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

  • End date
    Apr 1, 2022
  • participants needed
  • sponsor
    National Cancer Institute (NCI)
Updated on 12 September 2021
urine tests
measurable disease
neutrophil count
urine test
cytotoxic agents
bintrafusp alfa
metastatic cancer



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.


To learn if M7824 and M9241, with or without SBRT, can help the immune system to fight cancer better.


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.


Participants will be screened with:

medical history

physical exam

ability to do their normal activities

blood tests

urine tests


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.


  • 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 singleand 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.

-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

  • 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.
  • 18 years of age or older

-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.

Condition urinary tract neoplasm, bladder cancer, bladder disorder, Genitourinary Neoplasms, Urothelial Cancer, Bladder Disorders, Genitourinary Cancer, Bladder Carcinoma, Urologic Cancer, carcinoma of the bladder, bladder tumor
Treatment Stereotactic Body Radiation Therapy (SBRT), M7824, M9241
Clinical Study IdentifierNCT04235777
SponsorNational Cancer Institute (NCI)
Last Modified on12 September 2021


Yes No Not Sure

Inclusion Criteria

Participants must have histologically or cytologically confirmed diagnosis of a metastatic non-prostate genitourinary tumor
Participants must have metastatic disease defined as new or progressive lesions on cross-sectional imaging. Radiological evaluation should occur within 21 days prior to enrollment
Participants must have evaluable or measurable disease
Participants in Arms 2 and 3 must have at least one site of disease that is amenable to irradiation (irradiation of up to 4 different sites is permitted)
Participants must have at least one measurable site of disease that will not be irradiated
Participants may have been previously treated with cytotoxic chemotherapy regimen or targeted agent. Partaicipants may have received any number of prior cytotoxic agents
Participants may have been previously treated with radiation therapy. However, re-irradiation of a previously irradiated site is not permitted unless explicitly discussed with protocol PI and treating radiation oncologist
Participants may have had prior immunomodulating therapy including therapy with a checkpoint inhibitor but excluding prior treatment with M7824 and/or M9241
Pre-treatment tissue availability (collected less than or equal to 1 year) for PD-L1 expression testing is mandatory for enrollment. If tissue is determined to be of insufficient/unsuitable quality/quantity, a pre-treatment biopsy prior to initiation of study therapy will be required
Male and female participants who are at least 18 years of age on the day of signing the informed consent will be enrolled in the study
ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to 60%)
Patients must have adequate organ and marrow function as defined below
leukocytes greater than or equal to 2500mcL
absolute neutrophil count greater than or equal to 1500/mcL
platelets greater than or equal to 100,000/mcL
AST(SGOT)/ALT(SGPT) less than or equal to 1.5 X institutional upper limit of normal
Hgb greater than or equal to 9g/dL (pRBC transfusions are allowed to achieve acceptable Hgb)
Participants may have mild to moderate hepatic impairment with total bilirubin less than or equal to 3.0 (SqrRoot) ULN
For Participants with liver involvement in their tumor, we allow the following: AST less than or equal to 5.0 (SqrRoot) ULN, ALT less than or equal to 5.0 (SqrRoot) ULN, and bilirubin less than or equal to 3.0 (SqrRoot) ULN
Calculated Creatinine clearance greater than or equal to 20 mL/min (using either CKD-EPY equation)
The effects of M7824 and/or M9241 on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use strict and effective contraception during treatment and for at least 65 days for women and 125 days for men after the last dose of M7824 administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
HIV-positive participants are eligible if on stable dose of highly active antiretroviral therapy (HAART), CD4 counts are greater than 350 cells/mm3 and viral load is undetectable
Participants with previously treated brain or CNS metastases are eligible provided that the subject has recovered from any acute effects of radiotherapy and is not requiring steroids, and any whole brain radiation therapy was completed at least 2 weeks prior to M7824 administration, or any stereotactic radiosurgery was completed at least 2 weeks prior to M7824 administration
HBV positive Participants are eligible-they must have been treated and on a stable dose of antivirals [eg, entecavir, tenofovir, or lamivudine; (adefovir or interferon are not allowed)] at study entry and with planned monitoring and management according to appropriate labeling guidance
HCV positive Participants are eligible if participants are on active HCV therapy at study entry and must be on a stable dose without documented clinically significant impaired liver function test or hematologic abnormalities and with planned monitoring and management according to appropriate labeling guidance
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

History of allergic reactions attributed to compounds of similar chemical or biologic composition to M7824 and/or M9241 investigational agents used in the study
Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patients with a history of bleeding diathesis or recent clinically significant bleeding events considered by the Investigator as high risk for investigational drug treatment are also excluded with the exception of hematuria
Pregnant women are excluded from this study because M7824 and/or M9241 are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M7824 and/or M9241, breastfeeding should be discontinued if the mother is treated with these agents
Subjects unwilling to accept blood products as medically indicated
Participants with any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required treatment with either systemic corticosteroids (>10 mg daily prednisone equivalent) or immunosuppressive medications. Inhaled steroids and adrenal replacement steroid doses up to 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
Participants with any active or recent history of inflammatory bowel disease, active lupus or scleroderma or other medical conditions (i.e pneumonits with planned SBRT to lung lesion) or genetic radiosensitivity syndromes will be excluded from the study unless deemed eligible by Principal Investigator because these diseases make the subject unsafe or ineligible for radiation therapy with SBRT
Participants having tumor lesion(s) in the liver or chest which are 10 cm or larger
Patients with a currently active second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ or incidental organ-confined prostate cancer found on cystoprostatectomy (provided that the following criteria are met: Stage T2N0M0 or lower; Gleason score <= 3+4, PSA undetectable). Patients are not considered to have a currently active malignancy if they have completed therapy and are free of disease for >= 2 years and currently do not require systemic therapy
Clear my responses

How to participate?

Step 1 Connect with a site
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact


Preferred Language
Other Language
Please verify that you are not a bot.

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider


Browse trials for

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 



Reply by • Private

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note