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Immunomodulating Agents

Interleukin-12

De-escalating doses of M9241 if appropriate + SBRT

In the safety lead in, M9241 will be given in de-escalating doses (starting dose 16.8 mcg/kg, and de-escalated if needed to 12 mcg/kg, or 8 mcg/kg) every 4 weeks for 3 doses. Within 4 weeks after completing SBRT, those participants receiving immunotherapy agents will receive M9241 by subcutaneous injection at dose determined during the safety lead in every 4 weeks for 3 doses.

M9241

SBRT to the prostate will be delivered in 5 fractions of radiation each of 7.25-8.0 Gy, every other day over the course of 10 business days (2-3 weeks). The total dose will be 36.25-40 Gy

Stereotactic Body Radiation Therapy (SBRT)

Amy R Hankin, P.A.-C

Ravi A Madan, M.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Background:

Prostate cancer is often treated with radiation and ADT (ADT is androgen deprivation therapy). Up to 30% of these cancers recur within 5 years of treatment. Researchers want to see if a new drug (M9241) can help the immune system to fight prostate cancer.

Objective:

To find what doses of M9241 are safe in people who are treated for prostate cancer. Also, to see what effects M9241 has on the immune system.

Eligibility:

People aged 18 and older with high- and intermediate-risk prostate cancer. Their cancer must not have spread to other parts of the body.

Design:

The study will last 7 months.

Participants will be screened. They will share their medical history. They will also have:

\<TAB\>A physical exam

\<TAB\>Routine blood and urine tests

\<TAB\>Imaging scans of the chest, abdomen, and pelvis

\<TAB\>A bone scan

\<TAB\>A tumor biopsy

\<TAB\>A specialized MRI. Participants will lie face down on the MRI scanner table. An antenna that receives a signal may be placed in the rectum.

All participants will be treated with radiation therapy and ADT.

Some participants will also receive M9241 as an injection under the skin. This treatment will start 4 weeks after the radiation has ended. Participants will receive a total of 3 doses. The injections will be 4 weeks apart. Some screening tests will be repeated at each visit.

Participants who do not receive M9241 will also have screening tests during the treatment period.

Participants will return for follow-up about 1 month after the last treatment or set of tests.

Background:

* Patients with intermediate and high risk localized prostate cancer often receive radiotherapy with androgen deprivation therapy as a potentially curative treatment. With any local treatment for prostate cancer (radiation or surgery), as many as 20-30% of these intermediate and high risk patients will eventually develop biochemical recurrence within 5 years of treatment.
* 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 is now considered a reasonable alternative to conventional fractionated external beam radiation therapy (EBRT) by the National Comprehensive Cancer Network (NCCN) guidelines and has rapidly proliferated in clinical use.
* M9241 (NHS-IL12) 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.
* 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 M9241.
* This study will evaluate the proof of concept that immunocytokines can synergize with standard radiation + ADT in prostate cancer with a focus on T-cell clonality.

Objectives:

* Safety Lead-In: To determine the safety and tolerated doses of the immunocytokine M9241 and Stereotactic Body Radiation Therapy (SBRT) in participants with localized high and intermediate risk prostate cancer receiving standard of care Androgen Deprivation Therapy (ADT)
* To evaluate T-cell clonality, as a measure of immunologic activity, after treatment with SBRT alone or in combination with immunotherapy agent M9241 in participants with prostate cancer receiving standard of care ADT

Eligibility:

* Participants with intermediate or high risk localized prostate cancer
* Participants with no history of prior radiation to the prostate or prior prostatectomy
* Participants without autoimmune disease or history of bleeding disorder
* Participants with adequate organ and bone marrow function

Design:

* This is an open label, randomized, Phase II trial evaluating T-cell clonality after treatment with SBRT alone or in combination with immunotherapy agent M9241in participants with localized intermediate or high risk prostate cancer receiving standard of care ADT.
* The trial will begin with a safety lead-in cohort with de-escalating doses of M9241 (starting dose 16.8 mcg/kg, and de-escalated if needed to 12 mcg/kg, or 8 mcg/kg) only if needed, to evaluate safety and tolerability of the combination of treatments.
* ADT will be administered to all participants on the study as standard care.
* Those participants receiving immunotherapy agents will receive M9241 by subcutaneous injection (sc) at a dose determined during the safety lead-in, every 4 weeks for 3 doses.
* To account for 3 inevaluable participants and 10 screen failures, the accrual ceiling has been set at 65 participants (18 participants during the safety lead-in phase, 34 during the randomized phase II portion).

T-Cell Clonality After Stereotactic Body Radiation Therapy Alone and in Combination With the Immunocytokine M9241 in Localized High- and Intermediate-Risk Prostate Cancer Treated With Androgen Deprivation Therapy

A Phase II Study Evaluating T-Cell Clonality After Stereotactic Body Radiation Therapy Alone and in Combination With the Immunocytokine M9241 in Localized High and Intermediate Risk Prostate Cancer Treated With Androgen Deprivation Therapy

.All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing will be shared with subscribers to dbGAP

For the safety lead-in: grade and type of toxicities at each dose level will be assessed to determine safety and tolerated doses of M9241 in combination with SBRT in participants with high and intermediate risk prostate cancer receiving standard of care ADT

Relative T-cell antigen receptor (TCR) clonality for each participant will be formed and these ratios will be compared between the two arms.

Immune cell subsets will be evaluated to determine peripheral immune response and compare between the two arms

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
T-Cell Clonality After Stereotactic Body Radiation Therapy Alone and in Combination With the Immunocytokine M9241 in Localized High- and Intermediate-Risk Prostate Cancer Treated With Androgen Deprivation Therapy	NCT05361798	Cancer Of Prost...	M9241 Stereotactic Bo...	18 Years -	National Institutes of Health Clinical Center (CC)
T-Cell Clonality After Stereotactic Body Radiation Therapy Alone and in Combination With the Immunocytokine M9241 in Localized High- and Intermediate-Risk Prostate Cancer Treated With Androgen Deprivation Therapy	NCT05361798	Cancer Of Prost...	M9241 Stereotactic Bo...	18 Years -	National Institutes of Health Clinical Center (CC)

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