Pocenbrodib for Prostate Cancer

(P300 Trial)

Recruiting at 5 trial locations

Overseen By Michael Maitland, MD

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: Pathos AI, Inc.

Must not be taking: Chemotherapy, Enzalutamide, Apalutamide, others

Disqualifiers: Small cell histology, Liver metastases, others

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

Compensation: Varies

Number of Visits: Unknown

252 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a dose-finding study to assess the safety and preliminary antitumor activity of Pocenbrodib alone or with Abiraterone acetate, Olaparib or 177Lu-PSMA-617 in patients with metastatic castration-resistant prostrate cancer (mCRPC).

Will I have to stop taking my current medications?

The trial requires that you stop taking any chemotherapy, investigational agents, or other anticancer drugs, including enzalutamide, apalutamide, or darolutamide, at least 14 days before screening.

What safety data exists for Pocenbrodib and related treatments for prostate cancer?

The research articles provided do not contain specific safety data for Pocenbrodib or its related treatments like 177Lu-PSMA-617, Abiraterone Acetate, or Olaparib. However, Abiraterone has been associated with an increased risk of cardiovascular events in patients with prostate cancer. ^{1 2 3 4 5}

How does the drug Pocenbrodib differ from other prostate cancer treatments?

Pocenbrodib may offer a unique approach by targeting the DNA damage response pathway, potentially overcoming resistance to standard androgen deprivation therapies in prostate cancer. This could make it effective in cases where traditional treatments fail due to resistance mechanisms. ^{2 6 7 8 9}

Eligibility Criteria

This trial is for patients with metastatic castration-resistant prostate cancer. Specific eligibility criteria are not provided, but typically include factors like age, health status, and progression of disease.

Inclusion Criteria

My prostate cancer is confirmed by tissue analysis.

My cancer has spread, confirmed by recent scans.

Exclusion Criteria

I have liver metastases confirmed by tests.

I haven't taken any cancer drugs, including enzalutamide, apalutamide, or darolutamide, in the last 14 days.

My latest prostate biopsy showed signs of small cell or neuroendocrine cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1b Treatment

Pocenbrodib monotherapy at multiple, sequential five rising doses (50, 100, 150, 200, and 250mg) using a QD dosing schedule of 5 days on/2 days off

28 days per dose level

Phase 2a Treatment

Participants receive Pocenbrodib monotherapy or in combination with Abiraterone acetate, Olaparib, or 177Lu-PSMA-617

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• 177Lu-PSMA-617
• Abiraterone Acetate
• Olaparib
• Pocenbrodib

Trial Overview The study is testing the safety and initial effectiveness of Pocenbrodib alone or combined with Abiraterone acetate, Olaparib, or 177Lu-PSMA-617 in treating advanced prostate cancer.

Participant Groups

Group I: Phase 2 portion Experimental Treatment 2 Interventions

Phase 2 involves Pocenbrodib monotherapy and in combination with abiraterone acetate, olaprib or 177Lu-PSMA0617

Group II: Phase 1 Portion Experimental Treatment 1 Intervention

Dose level 1: 50 mg QD (5 days on/2 days off) Dose level 2: 100 mg QD (5 days on/2 days off) Dose level 3: 150 mg QD (5 days on/2 days off) Dose level 4: 200 mg QD (5 days on/2 days off) Dose level 5: 250 mg QD (5 days on/2 days off)

Who Is Running the Clinical Trial?

Pathos AI, Inc.

Lead Sponsor

Trials

1

Recruited

250+

Duke University

Collaborator

Trials

2,495

Recruited

5,912,000+

Findings from Research

A 76-year-old man developed severe thrombocytopenia after 13 days of enzalutamide treatment for castration-resistant prostate cancer, indicating that this side effect can occur early in therapy.

After discontinuing enzalutamide, the patient's platelet count recovered, and he was able to restart the medication without recurrence of thrombocytopenia; however, he later experienced a seizure, suggesting that enzalutamide may also be associated with neurological adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzalutamide-induced severe thrombocytopenia complicated by a seizure in a 76-year-old man with castration-resistant prostate cancer. Murata, M., Takizawa, I., Maruyama, R., et al.[2022]

The study developed a computational algorithm called 'secDrugs' to identify potential new treatments for lethal metastatic prostate cancer, focusing on the NAMPT pathway, which is overexpressed in drug-resistant cancer cells.

The drug FK866, which targets NAMPT, showed significant efficacy in reducing cancer cell invasion and motility, and it also improved treatment outcomes when combined with standard therapies like taxanes and AR-inhibitors, suggesting it could be a promising option for overcoming drug resistance in advanced prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Integrating Pharmacogenomics Data-Driven Computational Drug Prediction with Single-Cell RNAseq to Demonstrate the Efficacy of a NAMPT Inhibitor against Aggressive, Taxane-Resistant, and Stem-like Cells in Lethal Prostate Cancer. Mazumder, S., Mitra Ghosh, T., Mukherjee, UK., et al.[2022]

Cediranib showed some anti-tumor activity in patients with metastatic castration-resistant prostate cancer (CRPC) who had previously undergone docetaxel treatment, with 43.9% of patients remaining progression-free at 6 months and a median progression-free survival of 3.7 months.

The treatment was generally well tolerated, with common side effects including hypertension and fatigue; however, adding prednisone helped reduce some of these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II clinical trial of cediranib in patients with metastatic castration-resistant prostate cancer. Dahut, WL., Madan, RA., Karakunnel, JJ., et al.[2023]

In a review of seven randomized controlled trials involving 7103 patients with castration-resistant prostate cancer, abiraterone was found to significantly increase the risk of both any grade (RR = 1.34) and severe grade (RR = 1.71) cardiac disorders.

Enzalutamide was associated with a much higher risk of developing any grade (RR = 2.66) and severe grade (RR = 2.79) hypertension, indicating that while both drugs have cardiovascular risks, they affect different aspects of heart health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abiraterone and enzalutamide had different adverse effects on the cardiovascular system: a systematic review with pairwise and network meta-analyses. Lee, HY., Chen, HL., Teoh, JY., et al.[2022]

In the IPATential150 trial involving 1097 patients with metastatic castration-resistant prostate cancer, adding ipatasertib to abiraterone and prednisone significantly improved radiographic progression-free survival for patients with PTEN-loss tumors.

While ipatasertib was associated with a higher rate of serious adverse events and treatment discontinuation compared to placebo, its overall safety profile was considered tolerable, suggesting that with proper management, the side effects could be mitigated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Profile of Ipatasertib Plus Abiraterone vs Placebo Plus Abiraterone in Metastatic Castration-resistant Prostate Cancer. Matsubara, N., de Bono, J., Sweeney, C., et al.[2023]

MYB is activated in prostate cancer cells when treated with androgen deprivation therapy, and silencing MYB can inhibit cancer growth in both cell cultures and mouse models, suggesting it plays a key role in tumor progression.

Targeting the DNA damage response pathway, particularly through the inhibition of MYB and other related proteins, enhances the effectiveness of PARP inhibitors like olaparib, offering a potential new treatment strategy for advanced prostate cancer that has become resistant to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting poly(ADP-ribose) polymerase and the c-Myb-regulated DNA damage response pathway in castration-resistant prostate cancer. Li, L., Chang, W., Yang, G., et al.[2021]

In prostate cancer, combining the SRC kinase inhibitor saracatinib with the hormonal therapy enzalutamide shows strong synergy in cell lines that express both full-length androgen receptors (AR-FL) and androgen receptor variants (AR-Vs), potentially improving treatment outcomes for patients with castration-resistant prostate cancer (CRPC).

The combination of saracatinib and enzalutamide not only reduces DNA replication but also significantly increases apoptosis in cancer cells, suggesting a more effective therapeutic strategy compared to using saracatinib with chemotherapy (docetaxel).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Saracatinib synergizes with enzalutamide to downregulate androgen receptor activity in castration resistant prostate cancer. White, RE., Bannister, M., Day, A., et al.[2023]

In prostate cancer, combining the SRC kinase inhibitor saracatinib with the hormonal therapy enzalutamide shows strong synergy in cell lines that express both full-length androgen receptors (AR-FL) and androgen receptor variants (AR-Vs), potentially improving treatment outcomes for patients with castration-resistant prostate cancer (CRPC).

The combination of saracatinib and enzalutamide not only decreases phosphorylation of key residues on androgen receptors but also leads to reduced DNA replication and increased apoptosis in cancer cells, suggesting a promising new strategy for enhancing the efficacy of existing therapies in CRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Saracatinib synergizes with enzalutamide to downregulate AR activity in CRPC. White, RE., Bannister, M., Day, A., et al.[2023]

PARP inhibitors (PARPi) combined with androgen receptor signaling inhibitors (ARSI) show significant benefits in treating metastatic castration-resistant prostate cancer (mCRPC), as demonstrated in the TALAPRO-2 and PROpel trials, which included both HRR-mutated and HRR-non-mutated patients.

The combination therapy works at a molecular level by inducing a state similar to homologous recombination repair deficiency, leading to synthetic lethality where DNA damage accumulates and cannot be repaired, ultimately causing cancer cell death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double trouble for prostate cancer: synergistic action of AR blockade and PARPi in non-HRR mutated patients. Giesen, A., Baekelandt, L., Devlies, W., et al.[2023]

References

1. Australia pubmed.ncbi.nlm.nih.gov

Enzalutamide-induced severe thrombocytopenia complicated by a seizure in a 76-year-old man with castration-resistant prostate cancer. [2022]

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

Integrating Pharmacogenomics Data-Driven Computational Drug Prediction with Single-Cell RNAseq to Demonstrate the Efficacy of a NAMPT Inhibitor against Aggressive, Taxane-Resistant, and Stem-like Cells in Lethal Prostate Cancer. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Phase II clinical trial of cediranib in patients with metastatic castration-resistant prostate cancer. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Abiraterone and enzalutamide had different adverse effects on the cardiovascular system: a systematic review with pairwise and network meta-analyses. [2022]

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

Safety Profile of Ipatasertib Plus Abiraterone vs Placebo Plus Abiraterone in Metastatic Castration-resistant Prostate Cancer. [2023]

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

Targeting poly(ADP-ribose) polymerase and the c-Myb-regulated DNA damage response pathway in castration-resistant prostate cancer. [2021]

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

Saracatinib synergizes with enzalutamide to downregulate androgen receptor activity in castration resistant prostate cancer. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Saracatinib synergizes with enzalutamide to downregulate AR activity in CRPC. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Double trouble for prostate cancer: synergistic action of AR blockade and PARPi in non-HRR mutated patients. [2023]