Trimodality Therapy for Prostate Cancer

(TALON Trial)

Overseen By Daniel George, MD

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: Duke University

Must not be taking: PD-1 inhibitors, PD-L1 inhibitors

Disqualifiers: Metastasis, Prior pelvic radiation, Autoimmune, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 7 weeks for Arm A, 3 weeks for Arm B

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will enroll prostate cancer patients with an unfavorable intermediate- or high-risk diagnosis. The purpose of this study is to determine whether a regimen of pembrolizumab and low dose prostate radiation or low dose prostate radiation alone prior to a prostatectomy affects cells of the immune system and if it is a safe option for this stage of prostate cancer. Participants will be randomized 1:1 (like flipping a coin) to receive pembrolizumab, low dose prostate radiation and a prostatectomy or low dose prostate radiation and a prostatectomy. Pembrolizumab is an investigational drug that increases the ability of the immune system to kill tumor cells. Low dose radiation can alter the way tumor cells look to the immune cells. For example, the immune cells may express different proteins that make them more susceptible to immune cell killing or the structure of the tumor may be altered to allow the immune cells to infiltrate the tumor more thoroughly. The prostate tissue collected from the prostatectomy will be analyzed for differences in pathology and local immune cell infiltration, and participants will be followed for 2 years to watch for prostate specific antigen (PSA) recurrence and prostate cancer recurrence.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are on certain cancer treatments or investigational drugs. It's best to discuss your specific medications with the trial team.

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

Pembrolizumab has shown some antitumor activity in patients with PD-L1-positive metastatic castration-resistant prostate cancer, but overall, late-stage trials have not been successful, indicating that new strategies are needed to improve its effectiveness in prostate cancer. ^{1 2 3 4 5}

Is the trimodality therapy for prostate cancer, including pembrolizumab, generally safe for humans?

Pembrolizumab, a part of the trimodality therapy, has been associated with some immune-related side effects like type 1 diabetes and pneumonitis (lung inflammation), which are rare but can be serious. Common side effects include fatigue, cough, nausea, and rash, but the benefits in treating certain cancers have been found to outweigh these risks. ^{3 6 7 8 9}

How is the Trimodality Therapy for Prostate Cancer different from other treatments?

Trimodality Therapy for Prostate Cancer is unique because it combines pembrolizumab, a drug that helps the immune system fight cancer, with short-term hormone therapy and precise radiation therapy. This combination aims to enhance the effectiveness of pembrolizumab, which has shown limited success alone in prostate cancer, by using additional treatments to potentially overcome the immune-suppressive environment of prostate tumors. ^{1 2 7 10 11}

Research Team

Daniel George, MD

Principal Investigator

Duke University

Eligibility Criteria

Men aged 18+ with intermediate/high-risk prostate cancer who can sign consent, have adequate organ function, and meet specific risk criteria (e.g., Gleason score, PSA levels) as per NCCN guidelines. Excluded are those with metastasis, prior pelvic treatments like radiation or cryotherapy, recent investigational drug use, active autoimmune diseases requiring systemic treatment within the past 2 years, chronic steroid/immunosuppressive drug use (with some exceptions), uncontrolled illnesses that could affect study compliance or safety.

Inclusion Criteria

I am fully active and can carry on all pre-disease activities without restriction.

I am willing and able to follow the study's treatment plan and attend all visits.

My organs and bone marrow are functioning well.

Exclusion Criteria

I have had or currently have lung inflammation treated with steroids.

My cancer has spread to my bones, brain, organs, or soft tissues.

I have had radiation, cryotherapy, or HIFU treatments in the pelvic area.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab and low dose prostate radiation or low dose prostate radiation alone prior to prostatectomy

7 weeks for Arm A, 3 weeks for Arm B

Prostatectomy

Participants undergo prostatectomy as part of the treatment regimen

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment, including PSA recurrence and prostate cancer recurrence

2 years

Treatment Details

Interventions

• Pembrolizumab
• Radical Prostatectomy
• Short-term androgen deprivation therapy
• Stereotactic body radiation therapy

Trial Overview The TALON trial is testing a 'trimodal therapy' for prostate cancer involving pembrolizumab (an immunotherapy drug), SBRT to the prostate gland, and short-term ADT followed by radical surgery to remove the prostate. The goal is to see if this combination delays the rise of PSA compared to historical data over a follow-up period of two years.

Participant Groups

Group I: Arm B: Low dose prostate radiation and prostatectomy Experimental Treatment 2 Interventions

Participants in Arm B will receive: * Low dose prostate radiation of one dose of 2 Gy to the prostate and seminal vesicles * Prostatectomy as part of the routine care for their cancer

Group II: Arm A: pembrolizumab, low dose prostate radiation and prostatectomy Experimental Treatment 3 Interventions

Participants in Arm A will receive: * Pembrolizumab 400 mg intravenously every 6 weeks for 9 cycles. * Low dose prostate radiation of one dose of 2 Gy to the prostate and seminal vesicles * Prostatectomy as part of the routine care for their cancer

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Duke University

Lead Sponsor

Trials

2,495

Recruited

5,912,000+

Bridget Koontz

Lead Sponsor

Trials

1

Recruited

30+

Daniel George, MD

Lead Sponsor

Trials

8

Recruited

250+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

In the phase II KEYNOTE-199 study involving 258 patients with metastatic castration-resistant prostate cancer (mCRPC), pembrolizumab demonstrated modest antitumor activity, with objective response rates of 5% in PD-L1-positive patients and 3% in PD-L1-negative patients, indicating some effectiveness in this challenging population.

The treatment was generally well-tolerated, with 60% of patients experiencing treatment-related adverse events, but only 5% discontinuing due to these events, suggesting that pembrolizumab has an acceptable safety profile while providing encouraging overall survival estimates, particularly in patients with bone-predominant disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. Antonarakis, ES., Piulats, JM., Gross-Goupil, M., et al.[2021]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

Pembrolizumab (Keytruda) is an approved treatment for metastatic or locally advanced esophageal and gastroesophageal junction cancer, indicating its efficacy in targeting these specific cancer types.

It is used in combination with platinum- and fluoropyrimidine-based chemotherapy, suggesting a synergistic approach to enhance treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. Aschenbrenner, DS.[2023]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

A 58-year-old patient with metastatic castration-resistant prostate cancer and microsatellite instability-high showed significant clinical improvement after treatment with pembrolizumab, including decreased prostate-specific antigen levels and reduced lymph node size.

This case suggests that pembrolizumab could be an effective treatment option for patients with microsatellite instability-high in castration-resistant prostate cancer, despite its rarity, marking a potential new avenue for therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for a patient with metastatic castration-resistant prostate cancer with microsatellite instability-high. Fujiwara, M., Komai, Y., Yuasa, T., et al.[2022]

In a phase II trial involving men with metastatic castration-resistant prostate cancer (mCRPC) who were progressing on enzalutamide, the anti-PD-1 antibody pembrolizumab showed unexpected antitumor activity, with three out of ten patients achieving significant reductions in prostate-specific antigen (PSA) levels.

The presence of immune cell infiltrates and PD-L1 expression in tumor biopsies from responders suggests that certain biological markers may predict the effectiveness of PD-1 inhibitors in prostate cancer, warranting further investigation into this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Graff, JN., Alumkal, JJ., Drake, CG., et al.[2022]

References

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

Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. [2021]

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

PD-1 Blockade Falls Short (Repeatedly) in Prostate Cancer. [2023]

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

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

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

Pembrolizumab Approved for Esophageal or Gastroesophageal Cancer. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

7. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

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

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. [2022]

10. Australia pubmed.ncbi.nlm.nih.gov

Pembrolizumab for a patient with metastatic castration-resistant prostate cancer with microsatellite instability-high. [2022]

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

Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. [2022]