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In other clinical studies, ON 01910.Na has been safely given intravenously to Patients with advanced cancers. However, to treat some Patients, it may be better if ON 01910.Na could be given by mouth. This study will determine if it is safe to give ON 01910.Na by mouth, what is the highest dose can be safely given by mouth, and how much of the drug gets from the stomach into the blood stream when it is given by mouth.
Full description
This is a three-part phase 1 study in which nineteen to one hundred two patients with Low, Intermediate-1, Intermediate-2, or High risk MDS will receive oral doses of ON 01910.Na Concentrate as escalating single or multiple doses (70mg to 700 mg bid) up to 14 days of a 21-day cycle.
Part I: Bioavailability and Tolerability of Single Oral Dosing (n=3):
In Part I of this trial the bioavailability and tolerability of oral ON1910.Na administered as single, oral, escalating doses in a fasting state (defined as no less than 30 minutes before next meal) will be determined in three patients with Low, Intermediate-1, Intermediate-2 or High Risk MDS. All three patients will receive during the first week a 70mg single oral dose and blood samples for pharmacokinetic analyses will be taken after dosing. In the absence of drug-related grade 2 toxicity or higher, single dosing will be escalated in each patient weekly to 140mg (week 2), 280mg (week 3), 560mg (week 4) and 700mg (week 5).
At the end of Part I (week 6), all patients will be eligible to be enrolled in Part II.
Part II: Determination of MTD (n=10-84):
Part II will proceed if measurable drug levels have been measured in Part I and in the absence of DLT at the 70 mg single dose level in Part I. The maximum tolerated dose of oral ON1910.Na administered in a fasting state (defined as no less than 30 minutes before next meal) twice a day for 14 consecutive days will be determined in patients in patients with Low, Intermediate-1, Intermediate-2 or High Risk MDS following an adaptive design.
If blood levels were detected only at the 560mg or 700mg dose level in Part I, then the starting dose will be 140 mg. If blood levels were detected at the 280mg dose level or below, then the starting dose will be 70mg. Initially, patients will be enrolled in two-patient cohorts.
DLT must be at least possibly attributable to ON 01910.Na and is defined as:
If a patient has a DLT (see definition above) beyond the completion of the first 21-day cycle, administration of oral ON 01910.Na, treatment will be discontinued or reduced (at the discretion of the Principal Investigator) to the lower dose level, or by 25% if the patient was treated at the 70mg dose level. Patients should return to within 20% of their baseline, pre-cycle ANC, platelet or hemoglobin levels prior to treatment with a subsequent cycle. Treatment can be delayed for up to 21 days (1 cycle length) until counts return to their pre-treatment baseline. If counts are still not adequate for treatment, the patient will be re-evaluated 2 weeks later. If any non-hematological toxicity of Grade 2 or 3 is present on the day of ON 01910.Na administration, the drug administration will be withheld until resolution to ≤ grade 1 toxicity is present.
ON 01910.Na blood concentrations will be determined 1 hours after first dosing on days 1, 7 and 14 in all patients recruited in Part II.
Treatment will be continued until progression or stopped in the absence of bone marrow response or hematological improvement after 16 weeks.
Part III: Food/Fast and Absolute Bioavailability PK analysis at MTD in confirming cohort (n=15):
Up to fifteen patients with Low, Intermediate-1, Intermediate-2 or High Risk MDS will be enrolled at the MTD dose level and treated until progression. The treatment will be stopped in the absence of bone marrow response or hematological improvement after 16 weeks.
A subset of twelve patients will undergo the following procedures:
On Day 1, patients will be dosed with ON 01910.Na 800 mg/m2 IV for 24 hours and pharmacokinetic analysis will be performed
Oral dosing at MTD level will resume in a fasting state on Day 1 of the second 21-day cycle (14 days of bid dosing followed by a 7-day off treatment period) until progression is noted. The treatment will be stopped in the absence of bone marrow response or hematological improvement after 16 weeks.
If a patient has a DLT (see definition above) beyond the completion of the first 21-day cycle, administration of oral ON 01910.Na, treatment will be discontinued or reduced (at the discretion of the Principal Investigator) to the lower dose cohort level, or by 25% if the patient was treated at the 70 mg dose level. Patients should return to within 20% of their baseline, pre-cycle ANC, platelet or hemoglobin levels prior to treatment with a subsequent cycle. Treatment can be delayed for up to 21 days (1 cycle length) until counts return to their pre-treatment baseline. If counts are still not adequate for treatment, the patient will be re-evaluated 2 weeks later. If any non-hematological toxicity of Grade 2 or 3 is present on the day of ON 01910.Na administration, the drug administration will be withheld until resolution to ≤ grade 1 toxicity is present.
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Data sourced from clinicaltrials.gov
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