Clinical trial NCT06188520: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: ER+ HER2- Advanced Breast Cancer
High-grade Serous Ovarian Cancer (HGSOC)
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2024-01-03
Enrollment: 348
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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 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.

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.

Primary outcomes:
measure: Incidence of dose limiting toxicities (DLTs) as defined in the protocol.
timeFrame: From start of treatment until the end of DLT period, assessed up to 28 days.
measure: Incidence of AEs/SAEs
timeFrame: From start of treatment until the end of safety follow-up, approximately 18 months.
measure: Clinically significant changes from baseline in clinical laboratory parameters, vital signs and ECGs.
timeFrame: From start of treatment until the end of safety follow-up, approximately 18 months.
measure: Discontinuation of AZD8421 due to toxicity
timeFrame: From start of treatment until the end of safety follow-up, approximately 18 months.
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: 8 weeks from start of treatment until end of treatment or objective disease progression, approximately 18 months.
measure: Duration of Response (DoR)
timeFrame: 8 weeks from start of treatment until end of treatment or objective disease progression, approximately 18 months.
measure: Disease control rate (DCR)
timeFrame: 24 weeks after the start of treatment.
measure: Percentage change in tumor size
timeFrame: 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.
measure: Progression Free Survival (PFS)
timeFrame: 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.
measure: PK of AZD8421 (Cmax)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.
measure: PK of AZD8421 (Tmax)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.
measure: PK of AZD8421 (AUCinf)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.
measure: PK of AZD8421 (AUClast)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.
measure: PK of AZD8421 (T1/2λZ)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.
measure: PK of AZD8421 (CL/F)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.
measure: PK of AZD8421 (Cssmax)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.
measure: PK of AZD8421 (Tssmax)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.
measure: PK of AZD8421 (ARCmax)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.
measure: PK of AZD8421 (AUCsslast)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.
measure: PK of AZD8421 (T1/2λssz)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.
measure: PK of AZD8421 (CLss/F)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.
measure: PK of AZD8421, camizestrant, and CDK4/6i (Cmax) (M2 only)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421, camizestrant and CDK4/6i.
measure: PK of AZD8421, camizestrant, and CDK4/6i (Tmax) (M2 only)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421, camizestrant and CDK4/6i.
measure: PK of AZD8421, camizestrant, and CDK4/6i (AUCinf) (M2 only)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421, camizestrant and CDK4/6i.
measure: PK of AZD8421, camizestrant, and CDK4/6i (T1/2λ) (M2 only)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421, camizestrant and CDK4/6i.
measure: PK of AZD8421, camizestrant, and CDK4/6i (CL/F) (M2 only)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421, camizestrant and CDK4/6i.
measure: PK of AZD8421, camizestrant, and CDK4/6i (Cssmax) (M2 only)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421, camizestrant and CDK4/6i.
measure: PK of AZD8421, camizestrant, and CDK4/6i (Tssmax) (M2 only)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421, camizestrant and CDK4/6i.
measure: PK of AZD8421, camizestrant, and CDK4/6i (AUC0-tau) (M2 only)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421, camizestrant and CDK4/6i.
measure: PK of AZD8421, camizestrant, and CDK4/6i (T1/2λssz) (M2 only)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421, camizestrant and CDK4/6i.
measure: PK of AZD8421, camizestrant, and CDK4/6i (CLss/F) (M2 only)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421, camizestrant and CDK4/6i.
measure: PD of AZD8421 (M1B only)
timeFrame: Baseline and Cycle 1 Day 15.
measure: PK of AZD8421 (ARAUC)
timeFrame: From start of treatment, at predefined intervals up to Cycle 6, approximately 6 months (each cycle is 28 days) of the administration of AZD8421.
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Research Site
state: Missouri
city: Providence
country: United States
facility: Research Site
state: Rhode Island
city: Nashville
country: United States
facility: Research Site
state: Tennessee
city: Houston
country: United States
facility: Research Site
state: Texas
city: East Melbourne
country: Australia
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Pamplona
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Leeds
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Cambridge University Hospitals
name: Richard Baird, MD, PhD
role: STUDY_CHAIR
References: