A Phase I/IIa Study of AZD8205 Given Alone or Combined, in Participants With Advanced/Metastatic Solid Malignancies

Official title

A Phase I/IIa Multi-center, Open-label Master Protocol Dose Escalation and Expansion Study of AZD8205 as Monotherapy and in Combination With Anticancer Agents in Participants With Advanced Solid Tumors (BLUESTAR)

Overview

This research study is studying a new compound, AZD8205, as a possible treatment for advanced or metastatic solid tumours alone or in combination with anti-cancer agents

Detailed description

This study is a Phase I/IIa Multi-center, Open-label Master Protocol Dose Escalation and Expansion Study of AZD8205 as Monotherapy and in Combination with Anticancer Agents in Participants with Advanced Solid Tumors

Interventions

• Drug AZD8205
  AZD8205 is an antibody drug conjugate that has the potential to treat a wide variety of solid tumors including but not limited to breast cancer, Biliary Tract Cancer, ovarian, endometrial cancers and squamous non-small cell lung cancers.
• Drug AZD8205 and AZD2936 (Rilvegostomig)
  AZD8205 is an antibody drug conjugate that has the potential to treat a wide variety of solid tumors including but not limited to breast cancer, Biliary Tract Cancer, ovarian, endometrial cancers and squamous non-small cell lung cancers. Rilvegostomig is a bispecific antibody that specifically binds to human TIGIT and PD-1 and is a potential anticancer therapy in patients with advanced or metastatic solid tumors.
• Drug AZD8205 and AZD5305 (saruparib)
  AZD8205 is an antibody drug conjugate that has the potential to treat a wide variety of solid tumors including but not limited to breast cancer, Biliary Tract Cancer, ovarian, endometrial and squamous non-small cell lung cancers. Saruparib is a PARP inhibitor that stops the PARP protein from doing its repair work in damaged cancer cells, resulting in cell death, and is a potential anticancer therapy in patients with advanced or metastatic solid tumors.
• Drug AZD8205 and AZD5305 (saruparib) and AZD2936 (rilvegostomig)
  AZD8205 is an antibody drug conjugate that has the potential to treat a wide variety of solid tumors including but not limited to breast cancer, Biliary Tract Cancer, ovarian, endometrial and squamous non-small cell lung cancers. Saruparib is a PARP inhibitor that stops the PARP protein from doing its repair work in damaged cancer cells, resulting in cell death, and is a potential anticancer therapy in patients with advanced or metastatic solid tumors. Rilvegostomig is a bispecific antibody th
• Drug AZD8205 in combination with AZD9574
  AZD8205 is an antibody drug conjugate that has the potential to treat a wide variety of solid tumors including but not limited to breast cancer, Biliary Tract Cancer, ovarian, endometrial and squamous non-small cell lung cancers. AZD9574 is a PARP inhibitor that stops the PARP protein from doing its repair work in damaged cancer cells, resulting in cell death, and is a potential anticancer therapy in patients with advanced or metastatic solid tumors.
• Drug AZD8205 in combination with AZD9574 plus rilvegostomig (AZD2936)
  AZD8205 is an antibody drug conjugate that has the potential to treat a wide variety of solid tumors including but not limited to breast cancer, Biliary Tract Cancer, ovarian, endometrial and squamous non-small cell lung cancers. AZD9574 is a PARP inhibitor that stops the PARP protein from doing its repair work in damaged cancer cells, resulting in cell death, and is a potential anticancer therapy in patients with advanced or metastatic solid tumors. Rilvegostomig is a bispecific antibody that

Primary outcome measures

• The number of patients with adverse events [Time frame: From time of Informed consent to 30 days post last dose (approximately 1 year).]
• The number of patients with serious adverse events [Time frame: From time of Informed consent to 30 days post last dose (approximately 1 year)]
• The number of patients with dose-limiting toxicity (DLT), as defined in the protocol. [Time frame: From first dose of study treatment until the end of Cycle 1 (approximately 21 days).]
• The number of patients with changes from baseline laboratory findings, ECGs and vital signs [Time frame: From time of informed consent to 30 days post last dose (approximately 1 year)]

Secondary outcome measures (12)

• Objective Response Rate (ORR) [Time frame: From first dose of AZD8205 to progressive disease or death in the absence of disease progression ( approx. 2 years )]
• Duration of response (DoR) [Time frame: From the first documented response to confirmed progressive disease or death ( approx. 2 years )]
• Progression free Survival (PFS) [Time frame: From first dose of AZD8205 to progressive disease or death in the absence of disease progression ( approx. 2 years )]
• Disease Control Rate at 12 weeks (DCR-12) [Time frame: Measured from first dose until progression. For each patient, this is expected to be at 12 weeks]
• Overall Survival (OS) [Time frame: From first dose of AZD8205 to death ( approx. 2 years )]
• Pharmacokinetics of AZD8205: Area Under the concentration-time curve (AUC) [Time frame: From the first dose of study intervention, at predefined intervals throughout the administration of AZD8205 ( approx 2 years )]
• Pharmacokinetics of AZD8205: Maximum plasma concentration of the study drug (Cmax) [Time frame: From the first dose of study intervention, at predefined intervals throughout the administration of AZD8205 ( approx 2 years )]
• Pharmacokinetics of AZD8205: Time to maximum plasma concentration of the study drug (T-max) [Time frame: From the first dose of study intervention, at predefined intervals throughout the administration of AZD8205 ( approx 2 years )]
• Pharmacokinetics of AZD8205: Clearance [Time frame: From the first dose of study intervention, at predefined intervals throughout the administration of AZD8205 ( approx 2 years )]
• Pharmacokinetics of AZD8205: Terminal elimination half-life (t 1/2) [Time frame: From the first dose of study intervention, at predefined intervals throughout the administration of AZD8205 ( approx 2 years )]
• Immunogenicity of AZD8205. [Time frame: From the first dose of study intervention, at predefined intervals throughout the administration of AZD8205 ( approx 2 years )]
• Sub Study 1: AZD8205 monotherapy Pharmacodynamics [Time frame: From the first dose of study intervention, at predefined intervals throughout the administration of AZD8205 ( approx 2 years )]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years
• Relapsed/metastatic solid tumors treated with prior adequate standard of care therapy for tumor type and stage of disease or where in the opinion of the Investigator, a clinical trial is the best option for the next treatment based on response and/or tolerability to prior therapy.
• Measurable disease per RECIST v1.1
• Eastern Cooperative Oncology Group (ECOG) Performance Status: 0-1
• Life expectancy ≥ 12 weeks
• Adequate bone marrow, hepatic, and renal function as defined in the protocol

Additional Inclusion Criteria For Sub-Study 1 Part A:

• Histologically or cytologically confirmed metastatic or locally advanced/recurrent breast cancer, ovarian cancer, BTC or endometrial cancer

Additional Inclusion Criteria For Sub-Study 1 Part B:

• Histologically or cytologically confirmed metastatic or locally advanced and recurrent disease for the respective cohort:

• Cohort B1 (Biliary Tract Cancer)
• Cohort B2 (Ovarian Cancer)
• Cohort B3 (Breast Cancer)
• Cohort B4 (Endometrial Cancer)
• Cohort B5 (Squamous Non-Small Cell Lung Cancer)

Additional Inclusion Criteria For Sub-Study 2 Part A:

• Minimum body weight ≥ 30 kg.
• Histologically or cytologically confirmed metastatic or locally advanced/recurrent breast cancer, ovarian cancer, BTC, endometrial cancer or squamous non-small cell lung cancer.

Additional Inclusion Criteria For Sub-Study 3 Part A:

• Minimum body weight ≥ 30 kg (for participants enrolled in cohorts including rilvegostomig only).
• Histologically or cytologically confirmed metastatic or locally advanced/recurrent breast cancer, ovarian cancer, BTC, endometrial cancer or squamous non-small cell lung cancer.

Additional Inclusion Criteria For Sub-Study 4 Part A:

• Minimum body weight ≥ 30 kg (for participants enrolled in cohorts including rilvegostomig only).
• Histologically or cytologically confirmed metastatic or locally advanced/recurrent breast cancer, endometrial cancer or squamous non-small cell lung cancer.
• Participants must have progressed following at least one but no more than 3 prior lines of treatment for metastatic or relapsed disease and have no satisfactory alternative treatment option as judged by the Investigator.

Exclusion criteria

• Treatment with any of the following:

• Nitrosourea or mitomycin C within 6 weeks prior to the first dose of study treatment
• Any investigational agents or study drugs from a previous clinical study within 5 half-lives or 28 days (whichever is shorter) prior to the first dose of study treatment
• Any other anticancer treatment within the following time periods prior to the first dose of study intervention:

• Cytotoxic treatment: 21 days
• Non-cytotoxic drugs: 21 days or 5 half-lives (whichever is shorter)
• Biological products including immuno-oncology agents: 28 days
• Spinal cord compression or a history of leptomeningeal carcinomatosis.
• Brain metastases unless treated, asymptomatic, stable, and not requiring continuous corticosteroids at a dose of > 10 mg prednisone/day or equivalent for at least 4 weeks prior to start of study.
• Active infection including tuberculosis and HBV, HCV or HIV
• History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses
• Participants with any of the following cardiac criteria:

• History of arrhythmia which is symptomatic or requires treatment (NCI CTCAE v5.0 Grade 3); symptomatic or uncontrolled atrial fibrillation, or asymptomatic sustained ventricular tachycardia.
• Uncontrolled hypertension.
• Acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention, or coronary artery bypass grafting within 6 months.
• History of brain perfusion problems (eg, carotid stenosis) or stroke, or transient ischemic attack in the last 6 months prior to screening.
• Symptomatic heart failure (NYHA class ≥ 2).
• Prior or current cardiomyopathy.
• Severe valvular heart disease.
• Mean resting QTcF > 470 msec.
• Risk factors for QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age.
• Patients with history of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML (as determined by prior diagnostic investigation)

Additional Exclusion Criteria For Sub-Study 2 Part A:

• Thromboembolic event within 3 months before the first dose of study intervention - No longer applicable per amendment 7
• Experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
• Active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.
• History of organ transplant

Additional Exclusion Criteria For Sub-Study 2 Part B

• Previous treatment with any therapy that contains a TOP1i (eg. irinotecan, topotecan, trastuzumab deruxtecan, etc.)

Additional Exclusion Criteria For Sub-Study 3 Part A:

• Concomitant use of medications or herbal supplements known to be strong cytochrome P (CYP) 3A4 inducers/inhibitors.
• Any history of persisting (> 2 weeks) severe cytopenia due to any cause
• Patients with any known predisposition to bleeding
• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of saruparib.
• Previous treatment with any therapy that contains a TOP1i (eg. irinotecan, topotecan, trastuzumab deruxtecan, etc.)

Additional Exclusion Criteria For Sub-Study 4 Part A:

• Patients have received prior therapy with AZD9574 or more than 1 prior line of any other PARPi-based regimen
• Concomitant use of medications or herbal supplements known to be strong cytochrome P (CYP) 3A4 inducers/inhibitors.
• Previous treatment with rilvegostomig for the cohort treated with rilvegostomig
• Previous treatment with any therapy that contains a TOP1i (eg. irinotecan, topotecan, trastuzumab deruxtecan, etc.)
• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD9574

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

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 14 centers

• Research Site — Duarte
• Research Site — Irvine
• Research Site — Santa Monica
• Research Site — Santa Rosa
• Research Site — Shreveport
• Research Site — Baltimore
• Research Site — Boston
• Research Site — St Louis
• … and 6 more centers

China · 8 centers

• Research Site — Beijing
• Research Site — Beijing
• Research Site — Changsha
• Research Site — Changsha
• Research Site — Chongqing
• Research Site — Guangzhou
• Research Site — Kunming
• Research Site — Shandong

Japan · 6 centers

• Research Site — Chūōku
• Research Site — Hidaka-shi
• Research Site — Kashiwa
• Research Site — Kōtoku
• Research Site — Kurume-shi
• Research Site — Sunto-gun

Canada · 5 centers

• Research Site — Calgary
• Research Site — Vancouver
• Research Site — Ottawa
• Research Site — Toronto
• Research Site — Montreal

Spain · 5 centers

• Research Site — Barcelona
• Research Site — L'Hospitalet de Llobregat
• Research Site — Madrid
• Research Site — Málaga
• Research Site — Pamplona

Taiwan · 5 centers

• Research Site — Taichung
• Research Site — Tainan
• Research Site — Taipei
• Research Site — Taipei
• Research Site — Taoyuan

Italy · 4 centers

• Research Site — Milan
• Research Site — Milan
• Research Site — Modena
• Research Site — Roma

South Korea · 4 centers

• Research Site — Seoul
• Research Site — Seoul
• Research Site — Seoul
• Research Site — Seoul

Australia · 3 centers

• Research Site — Clayton
• Research Site — Melbourne
• Research Site — Nedlands

Hungary · 3 centers

• Research Site — Budapest
• Research Site — Budapest
• Research Site — Budapest

United Kingdom · 3 centers

• Research Site — Cambridge
• Research Site — Cardiff
• Research Site — London

Belgium · 2 centers

• Research Site — Anderlecht
• Research Site — Leuven

Poland · 2 centers

• Research Site — Gdansk
• Research Site — Warsaw

Thailand · 2 centers

• Research Site — Bangkok
• Research Site — Chiang Mai

Netherlands · 1 center

• Research Site — Amsterdam

Publications

• Huang Y, Tan HY, Yuan J, Mu R, Yang J, Ball K, Vijayakrishnan B, Masterson L, Kinneer K, Luheshi N, Liang M, Rosenbaum AI. Extensive Biotransformation Profiling of AZD8205, an Anti-B7-H4 Antibody-Drug Conjugate, Elucidates Pathways Underlying Its Stability In Vivo. Anal Chem. 2024 Oct 22;96(42):16525-16533. doi: 10.1021/acs.analchem.4c02309. Epub 2024 Oct 11. PMID 39392424

Identifiers

NCT: NCT05123482 · D6900C00001 · 2022-502759-70-01 · 2021-000736-66

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗