Study of AZD0466 Monotherapy or in Combination in Patients With Advanced Haematological Malignancies

Sponsor
AstraZeneca (Industry)
Overall Status
Recruiting
CT.gov ID
NCT04865419
Collaborator
(none)
141
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2
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Study Details

Study Description

Brief Summary

The purpose of the study is to the evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of AZD0466 as monotherapy in partciapants with advanced haematological malignancies and also to assess drug-drug interaction (DDI) potential between AZD0466 and the azole antifungal voriconazole.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

The study consists of 2 individual modules as: Module 1 (AZD0466 monotherapy), and Module 2 (DDI study of AZD0466 with voriconazole).

Eligible participants will be assigned to study treatments across Modules 1 and 2.

  1. Module 1: AZD0466 monotherapy will include 2 parts- Part A dose escalation cohorts and Part B dose expansion cohorts. Initiation of Part B will depend on the evaluation of safety, tolerability, and PK in Part A.

  2. Module 2: AZD0466 and voriconazole DDI study.

All participants will receive AZD0466, and administration will continue until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study treatment.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
141 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Modular Phase I/II, Open-Label, Multi-Centre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of AZD0466 Monotherapy or in Combination in Patients With Advanced Haematological Malignancies
Actual Study Start Date :
Jun 11, 2021
Anticipated Primary Completion Date :
Jun 14, 2024
Anticipated Study Completion Date :
Jun 14, 2024

Arms and Interventions

Arm Intervention/Treatment
Experimental: Module 1: AZD0466 monotherapy

Participants will receive intravenous infusion of AZD0466 monotherapy once weekly during Cycle 1 (35 days), Cycle 2 (28 days) and Cycle 3 (28 days) and also beyond Cycle 3 until progressive disease, unacceptable toxicity, or withdrawal of consent.

Drug: AZD0466
AZD0466 powder for concentrate for solution for infusion will be administered by IV infusion.

Experimental: Module 2: AZD0466 + Voriconazole

Participants may receive IV infusion of AZD0466 in combination with or without voriconazole during Cycle 1 (21 days), and Cycle 2 (28 days) and Cycle 3 (28 days) and also beyond Cycle 3 until progressive disease, unacceptable toxicity, or withdrawal of consent.

Drug: AZD0466
AZD0466 powder for concentrate for solution for infusion will be administered by IV infusion.

Drug: Voriconazole
Voriconazole film-coated tablet will be administered orally.

Outcome Measures

Primary Outcome Measures

  1. Number of participants with adverse events (AEs) and serious adverse events (SAEs) [Module 1] [Until 28 days after last dose (Upto 3.5 Years)]

    Assessment of the safety and tolerability of AZD0466 in participants with advanced haematological malignancies.

  2. Number of participants with adverse events (AEs) and serious adverse events (SAEs) [Module 2] [Until Day 19]

    Assessment of the safety and tolerability of AZD0466 in participants with advanced haematological malignancies.

  3. Number of participants with Dose-limiting toxicity (DLT) [Module 1] [35 days]

    Assessment of DLT to evaluate safety and tolerability of AZD0466 in participants with advanced haematological malignancies.

Secondary Outcome Measures

  1. Module 1: Complete Response Rate (CR+CRi) [Day 1 until post treatment follow-up (28 days after last dose) (up to 3.5 Years)]

    To estimate the preliminary anti-tumor activity of AZD0466 by assessment of complete response rate [complete remission+complete remission with incomplete recovery (CR+CRi)] defined as the proportion of participants with a best response of CR or CRi.

  2. Module 1: Time to Response (TTR) [Day 1 until post treatment follow-up (28 days after last dose) (up to 3.5 Years)]

    To estimate the preliminary antitumor activity of AZD0466 by assessment of TTR defined as the time from date of first dose until the date of first documented CR or CRi.

  3. Module 1: Duration of Response (DoR) [Day 1 until post treatment follow-up (28 days after last dose) (up to 3.5 Years)]

    To estimate the preliminary antitumor activity of AZD0466 by assessment of DoR defined as the time from the date of first documented response (CR or CRi) until date of documented progression, relapse or failure or death due to any cause.

  4. Module 1: Overall Survival (OS) [Day 1 until post treatment follow-up (28 days after last dose) and survival follow-up (every month after last dose) (up to 3.5 Years)]

    To estimate preliminary anti-tumor activity of AZD0466 by assessment of OS defined as time from date of first dose until the date of death due to any cause.

  5. Module 2: Area under the plasma concentration-curve (AUC) of AZD4320 after administration of AZD0466 alone and in combination with voriconazole [Cycle 1 Days 1, 2, 3, 4, 8 and days 15, 16, 17, 18, 19, and Cycle 2 Day 1, Cycle 3 Day 1 and beyond (Cycle length 28-days) (up to 3.5 Years)]

    Assessment of AUC to evaluate the drug-drug interaction potential between AZD0466 and the azole antifungal voriconazole.

  6. Module 2: Maximum observed plasma (peak) drug concentration (Cmax) of AZD4320 after administration of AZD0466 alone and in combination with voriconazole [Cycle 1: Days 1, 2, 3, 4, 8 and days 15, 16, 17, 18, 19, and Cycle 2 Day 1, Cycle 3 Day 1 and beyond (Cycle length 28-days) (up to 3.5 Years)]

    Assessment of Cmax to evaluate the drug-drug interaction potential between AZD0466 and the azole antifungal voriconazole.

  7. Module 1 and Module 2: Plasma concentration of AZD4320 [Module 1: Cycle 1 Days 1-30 (Cycle length 21 days) to Cycle 3 Days 1-28, and beyond (Cycle length 28 days); Module 2: Cycle 1 Days 1-8, Days 15-19 (Cycle length 21 days), Cycle 2 Day 1, Cycle 3 Day 1 and beyond (Cycle length 28-days) (up to 3.5 Years)]

    Assessment of AZD4320 to characterise the PK profile of AZD0466 following intravenous administration (via PK profiles of the active moiety AZD4320 in plasma).

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 130 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • Histologically confirmed acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL) for which there are limited treatment options known to provide clinical benefit.

  • Eastern cooperative oncology group performance status ≤2. Performance status must not have deteriorated by ≥2 levels within 2 weeks after providing informed consent.

  • Predicted life expectancy ≥8 weeks.

  • Adequate organ function at screening as per the protocol defined criteria.

  • Adequate cardiac function as demonstrated by LVEF > 50% on screening cardiac multigated acquisition, magnetic resonance image or echocardiogram.

  • Willing and able to participate in all required study evaluations and procedures including receiving IV administration of study treatment and admission to the hospital, when required, for administration of study treatment and monitoring.

  • For inclusion in the genetic component of the study, participants must fulfil protocol defined criteria.

  • White blood cell count must be <10 x 10^9/L. Treatment with hydroxyurea during screening and Cycle 1 to achieve this level is permitted.

  • Women of childbearing potential and men should use protocol defined contraceptive measures.

Exclusion Criteria:
  • Unresolved toxicity from prior anticancer therapy of Common Terminology Criteria for Adverse Events Grade ≥2. Participants with Grade 2 neuropathy or Grade 2 alopecia are eligible.

  • Active idiopathic thrombocytopenic purpura.

  • Stem cell transplant < 100 days prior to the first dose of study treatment.

  • Immunosuppression for graft versus host disease (GVHD) or GVHD prophylaxis within 4 weeks prior to the first dose of study treatment.

  • Active central nervous system (CNS) leukaemia/leptomeningeal disease/spinal cord compression. Participants who have a history of CNS leukaemia must be free of CNS leukaemia for >30 days prior to the first dose of study treatment, and the most recent 2 lumbar punctures must be negative for leukaemic cells, to be eligible.

  • Known uncontrolled infection with cytomegalovirus (CMV) infection (positive CMV Immunoglobulin M (IgM) and/or positive polymerase chain reaction (PCR) result).

  • Active infection including human immunodeficiency virus, Hepatitis B, Hepatitis C, or severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2).

  • As judged by the Investigator: any evidence of severe or uncontrolled systemic diseases, (eg, 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 (eg, haemophilia or von Willebrand disease); uncontrolled active systemic fungal, bacterial, or other infection.

  • Any of the given cardiac criteria: history of myocarditis within one year of study entry, or heart failure New York Heart Association Functional Classification Class 3 or 4; mean resting corrected QT interval (QTcF) ≥470 msec obtained from 3 electrocardiogram (ECGs), in the absence of a cardiac pacemaker; abnormalities in rhythm, conduction or morphology of resting ECG; any factors that increase the risk of QTc prolongation or risk of arrhythmic events such congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age.

  • History of another life-threatening malignancy ≤2 years prior to first dose of study treatment. The following are permitted: myelodysplastic syndrome or myeloproliferative neoplasm (including chronic myelomonocytic leukaemia [CMML]); malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and considered to be at low risk of recurrence by the treating physician; adequately treated lentigo malignant melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer; adequately treated carcinoma in situ without current evidence of disease.

  • Any of the mentioned procedures or conditions currently or in the 6 months prior to the first dose of study treatment: coronary artery bypass graft; angioplasty; vascular stent; myocardial infarction; angina pectoris; haemorrhagic or thrombotic stroke, including transient ischaemic attacks or any other CNS bleeding.

  • Treatment with any of the mentioned therapy: radiotherapy less than 3 weeks prior to first study treatment; chemotherapy within ≤14 days or 5 half-lives prior to the first dose of study treatment. Treatment with high-dose steroids for primary malignancy control is permitted but must be discontinued at least 2 days prior to the first dose of study treatment. Treatment with hydroxyurea is permitted; immunotherapies and cellular therapies within 4 weeks prior to the first dose of study treatment; investigational drugs within ≤14 days or 5 half-lives (whichever is shorter) prior to the first dose of study treatment; major surgery (excluding placement of vascular access) ≤21 days, or minor surgical procedures ≤7 days, prior to the first dose of study treatment. No waiting is required mentioned implantable port or catheter placement; prescription or non-prescription drugs or other products known to be sensitive substrates of BCRP, OCT2, OAT3, OATP1B1, OATP1B3, CYP2B6, CYP2C8, CYP2C9 or CYP2D6, or reversible moderate or strong CYP3A inhibitors, which cannot be discontinued within 5 half-lives prior to the first dose of study treatment and withheld throughout the study until 14 days after the last dose of AZD0466; moderate or strong mechanism-based inhibitors or inducers of CYP3A4 which cannot be discontinued within 5 half-lives plus of the specific drug 12 days of the drug prior to the first dose of study treatment and withheld until 14 days after the last dose of AZD0466; concurrent anti-coagulation therapy, including aspirin and heparin, which cannot be stopped; medications with known risk of Torsades de Pointes which cannot be discontinued within 5 half-lives of the first dose of study treatment and withheld until 14 days after the last dose of AZD0466; IV anti infection treatment within 14 days before first dose of study treatment.

  • History of hypersensitivity to polyethylene glycol (PEG), PEGylated products or drugs with a similar chemical structure or class to AZD0466 or other BH3 mimetic.

Module 2:

• Patients for whom treatment with voriconazole is contraindicated per the local prescribing information must not enter the study.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Research Site Scottsdale Arizona United States 85259
2 Research Site Duarte California United States 91010
3 Research Site Jacksonville Florida United States 32224
4 Research Site Miami Florida United States 33136
5 Research Site Tampa Florida United States 33612
6 Research Site Atlanta Georgia United States 30322
7 Research Site Chicago Illinois United States 60611
8 Research Site Chicago Illinois United States 60612
9 Research Site Boston Massachusetts United States 02114
10 Research Site Ann Arbor Michigan United States 48109
11 Research Site Rochester Minnesota United States 55905
12 Research Site Omaha Nebraska United States 68105
13 Research Site New York New York United States 10021
14 Research Site Columbus Ohio United States 43210
15 Research Site Portland Oregon United States 97239
16 Research Site Houston Texas United States 77030
17 Research Site Milwaukee Wisconsin United States 53226
18 Research Site Melbourne Australia 3004
19 Research Site Parkville Australia 3050
20 Research Site Le Mans Cedex France 72037
21 Research Site Pessac France 33604
22 Research Site Toulouse France 31059
23 Research Site Aachen Germany 52074
24 Research Site Berlin Germany 13353
25 Research Site Hannover Germany 30625
26 Research Site Heidelberg Germany 69120
27 Research Site Kiel Germany 24105
28 Research Site Bologna Italy 40138
29 Research Site Meldola Italy 47014
30 Research Site Rome Italy 00168
31 Research Site Rozzano Italy 20089
32 Research Site Busan Korea, Republic of 47392
33 Research Site Seoul Korea, Republic of 03080
34 Research Site Seoul Korea, Republic of 06351
35 Research Site Seoul Korea, Republic of 6591

Sponsors and Collaborators

  • AstraZeneca

Investigators

  • Principal Investigator: Dr. Marina Konopleva, MD, PhD, The University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard, Unit 428 Houston, Texas 77030 United States of America

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT04865419
Other Study ID Numbers:
  • D8241C00001
First Posted:
Apr 29, 2021
Last Update Posted:
Jul 11, 2022
Last Verified:
Jul 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by AstraZeneca
Additional relevant MeSH terms:

Study Results

No Results Posted as of Jul 11, 2022