A First-in-human Dose Escalation and Expansion Study to Evaluate the Safety, and Tolerability of AZD8421 Alone or in Combination in Participants With Selected Advanced or Metastatic Solid Tumors

Official title

A Phase I/IIa, First-in-human, Open-label, Dose Escalation and Expansion Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of AZD8421 Alone or in Combination in Participants With Selected Advanced or Metastatic Solid Tumors

Overview

This study is designed to evaluate AZD8421 alone and in combination with selected targeted anti-cancer drugs in patients with ER+HER2- advanced breast cancer, and patients with metastatic high-grade serious ovarian cancer.

Detailed description

This is a first in-human study of AZD8421 administered to participants with advanced or metastatic solid tumors. The study will evaluate the safety, tolerability, preliminary efficacy, pharmacokinetics, and pharmacodynamics of AZD8421 alone and in combination with selected targeted anti-cancer drugs.

AZD8421 monotherapy (M1) will evaluate the safety, tolerability and pharmacokinetics of AZD8421 as monotherapy to identify a recommended Phase II dose (RP2D) in participants with ER+ HER2- advanced breast cancer previously treated with a CDK4/6i (Parts A and B) and participants with metastatic high-grade serous ovarian cancer previously treated with a platinum-based chemotherapy in the metastatic setting (Part B).

AZD8421 combination therapy (M2) will evaluate the safety, tolerability, and pharmacokinetics of different formulations of AZD8421 in combination with a CDK4/6 inhibitor (one or more of abemaciclib, ribociclib and palbociclib) and camizestrant (next generation oral SERD; referred to throughout as 'camizestrant') in participants with ER+ HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor.

Interventions

• Drug AZD8421
  CDK2 inhibitor
• Drug Camizestrant
  SERD
• Drug Ribociclib
  CDK4/6 inhibitor
• Drug Palbociclib
  CDK4/6 inhibitor
• Drug Abemaciclib
  CDK4/6 inhibitor

Primary outcome measures

• Incidence of dose limiting toxicities (DLTs) as defined in the protocol. [Time frame: From start of treatment until the end of DLT period, assessed up to 28 days.]
• Incidence of AEs/SAEs [Time frame: From start of treatment until the end of safety follow-up, approximately 18 months.]
• Clinically significant changes from baseline in clinical laboratory parameters, vital signs and ECGs. [Time frame: From start of treatment until the end of safety follow-up, approximately 18 months.]
• Discontinuation of AZD8421 due to toxicity [Time frame: From start of treatment until the end of safety follow-up, approximately 18 months.]

Secondary outcome measures (12)

• Overall Response Rate (ORR) [Time frame: 8 weeks from start of treatment until end of treatment or objective disease progression, approximately 18 months.]
• Duration of Response (DoR) [Time frame: 8 weeks from start of treatment until end of treatment or objective disease progression, approximately 18 months.]
• Disease control rate (DCR) [Time frame: 24 weeks after the start of treatment.]
• Percentage change in tumor size [Time frame: From start of treatment through to EOT, progressive disease, death (in the absence of progression), start of subsequent anti-cancer therapy, whichever occurs first, approximately 18 months.]
• Progression Free Survival (PFS) [Time frame: From start of treatment through to progressive disease, death (in the absence of progression), EOT (last evaluable disease assessment), whichever occurs first, approximately 18 months.]
• PK of AZD8421 (Cmax) [Time frame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.]
• PK of AZD8421 (Tmax) [Time frame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.]
• PK of AZD8421 (AUCinf) [Time frame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.]
• PK of AZD8421 (AUClast) [Time frame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.]
• PK of AZD8421 (T1/2λZ) [Time frame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.]
• PK of AZD8421 (CL/F) [Time frame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.]
• PK of AZD8421 (Cssmax) [Time frame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.]

Eligibility criteria

Inclusion criteria

• Female participants only, aged 18 or above
• Participants with advanced solid tumors must have received prior adequate therapy in accordance with local practice for their tumor type and stage of disease, or, in the opinion of the Investigator, a clinical study is the best option for their next treatment based on response to and/or tolerability of prior therapy.
• Metastatic or locoregionally recurrent disease and radiological or objective evidence of progression on or after the last systemic therapy prior to starting IMP.
• ECOG/WHO performance status 0 to 1, and a minimum life expectancy of 12 weeks.
• At least one lesion that is measurable and/or non-measurable, as per RECIST v1.1 and that can be accurately assessed at baseline and is suitable for repeated assessment.

Exclusion criteria

• Intervention with any of the following:
• Any cytotoxic chemotherapy, investigational agents, or other anti-cancer drugs for the treatment of advanced cancer from a previous treatment regimen or clinical study within 14 days or 5 half-lives (whichever is shorter) of the first dose of IMP (21 days for myelosuppressive therapies) other than GnRHa (eg, goserelin) and bone-stabilizing agents (eg, zoledronic acid, denosumab).
• Any prescription or non-prescription drugs or other products, including herbal products, known to be moderate or strong inhibitors/inducers of CYP3A4/5 which cannot be discontinued prior to first dose of IMP and withheld throughout the study until 2 weeks after the last dose of study drug.
• Drugs that have a known risk of Torsades de Pointes.
• Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of IMP.
• Major surgical procedure or significant traumatic injury, within 4 weeks of the first dose of IMP, or an anticipated need for major surgery and/or any surgery requiring general anesthesia during the study.
• Any unresolved toxicities of Grade ≥ 2 from prior anti-cancer therapy (with the exception of alopecia). Participants with stable ≤ Grade 2 neuropathy are eligible.
• Presence of life-threatening metastatic visceral disease, as judged by the Investigator, uncontrolled CNS metastatic disease. Participants with spinal cord compression and/or brain metastases may be enrolled if definitively treated (eg, surgery or radiotherapy) and stable off steroids for at least 4 weeks prior to start of IMP.
• Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, or eg, infection requiring IV antibiotic therapy, or active infection including hepatitis B, hepatitis C, and HIV (active viral infection is defined as requiring antiviral therapy; screening for chronic conditions is not required).
• Any of the following cardiac criteria:
• Mean resting QTcF > 470 msec obtained from a triplicate ECG
• Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (eg, complete left bundle branch block, second- and third-degree heart block), or clinically significant sinus pause. Participants with controlled atrial fibrillation can be enrolled.
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as symptomatic heart failure, hypokalemia, congenital long QT syndrome, immediate family history of long QT syndrome or unexplained sudden death at < 40 years of age. Hypertrophic cardiomyopathy and clinically significant stenotic valve disease.
• LVEF < 50%, and/or experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, unstable angina pectoris, congestive heart failure NYHA Grade ≥ 2, cerebrovascular accident, or transient ischemic attack.
• Uncontrolled hypertension.
• Inadequate bone marrow reserve or organ function as demonstrated by relevant laboratory values:
• Refractory nausea and vomiting, uncontrolled chronic gastrointestinal diseases, or previous significant bowel resection that would preclude adequate absorption of IMP(s).
• History of hypersensitivity to active or inactive excipients of AZD8421 or drugs with a similar chemical structure or class to AZD8421.
• Previous treatment with AZD8421 or with any CDK2-selective inhibitor, or protein kinase membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase 1 (PKMYT1) inhibitor, or WEE1 inhibitor.
• Currently pregnant (confirmed with positive pregnancy test), breast feeding, or planning to become pregnant. Participants of childbearing potential must agree to use one highly effective contraceptive measure.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 4 centers

• Research Site — St Louis
• Research Site — Providence
• Research Site — Nashville
• Research Site — Houston

United Kingdom · 4 centers

• Research Site — Cambridge
• Research Site — Leeds
• Research Site — London
• Research Site — Manchester

Spain · 3 centers

• Research Site — Barcelona
• Research Site — Pamplona
• Research Site — Valencia

South Korea · 2 centers

• Research Site — Seoul
• Research Site — Seoul

Australia · 1 center

• Research Site — East Melbourne

Identifiers

NCT: NCT06188520 · D8470C00001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗