Bintrafusp Alfa (M7824) and PDS01ADC Alone and in Combination With Stereotactic Body Radiation Therapy (SBRT) in Adults With Metastatic Non-Prostate Genitourinary Malignancies
- Conditions
- Urothelial CancerGenitourinary CancerUrogenital NeoplasmsBladder CancerUrogenital Cancer
- Interventions
- Registration Number
- NCT04235777
- Lead Sponsor
- National Cancer Institute (NCI)
- 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 PDS01ADC 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 PDS01ADC, 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 PDS01ADC . 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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- 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.
* PDS01ADC 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. PDS01ADC has 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 PDS01ADC. Preclinical data suggest synergy between these agents and the available clinical data suggest that the combination of M7824 plus PDS01ADC 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, PDS01ADC. Preclinical models have demonstrated impressive synergy with radiation plus M7824 and radiation plus PDS01ADC.
* We hypothesize that an immune-intensification approach involving M7824 plus PDS01ADC 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 PDS01ADC 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 PDS01ADC 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.
* 18 years of age or older
Design:
* This is an open label, non-randomized, three-stage phase I trial of M7824 and PDS01AD or M7824 and PDS01ADC 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 PDS01ADC. Dose de-escalation of PDS01ADC will be done if toxicities start at dose 16.8 mcg/kg.
* Up to 66 evaluable participants will be seen.
* Participants will receive treatment in cycles consisting of 4 weeks.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 100
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Arm 1 PDS01ADC Treatment with M7824 and de-escalating doses of PDS01ADC if appropriate Arm 2 M7824 Treatment with M7824 and de-escalating doses of PDS01ADC (if appropriate) with sequential SBRT Arm 3 Stereotactic body radiation therapy (SBRT) Treatment with M7824 and de-escalating doses of PDS01ADC (if appropriate) with concurrent SBRT Arm 3 PDS01ADC Treatment with M7824 and de-escalating doses of PDS01ADC (if appropriate) with concurrent SBRT Arm 3 M7824 Treatment with M7824 and de-escalating doses of PDS01ADC (if appropriate) with concurrent SBRT Arm 1 M7824 Treatment with M7824 and de-escalating doses of PDS01ADC if appropriate Arm 2 Stereotactic body radiation therapy (SBRT) Treatment with M7824 and de-escalating doses of PDS01ADC (if appropriate) with sequential SBRT Arm 2 PDS01ADC Treatment with M7824 and de-escalating doses of PDS01ADC (if appropriate) with sequential SBRT
- Primary Outcome Measures
Name Time Method safety and tolerability of PDS01ADC and M7824 alone or in combination with SBRT until confirmed progression, unacceptable toxicity or trial withdrawal The fraction of participants with toxicity noted at each dose level will be reported by grade and type of toxicity identified. Maximum tolerated dose will also be reported.
- Secondary Outcome Measures
Name Time Method Progression free survival (PFS) From start of treatment to time of progression or death, whichever occurs first duration of time from start of treatment to time of progression or death, whichever occurs first
Overall Survival (OS) Time from treatment to the date of death from any cause Time from the start of treatment that participants are still alive.
Objective response rate (ORR) From time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented the fraction of evaluable participants with a PR or CR at the end of treatment with M7824 will be reported along with 80% and 95% two-sided confidence intervals for each arm
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States