Safety, Tolerability, Pharmacokinetics, and Efficacy of AZD2811 Nanoparticles as Monotherapy or in Combination in Acute Myeloid Leukemia Participants.

Acute Myeloid Leukaemia Clinical Trial

Official title: A Phase I/II, Open-Label, Multicentre 2-Part Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of AZD2811 as Monotherapy or in Combination in Treatment-Naïve or Relapsed/Refractory Acute Myeloid Leukaemia Patients Not Eligible for Intensive Induction Therapy.

Status Terminated

Clinical Trial Summary

This is a Phase I/II clinical study to determine the maximum tolerated dose (MTD), and schedule, safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD2811 monotherapy or with combination agent(s) in relapsed/refractory acute myeloid leukaemia (AML) participants or treatment-naïve AML participants not eligible for intensive induction therapy. In addition, the study will explore the potential clinical activity by assessing anti-tumour activity in participants. The study was terminated early as a result of AstraZeneca's strategic review across the AZD2811 programme. Part A data were collected for initial cohorts; the MTD/recommended Phase 2 dose (RP2D) dose and schedule of AZD2811 monotherapy or with combination agents were not determined. Part B of the study was not initiated

Clinical Trial Description

This is a Phase I/II clinical study to determine the MTD and schedule, safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD2811 monotherapy or with combination agent(s) in relapsed/refractory AML participants or treatment-naïve AML participants not eligible for intensive induction therapy. The study will also explore the potential clinical activity by assessing anti-tumour activity in participants. The study will be conducted in two parts, designated Part A, dose escalation, and Part B, dose expansion. Participants will be enrolled in either Part A or Part B according to the Investigator's judgment of the most appropriate treatment for the individual participant and slot availability.

Part A - Dose Escalation

Approximately 48 evaluable treatment-naïve AML participants not eligible for intensive induction therapy or relapsed/refractory AML participants will be enrolled in Arm 1 and Arm 2 of the monotherapy escalation in Part A of this study.

The dose escalation and de-escalation plan for evaluating AZD2811 will follow the Bayesian Adaptive Design scheme which combines prior expectations about the dose toxicity relationship and applies the data at the end of each cohort to recommend a dose and schedule for the next cohort. The total number of participants will depend upon the number of dose escalations, de-escalations, and schedule changes necessary. At least 3 and up to 6 evaluable participants will be required for each dose cohort.

Part A Group 1, Arm A - Day 1 and 4 Monotherapy Dose Escalation:

Participants will receive a single 2- or 4- hour IV infusion on Day 1 and Day 4 of each 28-day cycle. Dosing frequency and schedule may be adjusted during the study on the basis of emerging safety and pharmacokinetic data. Approximately 22 participants will be enrolled.

Part A Group 1, Arm B - Day 1, 4, 15, and 18 Monotherapy Dose Escalation:

A Day 1, 4, 15, and 18 every 4 weeks or 28 days (Q4W) schedule will be investigated in addition to the Day 1 and 4 Q4W schedule. The proposed starting dose for this schedule is 300 mg/infusion AZD2811 on Day 1, 4, 15 and 18 (i.e. cumulative dose 1200 mg/Q4W). This starting dose is less than daily doses shown to be tolerated in the AML setting, and the cumulative cycle dose/Q4W does not exceed the highest dose shown to be tolerated (600 mg/infusion Day 1, 4 cumulative 1200 mg Q4W). Approximately 18 participants will be enrolled.

Combination Escalation:

AZD2811 can be escalated (in the combination setting) independent of the monotherapy dose explored, after thorough examination of the available safety data. The combination therapy exploration will not impact the dose to be further explored in the monotherapy setting nor will the monotherapy impact the dose in the combination setting. As such, the number of cohorts in the monotherapy setting can differ from the number of cohorts in the combination setting. The safety observations of the monotherapy will be considered by the Safety Review Committee (SRC) in the overall decision-making process for subsequent dose exploration decision.

A rolling 6 design will be applied to both of the AZD2811 and combination arms. The rolling 6 method allows accrual of 3 to 6 participants concurrently onto a dose level based on the numbers of participants who are currently enrolled and evaluable, who experience a dose-limiting toxicity (DLT), and who remain at risk of developing a DLT.

Part A Group 2 Arm A - Day 1 and 4 Azacitidine Combination Escalation:

A starting dose of 400 mg of AZD2811 will be used for investigation in combination with the standard dose of the hypomethylating agent (HMA) azacitidine. In this dose escalation part, approximately 12-15 evaluable treatment-naïve AML participants not eligible for intensive induction therapy or relapsed/refractory AML will be enrolled and dosed in ascending doses of AZD2811 and standard dose of azacitidine at 75 mg/m² of body surface area subcutaneously (SC) in all territories or optionally/alternatively by IV in the United States (US) as per national prescribing information.

Part A Group 2 Arm B - Day 1, 4, 15, and 18 Azacitidine Combination Dose Escalation

In order to increase dose intensity during the 4 week cycle, and improve efficacy in the combination setting, AZD2811 will also be explored on the Days 1, 4, 15 and 18 schedule in the azacitidine combination and start at a lower daily dosage that has been shown to be safe while administered every 28 days. The proposed starting dose for this schedule is 300 mg/infusion AZD2811 on Day 1, 4, 15 and 18 (i.e., cumulative dose per 28 days is 1200 mg/Q4W) and standard dose and use of azacitidine 75 mg/m² of body surface area SC in all territories or optionally/alternatively by IV in the US as per national prescribing information. Approximately 18 participants will be enrolled.

Venetoclax Combination:

Approximately 18-21 evaluable relapsed/refractory AML participants will be enrolled and dosed with AZD2811 and venetoclax. In cohort 1v, AZD2811 will be administered at 200 mg IV on Days 1 and 4 every 28 days (Q4W) and venetoclax will be given 100 mg orally (PO) on Day 1 and 200 mg (PO) with a meal and water on Days 2- 28 for the 1st cycle. The third participant in cohort 1 (AZD2811 at 200 mg) will only be enrolled after the first 2 participants have received ≥ 2 weeks of treatment and have shown no evidence of toxicity observed to be compatible with a DLT, and further dose escalations of AZD2811 will occur at the discretion of the SRC.

The dose of AZD2811 can be escalated (in the combination setting) independent of the monotherapy dose explored, after thorough examination of the available safety data of the current and the previous cohorts. The combination therapy exploration will not impact the dose further explored in the monotherapy setting nor will the monotherapy impact the dose in the combination setting. As such, the number of cohorts in the monotherapy setting can differ from the number of cohorts in the combination setting. The safety observations of the monotherapy will be considered by the SRC in the overall decision-making process for subsequent dose exploration decision.

Part A Group 3 Arm A - Day 1 and 4 Venetoclax Combination Dose Escalation

In Group 3 Arm A, AZD2811 is planned to be administered at 200 mg IV on Day 1 and Day 4 every 28 days (Q4W) and venetoclax is planned to be given (with a meal and water) at a dose of 100 mg orally (PO) on Day 1 and ramping up to 200 mg (PO) on Days 2-28 for the 1st cycle. The third participant in cohort 1 (AZD2811 at 200 mg) will only be enrolled after the first 2 participants have received ≥2 weeks of treatment and have shown no evidence of toxicity observed to be compatible with a DLT.

Further dose escalations of AZD2811 in Group 3 Arm A will occur at the discretion of the SRC.

Part A Group 3 Arm B - Day 1, 4, 15, and 18 Venetoclax Combination Dose Escalation

If data from Groups 1 and/or 2 suggest that participants could benefit from a more intense AZD2811 dosing regimen, a schedule of venetoclax with AZD2811 dosing on Days 1, 4, 15 and 18 (see below) may be explored.

Group 3 Arm B will not exceed the registered venetoclax dose when combined with a starting dose of AZD2811 that is considered safe based on Group 3 Arm A observations. Subsequent cohorts will explore how to escalate AZD2811 in a more intensified schedule towards a recommended Phase 2 dose.

Part B - Dose Expansion

In Part B approximately 18 AML participants (6 additional participants in each group [AZD2811 monotherapy, Group 1], [AZD2811 in the azacitidine combination setting, Group 2], and [AZD2811 and venetoclax combination, Group 3]) will follow the affiliated dose/schedule from Part A that was found to be the most tolerable and/or efficacious. ;

Related Conditions & MeSH terms

• Acute Myeloid Leukaemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

• NCT number: NCT03217838
• Study type: Interventional
• Source: AstraZeneca
• Status: Terminated
• Phase: Phase 1
• Start date: July 31, 2017
• Completion date: March 25, 2021