Bintrafusp Alfa (M7824) and NHS-IL12 (M9241) Alone and in Combination With Stereotactic Body Radiation Therapy (SBRT) in Adults With Metastatic Non-Prostate Genitourinary Malignancies

Bladder Cancer Clinical Trial

Official title: A Phase I Study of Bintrafusp Alfa (M7824) and NHS-IL12 (M9241) Alone and in Combination With Stereotactic Body Radiation Therapy (SBRT) in Adults With Metastatic Non-Prostate Genitourinary Malignancies

Status Recruiting

Clinical Trial Summary

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 M9241 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 M9241, 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 M9241. 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.

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Clinical Trial Description

Background:

• Urothelial carcinoma, renal cell carcinoma and other non-prostate genitourinary cancers are lethal in the metastatic state.

• Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have greatly changed clinical management of metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma (mRCC).

• Several PD-1/PD-L1 inhibitors are FDA-approved for non-prostate genitourinary cancers including five agents for second-line mUC, two agents for first-line cisplatin-ineligible mUC and one approval for second-line mRCC. However, response rates are modest (approximately 25% in mRCC and 15-21% in mUC).

• Therefore, novel combination strategies are needed to extend benefit of immunotherapy to the remaining approximate 75% of non-responders.

• Bintrafusp alfa (M7824) is a novel first-in-class bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II (TGF beta RII), which effectively functions to sequester or trap all three TGF- beta isoforms. A phase I study of M7824 (NCT02517398) demonstrated a manageable safety profile and clinical efficacy among patients with heavily pre-treated advanced solid tumors.

• NHS-IL12 (M9241) is an immunocytokine composed of two IL-12 heterodimers, each fused to the H-chain of the NHS76 antibody. The NHS76 IgG1 antibody has affinity for both single- and double-stranded DNA (dsDNA) allowing for targeted delivery of pro-inflammatory cytokine, IL-12, to necrotic portions of tumor at sites of DNA exposure to promote local immunomodulation. M9241has demonstrated promising pre-clinical activity (including durable responses) as well as an encouraging safety and anti-tumor activity in an ongoing phase Ib clinical trial in combination with an anti-PD-L1 agent (NCT02994953).

• Currently, no clinical data exists for the combination of M7824 plus M9241. Preclinical data suggest synergy between these agents and the available clinical data suggest that the combination of M7824 plus M9421 is likely to be well-tolerated.

• There is a growing body of evidence suggesting that stereotactic body radiation therapy (SBRT), which delivers highly conformal high-dose radiation, can promote anti-tumor immune responses both locally and systemically as well as synergize with immune checkpoint inhibitors and other forms of immunotherapy.

• SBRT-induced dsDNA breaks are tumoricidal and may promote immunogenicity. SBRT also upregulates PD-L1 expression and leads to activation of TGF-beta. SBRT may enhance intratumoral binding of DNA-damage localizing agent, M9241. Preclinical models have demonstrated impressive synergy with radiation plus M7824 and radiation plus M9241.

• We hypothesize that an immune-intensification approach involving M7824 plus M9241 combined with SBRT will enhance therapeutic efficacy and clinical benefit in patients with metastatic non-prostate genitourinary cancers with an acceptable safety profile.

• The combination of M7824 with M9241 with or without administration of SBRT (sequential or concurrent) will aid evaluation of safety signals contributed by each agent and will provide insight into a currently unanswered question regarding the optimal timing and sequencing of SBRT and immunotherapy.

Objectives:

-Determine the safety and tolerated doses of M9241 and M7824 alone or in combination with SBRT (Stereotactic Body Radiation Therapy) administered sequentially or concurrently in participants with metastatic non-prostate genitourinary cancers

Eligibility:

• Participants must have a histologically confirmed diagnosis of metastatic non-prostate genitourinary cancer.

• Participants must have metastatic disease defined as new or progressive lesions on cross-sectional imaging.

• Participants must have at least:

• One site of disease that is amenable to irradiation (a maximum of four sites may be irradiated) (in arm 2 and 3 only)

• One measurable site of disease (according to RECIST criteria) that will not be irradiated.

• Men and women 18 years of age or older

Design:

-This is an open label, non-randomized, three-stage phase I trial of M7824 and M9241 or

M7824 and M9241 in combination with either sequential or concurrent SBRT.

-M7824 (intravenous 1200 mg) and SBRT (8 Gy x 3 fractions) are planned with de-escalating

dose schedule for M9241. Dose de-escalation of M9241 will be done if toxicities

start at dose 16.8 mcg/kg.

• The accrual ceiling has been set at 66 participant.

• Participants will receive treatment in cycles consisting of 4 weeks. ;

Related Conditions & MeSH terms

• Bladder Cancer
• Genitourinary Cancer
• Urogenital Cancer
• Urogenital Neoplasms
• Urothelial Cancer

• NCT number: NCT04235777
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Lisa Ley, R.N.
• Phone: (240) 858-3524
• Email: lisa.ley@nih.gov
• Status: Recruiting
• Phase: Phase 1
• Start date: July 13, 2020
• Completion date: December 1, 2024