AZD2284 for Prostate Cancer

Recruiting at 8 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Male

Trial Phase: Phase 1

Sponsor: AstraZeneca

Must be taking: Androgen-deprivation therapy

Must not be taking: Radiopharmaceuticals, Cytotoxic therapy

Disqualifiers: Severe illness, Proteinuria, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

134 Participants Needed

Trial Summary

What is the purpose of this trial?

The main purpose of the study is to assess the safety and tolerability of AZD2284, AZD2287, and AZD2275.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop your current medications, but you should not have had any systemic cytotoxic or investigational therapy within 28 days before starting the trial.

What data supports the effectiveness of the drug AZD2284 for prostate cancer?

The effectiveness of [225Ac]-AZD2284 for prostate cancer may be indirectly supported by the success of [225Ac]Ac-PSMA-617, a similar targeted alpha therapy, which has shown promising long-term survival outcomes in patients with advanced prostate cancer. Additionally, radium-223, another alpha-emitting treatment, has been shown to improve survival in prostate cancer patients with bone metastases. ^{1 2 3 4 5}

What makes the treatment [225Ac]-AZD2284 unique for prostate cancer?

[225Ac]-AZD2284 is a novel treatment that uses targeted alpha therapy (TAT) to deliver alpha-particle radiation directly to prostate cancer cells, similar to [225Ac]Ac-PSMA-617, which is used for patients with advanced prostate cancer who have no other treatment options. This approach is unique because it specifically targets cancer cells, potentially reducing damage to healthy cells compared to traditional radiation therapies. ^{3 6 7 8 9}

Eligibility Criteria

This trial is for men with advanced prostate cancer that's resistant to hormone therapy. They must have low testosterone from treatment, good organ function, and be relatively fit (ECOG 0 or 1). They need at least one metastatic lesion visible on scans and a confirmed diagnosis of adenocarcinoma or neuroendocrine prostate cancer.

Inclusion Criteria

I have undergone treatment to lower my testosterone for prostate cancer.

My organs are working well.

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

Clinically relevant proteinuria

Concurrent severe and/or uncontrolled illness not related to cancer and/or social situation that would limit compliance with study requirements

I haven't had radiopharmaceutical treatment in the last 6 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Part A (Imaging)

Participants receive imaging to determine optimal dosing regimen and explore PSMA and STEAP2 expression

4-6 weeks

Multiple visits for imaging and assessments

Part B (Therapeutic)

Participants receive escalating doses of AZD2284 to assess safety, tolerability, and efficacy

8-12 weeks

Regular visits for dose administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• [225Ac]-AZD2284

Trial Overview The study tests the safety and tolerability of three drugs: AZD2284, AZD2287, and AZD2275 in patients with metastatic castration-resistant prostate cancer. It aims to find out what doses are safe and how the body handles these drugs.

Participant Groups

Group I: Part B: Cohort E2 Experimental Treatment 3 Interventions

Participants will receive dose of AZD2284 determined by the earlier results. Expansion cohort may be opened to further characterize the safety and efficacy of the dose level.

Group II: Part B: Cohort E1 Experimental Treatment 3 Interventions

Participants will receive dose of AZD2284 determined by the earlier results. Expansion cohort may be opened to further characterize the safety and efficacy of the dose level.

Group III: Part B (Actinium-225 Dose Escalation): medium dose: AZD2284 Experimental Treatment 3 Interventions

Participants will receive AZD2287 (± AZD2275 as determined in Part A). If eligible for treatment, will receive medium dose of AZD2284.

Group IV: Part B (Actinium-225 Dose Escalation): low dose: AZD2284 Experimental Treatment 3 Interventions

Participants will receive AZD2287 (± AZD2275 as determined in Part A). If eligible for treatment, will receive low dose of AZD2284.

Group V: Part B (Actinium-225 Dose Escalation): high dose 2: AZD2284 Experimental Treatment 3 Interventions

Participants will receive AZD2287 (± AZD2275 as determined in Part A). If eligible for treatment, will receive high dose of AZD2284.

Group VI: Part B (Actinium-225 Dose Escalation): high dose 1: AZD2284 Experimental Treatment 3 Interventions

Participants will receive AZD2287 (± AZD2275 as determined in Part A). If eligible for treatment, will receive high dose of AZD2284.

Group VII: Part A: Cohort A3: AZD2275 + AZD2287 (Cold +Hot) Experimental Treatment 3 Interventions

Participants will receive medium dose of AZD2275 followed by 1 dose of AZD2287. If eligible for treatment, will receive low dose of AZD2284.

Group VIII: Part A: Cohort A2: AZD2275 + AZD2287 (Cold +Hot) Experimental Treatment 3 Interventions

Participants will receive low dose of AZD2275 followed by 1 dose of AZD2287. If eligible for treatment, will receive low dose of AZD2284.

Group IX: Part A: Cohort A1: AZD2287 (Hot only) Experimental Treatment 2 Interventions

Participants will receive 1 dose of AZD2287. If eligible for treatment, will receive low dose of AZD2284.

Group X: Part A Expansion: AZD2287 + AZD2275 (Cold + Hot) Experimental Treatment 2 Interventions

Participants will receive dose of AZD2275 determined earlier in the study followed by 1 dose of AZD2287.

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

Parexel

Industry Sponsor

Trials

322

Recruited

137,000+

Peyton Howell

Parexel

Chief Executive Officer

Master of Healthcare Administration from The Ohio State University, Bachelor of Arts in Health Communications from the University of Illinois

Dr. Austin Smith

Parexel

Chief Medical Officer since 2023

MD from the Royal College of Surgeons in Ireland

Findings from Research

In a phase II trial involving 28 patients with advanced castration-resistant prostate cancer, the oral Src-family kinase inhibitor AZD0530 was found to be well tolerated but showed limited clinical efficacy as a standalone treatment, with only 32% of patients experiencing transient PSA reductions.

The median progression-free survival was only 8 weeks, suggesting that while AZD0530 is safe for use in this patient population, further research is needed to explore its potential in earlier-stage prostate cancer or in combination with other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of the Src-kinase inhibitor AZD0530 in patients with advanced castration-resistant prostate cancer: a California Cancer Consortium study. Lara, PN., Longmate, J., Evans, CP., et al.[2021]

In the ALSYMPCA trial involving 600 patients treated with radium-223, the treatment was found to be well tolerated with a low incidence of myelosuppression and no new safety concerns reported up to 3 years after the first injection.

While 94% of radium-223 patients experienced treatment-emergent adverse events, serious hematologic issues were rare, and long-term follow-up showed no cases of acute myelogenous leukemia or myelodysplastic syndrome, indicating a favorable safety profile for radium-223 in treating symptomatic prostate cancer with bone metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three-year Safety of Radium-223 Dichloride in Patients with Castration-resistant Prostate Cancer and Symptomatic Bone Metastases from Phase 3 Randomized Alpharadin in Symptomatic Prostate Cancer Trial. Parker, CC., Coleman, RE., Sartor, O., et al.[2022]

In a study of 56 patients with metastatic castration-resistant prostate cancer (mCRPC) who had exhausted standard treatments, [225Ac]Ac-PSMA-617 targeted alpha therapy showed promising efficacy, with 91% of patients experiencing a decline in prostate-specific antigen (PSA) levels, and a median overall survival of 15 months.

The treatment was well-tolerated, with most adverse events being mild to moderate, such as transient fatigue in 70% of patients and xerostomia in about one-third, indicating that [225Ac]Ac-PSMA-617 could be a viable option for patients with advanced mCRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival outcomes of salvage [225Ac]Ac-PSMA-617 targeted alpha therapy in patients with PSMA-expressing end-stage metastatic castration-resistant prostate cancer: a real-world study. Ballal, S., Yadav, MP., Satapathy, S., et al.[2023]

Recent advancements in prostate cancer treatment include new drugs like abiraterone acetate and enzalutamide, which effectively target androgen receptor signaling and have shown significant benefits when combined with androgen deprivation therapy (ADT) for advanced stages of the disease.

Ongoing clinical trials are exploring various innovative therapies, including second-generation AR antagonists and targeted treatments based on molecular profiling, which aim to personalize and improve treatment outcomes for prostate cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent Advances in Prostate Cancer Treatment and Drug Discovery. Nevedomskaya, E., Baumgart, SJ., Haendler, B.[2022]

In a study of 150 men with metastatic castration-resistant prostate cancer treated with radium-223, the median overall survival was 14.5 months, highlighting its efficacy in improving survival for patients with bone metastases.

Key pre-treatment factors such as low albumin, high alkaline phosphatase, poor performance status, and high prostate-specific antigen levels were identified as predictors of poor survival, allowing for the development of a prognostic model to better select patients who may benefit from radium-223 treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinicopathologic factors that influence prognosis and survival outcomes in men with metastatic castration-resistant prostate cancer treated with Radium-223. Al-Ezzi, EM., Alqaisi, HA., Iafolla, MAJ., et al.[2022]

In a study involving 26 patients with hormone refractory prostate cancer, the maximum tolerated dose (MTD) of AZD2171 was determined to be 20 mg daily, with dose-limiting toxicities observed at 30 mg, including fatigue and muscle weakness.

Pharmacokinetic analysis showed that AZD2171 maintained effective drug levels in the body, and some patients experienced significant reductions in PSA levels after stopping the drug, indicating potential delayed clinical efficacy despite initial toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I dose escalation and pharmacokinetic study of AZD2171, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinase, in patients with hormone refractory prostate cancer (HRPC). Ryan, CJ., Stadler, WM., Roth, B., et al.[2018]

The combination of olaparib and radium-223 is safe for patients with metastatic castration-resistant prostate cancer (mCRPC), with a recommended phase II dose of olaparib at 200 mg taken twice daily alongside radium-223.

Early results show promising efficacy, with a 6-month radiographic progression-free survival (rPFS) rate of 58%, particularly in patients with specific HRR gene alterations, indicating potential for further investigation in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I Study of Combination Olaparib and Radium-223 in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) with Bone Metastases (COMRADE). Pan, E., Xie, W., Ajmera, A., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

A phase II trial of the Src-kinase inhibitor AZD0530 in patients with advanced castration-resistant prostate cancer: a California Cancer Consortium study. [2021]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Three-year Safety of Radium-223 Dichloride in Patients with Castration-resistant Prostate Cancer and Symptomatic Bone Metastases from Phase 3 Randomized Alpharadin in Symptomatic Prostate Cancer Trial. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

Long-term survival outcomes of salvage [225Ac]Ac-PSMA-617 targeted alpha therapy in patients with PSMA-expressing end-stage metastatic castration-resistant prostate cancer: a real-world study. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Recent Advances in Prostate Cancer Treatment and Drug Discovery. [2022]

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

Clinicopathologic factors that influence prognosis and survival outcomes in men with metastatic castration-resistant prostate cancer treated with Radium-223. [2022]

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

Phase I dose escalation and pharmacokinetic study of AZD2171, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinase, in patients with hormone refractory prostate cancer (HRPC). [2018]

7. Germany pubmed.ncbi.nlm.nih.gov

Ra223 in Bone Metastases with Osteolytic Activity. [2020]

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

A Phase I Study of Combination Olaparib and Radium-223 in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) with Bone Metastases (COMRADE). [2023]

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

ProCAID: a phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone chemotherapy for metastatic castration resistant prostate cancer. [2019]