A Study of AZD0466 in Patients With Advanced Hematologic or Solid Tumors

NCT04214093 | Terminated Phase 1 FDA Drug

• 2 other identifiers: D8240C00003REFMAL 661
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 5

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.

Conditions

Advanced Solid Tumors; Lymphoma; Multiple Myeloma; Hematologic Malignancies

Keywords

AZD0466; Advanced solid tumors; Relapsed, refractory hematologic malignancies; Multiple myeloma; Tumor lysis syndrome

Outcome Measures

Primary Outcomes (2)

• The incidence of Dose Limiting Toxicities (DLTs)

  The maximum tolerated dose (MTD) will be determined by assessing the incidence of DLTs.

  28 days for Arm A; between 35 and 56 days for Arm B due to varying number of ramp-up doses

• The incidence of adverse events

  Safety and tolerability will be assessed in terms of adverse events as measured by Common Terminology Criteria for Adverse Events (CTCAE) version 5.

  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)

Secondary Outcomes (5)

• 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 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.

• 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.

• 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.

• Number of patients with a tumor response

  Every 2 cycles (approximately 8 wks) from initiation of study treatment for up to approximately 6 months.

Study Arms (2)

Arm A

EXPERIMENTAL

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.

Drug: AZD0466

Arm B

EXPERIMENTAL

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.

Drug: AZD0466

Interventions

AZD0466 DRUG

In Arm A, AZD0466 will initially be administered IV over one hour, once weekly to the first cohort of patients. Subsequent cohorts of patients within Arm A are planned to receive sequentially higher doses. In Arm B, intrapatient dose ramp-ups will involve beginning at a specified starting dose and weekly increasing the dose to a maximum target dose for the cohort.

Arm A; Arm B

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Adequate cardiac function demonstrated by left ventricular ejection fraction ˃50% on screening echocardiogram
• International normalized ratio ˂1.2 x ULN
• Lipase ≤1.5 x ULN and serum amylase ≤1.5 x ULN and no prior history of pancreatitis
• Patient agrees to the collection of formalin fixed paraffin embedded block or slides from archival diagnostic samples or a pre-treatment tumor biopsy
• Willing and able to participate in all required study evaluations and procedures including receiving IV administration of study drug and admission to the hospital, when required, for at least 24 hrs during administration of study drug

You may not qualify if:

• Patient has non-secretory myeloma
• Patient has idiopathic thrombocytopenic purpura
• Previously refractory to platelet transfusion within 1 yr
• Treatment with any of the following:
• Most recent radiotherapy ˂ 3 wks prior to first study treatment
• Treated with hormonal therapy, immunotherapy, chemotherapy or investigational drugs within ≤21 days or 5 half-lives (whichever is shorter) from enrollment
• Major surgery (excluding placement of vascular access) ≤21 days from beginning of the study drug or minor surgical procedures ≤7 days.
• Treatment with hematopoietic colony stimulating factors (e.g., filgrastim, sargramostim) within 7 days of the first dose of study drug, or pegfilgrastim or darbepoetin within 14 days of the first dose of study drug
• Patient has prescription/non-prescription drugs or other products known to be sensitive BCRP, OCT2, OAT3, OAT P1B1, OAT P1B3, CYP2B6, CYP2C8, CYP2C9, or CYP 2D6 substrates, or reversible strong and moderate CYP3A inhibitors, which cannot be discontinued within 5 half-lives of the drug before Day 1 of dosing and withheld throughout the study until 14 days after the last dose of AZD0466
• Co-administration of CYP3A4 strong and moderate mechanism-based inhibitors or inducers which cannot be discontinued within 5 half-lives plus 12 days of the drug before Day 1 of dosing and withheld until 14 days after the last dose of AZD0466
• Concurrent anti-coagulation therapy including aspirin which cannot be stopped
• History of medications with known risk of Torsades de Pointes (cardiac arrhythmia due to drug-induced QTc prolongation) ≤5 half-lives before the start of treatment and continuing until 5 half-lives after the last dose of AZD0466
• The use of live attenuated vaccines during the study through 30 days after the last dose of study drug
• All toxicities from prior cancer therapy greater than NCI-CTCAE Grade (Gr) 1 will have returned to Gr1 at the time of enrollment with the exception of alopecia. Patients with Gr≤2 neuropathy are eligible.
• Previously untreated brain metastases. Patients who have received radiation or surgery for brain metastases are eligible if therapy was completed at least 21 days previously and there is no evidence of CNS disease progression or mild neurologic symptoms.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (5)

Research Site

New Haven, Connecticut, 06510, United States

Location

Research Site

Boston, Massachusetts, 02215, United States

Location

Research Site

Oklahoma City, Oklahoma, 73104, United States

Location

Research Site

Nashville, Tennessee, 37203, United States

Location

Research Site

Houston, Texas, 77030, United States

Location

Related Links

• Results of this clinical trial are available on www.astrazenecaclinicaltrials.com
• CSR Synopsis

MeSH Terms

Conditions

Lymphoma; Multiple Myeloma; Hematologic Neoplasms; Recurrence; Tumor Lysis Syndrome

Interventions

AZD0466

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Neoplasms by Site; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 12, 2019
• First Posted: December 30, 2019
• Study Start: December 16, 2019
• Primary Completion: June 18, 2021
• Study Completion: June 18, 2021
• Last Updated: August 2, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

US (5)