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BRIEF TITLE: 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

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


  • Org Study ID: 200012
  • Secondary ID: 20-C-0012
  • NCT ID: NCT04235777
  • NCT Alias:
  • Sponsor: National Cancer Institute (NCI) - NIH
  • Source: National Institutes of Health Clinical Center (CC)

Brief 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.

Detailed 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 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.

Objective:

-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

Eligibility:

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

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

- Patients 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

Overal Status Start Date Phase Study Type
Recruiting July 14, 2020 Phase 1 Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: safety and tolerability of M9241 and M7824 aone or in combination with SBR

Primary Outcome 1 - Time Frame: until confirmed progression, unacceptable toxicity or trial withdrawal

Condition:

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

Eligibility

Criteria:
- INCLUSION CRITERIA:

- Patients must have histologically or cytologically confirmed diagnosis of a metastatic
non-prostate genitourinary tumor.

- Patients must have metastatic disease defined as new or progressive lesions on
> cross-sectional imaging. Radiological evaluation should occur within 21 days prior to
enrollment.

- Patient must have evaluable or measurable disease.

- Patients 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)

- Patients must have at least one measurable site of disease that will not be
irradiated.

- Patients may have been previously treated with cytotoxic chemotherapy regimen or
targeted agent. Patients may have received any number of prior cytotoxic agents.

- Patients 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.

- Patients 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 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
normal

- Hgb greater than or equal to 9g/dL (pRBC transfusions are allowed to achieve
acceptable Hgb)

- Patients may have mild to moderate hepatic impairment with total bilirubin less than
or equal to 3.0 (SqrRoot) ULN.

- For patients 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 patients 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.

- Patients 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 patients 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 patients 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.

- Patients 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.

- Patients 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.

- Patients 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.

- Patients having tumor lesion(s) in the liver or chest which are 10 cm or larger.
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Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Official Information

Name: Andrea B Apolo, M.D.

Role: Principal Investigator

Affiliation: National Cancer Institute (NCI)

Overall Contact

Name: Lisa Ley, R.N.

Phone: (240) 760-6097

Email: lisa.ley@nih.gov

Link: NIH Clinical Center Detailed Web Page

Location

Facility Status Contact
National Institutes of Health Clinical Center
Bethesda, Maryland 20892
United States
Recruiting For more information at the NIH Clinical Center contact National Cancer Institute Referral Office
888-624-1937