A Phase I, Open-Label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of Ascending Doses of AZD0466 in Patients With Advanced Hematologic or Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- AZD0466
- Conditions
- Advanced Solid Tumors
- Sponsor
- AstraZeneca
- Enrollment
- 9
- Locations
- 1
- Primary Endpoint
- The incidence of Dose Limiting Toxicities (DLTs)
- Status
- Terminated
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a first-time-in-human (FTIH), Phase 1 study to determine the safety, tolerability, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and pharmacokinetics (PK) of AZD0466 in patients with solid tumors, lymphoma and multiple myeloma at low risk for tumor lysis syndrome (TLS), as well as in patients at intermediate risk or high risk of TLS with hematologic malignancies for whom no standard therapy exists. Once an MTD/RP2D has been determined in the dose escalation portion, further disease-specific expansions (solid tumor and hematologic) will be undertaken. Combinations of AZD0466 with other standard of care treatments may be evaluated in the future.
Detailed Description
This is a FTIH study designed to evaluate the safety and tolerability of AZD0466 at increasing doses in patients with malignancies for whom no standard therapy exists, including advanced solid tumors, lymphoma and multiple myeloma with a low risk for TLS (Arm A), and relapsed, refractory hematological malignancies with an intermediate to high risk of TLS (Arm B). The study will also characterize the PK of AZD0466 and explore potential biological activity by assessing pharmacodynamics, exploratory biomarkers, and anti-tumor activity. Once an MTD/RP2D has been determined during escalation, further disease-specific expansions, possibly including, but not limited to small cell lung cancer, acute lymphoblastic leukemia, and acute myeloid leukemia will begin.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Signed and dated written informed consent prior to any study specific procedures, sampling and analyses
- •Documented active disease requiring treatment that is relapsed or refractory as determined by RECIST or clinically defined changes.
- •Aged ≥18 yrs
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤1 without 2 levels of ECOG deterioration within 2 weeks (wks) of signing the ICF
- •Life expectancy ≥12 wks
- •Measurable or evaluable disease according to disease-specific tumor assessment criteria
- •Adequate hepatic/renal function at screening:
- •AST and ALT ≤2.5 x Upper Limit of Normal (ULN)
- •Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or is of non-hepatic origin)
- •Creatinine ≤1.5 x ULN and creatinine clearance (CrCl) ≥50 mL/min, measured or calculated by Cockgroft-Gault method
Exclusion Criteria
- Not provided
Arms & Interventions
Arm A
Dose escalation for patients with solid tumors, lymphoma and multiple myeloma with low risk of TLS. Each cohort within Arm A will test a single dose level.
Intervention: AZD0466
Arm B
Dose escalation for patients with hematologic malignancies with an intermediate to high risk of TLS. Intrapatient dose ramp-ups within each cohort will be used.
Intervention: AZD0466
Outcomes
Primary Outcomes
The incidence of Dose Limiting Toxicities (DLTs)
Time Frame: 28 days for Arm A; between 35 and 56 days for Arm B due to varying number of ramp-up doses
The maximum tolerated dose (MTD) will be determined by assessing the incidence of DLTs.
The incidence of adverse events
Time Frame: Minimum observation period 28 days for Arm A and between 35 and 56 days for Arm B due to varying number of ramp-up doses; and will continue until the subject is off the study (approximately 6 months)
Safety and tolerability will be assessed in terms of adverse events as measured by Common Terminology Criteria for Adverse Events (CTCAE) version 5.
Secondary Outcomes
- Characterize the pharmacokinetic profile of AZD4320 by estimating maximum plasma concentration (Cmax)(Plasma PK will be measured at each cycle throughout study treatment for approximately 6 months. Cylce length is 28 days for Arm A and between 28-56 days for Arm B due to varying number of ramp-up doses.)
- Characterize urine pharmacokinetic profile of AZD4320 by amount excreted unchanged(Urine PK will be measured up to 48 hrs after the first treatment dose for select cohorts in Arm A, and pre-infusion and up to 48 hrs after the target dose for select cohorts in Arm B.)
- Characterize the pharmacokinetic profile AZD4320 by estimating area under the plasma concentration-time curve (AUC)(Plasma PK will be measured at each cycle throughout study treatment for approximately 6 months. Cycle length is 28 days for Arm A and between 28-56 days for Arm B due to varying number of ramp-up doses.)
- Number of patients with a tumor response(Every 2 cycles (approximately 8 wks) from initiation of study treatment for up to approximately 6 months.)
- Characterize urine pharmacokinetic profile of AZD4320 by renal clearance(Urine PK will be measured up to 48 hrs after the first treatment dose for select cohorts in Arm A, and pre-infusion and up to 48 hrs after the target dose for select cohorts in Arm B.)