AZD8205 for Endometrial Cancer

Recruiting in Palo Alto (17 mi)

+54 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: AstraZeneca

Must not be taking: Nitrosourea, Mitomycin C, others

Disqualifiers: Brain metastases, Active infection, Cardiac issues, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called AZD8205 to see if it can help treat advanced or spreading solid tumors. The study includes patients whose cancer is advanced or has spread and may not respond to current treatments. AZD8205 might work by stopping or slowing down the growth of cancer cells.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting, such as nitrosourea or mitomycin C within 6 weeks, and other anticancer treatments within specific time frames. It's best to discuss your current medications with the trial team to see if any need to be paused.

What data supports the effectiveness of the drug AZD8205 for endometrial cancer?

Research on similar antibody-drug conjugates (ADCs) like sacituzumab govitecan shows promising results in targeting specific proteins on cancer cells, leading to tumor growth inhibition in endometrial cancer models. Additionally, ADCs targeting B7-H4, a protein overexpressed in endometrial cancer, have shown complete tumor regression in preclinical models, suggesting potential effectiveness for AZD8205. ^{1 2 3 4 5}

What makes the drug AZD8205 unique for treating endometrial cancer?

AZD8205 is unique because it is an antibody-drug conjugate (ADC) that specifically targets the B7-H4 protein, which is overexpressed in endometrial cancer. This allows for targeted delivery of the drug to cancer cells, potentially improving effectiveness and reducing side effects compared to traditional chemotherapy. ^{1 3 4 5 6}

Research Team

Eligibility Criteria

Adults (18+) with advanced or metastatic solid tumors, specifically breast cancer, ovarian cancer, bile duct cancer (cholangiocarcinoma), or endometrial cancer. Participants must have measurable disease and an ECOG performance status of 0-1. They should expect to live at least 12 weeks and have proper organ/marrow function. Prior treatments vary by sub-study group.

Inclusion Criteria

Life expectancy ≥ 12 weeks

For Sub-Study 1 Part B: Histologically or cytologically confirmed metastatic or locally advanced and recurrent disease for the respective cohort: Cohort B1 (Cholangiocarcinoma): at least one prior systemic line of therapy for metastatic/relapsed disease. Cohort B2 (Serous Ovarian Cancer): at least one prior systemic line of therapy for metastatic/relapsed disease. Cohort B3 (Triple Negative Breast Cancer): no more than one prior systemic line of therapy for metastatic/relapsed disease.

My cancer has returned or spread and I've had standard treatment or a trial is my best next step.

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.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Part A: Dose escalation to determine the safety, tolerability, and maximum tolerated dose of AZD8205 alone or in combination with anticancer agents

21 days per cycle

Dose Expansion

Part B: Dose expansion to evaluate anti-tumor activity of AZD8205 alone or in combination with anticancer agents in select solid tumors

Approx. 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days post last dose

Treatment Details

Interventions

• AZD8205 (Unknown)

Trial Overview The trial is testing AZD8205 for patients with certain types of advanced cancers that have spread beyond the original site. It's a first-in-human study to see if this new compound can be effective in treating these conditions.

Participant Groups

Group I: Sub-Study 3 AZD8205 in combination with saruparib, with or without rilvegostomig Experimental Treatment 2 Interventions

Sub-Study 3 has two parts: Part A : Dose escalation to determine the safety, tolerability of AZD8205 + saruparib. Rilvegostomig may be added in a triplet combination once an AZD8205 + saruparib combination dose/schedule has been considered safe. Part B: Dose expansion to evaluate anti-tumor activity of AZD8205 + saruparib with or without rilvegostomig in select solid tumors.

Group II: Sub-Study 1 AZD8205 Monotherapy Experimental Treatment 1 Intervention

Sub-Study 1 has two parts: Part A : The aim is to determine the safety, tolerability, Recommended Phase 2 Dose(RP2D), and/or the Maximum Tolerated Dose (MTD) of AZD8205. Part B: The aim of dose expansion is to evaluate anti-tumor activity of AZD8205 as monotherapy in select solid tumors.

Group III: Sub Study 2: AZD8205 in combination with rilvegostomig Experimental Treatment 1 Intervention

Sub-Study 2 has two parts: Part A : Dose escalation to determine the safety, tolerability of AZD8205 + rilvegostomig Part B: Dose expansion to evaluate anti-tumor activity of AZD8205 + rilvegostomig in select solid tumors.

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

Sacituzumab govitecan (SG) effectively targets and inhibits the growth of poorly differentiated endometrial cancer (EC) cells that overexpress the Trop-2 protein, with 84% of analyzed tumors showing moderate-to-strong Trop-2 expression.

In preclinical models, SG demonstrated significant tumor growth inhibition in chemotherapy-resistant EC xenografts and was well tolerated, suggesting its potential as a promising treatment option for patients with this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacituzumab govitecan, an antibody-drug conjugate targeting trophoblast cell-surface antigen 2, shows cytotoxic activity against poorly differentiated endometrial adenocarcinomas in vitro and in vivo. Perrone, E., Manara, P., Lopez, S., et al.[2021]

The study introduces a new class of small molecule-based immune checkpoint-targeting maytansinoid conjugates, specifically conjugate 40a, which effectively regressed tumors in pancreatic cancer, triple-negative breast cancer, and sorafenib-resistant liver cancer.

Conjugate 40a not only reduced tumor growth but also transformed the tumor microenvironment from immunosuppressive to 'inflamed hot,' enhancing immune response and gene expression, suggesting its potential for combination therapy with existing immuno-oncology treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the Phosphatidylserine-Immune Checkpoint with a Small-Molecule Maytansinoid Conjugate. Lo, CF., Chiu, TY., Liu, YT., et al.[2022]

Mirvetuximab soravtansine (IMGN853) demonstrated a manageable safety profile in patients with platinum-resistant ovarian cancer, with most adverse events being mild and primarily consisting of diarrhea, blurred vision, nausea, and fatigue.

The treatment showed clinical activity, with a confirmed objective response rate of 26% overall, and a higher response rate of 39% in patients who had received three or fewer prior lines of therapy, indicating potential effectiveness in earlier treatment settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Activity of Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha-Targeting Antibody-Drug Conjugate, in Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer: A Phase I Expansion Study. Moore, KN., Martin, LP., O'Malley, DM., et al.[2019]

The antibody drug conjugate MEDI-547 effectively targets EphA2, which is overexpressed in endometrial cancer, leading to significant reductions in tumor growth (86% to 88% inhibition) in mouse models.

MEDI-547 not only decreased cancer cell viability and increased apoptosis in vitro but also reduced the incidence of distant metastasis in vivo, indicating its potential as a powerful treatment for endometrial cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EphA2 targeted chemotherapy using an antibody drug conjugate in endometrial carcinoma. Lee, JW., Stone, RL., Lee, SJ., et al.[2023]

SYD985, a novel HER2-targeting antibody-drug conjugate, shows significant efficacy against uterine serous carcinoma (USC), demonstrating activity in tumors with both high (3+) and low to moderate (1+/2+) HER2 expression levels.

In comparative studies, SYD985 was found to be 10- to 70-fold more potent than the FDA-approved ADC trastuzumab emtansine (T-DM1), suggesting it could be a promising treatment option for patients with chemotherapy-resistant USC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody-Drug Conjugate, Shows Antitumor Activity in Uterine Serous Carcinoma with HER2/Neu Expression. Black, J., Menderes, G., Bellone, S., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Sacituzumab govitecan, an antibody-drug conjugate targeting trophoblast cell-surface antigen 2, shows cytotoxic activity against poorly differentiated endometrial adenocarcinomas in vitro and in vivo. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Targeting the Phosphatidylserine-Immune Checkpoint with a Small-Molecule Maytansinoid Conjugate. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Safety and Activity of Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha-Targeting Antibody-Drug Conjugate, in Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer: A Phase I Expansion Study. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

EphA2 targeted chemotherapy using an antibody drug conjugate in endometrial carcinoma. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Discovery and Preclinical Characterization of XMT-1660, an Optimized B7-H4-Targeted Antibody-Drug Conjugate for the Treatment of Cancer. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody-Drug Conjugate, Shows Antitumor Activity in Uterine Serous Carcinoma with HER2/Neu Expression. [2022]