M7824, M9241, and SBRT for Genitourinary Cancer

Overseen By Andrea B Apolo, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Systemic corticosteroids, Immunosuppressive medications

Disqualifiers: Autoimmune disease, Uncontrolled illness, Pregnancy, others

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

Compensation: Varies

Number of Visits: 7826

Duration: Until progression or unacceptable toxicity

100 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Genitourinary cancers are some of the most common types of cancer. They are lethal when they spread. The drug M7824 blocks the paths that cancer cells use to stop the immune system from fighting cancer. The drug PDS01ADC triggers the immune system to fight cancer. Researchers want to learn if these drugs can help fight these cancers when given with and without Stereotactic Body Radiation Therapy (SBRT) radiation. Objective: To learn if M7824 and PDS01ADC, with or without SBRT, can help the immune system to fight cancer better. Eligibility: People 18 and older with cancer that started in the bladder, kidneys, or other genitourinary organs (but not the prostate) and has spread to other parts of the body. Design: Participants will be screened with: medical history physical exam ability to do their normal activities blood tests urine tests electrocardiogram body scans. Participants will give a tumor sample or have a tumor biopsy. Screening tests will be repeated during the study. Participants will get PDS01ADC . It is injected under the skin every 4 weeks. They will also get M7824 through an intravenous (IV) infusion every 2 weeks. For this, a small plastic tube is put into a vein in the arm. They will get these drugs in 28-day cycles until they leave the study. They may have SBRT. Participants will give tissue and saliva samples. Participants will have a follow-up visit 30 days after treatment ends. Then they will get phone calls or emails every 12 weeks indefinitely.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on certain treatments like systemic corticosteroids or immunosuppressive medications, you may need to adjust them. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Bintrafusp Alfa (M7824) for genitourinary cancer?

Research shows that drugs targeting PD-1/PD-L1, like Bintrafusp Alfa, have shown promise in treating urothelial bladder cancer, offering new hope for patients. These types of drugs are becoming a standard treatment option due to their effectiveness in improving survival rates in certain cancers. ^{1 2 3 4 5}

Is the treatment with Bintrafusp Alfa, M9241, and SBRT generally safe for humans?

Bintrafusp Alfa has been studied in various cancer types and has shown a manageable safety profile, meaning that while there may be some side effects, they are generally considered acceptable and can be managed. The recommended doses have been determined to maintain effectiveness while minimizing adverse effects. ^{6 7 8 9 10}

What makes the drug Bintrafusp Alfa unique for treating genitourinary cancer?

Bintrafusp Alfa is unique because it is a first-in-class bifunctional fusion protein that targets both TGF-β (a protein that can help cancer cells grow) and PD-L1 (a protein that helps cancer cells hide from the immune system), potentially offering a new way to treat cancers that are resistant to other therapies. ^{7 8 9 10 11}

Research Team

Andrea B Apolo, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults over 18 with genitourinary cancers (excluding prostate cancer) that have spread, who can provide a tumor sample and are not pregnant or breastfeeding. Participants must be able to perform daily activities, have adequate organ function, agree to use contraception, and may have had prior treatments but not with M7824/M9241.

Inclusion Criteria

You have a condition that can be measured or evaluated by the doctors.

I have had radiation therapy before, but not on the same area twice.

I have advanced kidney cancer and cannot take standard treatments.

Exclusion Criteria

I am unwilling to receive blood products even if needed for my treatment.

I have an autoimmune disease or have been treated with high-dose steroids or immunosuppressants.

I have a tumor in my liver or chest that is larger than 10 cm.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive PDS01ADC injections every 4 weeks and M7824 infusions every 2 weeks in 28-day cycles, with optional SBRT

Until progression or unacceptable toxicity

Bi-weekly visits for M7824 infusion

Follow-up

Participants have a follow-up visit 30 days after treatment ends, followed by phone calls or emails every 12 weeks indefinitely

Indefinite

1 in-person visit, then remote follow-ups

Treatment Details

Interventions

• Bintrafusp Alfa (M7824)
• NHS-IL12 (M9241)
• Stereotactic Body Radiation Therapy (SBRT)

Trial Overview The trial is testing the effectiveness of two drugs, M7824 and M9241 alone or combined with SBRT radiation therapy in treating metastatic non-prostate genitourinary cancers. The goal is to see if these treatments improve the immune system's ability to fight cancer.

Participant Groups

Group I: Arm 3 Experimental Treatment 3 Interventions

Treatment with M7824 and de-escalating doses of PDS01ADC (if appropriate) with concurrent SBRT

Group II: Arm 2 Experimental Treatment 3 Interventions

Treatment with M7824 and de-escalating doses of PDS01ADC (if appropriate) with sequential SBRT

Group III: Arm 1 Experimental Treatment 2 Interventions

Treatment with M7824 and de-escalating doses of PDS01ADC if appropriate

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Nivolumab has become the new standard treatment for locally advanced or metastatic renal cell cancer after patients have not responded to tyrosine kinase inhibitors, highlighting its efficacy in this setting.

Sipuleucel-T has been shown to prolong survival in patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer, although it does not improve progression-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immunotherapy in the treatment of genitourinary cancers]. Géczi, L., Ladányi, A., Vajdics, T., et al.[2018]

In a large registry study involving 1976 patients with metastatic castration-resistant prostate cancer, sipuleucel-T immunotherapy demonstrated a median overall survival of 30.7 months, indicating its potential effectiveness in prolonging life for this patient group.

The treatment was associated with a low incidence of serious adverse events (3.9%) and cerebrovascular events (2.8%), suggesting that sipuleucel-T is a relatively safe option for patients with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world outcomes of sipuleucel-T treatment in PROCEED, a prospective registry of men with metastatic castration-resistant prostate cancer. Higano, CS., Armstrong, AJ., Sartor, AO., et al.[2021]

Sipuleucel-T is an innovative immunotherapy that uses a patient's own dendritic cells to target prostate cancer, showing promising results in reducing prostate-specific antigen levels and extending the time before these levels double in men with biochemically relapsed prostate cancer.

In Phase III trials, sipuleucel-T significantly improved median overall survival in men with asymptomatic, metastatic hormone-refractory prostate cancer compared to placebo, indicating its potential as an effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sipuleucel-T (APC8015) for prostate cancer. So-Rosillo, R., Small, EJ.[2022]

Pembrolizumab, a PD-1 antibody, has shown a significant survival benefit in second-line treatment for metastatic urothelial cancer compared to standard chemotherapy, indicating its potential as a new standard of care.

Ongoing trials are exploring PD-1/PD-L1 antibodies not only as second-line treatments but also as first-line therapies and in perioperative settings, with results expected by the end of 2017 and recruitment for phase III trials completing in 2018.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The role of immunooncology in the treatment of urothelial cancer]. Retz, M., Tauber, R., Horn, T.[2019]

In a phase 2 study involving 91 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin and had previously received PD-1 or PD-L1 therapy, enfortumab vedotin demonstrated a confirmed objective response rate of 52%, indicating significant efficacy in this difficult-to-treat population.

While enfortumab vedotin was generally tolerable, 55% of patients experienced grade 3 or worse treatment-related adverse events, highlighting the need for careful monitoring, especially since some serious adverse events, including treatment-related deaths, were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV‑201): a multicentre, single-arm, phase 2 trial. Yu, EY., Petrylak, DP., O'Donnell, PH., et al.[2023]

Bintrafusp alfa, a novel treatment for advanced solid tumors, demonstrated a manageable safety profile and clinical activity in phase I studies involving heavily pretreated patients.

The recommended phase 2 dose of bintrafusp alfa is 1,200 mg every 2 weeks or 2,400 mg every 3 weeks, which effectively maintains drug levels that inhibit its targets in over 95% of patients, with exposure showing a weak correlation to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selection of the Recommended Phase 2 Dose for Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1. Vugmeyster, Y., Wilkins, J., Koenig, A., et al.[2021]

In a study of 80 patients with advanced non-small cell lung cancer (NSCLC) who had previously undergone platinum-based therapy, bintrafusp alfa demonstrated an overall response rate (ORR) of 21.3%, with higher efficacy observed in patients with PD-L1-positive tumors (36.0% ORR) and those with high PD-L1 expression (85.7% ORR).

The treatment was generally well-tolerated, with 69% of patients experiencing treatment-related adverse events, but only 10% discontinuing treatment due to these events, indicating that bintrafusp alfa has a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Second-Line Treatment of Patients With NSCLC: Results From an Expansion Cohort of a Phase 1 Trial. Paz-Ares, L., Kim, TM., Vicente, D., et al.[2023]

In a phase 3 trial involving 304 patients with PD-L1-high advanced NSCLC, bintrafusp alfa did not show superior efficacy compared to pembrolizumab, with similar progression-free survival and overall survival rates.

Bintrafusp alfa was associated with a higher rate of treatment-related adverse events, with 42.4% of patients experiencing grade 3-4 side effects compared to only 13.2% for pembrolizumab, leading to the study's discontinuation at an interim analysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bintrafusp Alfa Versus Pembrolizumab in Patients With Treatment-Naive, Programmed Death-Ligand 1-High Advanced NSCLC: A Randomized, Open-Label, Phase 3 Trial. Cho, BC., Lee, JS., Wu, YL., et al.[2023]

In a study involving 83 patients with advanced non-small cell lung cancer (NSCLC) who had previously undergone anti-PD-(L)1 therapy, bintrafusp alfa demonstrated a modest objective response rate of 4.8%, indicating some clinical activity despite not meeting the primary endpoint.

The treatment was generally well-tolerated, with 22.9% of patients experiencing grade ≥3 treatment-related adverse events, suggesting a manageable safety profile for this heavily pretreated patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Patients With Non-Small Cell Lung Cancer Resistant or Refractory to Immune Checkpoint Inhibitors. Barlesi, F., Isambert, N., Felip, E., et al.[2023]

Bintrafusp alfa, a novel treatment for solid tumors, has shown promising antitumor activity and manageable safety in a study involving 644 patients, supporting its potential as an effective therapy.

The pharmacokinetic analysis suggests that a flat dosing regimen (1200 mg every 2 weeks) is preferable, as it results in less variability in drug exposure compared to weight-based dosing, with no significant dosage adjustments needed based on patient characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetic Analysis of Bintrafusp Alfa in Different Cancer Types. Wilkins, JJ., Vugmeyster, Y., Dussault, I., et al.[2020]

In a phase I trial involving 31 heavily pretreated Asian patients with advanced gastric/gastroesophageal junction cancer, bintrafusp alfa showed a manageable safety profile, with 19% experiencing grade 3 treatment-related adverse events and no grade 4 events reported.

The treatment demonstrated clinical activity, with a confirmed objective response rate of 16% and a disease control rate of 26%, suggesting potential effectiveness regardless of PD-L1 expression or microsatellite instability status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Tolerability of Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGFβ and PD-L1, in Asian Patients with Pretreated Recurrent or Refractory Gastric Cancer. Kang, YK., Bang, YJ., Kondo, S., et al.[2021]

References

1. Hungary pubmed.ncbi.nlm.nih.gov

[Immunotherapy in the treatment of genitourinary cancers]. [2018]

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

Real-world outcomes of sipuleucel-T treatment in PROCEED, a prospective registry of men with metastatic castration-resistant prostate cancer. [2021]

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

Sipuleucel-T (APC8015) for prostate cancer. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

[The role of immunooncology in the treatment of urothelial cancer]. [2019]

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

Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV‑201): a multicentre, single-arm, phase 2 trial. [2023]

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

Selection of the Recommended Phase 2 Dose for Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1. [2021]

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

Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Second-Line Treatment of Patients With NSCLC: Results From an Expansion Cohort of a Phase 1 Trial. [2023]

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

Bintrafusp Alfa Versus Pembrolizumab in Patients With Treatment-Naive, Programmed Death-Ligand 1-High Advanced NSCLC: A Randomized, Open-Label, Phase 3 Trial. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Patients With Non-Small Cell Lung Cancer Resistant or Refractory to Immune Checkpoint Inhibitors. [2023]

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

Population Pharmacokinetic Analysis of Bintrafusp Alfa in Different Cancer Types. [2020]

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

Safety and Tolerability of Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGFβ and PD-L1, in Asian Patients with Pretreated Recurrent or Refractory Gastric Cancer. [2021]