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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatments for genitourinary cancers, such as those originating in the bladder or kidneys, which become difficult to treat once they spread. The trial tests two drugs, Bintrafusp Alfa (M7824) and PDS01ADC, designed to enhance the immune system's ability to combat cancer. Some participants may also receive Stereotactic Body Radiation Therapy (SBRT), a precise form of radiation targeting cancer cells. Individuals with metastatic cancer that began in genitourinary organs, excluding the prostate, and has spread elsewhere might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive these new therapies.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that bintrafusp alfa (M7824) is generally safe for patients. In previous studies, most participants took the drug without serious problems, and no new safety issues emerged. This drug has shown promise, particularly for certain types of cancer.

For PDS01ADC, specific safety data from other studies is not mentioned. As this is an early phase trial, the primary focus is on ensuring the treatment's safety for participants. The drug is expected to be fairly well-tolerated, but careful monitoring remains crucial.

In summary, bintrafusp alfa appears safe based on past studies. PDS01ADC is still under investigation for safety as it is in the early stages of testing. Participants in the trial will be closely monitored to ensure their safety while receiving these treatments. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for genitourinary cancer, which typically include surgery, chemotherapy, and radiation, the investigational treatment Bintrafusp Alfa (M7824) offers a unique dual-action mechanism. It combines a TGF-β trap with a PD-L1 inhibitor to potentially block cancer growth pathways while simultaneously enhancing the immune system's response to tumors. This innovative approach could lead to more effective cancer control and possibly fewer side effects compared to conventional therapies. Researchers are particularly excited about the potential for Bintrafusp Alfa to work synergistically with NHS-IL12 (M9241), an immunocytokine designed to further boost immune activation directly at the tumor site, potentially leading to improved outcomes for patients.

What evidence suggests that this trial's treatments could be effective for genitourinary cancer?

Research shows that Bintrafusp Alfa (M7824), which participants in this trial may receive, can have positive effects and may cause important changes in the immune system. This suggests it might help the body fight cancer by preventing cancer cells from evading the immune system. NHS-IL12 (M9241), another treatment option in this trial, has also demonstrated positive effects and is usually well-tolerated, often used with other treatments. These findings suggest that these drugs, whether used alone or together, could help the immune system better target genitourinary cancers. Stereotactic Body Radiation Therapy (SBRT) is known for its safety and effectiveness in treating certain cancers, and it might enhance the overall treatment effect when combined with these drugs. This combination aims to boost the body's ability to fight cancer. ^{3 4 6 7 8}

Who Is on the Research Team?

Andrea B Apolo, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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 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]

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]

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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38485188/

Efficacy, safety, and biomarker analyses of bintrafusp alfa, a ... Bintrafusp alfa was observed to have modest clinical activity and manageable safety, and was associated with notable immunologic changes.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02517398

Study Details | NCT02517398 | MSB0011359C (M7824) in ... Additional purposes of the study are to find out whether the study drug has anti-cancer effects and how the study drug is processed by the body. Detailed ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0169500225004374

Efficacy and safety of bintrafusp alfa evaluated in a phase II ... Bintrafusp alfa did not reach the expected efficacy in patients with advanced PM. We did not identify new safety signals with bintrafusp alfa, and no case of ...

4. urotoday.com urotoday.com/conference-highlights/esmo-2023/esmo-2023-bladder-cancer/147510-esmo-2023-a-phase-1b-single-arm-trial-of-bintrafusp-alfa-for-pretreated-locally-advanced-unresectable-or-metastatic-urothelial-cancer.html

ESMO 2023: A Phase 1b Single-Arm Trial of Bintrafusp Alfa ... Patients with advanced urothelial carcinoma have poor prognosis after progression on platinum-based chemotherapy with the need to develop more ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.6020

Long-term follow-up of bintrafusp alfa, a bifunctional fusion ... While the clinical activity of bintrafusp alfa may be improved in patients with HPV-positive tumors (Table), outcomes were generally similar ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33323462/

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β ... Bintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32641320/

Bintrafusp alfa, a bifunctional fusion protein targeting TGF- ... Bintrafusp alfa showed clinical activity across subgroups of PD-L1 expression and in HPV-positive tumors and had a manageable safety profile in patients with ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.5509

Evaluation of bintrafusp alfa, a bifunctional fusion protein ... Bintrafusp alfa had a manageable safety profile and demonstrated clinical activity in pts with heavily pretreated, immune checkpoint inhibitor–naive recurrent/ ...