Clinical Trials /

TGF-beta Trap (M7824) and NHS-IL12 (M9241) Alone and in Combination With Stereotactic Body Radiation Therapy (SBRT) in Adults With Metastatic Non-Prostate Genitourinary Malignancies

NCT04235777

Description:

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.

Related Conditions:
  • Bladder Small Cell Neuroendocrine Carcinoma
  • Cervical Carcinoma
  • Extragonadal Embryonal Carcinoma
  • Malignant Bladder Neoplasm
  • Malignant Ovarian Germ Cell Tumor
  • Malignant Renal Pelvis Neoplasm
  • Malignant Reproductive System Neoplasm
  • Malignant Ureter Neoplasm
  • Malignant Urethral Neoplasm
  • Ovarian Embryonal Carcinoma
  • Renal Pelvis and Ureter Carcinoma
  • Testicular Embryonal Carcinoma
  • Transitional Cell Carcinoma
  • Ureter Small Cell Carcinoma
  • Urothelial Carcinoma
  • Uterine Corpus Neuroendocrine Neoplasm
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: TGF-beta Trap (M7824) and NHS-IL12 (M9241) Alone and in Combination With Stereotactic Body Radiation Therapy (SBRT) in Adults With Metastatic Non-Prostate Genitourinary Malignancies
  • Official Title: A Phase I Study of TGF-Beta Trap (M7824) and NHS-IL12 (M9241) Alone and in Combination With Stereotactic Body Radiation Therapy (SBRT) in Adults With Metastatic Non-Prostate Genitourinary Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 200012
  • SECONDARY ID: 20-C-0012
  • NCT ID: NCT04235777

Conditions

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

Interventions

DrugSynonymsArms
M7824Arm 1
M9241Arm 1

Purpose

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 genital or urinary 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.

        -  Anti-PD-L1/TGF-beta trap (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
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1ExperimentalTreatment with M7824 and deescalating doses of M9241 if appropriate
  • M7824
  • M9241
Arm 2ExperimentalTreatment with M7824 and deescalating doses of M9241 (if appropriate) with sequential SBRT
  • M7824
  • M9241
Arm 3ExperimentalTreatment with M7824 and deescalating doses of M9241 (if appropriate) with concurrent SBRT
  • M7824
  • M9241

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 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 normal 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 2.5 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 4 months 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 systemic corticosteroids (>10 mg daily
             prednisone equivalent) or immunosuppressive medications except 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:safety and tolerability of M9241 and M7824 aone or in combination with SBR
Time Frame:until confirmed progression, unacceptable toxicity or trial withdrawal
Safety Issue:
Description:-The fraction of patients 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

Measure:Objective response rate (ORR)
Time Frame: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
Safety Issue:
Description:the fraction of evaluable patients 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
Measure:Progression free survival (PFS)
Time Frame:From start of treatment to time of progression or death, whichever occurs first
Safety Issue:
Description:duration of time from start of treatment to time of progression or death, whichever occurs first
Measure:Overall Survival (OS)
Time Frame:Time from treatment to the date of death from any cause
Safety Issue:
Description:Time from the start of treatment that patients are still alive.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Immunocytokine
  • Renal Cell Carcinoma
  • Urothelial Cancinoma
  • Immune Therapy

Last Updated

January 21, 2020