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.
- 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 15-21% in mUC and 25% in mRCC).
- 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 proinflammatory
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
patients 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
- Men and women 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 deescalating
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 participantpatients.
- Participants will receive treatment in cycles consisting of 4 weeks.
|Overal Status||Start Date||Phase||Study Type|
|Recruiting||July 13, 2020||Phase 1||Interventional|
Primary Outcome 1 - Measure: safety and tolerability of M9241 and M7824 aone or in combination with SBRT
Primary Outcome 1 - Time Frame: until confirmed progression, unacceptable toxicity or trial withdrawal
- 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
- 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
- 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
- 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 1200/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
- Hgb greater than or equal to 9g/dL (pRBC transfusions are allowed to achieve
- 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
- 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.
- 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.
- 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 with prior malignancy active within the previous 3 years except for
locally curable cancers that have been apparently cured such as basal or squamous cell
skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast or
low risk Gleason 6 prostate cancer.
- Participants having tumor lesion(s) in the liver or chest which are 10 cm or larger.
Minimum Age: 18 Years
Maximum Age: N/A
Healthy Volunteers: No
Name: Andrea B Apolo, M.D.
Role: Principal Investigator
Affiliation: National Cancer Institute (NCI)
Name: Lisa Ley, R.N.
Phone: (240) 858-3524
|National Institutes of Health Clinical Center
Bethesda, Maryland 20892
For more information at the NIH Clinical Center contact National Cancer Institute Referral Office