Neoplasms

Skin and Connective Tissue Diseases

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Rare Diseases

Melanoma

Melanoma, Cutaneous Malignant

Skin Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Measure of cutaneous melanomas by ultrasound biomicroscopy

Measure of cutaneous melanomas by ultrasound Biomicroscopy

Ultrasound Biomicroscopy

Nicolas AZULAY

Charles RAFFAELLI

Cutaneous melanomas represent 4 to 11% of cutaneous cancers, but is responsible for 75% of the deaths reported for these pathologies. The incidence rate double every 10 years. Fourteen thousand cases and 1700 deaths were reported in France in 2015.

The local staging of the cancer is represented by the Breslow index, which is measured on histological analysis, corresponding to the maximum depth of the cancer. Breslow index is a good pronostic value, and is used to choose for the best treatment for the patient.

Having access to the Breslow index before the first resection of the tumor would allow dermatologists to make a complete resection with the best treatment, and the analysis of the sentinel lymph node, all during the same surgical time. Currently, patients need 2 surgeries : one before the Breslow index, and a second one after.

The depth of cutaneous melanoma was already evaluated with High-Frequency Ultrasound (HF-US), but gave disappointing results, with Breslow index not being accurately measured.

Only 50% of tumors less than 2mm depth were efficiently measured. Results were even worst for bigger tumors.

Ultrasound biomicroscopy (UBM) is a new approach, depending on the use of ultra high frequency and large-band transducer. Nice's CHU acquired the only ultrasound device capable of applying such ultra high frequency ultrasound (UHF-US) to human tissues. The device is a VEVO MD (Vevo MD, Toronto, Canada) and equip the Ultrasound Department since June 2018.

The images investigators can assess with this device have an axial resolution of 30µm, for a maximum emission frequency of 70MHz, which was not attainable until this day in human care.

Furthermore, when compared to some of the mono-frequency devices investigators experimented before, this device allow investigators to attain a maximum depth of analysis up to 8mm.

In consequence, this device seems to be able to realize an extremely precise analysis of the skin, and of the cutaneous melanomas, for a structural analysis, as well as a precise depth measurement, and should be evaluated in the measurement of the Breslow Index.

The objective of the study is to analyze the interest of ultrasound biomicroscopy in the pre-therapeutic evaluation of the Breslow index of cutaneous melanoma, compared to histological findings.

The study will include 60 patients with cutaneous melanomas, recently diagnosed in the Dermatology Department of the Nice University Hospital (Pr Bahadoran, Pr Passeron, Pr Lacour). Each patient will beneficiate from complete Ultrasound biomicroscopy analysis of the tumor The examination will be made blindly by 2 operator, both with experience in Ultra High frequency Ultrasound examinations (Dr Azulay, Dr Raffaelli).

The maximum depth of the melanoma (Breslow index) will be recorded in µm. After surgical resection, the histologic analysis (Dr Long, Pr Hofman, Clinical and Experimental AnatomoPathologic laboratory, Nice's University Hospital) will measure the gold-standard Breslow Index.

The comparison will analyze the capacity of Ultrasound biomicroscopy for a precise measurement of the Breslow Index, as well as the inter and intra-operator concordance.

If the results of this study are positives and suggest a modification of the therapeutic strategy, a larger multicentric study would be launched in the near future.

Evaluation of Ultrasound Biomicroscopy in the Local Staging of Cutaneous Melanoma

The measurement of the thickness of the malignant melanoma will be carried out in Ultrasound Biomicroscopy in two orthogonal planes using the maximum value obtainedThe measurement will be performed pre-operatively with the device (transducer) attached to an articulated arm from the anterior edge of the lesion to the interface between the posterior border of the lesion and the underlying dermis or hypodermis.

The measurement will be expressed in mm. The histological measurement will be performed according to the usual techniques after fixation of the surgical specimen. It will also be expressed in µm.

Conventional High Frequency Ultrasound (18MHz) will be performed prior to Ultrasound Biomicroscopy analysis using an 18 MHz probe according to the usual technique used in High Frequency Ultrasound (freehand) and the thickness of the malignant melanoma will be expressed in µm. Standard gold is defined as at the main objective.

High Frequency Ultrasound (33MHz) will be performed prior to Ultrasound Biomicroscopy analysis using an 33 MHz probe according to the usual technique used in High Frequency Ultrasound (freehand) and the thickness of the malignant melanoma will be expressed in µm. Standard gold is defined as at the main objective.

Global echogenicity of the malignant melanoma in relation to the dermis: hypoechoic, isoechoic, hyperechoic

Presence of Avascular areas of malignant melanoma using power Doppler in Ultrasound Biomicroscopy Data will be compared with the histological data

Measurement of the thickness of malignant melanoma Ultrasound Biomicroscopy by 2 differents investigators to evaluate the intra and inter-observer matching.

The radiofrequency signal acquired in Ultrasound Biomicroscopy will be analyzed on a platform dedicated to image processing, looking for radio frequency signal specifics of melanoma, compared to adjacent healthy skin.

Homogeneous or heterogeneous structure of the malignant melanoma in Ultrasound Biomicroscopy

Presence of hyperechoic or anechogenic foci in Ultrasound Biomicroscopy

Presence of hyperechoic spans in Ultrasound Biomicroscopy

Appearance of the contours of the melanoma in Ultrasound Biomicroscopy : regular, irregular, or blurred

Type of vascularization of malignant melanoma using power Doppler in Ultrasound Biomicroscopy: homogeneous, heterogeneous Data will be compared with the histological data

Intensity of vascularization relative to the adjacent normal dermis, with Doppler parameters fixed Data will be compared with the histological data

Centre Hospitalier Universitaire de Nice

Eye Diseases

Diseases and Abnormalities at or Before Birth

Retinoblastoma

Neoplasms, Neuroepithelial

Neoplasms, Glandular and Epithelial

Retinal Neoplasms

Eye Neoplasms

Eye Diseases, Hereditary

Retinal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Central Nervous System Depressants

Dermatologic Agents

Amino Acids

Etoposide

Anesthetics

Carboplatin

Vincristine

Melphalan

Etoposide phosphate

Podophyllotoxin

Mechlorethamine

Nitrogen Mustard Compounds

Enzyme Inhibitors

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Alkylating

Alkylating Agents

Immunosuppressive Agents

Immunologic Factors

Keratolytic Agents

Phenylalanine

Alanine

Biospecimen Collection

Examination Under Anesthesia

Site Public Contact

Elizabeth D. Alva

Jay Michael S. Balagtas

Sandra Luna-Fineman

Laura Sedig

Daniel Willis

Jessica M. Sun

Erin Wright

Rabi Hanna

Carlos Rodriguez-Galindo

Shannon M. Cohn

Daniel C. Bowers

Murali M. Chintagumpala

Najat C. Daw

Marianne B. Phillips

Rachana Shah

This phase II trial tests the safety and side effects of adding melphalan (by injecting it into the eye) to standard chemotherapy in early treatment of patients with retinoblastoma (RB). RB is a type of cancer that forms in the tissues of the retina (the light-sensitive layers of nerve tissue at the back of the eye). It may be hereditary or nonhereditary (sporadic). RB is considered harder to treat (higher risk) when there are vitreous seeds present. Vitreous seeds are RB tumors in the jelly-like fluid of the eye (called the vitreous humor). The term, risk, refers to the chance of the cancer not responding to treatment or coming back after treatment. Melphalan is in a class of medications called alkylating agents. It may kill cancer cells by damaging their deoxyribonucleic acid (DNA) and stopping them from dividing. Other chemotherapy drugs given during this trial include carboplatin, vincristine, and etoposide. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of cancer cells. Vincristine is in a class of medications called vinca alkaloids. It works by stopping cancer cells from growing and dividing and may kill them. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and DNA repair and may kill cancer cells. Adding melphalan to standard chemotherapy early in treatment may improve the ability to treat vitreous seeds and may be better than standard chemotherapy alone in treating retinoblastoma.

PRIMARY OBJECTIVE:

I. To determine the feasibility of administering intravitreal melphalan by cycle 6 when given in combination with systemic carboplatin, vincristine, and etoposide (CVE) for the treatment of Group D retinoblastoma with vitreous seeding.

SECONDARY OBJECTIVES:

I. To determine the safety and toxicity profile associated with intravitreal melphalan in combination with systemic CVE for the treatment of Group D retinoblastoma with vitreous seeding.

II. To evaluate the efficacy of intravitreal melphalan in conjunction with systemic chemotherapy in Group D intraocular retinoblastoma with vitreous seeding.

EXPLORATORY OBJECTIVES:

I. To determine if eyes that become eligible for injection at cycle 3 or later would have been eligible for injection at diagnosis by retrospective central review of examination under anesthesia (EUA) and ultrasound biomicroscopy (UBM) images from diagnosis.

II. To validate and standardize the extraction, storage and collection protocols across multiple centers to demonstrate that aqueous humor from eyes undergoing therapy have high enough tumor-derived deoxyribonucleic acid (DNA) concentration for whole genome sequencing and RB1 testing.

III. To explore the relationship between highly-recurrent retinoblastoma (RB) somatic copy number alterations (SCNAs) and ocular salvage as well as tumor fraction (% of tumor DNA) as a marker of minimal residual disease and risk of intraocular disease relapse.

IV. To evaluate the effects of intravitreal melphalan therapy in the histopathology of enucleated eyes for progressive or recalcitrant retinoblastoma while on therapy.

V. To evaluate the long-term visual potential of eyes salvaged using intravitreal therapy.

OUTLINE:

CYCLES 1-2: Patients receive CVE regimen consisting of: carboplatin intravenously (IV) over 15-60 minutes on days 1 and 2 of each cycle, vincristine IV on day 1 of each cycle, and etoposide IV over 90-120 minutes on day 1 and 2 of each cycle. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ultrasound biomicroscopy (UBM) and imaging of the eye during a procedure called examination under anesthesia (EUA) at baseline and prior to each cycle. NOTE: UBM is completed prior to cycle 1 only.

CYCLES 3+: Patients receive CVE regimen as in cycles 1-2. Patients also undergo EUA prior to each cycle to determine eligibility to receive melphalan. If found eligible, patients receive intravitreal injection of melphalan once between days -14 to 14 of each cycle. Patients who are not eligible for melphalan for any cycle receive CVE only regimen for that cycle. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients may be eligible to receive additional cycles of melphalan alone (maximum of 6 injections).

After completion of study treatment, patients are followed up periodically until 5 years from study enrollment.

A Study to Give Treatment Inside the Eye to Treat Retinoblastoma

Intravitreal Melphalan for Intraocular Retinoblastoma

In order to determine if eyes that become eligible for injection at cycle 3 or later would have been eligible for injection at diagnosis, the retrospective central review on images from diagnosis for eyes that are eligible for injection at cycle 3 or later will be summarized.

Extract tumor-derived deoxyribonucleic acid (DNA), from aqueous humor, for whole genome sequencing and retinoblastoma (RB)1 testing.

Will explore the relationship between highly-recurrent RB SCNAs and tumor fraction (% of tumor DNA) as a marker of minimal residual disease and risk of intraocular disease relapse.

Will explore the relationship between highly-recurrent RB SCNAs and ocular salvage as well as tumor fraction (% of tumor DNA) as a marker of minimal residual disease and risk of intraocular disease relapse.

Will be calculated along with the 95% confidence interval. The number of evaluable eyes for this aim will depend on the ocular salvage rate.

Eligible patients who retain the affected eye will be evaluated for visual acuity. The visual acuity will be evaluated prior to cycle 1 and at one year from end of therapy, if age-appropriate. The visual acuity data will be summarized by evaluation time points.

A patient will be considered to have experienced intravitreal injection feasibility success if intravitreal melphalan can be delivered by cycle 6. If the treating physician does not inject because the eye has a full complete response (CR) for vitreous seeds after 2 cycles of systemic chemotherapy, it will be counted as a success in the feasibility analysis. Any feasibility evaluable patient who does not experience feasibility success will be considered a feasibility failure. For a bilateral patient with two Group D eyes with vitreous seeds, he/she will be categorized based on the worse results with the intent of being conservative, i.e., if intravitreal melphalan can be delivered in one eye but not the other by cycle 6 for any reason other than a CR of vitreal seeds, the patient will be deemed as experiencing a failure.

Any eligible patient who receives protocol therapy will be considered as evaluable for toxicity.

Any eligible patient who receives protocol therapy will be considered as evaluable for EFS. Patients who need non-protocol chemotherapy, external beam radiotherapy, or enucleation will be considered as having a treatment failure and be considered as experiencing EFS events. The analysis will be conducted per patient level. The EFS along with the 95% confidence intervals will be estimated using the Kaplan-Meier method.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Evaluation of Ultrasound Biomicroscopy in the Local Staging of Cutaneous Melanoma	NCT04702854	Cutaneous Melan...	Ultrasound Biom...	18 Years -	Centre Hospitalier Universitaire de Nice
A Study to Give Treatment Inside the Eye to Treat Retinoblastoma	NCT05504291	Bilateral Retin... Childhood Intra... Group D Retinob... Stage I Retinob... Unilateral Reti...	Biospecimen Col... Carboplatin Etoposide Examination Und... Melphalan Ultrasound Biom... Vincristine	- 18 Years	Children's Oncology Group

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