Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Behaviors and Mental Disorders

Rare Diseases

Lymphoma

Lymphoma, B-Cell

Aggression

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphoma, Non-Hodgkin

Lymphosarcoma

B-cell Lymphoma

Antineoplastic Agents

All Drugs and Chemicals

Gemcitabine

Melphalan

Busulfan

Antimetabolites

Antineoplastic Agents, Alkylating

Alkylating Agents

Immunosuppressive Agents

Immunologic Factors

Participants will receive high-dose chemotherapy followed by stem-cell reinfusion, and a fixed dose of CNCT19 (2×10\^6/kg) will be infused in a single-dose on day +2, +3 or +4.

2×10\^6/kg, infused in a single-dose on day +2, +3 or +4 following stem-cell infusion

CNCT19

600mg/m2/h, infused for 3 hours with loading bolus of 75mg/m2, day -7, -3,

Gemcitabine Injection

busulfan

Melphalan Injection

Dehui Zou, Dr.

The primary objective of this study is to explore the safety and efficacy of CNCT19 (a second-generation anti-CD19 CAR T-cell using 4-1BB as co-stimulatory domain provided by Juventas, Tianjin, China) infusion following ASCT in patients with relapsed or refractory B-cell lymphoma.

This is a single-center, non-randomized, open-label, prospective clinical trial to evaluate the safety and efficacy of CNCT19 infusion following high-dose chemotherapy and autologous stem-cell transplantation (HDT/ASCT) in patients with relapsed or refractory B-cell lymphoma. CNCT19 cells will be infused on day +3 (±1d) with a fixed dose of 2×10\^6/kg. The study will assess the safety and efficacy of this combinational therapy, including the incidence and severity of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hematological, and other non-hematological toxicities, and objective response rates and complete response rates and survivals of the subjects.

CNCT19 Following ASCT in Patients With Relapsed or Refractory B-cell Lymphoma

CNCT19 Following Autologous Stem Cell Transplantation in Patients With Relapsed or Refractory Aggressive B-cell Lymphoma

IPD that underlie results in a publication

Complete Response rate is defined as the incidence of a CR per the Lugano Classification (Cheson et al, 2014), as determined by study investigators.

ORR is defined as the incidence of either a CR or a partial response (PR) per the Lugano Classification as determined by study investigators.

PFS is defined as the time from the CNCT19 infusion date to the date of disease progression or death from any cause.

DOR is defined only for participants who experience an objective response after CNCT19 infusion and is the time from the first objective response to disease progression or death from any cause.

DFS is defined only for participants who achieve complete response after CNCT19 infusion and is the time from complete response to disease progression or death from any cause.

OS is defined as the time from CNCT19 infusion to the date of death from any cause.

Juventas Cell Therapy Ltd.

Zou Dehui

Principal Investigator

Skin and Connective Tissue Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Ocular Melanoma

Intraocular Melanoma

Neuroendocrine Tumor

Neuroepithelioma

Participants will undergo intra-arterial catheterization of the ophthalmic artery, with administration of 7.5mg of melphalan. After 4±1 weeks, they will receive Ru-106 plaque brachytherapy, which will be performed using a 24-mm notched plaque. Due to tumor thickness and the previous IAC, the target dose to the tumor apex shall be as close as possible to 80 Gy, respecting the safety limits regarding the risk of excessive dosage to the tumor base and scleral melting.

7.5mg of melphalan injected via intra-arterial catheterization of the ophthalmic artery.

Brachytherapy will be performed using a 24-mm notched plaque with Ruthenium-106 seeds.

Plaque brachytherapy

Rodrigo Jorge, MD, PhD

The goal of this clinical trial is to investigate a new approach for treating large uveal melanomas, a type of eye cancer. The study aims to determine the effectiveness of using intra-arterial melphalan, a chemotherapy drug, to reduce tumor thickness, allowing for subsequent radiation therapy using a Ru-106 plaque.

The main questions this trial seeks to answer are:

* Can intra-arterial melphalan effectively reduce the thickness of large uveal melanomas?
* Is the combination of intra-arterial melphalan and brachytherapy a safe and effective treatment option for these tumors?

Participants enrolled in the trial have clinically diagnosed choroidal melanoma with tumor thickness equal to or greater than 8.00 mm. They will undergo a procedure where the chemotherapy drug is injected directly into the blood vessels that supply the tumor. After a few weeks, they will receive the radiation treatment using a small device placed on the eye. Throughout the trial, participants will have different tests to monitor the tumor and their vision, such as ultrasound scans, pictures of the inside of the eye, and a test called electroretinography (ERG) to check the function of the retina. These tests will be done at the start of the trial and at 1, 3, and 6 months later to track the progress of the treatment.

INTRODUCTION Choroidal melanoma is the most common primary intraocular malignancy in adults, thus being the focus of extensive research. The primary treatment goals of this disease consist in controlling local disease, reducing the risk of distant metastases, and avoiding enucleation whenever possible.

Plaque brachytherapy is currently the standard treatment for small and medium-sized uveal melanomas. In clinical practice, ruthenium (Ru-106) or iodine (I-125) are the most commonly employed radioisotopes. Ruthenium is the most utilized radioisotope in Europe and South America due to its availability and good clinical outcomes. It is currently the only available option in Brazil's public health system (SUS). However, its use for large tumors (greater than 10 mm in thickness and/or 22 mm in diameter) is limited by the inability of delivering an adequate therapeutic dose of radiation without causing further damage to the surrounding retinal tissue.

For this reason, researchers in medical physics have been investigating new treatment options in the last decades, including external beam radiotherapy (EBRT), radiosurgery (gamma knife or linear accelerator), and proton beam therapy. Although gamma knife radiosurgery and proton beam therapy are effective treatments with reliable tumor control rates, they are associated with poor visual outcomes, inadequate globe retention, and their use is reportedly limited in public health systems of low- or middle-income countries. EBRT carries potential side effects related to a broader radiation field, with an increased risk for complications in ocular and periocular structures, such as eyelids, sclera, lens, and retina. Finally, enucleation is an effective management for very large tumors, but it is usually a last resource.

Considering the above-mentioned treatment limitations for large choroidal melanomas, our group explored an alternative approach using intra-arterial melphalan for tumor chemoreduction, aiming to reduce thickness and allow subsequent brachytherapy using a Ru-106 plaque.

Intra-arterial chemotherapy (IAC) with melphalan has been used to treat multiple cancers, including liver metastases from uveal and skin melanomas, but it has never been described as a primary tumor treatment. Previous studies have demonstrated a reasonable safety profile of the therapy when used for the treatment of other tumors.

This is a phase I clinical trial that assesses the safety profile of chemoreduction with intra-arterial melphalan, followed by ruthenium brachytherapy, performed in patients that would otherwise need enucleation due to tumor size.

METHODS Patients enrolled in the trial shall have clinically diagnosed choroidal melanoma with tumor thickness equal to or greater than 8.00 mm. IAC with 7.5 mg of melphalan will be performed through selective catheterization of the ophthalmic artery followed by Ru-106 plaque brachytherapy 4±1 weeks after the IAC. All patients will be followed up with baseline and subsequent B-scan ultrasonography, SD-OCT studies, color fundus pictures, infrared photographs, and electroretinograms (ERG).

Baseline and follow-up visits At baseline, patients will undergo a comprehensive ophthalmologic examination including ETDRS best-corrected visual acuity (BCVA), slit lamp biomicroscopy, indirect ophthalmoscopy, spectral-domain optical coherence tomography (SD-OCT), electroretinogram (ERG) performed according to the recommendations of the International Society for Clinical Electrophysiology of Vision (ISCEV) standard,14 and ocular B-scan ultrasound.

OCT examinations will be performed using the Spectralis® HRA+OCT image system (Heidelberg Engineering, Germany). The OCT scan center will be determined at baseline based on patient fixation. In subsequent visits, the automatic follow-up from the Heidelberg machine will be used to scan the same region from the initial visit. Scans over the lesions located close to the posterior pole will also be performed.

Ocular ultrasound will be performed using the Accutome 4sight device in mode B, in the initial consultation, and in 1 month, 3 months, and 6 months after the intervention. The examination will take place with the patient in a seated position, in the most ergonomic and comfortable way as possible, respecting the individual characteristics of the participants.

After the initial assessment, confirmation of the signature of the informed consent, explanation about the procedure, and verbal consent, IAC will be performed in a surgical environment. The intraarterial injection of 7.5 mg of melphalan will be performed only once, in the ophthalmic artery corresponding to the eye affected by choroidal melanoma. Chemotherapy infusion will be performed directly into the ostium of the ophthalmic artery through a microcatheter guided by fluoroscopy via the femoral artery. The drug will be infused in a slow pulsatile manner for 30 minutes to avoid backflow of chemotherapy and arterial occlusion.

After 4±1 weeks, Ru-106 brachytherapy will be performed using a 24-mm notched plaque. Due to tumor thickness and previous IAC, the target dose to the tumor apex should be the closest possible to 80 Gy, respecting the safety limits regarding the risk of excessive dosage to the tumor base and scleral melting.

Melphalan Chemoreduction for Ocular Melanoma

Melphalan Intra-arterial Chemotherapy for Choroidal Melanoma Chemoreduction - a Phase I Clinical Trial

All IPD that underlie results in a publication will be shared.

Participants will undergo ERG exams at baseline, 1, 3, and 6 months after the first intervention. The researchers will assess the patterns of ERG waves to determine whether there are signs of retinal toxicity.

Measurements of tumor thickness and widest base diameter, in millimeters, as compared to baseline, to be assessed via b-scan ultrasonography.

Participants will undergo visual acuity testing at baseline, 1, 3, and 6 months after the first intervention. BCVA will be determined in ETDRS letter changes and the Snellen system.

Various evaluations including clinical assessment of systemic side effects, B-scan ultrasonography, color fundus pictures, near-infrared photographs, and electroretinography (ERG) will be performed at specific time points: baseline, 1, 3, and 6 months after the first intervention.

Participants will be clinically assessed for adverse events immediately after each intervention, as well as 1, 3, and 6 months after the initial intervention. This assessment will be provided by the medical sub-investigators through a thorough anamnesis and clinical examination. Additional investigation, specialty consultations, and laboratory testing may be ordered on an individual basis according to each patient's signs and symptoms.

We consider an adverse event any untoward medical occurrence or unfavorable sign, symptom, or disease that happens to a participant during the course of the trial, regardless of whether it is related to the interventions being studied. They can encompass a wide range of occurrences, including physical or psychological health problems, abnormal laboratory findings, or worsening of a pre-existing condition.

Number of enrolled patients that required enucleation or evisceration of the affected eye.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
CNCT19 Following ASCT in Patients With Relapsed or Refractory B-cell Lymphoma	NCT04690192	Large B-cell Ly...	CNCT19 Gemcitabine Inj... busulfan Melphalan Injec...	18 Years - 65 Years	Institute of Hematology & Blood Diseases Hospital, China
Melphalan Chemoreduction for Ocular Melanoma	NCT05893654	Uveal Melanoma	Melphalan Injec... Plaque brachyth...	18 Years -	Hospital das Clínicas de Ribeirão Preto
CNCT19 Following ASCT in Patients With Relapsed or Refractory B-cell Lymphoma	NCT04690192	Large B-cell Ly...	CNCT19 Gemcitabine Inj... busulfan Melphalan Injec...	18 Years - 65 Years	Institute of Hematology & Blood Diseases Hospital, China

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