A-dmDT390-bisFv(UCHT1) Fusion Protein With Ionizing Radiation and Pembrolizumab for the Treatment of Stage IV Melanoma
This study evaluates the effectiveness of adding a single four-day treatment of the fusion protein A-dmDT390-bisFv(UCHT1) — plus single palliative tumor radiation — with standard of care KEYTRUDA (Pembrolizumab) therapy for the treatment of metastatic melanoma. The results will be measured by comparing the combined therapy to historical data of KEYTRUDA alone.
Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms
An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.
An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.
|Eligible Ages||18 Years - 80 Years|
- - All patients must have histologically proven stage IV metastatic melanoma consisting of at least two lesions >= 1.5 cm that would not occupy the same radiation field.
- - Patients must have a performance status of < 2 on Eastern Cooperative Oncology Group scale (see Appendix).
- - Patients must have: - bilirubin < 1.5 mg/dL, - transaminases < 2.5 X ULN, - albumin > 3 gm/dL, - creatinine < 2.0 mg/dL, - adequate pulmonary function by physical exam and pulse oximetry and adequate cardiac reserve (EF > 50% normal).
- - Patients must have a normal echocardiogram without any evidence of cardiac chamber hypertrophy, dilatation or hypokinesis.
- - Patients must give written informed consent prior to registration (see Informed Consent).
- - Females and males must be willing to use an approved form of birth control while on this study and for 2 weeks after completion.
- - Patients of ages 18-80 are eligible provided they have stage IV melanoma and are negative for BRAF or have failed BRAF inhibitor treatment or if they have failed or are intolerant to other established therapy known to provide clinical benefit for their condition or if they have been adequately consented and agreed to forgo FDA approved clinically meaningful therapy.
- - Failure to meet any of the criteria set forth in Inclusion Criteria.
- - Inability to give informed consent because of psychiatric problems, or complicated medical problems.
- - Serious concurrent medical problems, uncontrolled infections, or disseminated intravascular coagulopathy (DIC).
- - Preexisting cardiovascular disease, the only exception being well controlled essential hypertension with a sitting B.
- - Congestive heart failure, - Atrial fibrillation, - Pulmonary hypertension, - Anticoagulant drug therapy, - Thromboembolic events, - Cardiomyopathy or a myocardial infarction within the past 8 months.
- - Pregnant or nursing women will be excluded from study.
- - History of congestive heart failure.
- - History of cirrhosis of the liver.
- - Prior treatment with alemtuzumab (Campath) or similar agents or procedures that depress blood T cell counts to below 50% of the lower limit of normal.
This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.
Phase 0: Exploratory study involving very limited human exposure to the drug to determine whether a drug is modulating its target.
Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.
Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.
Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.
Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.
|Phase 1/Phase 2|
The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.
Category of organization(s) involved as sponsor (and collaborator) supporting the trial.
|Overall Status||Not yet recruiting|
The disease, disorder, syndrome, illness, or injury that is being studied.
|Stage IV Melanoma|
The purpose of this trial is to test the hypothesis that A-dmDT390-bisFv(UCHT1) can act as an immunomodulator of late stage metastatic melanoma when combined with palliative radiation (to induce the priming of activated T cells with tumor antigens) and Pembrolizumab. A-dmDT390-bisFv(UCHT1), an anti-T cell immunotoxin is currently being studied as a treatment for cutaneous T cell lymphoma and other CD3+ malignant diseases (NCT00611208 and NCT02943642). During the course of this study, data accumulated that A-dmDT390-bisFv(UCHT1) could be acting as an immunomodulator. This was based on the observation that four out of six partial responses converted to complete responses at times ranging between 6 and 24 months following the completion of the 4-day treatment protocol (serum half life ~45 min.) and no other treatment took place. Complete response durations were 4-6+ years. Checkpoint inhibitors have revolutionized the treatment of certain solid tumors, notably melanoma, NSCLC and renal cancer. Yet the overall response rate remains low and the mechanisms limiting responses have not been elucidated. Based on the findings that checkpoint inhibitors have higher response rates when the tumor neoantigen burden is higher (over 1 mutation per megabase, Shumacher & Schreiber, 2015) the investigators propose to increase the neoantigen burden by combining two distinct manipulations: 1. Treatment with an anti-CD3 fusion protein Resimmune days 1-4 to induce a 20-fold increase in CD8+ central memory T cells and 2. Treatment with anti-PD1 day 16 and q. 3 weeks to block PD-1/PD-L1 negative regulation on the newly activated T cells (Blake et al., 2015) and to block high levels of PD-1 in the tumor microenvironment (Ahmadzadeh et al., 2009). Palliative tumor radiation day 5 will provide the tumor antigen release needed to convert the expanded central memory T cells to effector memory T cells. The study will be a single-arm, uncontrolled phase I/II trial to estimate the safely of the combined treatment and then estimate the efficacy in terms of RECIST 1.1 in patients with stage Stage IV metastatic melanoma. The primary endpoint is the clinical response as defined by progression-free survival (PFS). The second end point will be tolerability to treatment. Secondary end points to be considered are overall survival (OS). The study is conducted in 2 phases. In phase I (safety), the investigators will enroll 6 patients. In first stage, 25 total patients will be enrolled. Using Simon's two stage minimax design for phase II trials, the investigators plan to enroll a maximum of 63 patients.
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James Graham Brown Cancer Center
Louisville, Kentucky, 40202