In Situ Immunomodulation for Unresectable and Metastatic Solid Tumors
This phase I trial evaluates the safety and effectiveness of radiation therapy and intratumoral immune modulating drugs ([CDX-301, CDX-1140, and Poly-ICLC) for treating patients with melanoma, cutaneous squamous cell (SCC), Merkel cell carcinoma, bone and soft tissue sarcoma or HER2 negative breast cancer, that has spread to other places in the body (metastatic) or that cannot be removed by surgery (unresectable). Radiation therapy uses high energy rays to kill tumor cells and shrink tumors. CDX-301 is a drug that binds to a specific enzyme and induces the production of certain types of cells with immune functions. CDX-114 is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Poly ICLC is a drug that may stimulate the release of molecules that can enhance immune response (cytokines) and increase anti-tumor activity of immune cells. Tocilizumab is a monoclonal antibody that binds to receptors for a protein called interleukin-6 (IL-6). This may help lower the body’s immune response and reduce inflammation. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the tumor and may interfere with the ability of tumor cells to grow and spread. Giving these immune modulating drugs in combination with each other and radiation therapy may be more effective at treating metastatic or unresectable melanoma, cutaneous SCC, Merkel cell carcinoma, bone and soft tissue sarcoma or breast cancer than giving any of these treatments alone.
Inclusion Criteria
- Age >= 18 years of age
- Have clinically or pathologically confirmed diagnosis of unresectable and metastatic melanoma, cutaneous SCC, basal cell carcinoma, Merkel cell carcinoma, bone and soft tissue sarcoma or HER2/neu (-) breast cancer with no curative treatment options, failed at least one line of standard systemic therapy, and have been informed of other treatment options
- The unresectable disease to be irradiated and injected with medications must be located in breast, dermal, subcutaneous tissue or soft tissue or lymph nodes with the longest axis of the tumor 2-7 cm, and should be considered safe for injection by the investigator
- The metastatic disease must be measurable per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) criteria
- Patient must have lesion that can be biopsied and is willing to undergo the procedure as part of the protocol
- 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 location 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. (Palliative low dose hemostatic radiation therapy (RT) < 10 Gy within 6 months is allowed. 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 for 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
- 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 intratumoral 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
Exclusion Criteria
- Patients with a diagnosis of immunodeficiency or receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. (inhaled or topical steroids are allowed)
- Patients with HER2+ breast cancer
- Concurrent use of targeted therapy including CDK4/6, mTOR, PIK3CA, PARP, BRAF, MEK hedgehog inhibitors or chemotherapy (endocrine therapy is allowed)
- Targeted therapy including CDK4/6, mTOR, PIK3CA, PARP, BRAF, MEK hedgehog inhibitors, chemotherapy, or immunotherapy within 3 weeks prior to first dosing of study agent. (endocrine therapy is allowed)
- Patients with history of transplantation or active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
- Patients with history of (non-infectious) pneumonitis/interstitial lung disease or with current pneumonitis/interstitial lung disease, including grade 1 pneumonitis (asymptomatic; clinical or diagnostic observations only; intervention not indicated)
- Patients with prior history of 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 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, at therapeutic levels (low-molecular-weight heparin and direct oral anticoagulants are allowed if the injection is superficial and the investigator feels safe for injection)
- Patients who have had stroke/transient ischemic attack (TIA) and deep vein thrombosis (DVT)/pulmonary embolism (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
- Radiation induced angiosarcoma
- Patients with severe hypersensitivity (≥ grade 3) to pembrolizumab or tocilizumab
Additional locations may be listed on ClinicalTrials.gov for NCT04616248.
Locations matching your search criteria
United States
California
Los Angeles
PRIMARY OBJECTIVE:
I. To evaluate the safety profile of in situ immunomodulation with recombinant Flt3 ligand (CDX-301), radiotherapy, anti-CD40 agonist monoclonal antibody CDX-1140 (CDX-1140), and Poly-ICLC (Cohort A) and these with pembrolizumab (intravenously [IV]) and tocilizumab (subcutaneously [SC]) (Cohort B) in unresectable, metastatic melanoma, cutaneous SCC, Merkel cell carcinoma, 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-ICL (Cohort A) and these with pembrolizumab (IV) and tocilizumab (SC) (Cohort B).
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, 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 (Cohort A) and these with pembrolizumab (IV) and tocilizumab (SC) (Cohort B) by Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) response assessment.
II. To record the overall survival (OS) and progression free survival (PFS) in unresectable and metastatic melanoma, cutaneous SCC, Merkel cell carcinoma, 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 (Cohort A) and these with pembrolizumab (IV) and tocilizumab (SC) (Cohort B).
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, basal cell carcinoma, Merkel cell carcinoma, 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 (Cohort A) and these with pembrolizumab (IV) and tocilizumab (SC) (Cohort B).
OUTLINE: Patients are assigned to 1 of 2 cohorts.
COHORT A: Patients receive CDX-301 intratumorally (IT) on days 1-5, undergo radiotherapy on day 8, and receive CDX-1140 and Poly-ICLC IT on day 9 of each cycle. Cycles repeat every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI) during screening and computed tomography (CT) during screening and follow up. Patients also undergo biopsy and collection of blood samples throughout the study.
COHORT B: Patients receive CDX-301 IT on days 1-5, undergo radiotherapy on day 8, and receive CDX-1140 IT and Poly-ICLC IT on day 9 of each cycle. Patients also receive pembrolizumab IV on day 8 and tocilizumab SC on day 8 of each cycle. Cycles repeat every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI during screening and CT during screening and follow up. Patients also undergo biopsy and collection of blood samples throughout the study. Patients also undergo biopsy and collection of blood samples throughout the study.
After completion of study treatment, patients are followed up at 1-3 weeks, then every 3-6 months for 2 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationUSC / Norris Comprehensive Cancer Center
Principal InvestigatorFumito Ito
- Primary ID1B-22-2
- Secondary IDsNCI-2022-07303
- ClinicalTrials.gov IDNCT04616248