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About
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.
Full 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.
Enrollment
Sex
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Volunteers
Inclusion and exclusion 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:
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
Women should use adequate contraceptive measures, should not breast feed and should have a negative pregnancy test prior to start of dosing, or must have evidence of non-child-bearing potential by one of the following criteria at screening:
Men should be willing to use barrier contraception (i.e., condoms) and refrain from sperm donation during and after the conduct of the trial
Inclusion Criteria for Arm A low risk of TLS (dose escalation):
Patient has histologically or cytologically confirmed diagnosis or an advanced, unresectable and/or metastatic malignancy for which there are no treatment options available known to provide clinical benefit as follows: Solid tumor, Lymphoma that meets TLS low risk criteria, Multiple myeloma
Adequate hematologic function independent of transfusion and growth factor support for ≥7 days before screening assessment. Solid tumors/lymphoma/multiple myeloma without bone marrow (BM) involvement:
Inclusion Criteria for Arm B intermediate risk (IR) and high risk (HR) TLS (dose escalation):
Patients with histologically confirmed, relapsed or refractory hematologic malignancy for which there are no treatment options available known to provide clinical benefit. Patients must be classified as IR or HR TLS.
Adequate hematologic function independent of transfusion and growth factor support for ≥7 days before screening assessment
For AML and CMML patients, WBC must be ˂15,000/µL. Treatment with hydroxyurea (HU) prior to study entry and during ramp-up to achieve this level is permitted, as long as there is ˃24 hrs between the start of study drug and use of HU.
ALL/AML/MDS (IPSS-R intermediate/high/very high) and patients with BM involvement:
Exclusion Criteria
Patient has non-secretory myeloma
Patient has idiopathic thrombocytopenic purpura
Previously refractory to platelet transfusion within 1 yr
Treatment with any of the following:
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.
Presence or history of CNS lymphoma, leptomeningeal disease or spinal cord compression
Active infection including HIV, Hepatitis B, or Hepatitis C
As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, (e.g., severe hepatic impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease]); current unstable or uncompensated respiratory or cardiac conditions; uncontrolled hypertension; history of, or active, bleeding diatheses (e.g., hemophilia or von Willebrand disease); uncontrolled active systemic fungal, bacterial, viral, or other infection (exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics/other treatment); or IV anti-infection treatment within 14 days before first dose of study drug
Patients who have a high risk of developing renal dysfunction/renal involvement
Undergone any of the following procedures or experienced any of the following conditions currently or in the preceding 6 months:
Any of the following cardiac criteria:
Abnormal ECHO at screening LVEF ≤50%
History of hypersensitivity to polyethylene glycol (PEG), PEGylated products or drugs with a similar chemical structure or class to AZD0466 or other BH3 mimetic
Lactating, breastfeeding, or positive pregnancy test
Patient has a prior history of another life-threatening malignancy ≤2 yrs prior to first dose of study drug with the exception of:
Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol
Judgement by the Investigator or Medical Monitor that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements
Exclusion criteria for Arm A low risk of TLS (dose escalation):
Patients at IR or HR of developing TLS, including:
Patients with a low risk of TLS that have significant renal dysfunction and/or renal involvement. Patients with CrCl ˂80 mL/min and/or who have higher tumor burden may be handled as TLS IR or HR patients.
Exclusion criteria for Arm B IR and HR TLS (dose escalation):
Patients with hematologic malignancies at HR of developing TLS are excluded from the first three cohorts. This includes:
Patients with IR disease for TLS that also exhibits significant renal dysfunction, i.e., CrCl as calculated by Cockcroft-Gault method, if classified at investigator discretion as high-risk
Primary purpose
Allocation
Interventional model
Masking
9 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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