adverse events (AEs) and laboratory results; 2) efficacy as assessed with the International Working Group 2006 criteria; and 3) pharmacokinetics.
Results
Between June 2012 and February 2015, 7 male and 2 female pts (median age: 70; range: 63-84) were enrolled, and 3 and 6 pts were eventually assigned to the 1,200 and 1,800 mg arms, respectively. According to the FAB classification, 6, 2, and 1 pts were categorized to RAEB, RAEB-t, and RA, respectively. There were 3 pts each in the IPSS Int-1, Int-2, and high-risk groups, with 1 and 2 pts in each risk group in the 1,200 and 1,800 mg arms, respectively. The median numbers of delivered cycles in the 1,200 and 1,800 mg arms were 4 (2 to 4) and 2 (1 to 8), respectively. DLT occurred not in the 1,200 mg arm but in the 1,800 mg arm: 5 episodes of ≥grade 3 nonhematologic toxicities in 2 pts. One pt developed 2 episodes of sepsis and meningitis, and the other 3 episodes of hypochloremia, pustular rash, and hyponatremia. Thus, 2 among 6 pts in the 1,800 mg arm developed DLT, which led us to conclude that 1,800 mg/day is the RD for Japanese pts. No deaths occurred during the study period. However, 5 pts died during follow-up, 4 of whom died from primary disease progression. Furthermore, 1 pt died of grade 5 bacterial pneumonitis that was rated to “Unrelated”. In the 1,200 mg arm, 2 cases each of grade 3/4 thrombocytopenia, grade 4 neutropenia, and grade 3/4 leukopenia, as well as 1 case of grade 3 lymphopenia developed. In the 1,800 mg arm, 3 cases of grade 3/4 leukopenia, 2 cases each of grade 3 CD4 lymphopenia, grade 4 thrombocytopenia, and grade 3/4 neutropenia, as well as 1 case each of grade 4 lymphopenia, increased C-reactive protein, erythropenia, and hypochloremia developed. Three cases of SAEs, including grade 4 meningitis, grade 4 sepsis, and grade 3 catheter-related infection, developed in the 1,800 mg arm. Stable disease was obtained in 2 pts in the 1,800 mg arm. Hematological remission, hematological improvement, and cytogenetic response were not obtained in the two arms. The Cmax values in the 1,200 and 1,800 mg arms were 5.99±1.50 and 6.74±2.39 μg/mL, respectively. The AUC0-∞ values were 314.6±142.7 and 324.8±83.9 μg × hr/mL, respectively.
Conclusion
This Phase I study showed that intravenous rigosertib (1,800 mg daily) for consecutive 72 h was well tolerated, indicating that this is the RD for Japanese pts with MDS similar to a Phase III study in the U.S. Based on these clinical outcomes, Japanese pts with MDS are participating in a global randomized Phase III study to compare rigosertib with physicians’ choice of treatment.
Session topic: 10. Myelodysplastic syndromes - Clinical
Keyword(s): Phase I, Pharmacokinetic, MDS, Clinical Trial