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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Astrazeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

29 Apr 2024 → ongoing

Decision date (initial)

2024-03-01

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Astrazeneca AB

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Therapy, Pharmacogenetic, Safety, Efficacy, Pharmacokinetic, Dose response, Pharmacogenomic

To investigate the safety and tolerability, characterize DLTs and determine the MTD and/or MFD and/or recommended Phase II dose (RP2D) of AZD8421 as a monotherapy and also in combination with other anti-cancer drugs.

Secondary objectives 3

1. Efficacy: To assess the preliminary anti-tumor activity and efficacy of AZD8421 monotherapy and also in combination with other anti-cancer drugs
2. PK: To characterize the PK profiles and parameters of AZD8421 and its metabolites after monotherapy and in combination with other anti-cancer drugs after single and multiple doses.
3. Module 1B only : To assess pharmacodynamic activity of AZD8421 monotherapy by assessment of candidate biomarker in baseline and on-treatment tumor and blood samples in participants with ER+ HER2- metastatic breast cancer and other advanced solid tumors

Conditions and MedDRA coding

Patients with ER+ HER2- advanced breast cancer and patients with high-grade serious ovarian cancer (HGSOC)

Regulatory references

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Participant must be 18 years of age or more at the time of signing the informed consent form.
2. Participants must be female.
3. 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.
4. Metastatic or locoregionally recurrent disease and radiological or objective evidence of progression on or after the last systemic therapy prior to starting IMP.
5. ECOG/WHO performance status 0 to 1, and a minimum life expectancy of 12 weeks.
6. 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 by CT, MRI, or plain X-ray, or clinical examination. Blastic-only lesions in bone are not considered assessable.
7. Female participants of childbearing potential must agree to use one highly effective contraceptive measure.
8. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
9. Provision of signed and dated written optional genetic research information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative.
10. Provision of consent to enable submission of archival tumor tissue, and availability of appropriate tissue.

Exclusion criteria 9

1. Intervention with any of the following: a. Any cytotoxic chemotherapy, investigational agents, or other anticancer 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). Chemowarhead ADCs are considered to be myelosuppressive in this context. b. 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 2 weeks or 5 half-lives (whichever is longer) prior to first dose of IMP and withheld throughout the study until 2 weeks after the last dose of study drug, excluding CDK4/6is under study. c. Participants must be excluded who are unable to comply with the prohibited concomitant medication restrictions specific to each module of study. Drugs that have a known risk of Torsades de Pointes, as indicated in CredibleMeds® list (www.crediblemeds.org). d. Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of IMP, with the exception of participants receiving radiation to more than 30% of the bone marrow or a wide field of radiation within 4 weeks of the first dose of IMP. e. Major surgical procedure or significant traumatic injury, as judged by the Investigator, 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
2. Inability to swallow oral medications.
3. Any unresolved toxicities of Grade ≥ 2 from prior anti-cancer therapy (with the exception of alopecia). Participants with stable ≤ Grade 2 neuropathy are eligible.
4. 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.
5. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, or eg, infection requiring IV antibiotic therapy, which in the Investigator's opinion makes it undesirable for the participant to participate in the study or which would jeopardize compliance with the protocol, 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).
6. Any of the following cardiac criteria: a. Mean resting QTcF > 470 msec obtained from a triplicate ECG b. 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. c. Any clinically significant 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. d. 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. e. Uncontrolled hypertension. Participants may be rescreened and those with adequately controlled blood pressure as judged by the Investigator may be considered to be eligible.
7. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: a. Absolute neutrophil count (ANC) < 1.5 × 10^9/L b. Platelet count < 100 × 10^9/L c. Hemoglobin < 90 g/L d. Alanine aminotransferase (ALT) > 2.5 × ULN e. Aspartate aminotransferase (AST) > 2.5 × ULN f. Total bilirubin (TBL) > 1.5 × ULN or > 3 × ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) g. eGFR < 45 mL/min
8. Refractory nausea and vomiting, uncontrolled chronic gastrointestinal diseases, or previous significant bowel resection that would preclude adequate absorption of IMP(s).
9. History of hypersensitivity to active or inactive excipients of AZD8421 or drugs with a similar chemical structure or class to AZD8421.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Incidence of AEs, SAEs and DLTs
2. Clinically significant changes from baseline in clinical laboratory parameters, vital signs, and ECG results
3. Discontinuation of AZD8421 due to toxicity

Secondary endpoints 4

1. Efficacy: According to the RECIST v1.1 by Investigator assessment (Eisenhauer et al 2009): • ORR • BOR • DoR • DCR at 24 weeks • Percentage change in tumor size • PFS
2. Summary PK profiles and descriptive statistics of After first dose: following PK parameters may be evaluated for AZD8421; Cmax, AUCinf, AUClast, tmax, λz, t½λz, CL/F, V/F, and Vz/F (additional PK parameters may be determined where appropriate). If data allows following PK parameters for metabolite(s) may be evaluated; Cmax, AUCinf, AUClast, tmax, t½λz (additional PK parameters may be determined where appropriate).
3. continued...After multiple doses: following PK parameters may be evaluated for AZD8421; Cssmax, AUC0-tau, AUCsslast, AUCss0-t, tssmax, t½λssz, CLss/F, Vss/F (additional PK parameters may be determined where appropriate) If data allows following PK parameters for metabolite(s) may be evaluated; Cssmax, AUC0-tau, AUCsslast, tssmax, t½λssz, CLss/F, Vss/F, ARCmax, ARAUC (additional PK parameters may be determined where appropriate)
4. Module 1B only: Tumor protein analysis of the candidate biomarker and broader proteomic and phosphoproteomic profiling. Tumor and peripheral assessment including, but not limited to, DNA, mRNA, protein, epigenetic, and immune analyses.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 14

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Astrazeneca AB

Sponsor organisation

Astrazeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

Astrazeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

Astrazeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications