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
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:
ability to do their normal activities
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
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
Participants must have metastatic disease defined as new or progressive lesions on
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
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.
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.
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.