Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

All Drugs and Chemicals

Antineoplastic Agents

Androgens

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

National Cancer Institute (NCI)

Immune System Diseases

Hypersensitivity

Anti-Inflammatory Agents

Docetaxel

Prednisone

Tubulin Modulators

Antimitotic Agents

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Docetaxel plus M9241 dose escalation with optional prednisone and ADT as part of SOC

Docetaxel plus M9241 RP2D plus M7824 with optional prednisone and ADT as part of SOC

Docetaxel plus M9241 RP2D with optional prednisone and ADT as part of SOC

For mCSPC patients: Androgen Deprivation Therapy (ADT) may include GnRH agonist or monthly degarelix converted to GnRH agonist after 3 months. For mCRPC patients: ADT will be continued as per standard of care.

For mCSPC patients, prednisone is optional and if given, should be taken orally, at 5 mg once a day. For mCRPC patients, prednisone should be taken orally either, at 5mg twice a day for each dose or 10 mg once a day as is the patient s preference.

M7824 (2400 mg) will be administered as a 1 hour intravenous (IV) infusion once every three weeks.

M7824

Docetaxel 75mg/m\^2 will be administered intravenously every 21 days (i.e., a 3-week cycle) for up to 6 cycles in mCSPC and until progression or unacceptable toxicity in mCRPC.

M9241 at escalating doses and then at RP2D will be administered as a subcutaneous injection every three weeks.

Background:

Metastatic castration sensitive and castration resistant prostate cancer (mCSPC and mCRPC) are prostate cancers that have spread to other parts of the body. Use of the drug docetaxel with androgen deprivation therapy can improve survival for men with mCSPC. Researchers want to see if combining this treatment with other drugs can help delay the time it takes for mCSPC and mCRPC to get worse.

Objective:

To learn if giving docetaxel with M9241 is safe and effective for men with prostate cancer.

Eligibility:

Men age 18 and older with mCSPC or mCRPC.

Design:

Participants will be screened with a medical history and physical exam. Their diagnosis will be confirmed. Their symptoms and how well they do their normal activities will be reviewed. They will have blood and urine tests. Their heart will be evaluated. They will have imaging scans of the chest, abdomen, and pelvis. They will have bone scans with intravenous (IV) injections of Tc99 to check for tumor spread in the bones.

Some screening tests will be repeated during the study.

Participants may have tumor biopsies.

Participants will get treatment in cycles. Each cycle will last 21 days. They will get docetaxel through IV infusion. They will get M9241 as an injection under the skin.

Participants with mCSPC will have up to 6 cycles. Those with mCRPC will be treated until they cannot tolerate the side effects or their disease gets worse.

Participants will have a follow-up visit 30 days after treatment ends. Those with mCSPC will then have follow-up visits at the clinic every 3 months.

Background:

* A phase III trial demonstrated that combining docetaxel and androgen deprivation therapy (ADT) significantly improved survival (57.6 vs 44.0 months (hazard ratio HR=0.56, (0.44- 0.70), p \<0.0001) for men with metastatic castration sensitive prostate cancer (mCSPC). The greatest benefit was seen in men with high volume disease (visceral disease or 4+ bone lesions with at least one beyond the pelvis and spine.)
* Docetaxel has limited efficacy in metastatic castration resistant prostate cancer (mCRPC) patients who have already progressed on anti-androgen therapy (abiraterone or enzalutamide).
* Intensification of treatment in de novo mCSPC patients by adding abiraterone to docetaxel and ADT has been shown in a phase III trial to significantly improve OS (0.82, (0.69 - 0.98) p=0 (Summation)030) and rPFS (HR=0.54,(0.41-0.71) p \<0.0001)
* Clinical data have indicated that PSA \<=0.20 ng/ml eight months after starting androgen deprivation therapy (ADT) is prognostic for overall survival based on data from the phase III trial.
* Preclinical data demonstrates that docetaxel increases uptake of M9241, an IL-12 immunocytokine that targets necrosis.
* Additional preclinical data demonstrates the potential anti-tumor synergy of M9241 when combined with docetaxel.

Objectives:

Phase I:

To evaluate safety and tolerability of docetaxel in combination with M9241 in participants who have metastatic prostate cancer.

Phase II:

-Determine clinical efficacy in adults with prostate cancer treated when standard of care is combined with M9241. For mCSPC the standard of care is docetaxel + abiraterone. For mCRPC the standard of care is docetaxel.

* For mCSPC participants: Clinical efficacy will be measured by prostate specific antigen (PSA \<0.2 ng/ml) eight months after start of androgen deprivation therapy (ADT).
* For mCRPC participants: Clinical efficacy will be measured by an increase in their median progression free survival (PFS).

Eligibility:

* Men age \>=18 years
* Histopathological confirmation of prostate cancer. If no pathologic specimen is available, participants may enroll with a pathologist s report showing a histologic diagnosis of prostate cancer and a clinical course consistent with the disease.
* Participants must have metastatic disease

  * mCSPC participants must be within 134 days of starting ADT.
  * mCRPC participants must have been previously treated with ADT.

Design:

* Open-label, single-center, non-randomized Phase I/II study
* To ensure safety of the combination before using in larger numbers of mCSPC and mCRPC participants, M9241 will be escalated from a starting dose of 12 mcg/kg and a second dose level of 16.8 mcg/kg along with docetaxel. mCSPC participants will receive a maximum of 6 cycles. mCRPC participants will continue until progression or unacceptable toxicity.
* The remaining participants will be enrolled onto the trial in the following expansion cohorts, each of which will receive the determined safe dose of M9241. ADT will be maintained/given per standard of care throughout the study.

  * mCSPC participants: Once ADT established, simultaneous docetaxel 75 mg/m\^2 (given every 3 weeks x 6 cycles starting at Cycle 1), with M9241 at the RP2D, given every 3 weeks from cycle 2 through cycle 6). Abiraterone will be given in addition to docetaxel from the start of cycle 1 at a dose of 1000mg by mouth once daily. Prednisone will be given orally at 5 mg twice a day and will not be optional.
  * The first 6 participants in the mCSPC arm including abiraterone will be evaluated as a safety lead-in of M9241 at 12 mcg/kg. If there are 2 or more DLTs within these initial 6, then the doses will be de-escalated and 6 additional participants will be evaluated at this lower dose of M9241 at 8 mcg/kg.
  * mCRPC participants: docetaxel 75 mg/m\^2 (given every 3 weeks starting at Cycle 1) with M9241 at the RP2D, given every 3 weeks from cycle 2 onwards until disease progression or unacceptable toxicity. Prednisone will be given 5 mg twice a day for each dose or 10 mg once a day.
* It is anticipated that approximately 4 years may be required for accrual of up to 80 participants.

M9241 in Combination With Docetaxel in Adults With Metastatic Castration Sensitive and Castration Resistant Prostate Cancer

A Phase I/II Study of M9241 With Docetaxel and Abiraterone in Adults With Metastatic Castration Sensitive and M9241 With Docetaxel in Castration Resistant Prostate Cancer

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

of the number and type of toxicities noted for participants who are evaluable for toxicity

For castration sensitive: Increase in the proportion of participants who have less than 0.2 ng/ml of PSA. For castration resistant: Increase in median progression free survival

PSA levels and tumor progression on scans

Symptoms and General Pathology

Recurrence

Disease Attributes

Testosterone

Enzalutamide at 160 mg once daily on every day of the cycle (every 28 days)

Enzalutamide

M9241 at 12.0 microgram/kg by subcutaneous injection (every 28 days)

National Cancer Institute Referral Office

Background:

Prostate cancer may return after treatment in 30,000 to 50,000 people each year. There is no clear best way to treat these people. Better treatments are needed.

Objective:

To test a study drug (enzalutamide), both alone and combined with a second drug (M9241), in people with prostate cancer that returned after treatment.

Eligibility:

People aged 18 years and older with prostate cancer that returned after treatment.

Design:

Participants will be screened. They will have a physical exam, with blood tests. All their urine will be collected for 24 hours. They will have imaging scans of their chest, abdomen, pelvis, and bones. Their ability to perform everyday activities will be assessed. They may opt to give a stool sample.

Participants will be treated in 4-week cycles.

Enzalutamide is a pill taken by mouth once a day, every day. All participants will be given a supply of this drug to take at home.

M9241 is injected under the skin once a month, on the first day of each cycle. Half of the participants will receive both drugs.

All participants will visit the clinic once a month. Each visit should last no more than 8 hours. Blood and urine tests will be repeated.

All participants will receive the study treatment for 3 cycles. Some participants may need 3 more cycles of treatment with enzalutamide only. This re-treatment can be done only once.

Participants will have a follow-up visit 1 month after they finish treatment. After that, they will have visits every 6 weeks for up to 5 years. Imaging scans and blood tests will be repeated.

...

* Enzalutamide given with androgen deprivation therapy (ADT) is Food and Drug Administration (FDA) approved for the treatment of metastatic prostate cancer based on conventional computed tomography (CT) and Tc99 scan.
* Enzalutamide for 3 months (short course) given without ADT has demonstrated the ability to control prostate-specific antigen (PSA) in recurrent prostate cancer for nearly a year, delaying the need for additional therapy.
* Enzalutamide without ADT was very well tolerated in our previous study, a prerequisite for any therapy in recurrent disease where patients may not have symptoms from prostate cancer for 5-10 years.
* Enzalutamide without ADT demonstrated the ability to enhance natural killer (NK) cells and decrease myeloid-derived suppressor cells.
* M9241 is an immunocytokine that binds to areas of necrotic tumors. Preclinical data have demonstrated that M9241 delivery to the tumor is enhanced by cytotoxic therapies such as radiation and chemotherapy.
* M9241 has been shown to be well tolerated and even induce PSA responses in patients with recurrent prostate cancer.
* M9241 has also been able to enhance NK cells in prostate cancer patients.
* Higher levels of NK cells have been associated with better clinical outcomes in prostate cancer.
* Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging is now approved in recurrent prostate cancer. No trial has prospectively evaluated an anti-androgen therapy (e.g., enzalutamide) without ADT in this population. If changes in imaging are seen similar to the PSA responses noted previously, these findings may demonstrate the efficacy of enzalutamide-based regimens in recurrent prostate cancer.
* Given that enzalutamide is cytotoxic and will induce necrosis, there is a rationale to combine it with the necrosis-targeting agent M9241. The fact that both enhance NK cells, which have been associated with better clinical outcomes adds further rationale to this combination.

Objective:

-To determine if the combination of enzalutamide and immunotherapy (M9241) is associated with an increase in the duration of PSA suppression compared to that of enzalutamide alone in participants with PET Positive Recurrent Prostate Cancer (pprPC).

Eligibility:

* Participant must provide documentation of histologic or cytological confirmation of prostate cancer or tumor sample for diagnosis confirmation. Note: in the absence of pathology or documentation, participant must have a rising PSA, PSMA+ disease, and his history consistent with prostate cancer as documented by the investigator.
* History of primary treatment for prostate cancer (either surgery or radiation).
* PSA doubling time within less than 1 year before treatment initiation.
* Testosterone \>100 ng/dL.
* Age \>=18 years.
* Evidence of prostate cancer on PSMA PET/CT scan.
* Negative Tc99 Bone Scan.
* No evidence of soft tissue disease on the CT scan (or MRI) per the Response Evaluation Criteria in Solid Tumors (RECIST) guideline.

Design:

* This is an open-label phase II clinical trial with two treatment arms: Arm 1 (enzalutamide) and Arm 2 (enzalutamide + M9241).
* After enrollment, participants will be randomized between Arms 1 and 2 and receive 3 cycles of treatment of enzalutamide or enzalutamide and M9241.
* During off treatment monitoring period following the third cycle, participants who experience PSA recovery to baseline will have a second course of enzalutamide treatment only (3 cycles total).

Enzalutamide and M9241 in PET Positive Recurrent Prostate Cancer (pprPC) Without Testosterone Lowering Therapy

Phase II Trial of Enzalutamide and M9241 in PET Positive Recurrent Prostate Cancer (pprPC) Without Testosterone Lowering Therapy

.All IPD recorded in the medical record will be shared with intramural investigators upon request.

Kaplan-Meier curves and a one-tailed log-rank test. The median time to loss of PSA control on each arm will be reported along with a 95% confidence interval; in addition, based on the result from the prior trial, the probability of PSA control at 224 days (approximately 7 months) will also be reported on both arms, along with 95% confidence intervals

PET changes will be reported descriptively

Safety will be evaluated by determining the frequency of adverse events among treated participants and reporting the results, by maximum grade of event and type of toxicity noted

Results of peripheral immune cell subsets including CD4 and CD8 T cells, NK cells, Tregs, and MDSCs measurements will be reported descriptively

The proportion of participants with undetectable PSA at 12 months will be reported along with a 95% confidence interval

Avelumab

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Antineoplastic Agents, Immunological

Immunologic Factors

Subjects will receive avelumab intravenous (IV) infusion once a week on Day 1 and Day 15 of each cycle.

Subjects will receive Subcutaneous (SC) injection of M9241 in escalating doses on Day 1 of each cycle.

Subjects will receive avelumab once weekly in combination with M9241 every 4 weeks at M9241 maximum tolerated dose (MTD) for first 12 weeks followed by avelumab once every 2 weeks plus M9241 once every 4 weeks at M9241 MTD until a criterion for treatment discontinuation has been met.

Avelumab (Once weekly)

Subjects will receive M9241 at M9241 MTD once every 4 weeks until a criterion for treatment discontinuation has been met.

M9241 (MTD)

Subjects in the expansion cohorts will receive Induction Therapy (Avelumab once weekly + M9241 once every 4 weeks) through Cycle 3 (for 12 weeks) then starting at Cycle 4, Continuation Therapy (Avelumab once every 2 weeks + M9241 once every 4 weeks).

Avelumab (Expansion cohort)

Medical Responsible

The study consists of 2 parts: Dose Escalation phase (Part A) and Expansion phase (Part B). The dose escalation phase will evaluate the safety, tolerability, and PK of avelumab in combination with M9241 in subjects with locally advanced, unresectable, or metastatic solid tumors. Expansion phase will assess the safety and clinical activity of the combination regimen in selected tumor types. In Expansion phase subjects who have completed the combination treatment of avelumab at a given dose level of M9241, a safety review will be performed by the Safety monitoring committee in order to make a decision on the next dose level. Successive cohorts of 3 to 6 subjects will be treated with escalating doses of M9241 with avelumab intravenous (IV).

A Phase Ib Study to Evaluate the Safety, Tolerability, and Pharmacokinetics (PK) of Avelumab in Combination With M9241(NHS-IL12) (JAVELIN IL-12)

A Phase Ib Open-Label, Dose-Finding Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Avelumab in Combination With M9241(NHS-IL12) in Subjects With Locally Advanced, Unresectable, or Metastatic Solid Tumors

Merck KGaA, Darmstadt, Germany

EMD Serono Research & Development Institute, Inc.

Rare Diseases

Carcinoma

Carcinoma, Transitional Cell

Carcinoma, Renal Cell

Urinary Bladder Neoplasms

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Transitional Cell Carcinoma

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Treatment with M7824 and de-escalating doses of M9241 if appropriate

Treatment with M7824 and de-escalating doses of M9241 (if appropriate) with sequential SBRT

Treatment with M7824 and de-escalating doses of M9241 (if appropriate) with concurrent SBRT

1200 mg administered IV every two weeks while on M9241 and with or without SBRT

An initial dose of 16.8 mcg/kg administered subcutaneously every 4 weeks while on M7824 and with or without SBRT

A fixed dose of 8 Gy x 3 fractions sequential or concurrent with M7824 and M9241

Stereotactic body radiation therapy (SBRT)

Lisa Ley, R.N.

Andrea B Apolo, M.D.

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.

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 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 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. 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.

Objectives:

-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

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.
* Men and women 18 years of age or older

Design:

-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.

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

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

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.

duration of time from start of treatment to time of progression or death, whichever occurs first

Time from the start of treatment that participants are still alive.

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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)
M9241 in Combination With Docetaxel in Adults With Metastatic Castration Sensitive and Castration Resistant Prostate Cancer	NCT04633252	Cancer Of Prost... Prostate Neopla...	ADT Prednisone M7824 Docetaxel M9241	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)
Enzalutamide and M9241 in PET Positive Recurrent Prostate Cancer (pprPC) Without Testosterone Lowering Therapy	NCT06096870	Prostate Cancer Recurrent Prost... PET Positive	Enzalutamide M9241	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
A Phase Ib Study to Evaluate the Safety, Tolerability, and Pharmacokinetics (PK) of Avelumab in Combination With M9241(NHS-IL12) (JAVELIN IL-12)	NCT02994953	Advanced Solid ...	Avelumab M9241 Avelumab (Once ... M9241 (MTD) Avelumab (Expan...	18 Years -	EMD Serono
Enzalutamide and M9241 in PET Positive Recurrent Prostate Cancer (pprPC) Without Testosterone Lowering Therapy	NCT06096870	Prostate Cancer Recurrent Prost... PET Positive	Enzalutamide M9241	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
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	NCT04235777	Urothelial Canc... Bladder Cancer Genitourinary C... Urogenital Neop... Urogenital Canc...	M7824 M9241 Stereotactic bo...	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for m9241

Every month we try and update this database with for m9241 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for m9241

Every month we try and update this database with for m9241 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for m9241 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.