A Phase 1 Study To Assess The Tolerability, Pharmacokinetics and Clinical Activity of Rigosertib Administered Orally as Escalating Multiple Doses Twice or Three Times a Day up to 21 Days of a 21-Day Cycle in Patients With Advanced Cancer
Patients will be initially enrolled in two-patient cohorts starting with a 70 mg bid dosing.
- In the absence of drug-related grade 2 or higher toxicity in the two patients treated
for an entire 21-day first cycle, the next two patients will be receiving a dose
escalated by 100% from prior dose.
- If drug-related grade 2 or higher toxicity is observed in at least one of the two
patients treated for a full 21-day cycle, the cohort will be expanded in order to
obtain 3 evaluable (treated for an entire 21-day first cycle) patients.
- If no dose limiting toxicity (DLT) is observed in the first three patients treated for
an entire 21-day first cycle, then the next three patients will be enrolled at a dose
level increased by approximately 50% from prior dose.
- If one DLT is observed in the first three patients treated for an entire 21-day first
cycle, then the three next patients will be enrolled at the same dose level.
- If no more than one DLT is observed in the six patients treated for an entire 21-day
cycle, then the next six patients will be administered a dose level increased by
approximately 25% from prior dose.
- If two or more patients in any cohort experience DLT, then the maximum tolerated dose
(MTD) will have been exceeded and no further dose escalation will occur. The MTD will
be established as the immediate prior dosing level
- Identical rules will be applied to all cohorts of patients recruited to the study.
- A total of up to 24 patients may be treated at the MTD dose level in order to obtain
data on the onset and severity of dysuria symptoms in approximately 12 patients
including about 6 patients who will be treated with oral sodium bicarbonate at the time
of treatment initiation (early treatment) and ~6 patients who will be treated with oral
sodium bicarbonate at the time of symptom onset (late treatment). Alternating patients
on a 1-to-1 basis by enrollment date will receive oral sodium bicarbonate as 650 mg
tablets given twice daily with two 8-ounce glasses of water 1 hour after rigosertib
administration, either at the time of study initiation (early treatment) or at the time
of urinary symptom onset (late treatment).
Three additional cohorts will be treated with multiple escalating doses administered orally
three time daily (TID) (140 mg, 280 mg and 420 mg) for 21 consecutive days of a 21-day cycle
using identical rules as those described above (ie, starting with 2-patient cohorts at 140
mg dosing and expanding to 3-6 patient cohorts if at least 1 Grade 2 or higher drug-related
toxicity is observed in 2-patient cohorts).
Up to 12 patients may be treated at the MTD level identified with TID dosing.
Prior to escalating to the next planned dose level, a designated Cohort Review Committee
(CRC) consisting of the Principal Investigators (or their representatives), the Medical
Monitor and the Sponsor's Medical Representative will review all available safety data over
the 21 day duration of Course 1 for the previous cohort. Additional input may be provided
from the study monitors, pharmacokinetic or toxicology specialists as required. The CRC
also has to ability to recommend dose de-escalation for ON 01910.Na if warranted by the
observed toxicity profile.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Adverse events (AEs) will be regarded as treatment emergent signs and symptoms (TESS) if they started on or after the date and time of administration of the first dose of study drug, or if they were present prior to the administration of the first dose of study drug and increased in severity during the study. Adverse events include clinical laboratory parameters (e.g., Hematology Panel and Serum Chemistry Panel). Other safety parameters include vital signs, physical examination findings, concomitant medications, and drug exposure.
Antonio Jimeno, MD, PhD
University of Colorado at Denver Health and Sciences
United States: Food and Drug Administration
|University of Colorado at Denver Health and Sciences||Denver, Colorado 80045|