A phase I pharmacokinetic evaluation of oral arsenic trioxide in previously untreated patients with acute promyelocytic leukaemia (APML05)

Intervention

Intervention code Treatment: Drugs

This is a phase 1 study that looks at the bioavailability of an oral arsenic trioxide (ATO) in consolidation therapy for APML. Following standard induction therapy of All-Trans Retinoic Acid (ATRA, tretinoin) + IV ATO (+ idarubucin for high-risk patient), patients will be registered into the trial after documentation of haemotological complete remission. The study consists of two parts: (i) A 1-sequence, 4 ATO period single arm study over 28 weeks in total. Patients will be given 7 cycles of All .... This is a phase 1 study that looks at the bioavailability of an oral arsenic trioxide (ATO) in consolidation therapy for APML. Following standard induction therapy of All-Trans Retinoic Acid (ATRA, tretinoin) + IV ATO (+ idarubucin for high-risk patient), patients will be registered into the trial after documentation of haemotological complete remission. The study consists of two parts: (i) A 1-sequence, 4 ATO period single arm study over 28 weeks in total. Patients will be given 7 cycles of All-Trans Retinoic Acid (ATRA, tretinoin) (45mg/m^2, in 2 divided doses) + 4 cycles of IV ATO (0.15mg/kg/day) with the exception of week one of ATO cycle #2, and week one of ATO cycle # 4, when oral tablet ATO (0.15mg/kg/day) will be used. The pharmacokinetic data will be used to adjust each patient's oral dose for week 1 of cycle #4. (ii) A 2-sequence, 4 ATO period, randomised cross-over study over 28 weeks in total. Patients will be given 7 cycles of ATRA (45mg/m^2, in 2 divided doses) + 4 cycles of IV ATO, with the exception of week one of either ATO cycle #1 or ATO cycle #2, and week one of either ATO cycle #3 or ATO cycle #4, when oral tablet ATO will be used (sequence will be determined by randomisation). *ATO cycle= 5 days/week for 4 weeks; 4 weeks between cycles; *ATRA cycle= 7 days/week for 2 weeks; 2 weeks between cycles. ATRA is administered in oral capsule form; IV ATO is administered IV by infusion pump over 2 hours. Part (i) - There is an effective ATO washout period of 30 days between each cycle of consolidation (the weekend of week 4 followed by the 4-week interval before the subsequent cycle). The oral ATO capsule formulation will be used at a dose of 0.15mg/kg/d in week 1 of cycle #2. The oral ATO dose that will be administered in week 1 of cycle #4 will be determined on an individual patient basis by the trial management committee, based on the results of the PK data obtained in week 1 of cycles #1, #2 and #3. All ATO in part (ii) will be given IV at a dose of 0.15mg/kg/day, with the exception of week 1 of either cycle #1 or cycle #2 (determined by randomisation), when ATO will be given orally at a dose of 0.15mg/kg/day as determined by the TMC based on the aggregate PK data that was generated in part (i). Oral ATO will also be used at the same dose (0.15mg/kg/day) in week 1 of either cycle #3 or #4. Oral arsenic capsules should be taken 1 hour before food on an empty stomach. PK studies will again be performed in week 1 of each ATO cycle. Regardless of the PK data, the maximum oral dose of ATO will be 0.3mg/kg/day, and the minimum will be 0.08mg/kg/day. Maintenance therapy, typically involving ATRA + methotrexate + 6-mercaptopurine, will not be used for either part (i) or part (ii) of this study, regardless of initial risk category. The investigator, or a responsible party designated by the investigator such as the Pharmacy Department at participating institutions, must maintain a careful record of the inventory and disposition of the investigative agent. A pharmacy file will be provided for the purpose and will collect information such as drug name, batch number, expiry date, amount dispensed and disposal of supplies via approved procedures at the end of the study.
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Comparison

Control group Active

The IV ATO is the control formulation for the oral ATO with each patient in this cross over study.

Outcomes

Outcome: Composite outcomes: (a) To determine the absorption and PK characteristics of an oral capsule formulation of ATO (intrasubject comparison of peak serum level and AUC0-24); (b) To determine the recommended phase 2 dose (RP2D) or oral ATO for use in a subsequent phase 2 study to examine efficacy.
Timepoint: In part (ii), there are two co-primary endpoints. AUC: 0-24. The area under the curve of arsenic concentrations in the blood (micromol/l), from time zero (imme .... Outcome: Composite outcomes: (a) To determine the absorption and PK characteristics of an oral capsule formulation of ATO (intrasubject comparison of peak serum level and AUC0-24); (b) To determine the recommended phase 2 dose (RP2D) or oral ATO for use in a subsequent phase 2 study to examine efficacy.
Timepoint: In part (ii), there are two co-primary endpoints. AUC: 0-24. The area under the curve of arsenic concentrations in the blood (micromol/l), from time zero (immediately before the first dose on a cycle day) until the sample at 24 hours that precedes the dose on the following day. Cmax- The maximum observed arsenic concentration in the blood (micromol/l) in the 24 hours following administration of the dose, and prior to the next administration of the dose. The endpoints are assessed on days 1 and 4 of the first week in each cycle of ATO consolidation. 10ml of whole blood will be collected immediately prior to dosing (time 0), and at 0.5, 1, 2, 4, 6-8, and 24 hours after the start of dosing. Samples will be analysed for concentrations of ATO and other arsenical species by liquid chromatography coupled to ICPMS. A calculation of the bioavailability will be made based on the ratio of AUC 0-24 for the oral administration (day 1 of week 1, cycle #2), divided by the AUC0-24 for IV administration in the same patient (day 1 of week 1, cycle #1). In part (i), the oral dose that is used in week 1 of cycle #2 will be 0.15mg/kg/day, the same as used for IV ATO. The PK data will then be used to adjust each patient’s oral dose for week 1 of cycle #4. If necessary, part (i) will be extended to include more than 8 patients to ensure confidence in the oral dose selected for part (ii). The aggregate PK data for all patients in part (i) will be used to determine the oral ATO dose that will be used in part (ii) of the study, which will involve a randomisation to oral or IV ATO in the first week of cycle #1 to eliminate unanticipated bias. The alternative route will then be used in week 1 of cycle #2. The same schedule will be repeated for week 1 of cycle #3 and #4 to assess intrapatient PK variability. When all the PK data are available (from all patients in both part (i) and part (ii)), a further adjustment in the oral dose that is selected for the subsequent phase II study will be made, if necessary. Patients will be on 4 cycles of ATO (cycle = 5 days/week for 4 weeks; 4 weeks between cycles).
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