In Situ Immunomodulation With CDX-301, Radiation Therapy, CDX-1140 and Poly-ICLC in Patients w/ Unresectable and Metastatic Solid Tumors

Study Overview
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Brief Summary
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This phase I trial evaluates the side effects of radio-immunotherapy (CDX-301, radiotherapy, CDX-1140 and Poly-ICLC) in treating patients with unresectable and measurable metastatic melanoma, cutaneous squamous cell carcinoma (SCC), Merkel cell carcinoma, high-grade bone and soft tissue sarcoma or HER2/neu(-) breast cancer. CDX-301 may induce cross-presenting dendritic cells, master regulators in the immune system. Radiation therapy uses high energy to kill tumor cells and release antigens that may be picked up, processed and presented by cross-presenting dendritic cells. CDX-1140 and Poly-ICLC may activate tumor antigen-loaded,cross-presenting dendritic cells, and generate tumor-specific T lymphocytes, a type of immune cells, that can search out and attack cancers. Giving immune modulators and radiation therapy may stimulate tumor cell death and activate the immune system.

Detailed Description
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PRIMARY OBJECTIVE: I. To evaluate the safety profile of in situ immunomodulation with recombinant Flt3 ligand (CDX-301), radiotherapy, agonistic anti-CD40 monoclonal antibody CDX-1140, and Poly-ICLC in unresectable and metastatic melanoma, cutaneous squamous cell carcinoma, Merkel cell carcinoma, high-grade bone and soft tissue sarcoma or breast cancer patients with injectable palpable disease by determining the maximum tolerated dose (MTD) of CDX-1140 that has an acceptable adverse event profile. SECONDARY OBJECTIVE: I. To evaluate the immune signatures in the tumor microenvironment before and after in situ immunomodulation with CDX-301, radiotherapy, CDX-1140, and Poly-ICLC. EXPLORATORY OBJECTIVES: I. To record the overall response rate (ORR) (complete response [CR] and partial response [PR]) of injected as well as distant uninjected metastatic lesions in metastatic melanoma, cutaneous SCC, Merkel cell carcinoma, high-grade bone and soft tissue sarcoma or breast cancer patients with injectable palpable disease treated with in situ immunomodulation with CDX-301, radiotherapy, CDX-1140, and Poly-ICLC by immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) response assessment, and compare intratumoral alone versus (vs.) intratumoral + intravenous administration of CDX-1140. II. To record the overall survival (OS) and progression free survival (PFS) in unresectable and metastatic melanoma, cutaneous SCC, Merkel cell carcinoma, high-grade bone and soft tissue sarcoma or breast cancer patients with injectable palpable disease treated with in situ immunomodulation with CDX-301, radiotherapy, CDX-1140, and Poly-ICLC, and compare intratumoral alone vs. intratumoral + intravenous administration of CDX-1140. III. Examine changes in the levels of T-cell subsets/myeloid derived suppressor cells (MDSC)/cytokines in peripheral blood (PB) of unresectable and metastatic melanoma, cutaneous SCC, Merkel cell carcinoma, high-grade bone and soft tissue sarcoma or breast cancer patients with injectable palpable disease treated with in situ immunomodulation with CDX-301, radiotherapy, CDX-1140, and Poly-ICLC. OUTLINE:Cohort A will evaluate safety of intratumoral administration of CDX-1140 in combination with CDX-301, radiotherapy and Poly-ICLC. Once cohort A is finished, patients will be enrolled to cohort B to evaluate safety of intratumoral + intravenous administration of CDX-1140 in combination with CDX-301, radiotherapy and Poly-ICLC. COHORT A: Patients receive recombinant Flt3 ligand intratumorally (IT) on days 1-5 and agonistic anti-CD40 monoclonal antibody CDX-1140 IT with Poly-ICLC IT on day 9 or 10. Patients also undergo radiation therapy on day 8 or 9. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. COHORT B: Patients receive recombinant Flt3 ligand IT on days 1-5 and agonistic anti-CD40 monoclonal antibody CDX-1140 IT and intravenously (IV) over 90 minutes with Poly-ICLC IT on day 9 or 10. Patients also undergo radiation therapy on day 8 or 9. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 3-6 months for 2 years.

Official Title
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A Phase I Study of In Situ Immunomodulation With CDX-301, Radiotherapy, CDX-1140, and Poly-ICLC in Patients With Unresectable and Metastatic Solid Tumors With Injectable Palpable Disease

Conditions
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Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Breast Carcinoma, Prognostic Stage IV Breast Cancer AJCC v8, Unresectable Breast Carcinoma, Metastatic Melanoma, Unresectable Melanoma, Cutaneous Squamous Cell Carcinoma, Merkel Cell Carcinoma, Soft Tissue Sarcoma, Bone Sarcoma, Sarcoma,Soft Tissue, Sarcoma of Bone

Intervention / Treatment
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* Biological: Anti-CD40 Agonist Monoclonal Antibody CDX-1140
* Drug: Poly ICLC
* Radiation: Radiation Therapy
* Biological: Recombinant Flt3 Ligand


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have clinically or pathologically confirmed diagnosis of unresectable and metastatic melanoma, cutaneous SCC, Merkel cell carcinoma, high-grade bone and soft tissue sarcoma or HER2/neu (-) breast cancer with no curative treatment options. The unresectable disease to be irradiated and injected with medications must be located in breast, dermal, subcutaneous, or soft tissue, or lymph nodes with the longest axis of the tumor 2-7 centimeters, and should be considered safe for injection by the investigator. The metastatic disease must be measured per irRECIST criteria. Patient must have lesion that can be biopsied and is willing to undergo the procedure as part of the protocol. Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 1. Participants of child-bearing potential and men must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. 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. For patients with history of radiotherapy to the same side of chest wall/breast/extremity that will be treated on study, he/she will be eligible only if the prior radiation dose was under or equal to 68 Gy total and delivered more than 6 months prior to planned re-treatment. (The cumulative dose received to the irradiated area will be no more than 87 Gy total, including a maximum of 68 Gy allowed from prior treatment course.) Patient requires the use of radiation therapy to the target lesion of palliation of symptoms and/or achieving local control as part of standard of care as deemed appropriate by treating radiation oncologist. Patients must agree to radiation to the tumor. Any line of therapy allowed, radiologically or clinically confirmed progression on prior therapy Must have adequate organ and marrow function present as defined below: Platelets >= 100,000/uL Hemoglobin >= 8.0 g/dL Absolute neutrophil count (ANC) >= 1500/uL Total bilirubin =< 1.5 X institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional ULN. Creatinine =< 1.5 X ULN OR creatinine clearance >= 50 mL/min per Cockcroft-Gault equation for patients with creatinine levels greater than ULN. Participant or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure. Patients must agree to injections of CDX-301, CDX-1140, and poly-ICLC. Patients must agree to appropriate clinical monitoring to receive the study regimens. Patients must agree to photos of tumors and use of the photos for publication. Patients should have an administration site for all injections that is free of potentially complicating dermatologic conditions such as rashes and should not be located in an area where the integrity of the draining lymph node bed is potentially compromised (i.e., an extremity where a nodal resection was previously performed). Exclusion Criteria: Patients currently treated with systemic immunosuppressive agents, including steroids, are ineligible until 3 weeks after removal from immunosuppressive treatment. (inhaled steroids are allowed) Patients with HER2+ breast cancer Concurrent use of targeted therapy including CDK4/6, mTOR, PIK3CA, PARP, BRAF, MEK inhibitors or chemotherapy (endocrine therapy is allowed). Targeted therapy including CDK4/6, mTOR, PIK3CA, PARP, BRAF, MEK inhibitors, chemotherapy, radiation therapy, or immunotherapy within 3 weeks prior to first dosing of study agent. (endocrine therapy is allowed). Patients with active or history of autoimmune disease or history of transplantation Patients with history of (non-infectious) pneumonitis/interstitial lung disease, including grade 1 pneumonitis (asymptomatic; clinical or diagnostic observations only; intervention not indicated). Patients with prior history of acute myeloid leukemia (AML) or known FLT3 aberrations Pregnant or nursing female participants. Unwilling or unable to follow protocol requirements. Patients with known serious mood disorders. (Major depression diagnosis is an exclusion: Other stable mood disorders on stable therapy for > 6 months or not requiring therapy may be allowed after consultation with principal investigator [PI]). Cardiac risk factors including: Patients experiencing cardiac event(s) (acute coronary syndrome, myocardial infarction, or ischemia) within 3 months of signing consent. Patients with a New York Heart Association classification of III or IV. Patients with inflammatory breast cancer or uveal melanoma. Patients with uncontrolled diseases other than cancer may be excluded if after consultation with PI and research team it is decided it might affect the treatment efficacy or toxicity. Evidence of current drug or alcohol abuse or psychiatric impairment, which in the investigator's opinion will prevent completion of the protocol therapy or follow-up. Specific testing is not required, however may be done as clinically indicated. Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug. Participants with symptomatic known brain metastases < 4 weeks from radiation treatment should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Other invasive cancers diagnosed < 3 years back that required systemic treatment. If diagnosed with other invasive cancer >= 3 years, should have complete recovery from all systemic toxicity except neuropathy, vitiligo, alopecia, and endocrinopathies on stable hormone replacement therapy. Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected). Current use of anticoagulants (warfarin, heparin, direct thrombin inhibitors) at therapeutic levels. Patients who have had stroke/TIA and DVT/PE within the last 12 months. Patients at risk for impending visceral crisis of the liver and lungs as follows, or any condition which in the patient's primary treating oncologist's opinion deems the participant an unsuitable candidate to receive study drug: A visceral crisis of the liver exists when bilirubin levels increase very rapidly (>1.5 times the upper limit of normal) without the presence of Gilbert syndrome (i.e., Meulengracht syndrome) or a biliary tract obstruction. A visceral crisis of the lungs can be assumed when dyspnea at rest increases more rapidly and cannot be relieved by pleural drainage. Patients with previous history of intratumoral immunotherapy including T-VEC (Talimogene laherparepvec). Radiation induced sarcoma.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A (immunomodulators, radiation therapy)<br>Patients receive recombinant Flt3 ligand IT on days 1-5 and undergo radiation therapy on day 8 or 9. Patients also receive agonistic anti-CD40 monoclonal antibody CDX-1140 IT and Poly-ICLC IT on day 9 or 10. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. | Biological: Anti-CD40 Agonist Monoclonal Antibody CDX-1140<br>* Given IT<br>* Other names: CDX-1140;Drug: Poly ICLC<br>* Given IT<br>* Other names: Stabilized Polyriboinosinic/Polyribocytidylic Acid;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Biological: Recombinant Flt3 Ligand<br>* Given IT<br>* Other names: rhuFlt3L;|
| Experimental: Cohort B (immunomodulators, radiation therapy)<br>Patients receive recombinant Flt3 ligand IT on days 1-5 and undergo radiation therapy on day 8 or 9. Patients also receive agonistic anti-CD40 monoclonal antibody IT and IV over 90 minutes and Poly-ICLC IT on day 9 or 10. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. | Biological: Anti-CD40 Agonist Monoclonal Antibody CDX-1140<br>* Given IT<br>* Other names: CDX-1140;Drug: Poly ICLC<br>* Given IT<br>* Other names: Stabilized Polyriboinosinic/Polyribocytidylic Acid;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Biological: Recombinant Flt3 Ligand<br>* Given IT<br>* Other names: rhuFlt3L;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events |  | Up to 30 days | 
| Maximum tolerated dose or maximum administered dose | The dose limiting toxicity rate will be estimated by cohort and dose-level (if appropriate) using 90% confidence intervals obtained by Jeffrey's prior method. | Up to 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Immune signatures in the tumor microenvironment | Will examine changes in the immune biomarkers levels from baseline to end of treatment | Baseline up to 2 years | 
| Changes in the levels of infiltrating CD4+ and CD8+ T cells | Will examine changes in the levels of infiltrating CD4+ and CD8+ T cells and their proteomic, genomic and transcriptomic signatures in the tumor microenvironment. The immune biomarker levels are treated as continuous variables and will be summarized in the overall sample and within treatment-arm by time-point using the mean and standard error, and graphically using dot-plots. | Baseline up to 2 years | 
| Changes in the levels of infiltrating myeloid cell subsets | Will examine changes in the levels of infiltrating myeloid cell subsets including dendritic cells (DCs), macrophages, and monocytes, and their proteomic, genomic and transcriptomic signatures in the tumor microenvironment. The immune biomarker levels are treated as continuous variables and will be summarized in the overall sample and within treatment-arm by time-point using the mean and standard error, and graphically using dot-plots. | Baseline up to 2 years | 
| Changes in the levels of PD-L1 expression | Will examine changes in the levels of PD-L1 expression within both neoplastic and nonneoplastic stromal elements of the tumor microenvironment. The immune biomarker levels are treated as continuous variables and will be summarized in the overall sample and within treatment-arm by time-point using the mean and standard error, and graphically using dot-plots. | Baseline up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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High-grade bone sarcoma, High-grade soft tissue sarcoma