Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Melanoma, Cutaneous Malignant

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 Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Kristina Orlova, MD, PhD

Retrospective chart review Study of patients with BRAF V600 positive advanced (unresectable or metastatic) melanoma, who were treated with targeted therapy in routine clinical practice in Russian Federation

This study is an observational multicentral retrospective chart review study in patients with BRAF V600 positive advanced (unresectable or metastatic) cutaneous melanoma, who have treated by BRAF inhibitors (BRAFi) or MEK inhibitors (MEKi) in routine clinical practice in Russia. 300 patients will be included in the study.

The study does not aim to prove any formal hypothesis and does not imply any intervention in standard medical care, and all medical events recorded during the study have already occurred. The data sources of this study will be medical records, patients' charts and other related medical documentation that allows to fully follow the course of the disease and collect all the necessary information according to Protocol.

For identification of molecular genetic markers that cause resistance and sensitivity to targeted therapy, an analysis of tumor tissue will be provided in the laboratory of biological microchips "Institute of Molecular Biology. V.A. Engelhardt" of the Russian Academy of Sciences. The analyzed materials will be paraffin blocks with samples of tumor tissue of only patients with primary resistance to targeted therapy (inhibitors BRAF / +/- MEK inhibitor).

In the course of the study, the Contract Research Organization (CRO) "Crocus Medical B.V." will conduct periodic monitoring visits to ensure that the data collected are accurate and credible. Regular monitoring visits include Source Data Verification (SDV) in accordance with the monitoring plan, monitoring compliance with the research procedures, as well as the proper and timely maintenance of the main clinical study documents, including the reporting provided for by the rules of good clinical practice, the legislation of the Russian Federation and Standard Operating Procedures (SOPs) of the CRO.

The investigators will be responsible for the collection and provision of all clinical and laboratory data, as well as safety data, that are entered in electronic Case Report Forms (e-CRF), and must ensure data authenticity and compliance with the primary documentation.

Before hard database lock, the database will be inspected in order to reveal missing and suspicious data. The queries will be generated to correct or fill-in such data. In case the data failed to refine, their will be considered as missing, no data-imputation methods are planned.

One of the efficacy endpoints of the study is defined as overall survival which represents the time-to-event data, these data will be analyzed with Kaplan-Meyer method and Cox regression. Time to event will be defined as a number of days passed from start of treatment until any-cause death. Patients alive until the end of study will be right-censored by the end-of-study day or by the day of preliminary withdrawal. Based on Kaplan-Meyer curves the following parameters would be accessed: median survival, one- and two-year survival. The Cox regression will include the following covariates: age, sex, baseline therapy, presence of metastasis in brain, baseline level of lactic dehydrogenase (LDH), number of tissues with metastasis, time from the beginning of the target therapy, etc. Additional covariates could be also accessed when necessary. The hazard ratio (HR) along with 95% confidence interval will be evaluated for each covariate.

Analyses of categorical efficacy endpoints (number of patients taken different therapies, objective response rate, number of patients with molecular genetics alterations) will be performed with chi-square criterion or Fisher's exact test in case of any expected frequencies below 5. In addition, the logistic regression could be build based on the above mentioned covariates. The odds ratio (OR) along with 95% confidence interval will be evaluated for each covariate.

The progression-free survival (PFS) will be analyzed analogously as described above for the overall survival data. Time to event will be defined as a number of days passed from treatment start until either any-cause death or documented disease progression whichever occurs first. Patients without event will be right-censored by the end-of-study day or by the day of preliminary withdrawal. Based on Kaplan-Meyer curves the following parameters would be accessed for all the patients as well as for the subgroups of baseline therapy (target therapy, immunochemistry, chemotherapy): 6-, 12-, 18- and 24-months progression-free survival. In addition, the PFS will be analyzed for the patients treated with BRAFi as a monotherapy with successive inclusion of the MEKi.

Time to response and duration of response data will be analyzed similarly. Time to response will be defined as a number of days passed from treatment start until first documented response to the therapy. Non-responders will be right-censored by the end-of-study day or by the day of preliminary withdrawal. This analyses will be conducted for all the patients as well as for the subgroups of baseline therapy (target therapy, immunochemistry, chemotherapy).

Analyses of the duration of response will be performed only among the responders. Duration of the response will be defined as a number of days passed from the first documented response until either any-cause death or documented disease progression whichever occurs first. Patients responding until the study end will be right censored by the end-of-study day or by the day of preliminary withdrawal.

The data on duration of the therapy will be presented with descriptive statistics for each therapy line.

Adverse events (AE) and Serious Adverse Events (SAE) will be coded according to MedDRA. Each AE/SAE will be summarized with counts and frequencies. The data on AE will be tabulated by System Organ Classes (SOC) and presented with indication their preferred terms (PT) by baseline therapy and severity. When necessary, the comparison of frequencies of AEs/SAEs between subgroups will performed with chi-square criterion or Fisher's exact test in case of any expected frequencies below 5.

Advanced Melanoma in Russian Experience

Multicentral Retrospective Chart Review Study of Targeted Therapy Use in Patients With BRAF V600 Advanced (Unresectable or Metastatic) Cutaneous Melanoma in Routine Clinical Practice in Russian Federation

The rate of progression and type according to TNM classification for melanoma

Percentages of patients who were treated by targeted, immunotherapy and chemotherapy or other therapy types of treatment usage in each line of treatment

The median OS of patients with unresectable advanced BRAF mutant melanoma during targeted therapy

2 year OS rate of patients with unresectable advanced BRAF mutant melanoma during targeted therapy

The ORR by subgroup of patients with unresectable advanced BRAF mutant melanoma during targeted therapy

The DCR by subgroup of patients with unresectable advanced BRAF mutant melanoma

The median PFS and 24 months PFS rate of patients with unresectable advanced BRAF mutant melanoma during targeted therapy

The rate of all grade and grade 3-5 adverse events and the rate of discontinuation of study drug(s) due to adverse events.

The PFS rate according to the mutation BRAF subtype

The OS rate according to the mutation BRAF subtype

Crocus Medical B.V.

MelanomaPRO, Russia

Senior Сlinical Researcher

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Rituximab

Nivolumab

Ipilimumab

Antineoplastic Agents, Immunological

Immunologic Factors

Immune Checkpoint Inhibitors

This is standard of care arm: induction with 4 cycles (21 days each) of Ipilimumab and nivolumab followed by continuation with nivolumab alone every month X1 year (13 doses).

This includes induction with 4 cycles of ipilimumab and nivolumab X 4 cycles followed by continuation with nivolumab alone every month for 1 year as in standard of care arm. Each induction cycle is 21 days and includes ipilimumab on day 1 plus nivolumab on day 1. In addition, patients will receive 4 weekly doses of Rituxan (first dose intravenously and then 3 weekly doses subcutaneously). First dose of Rituxan will be administered one week following the start of cycle 1 of ipilimumab and nivolumab. All treatments will have a +/-3 business day window for administration.

Receive standard of care nivolumab therapy

Rituximab and Hyaluronidase Human

Receive standard of care ipilimumab therapy

Kavita Dhodapkar, MD

This phase II trial studies whether rituximab and hyaluronidase human (Rituxan Hycela) can prevent immune related adverse events in participants with stage III-IV melanoma that cannot be removed by surgery who are undergoing nivolumab and ipilimumab therapy.

PRIMARY OBJECTIVE:

I. To compare rates for grade 3-4 immune-related adverse event (IRAE)s in the first 6 months in patients treated with combination checkpoint blockade (CCB) therapy (anti-CTLA4 and anti-PD1) as a part of standard of care for advanced melanoma who are treated with a single course of 4 weekly doses of rituximab and hyaluronidase human (Rituxan) therapy versus those who are not treated with Rituxan.

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability (in terms of Rituxan-related adverse events) in patients with melanoma receiving CCB.

II. To compare objective response rate in patients receiving CCB therapy + Rituxan versus CCB therapy alone.

III. To compare 1 year overall and progression-free survival in patients receiving CCB therapy + Rituxan versus CCB therapy alone.

IV. To compare changes in cluster of differentiation 21lo (CD21lo) B cells in patients receiving CCB therapy + Rituxan versus CCB therapy alone.

V. To compare changes in T cells in patients receiving CCB therapy + Rituxan versus CCB therapy alone.

OUTLINE: Participants are randomized to 1 of 2 arms.

ARM A: Participants receive standard of care ipilimumab and nivolumab therapy.

ARM B: Participants receive standard of care ipilimumab and nivolumab therapy. On day 2 of each cycle, participants also receive rituximab and hyaluronidase human intravenously (IV) or subcutaneously (SC) weekly starting week 1 for 4 doses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up for 4 weeks.

Rituximab and Hyaluronidase Human in Patients With Advanced Melanoma Undergoing Nivolumab and Ipilimumab Therapy

A Randomized Phase 2 Study of Rituxan Hycela in Patients With Advanced Melanoma Undergoing Combination Immune Checkpoint Blockade With Nivolumab and Ipilimumab

All patients will be evaluable for toxicity from the time of their first treatment with ipilimumab/nivolumab. Investigators will review the toxicities, grade, and attribute each toxicity.

Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune-related (ir)RECIST. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.

Overall survival is defined as the duration of time from start of treatment to time of death or last follow-up, whichever occurs first.

PFS is defined as the duration of time from start of treatment to time of progression or death or last follow-up, whichever occurs first.

Genentech, Inc.

Emory University

Principal Investigator

Vaccines

Immunomodulating Agents

Adjuvants, Immunologic

Therapeutic Classification:

* Noncellular, Therapeutic Cancer Vaccine \> Immunomodulator

Route of Administration:

* Intratumoral injection of cutaneous, subcutaneous or nodal lesions

Mechanism of Action:

* Injection of the IFx-Hu2.0 plasmid DNA construct into the target lesion facilitates the localized expression of the highly immunogenic Emm55 protein by the tumor cells on their cell surface.

Physiological Effect:

* This expression then primes a cascade of immune events that exposes the patient-specific abnormal tumor antigens to the effector mechanisms of the immune system. The immune response becomes systemic as inter-antigenic epitope spreading produces neoantigens to naïve T cells. Therefore, injected lesions are targeted along with non-injected lesions (abscopal effect). This is especially important in conditions where the mutational phenotype varies greatly among individual lesions.

Subjects enrolled will receive a fixed IFx-Hu2.0 (plasmid DNA) dose of 0.1 mg injected in up to 3 lesions at a single time point (28-day follow-up post last injection).

IFx-Hu2.0

Joseph Markowitz, MD, PhD

Six patients will receive IFx-Hu2.0 on an outpatient basis at a single time point in a single lesion, two lesions, or three lesions, as a monotherapy (a maximum of three lesions could be injected). These patients will be assessed for any immediate adverse reactions and at Week 4 (Day 28+/-7 business days for any delayed adverse events.

Six male and/or female adult patients (greater than or equal to 18 years old), of any ethnicity and race, with unresectable stage III or stage IV cutaneous melanoma with accessible lesions, will be eligible for enrollment and treatment with IFx-Hu2.0.

To be eligible for this study, patients with unresectable metastatic disease must have failed, refused or been deemed not candidates for at least one form of systemic anti-PD-1-based immunotherapy as well as BRAF inhibition, if BRAF V600 mutated. Talimogene laherparepvec (IMLYGIC®) is indicated for local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. Therefore, patients with unresectable cutaneous, subcutaneous, and nodal melanoma lesions recurrent after initial surgery must have failed, refused or been deemed not candidates for talimogene laherparepvec to be eligible for this study.

Enrollees will receive IFx-Hu2.0 at a single time point. Depending on the number of accessible lesions, a patient could receive up to three doses across three lesions (one dose per lesion). Forty milliliters of peripheral blood will be collected from these patients prior to treatment administration and at the follow-up visit four weeks later. The target dose will be 100 μg of plasmid DNA per lesion injected at a final dose volume of 200 μL per lesion. To allow for the observation of any acute toxicity in the first subject enrolled and prevent any occurrence of excessive toxicities in subsequent subjects, the first subject enrolled will receive a single dose of IFx-Hu2.0. Subsequent subjects will be administered the product after at least seven days. Beyond the first subject, the maximum number of lesions to be injected at any given time point in the study phase proposed is three lesions. These samples will be used to perform complete blood counts (CBC) and clinical chemistry tests. A urine sample will be obtained for urinalysis for protein and blood at the same frequency. Blood samples will be drawn for immune response evaluation as well. At the end of the study period, a biopsy of the lesion injected and a non-injected lesion (if applicable) will be collected. If the patient has a response to therapy, the patient will have the option of continuing the study at three-week intervals so long as they have not progressed. Optional tumor biopsies and peripheral blood collections may be obtained on subsequent treatment cycles.

pDNA Intralesional Cancer Vaccine for Cutaneous Melanoma

Phase 1 Study Using a Plasmid DNA Coding for Emm55 Streptococcal Antigen in Patients With Unresectable Stage III or Stage IV Cutaneous Melanoma

Safety was reported using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Feasibility was defined as the ability to treat at least five of the six patients enrolled without drug-related dose-limiting toxicity (DLT).

Evaluation of response rate and assessment of the antitumor immune responses induced by IFx-Hu2.0 per RECIST v1.1 for target lesions.

Complete Response (CR), Disappearance of all target lesions. Partial Response (PR), ≥ 30% decrease in the sum of the longest diameters of target lesions compared with baseline.

Stable Disease (SD), Neither sufficient shrinkage to qualify for partial or complete response (CR or PR) nor sufficient increase to qualify for progressive disease (PD).

Progressive Disease (PD), Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

H. Lee Moffitt Cancer Center and Research Institute

TuHURA Biosciences, Inc.

Therapeutic Classification:

* Noncellular, Therapeutic Cancer Vaccine \> Immunomodulator

Route of Administration:

* Intratumoral injection of cutaneous, subcutaneous or nodal lesions

Mechanism of Action:

* Injection of the IFx-Hu2.0 plasmid DNA construct into the target lesion facilitates the localized expression of the highly immunogenic Emm55 protein by the tumor cells on their cell surface.

Physiological Effect:

* This expression then primes a cascade of immune events that exposes the patient-specific abnormal tumor antigens to the effector mechanisms of the immune system. The immune response becomes systemic as inter-antigenic epitope spreading produces neoantigens to naïve T cells. Therefore, injected lesions are targeted along with non-injected lesions (abscopal effect). This is especially important in conditions where the mutational phenotype varies greatly among individual lesions.

IFx-Hu2.0: Subjects enrolled will receive a fixed IFx-Hu2.0 (plasmid DNA) dose of 0.1 mg injected in up to 3 lesions at a single time point (28-day follow-up post last injection).

IFx-Hu2.0 (Plasmid DNA) 0.1 mg/Lesion/Time Point

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Stage III: tumor no more than 2mm thick and could be ulcerated. Cancer has spread to 1-3 nearby nodes. It has not spread to distant parts of the body.

Stage IIIC: tumor no more than 2mm thick with 1-3 macroscopic node metastases and an ulcerated primary melanoma. Patients with satellite(s)/in-transit metastases, or any patient with nodal disease regardless of ulceration status.

Stage IV: tumor of any thickness and could be ulcerated. Cancer could have spread to nearby nodes. It has spread to distant nodes or to organs.

Note: lesser stages correlate with improved outcomes.

AJCC Clinical Staging

James Bianco, MD - Chief Executive Officer

Participants Analyzed

Serious Adverse Events (SAEs)

Dose Limiting Toxicity (DLT)

The data analysis is described to assess the safety of the injection of the study agent in six patients the intention-to-treat (ITT) approach will be used for response to treatment data analysis of this trial (secondary objective).

Number of Participants With Serious Adverse Events (SAEs) and/or Dose Limiting Toxicities (DLTs)

The intention-to-treat (ITT) approach will be used for response to treatment data analysis of this trial.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Advanced Melanoma in Russian Experience	NCT03663647	Cutaneous Melan... BRAF V600 Mutat...		18 Years - 89 Years	MelanomaPRO, Russia
Rituximab and Hyaluronidase Human in Patients With Advanced Melanoma Undergoing Nivolumab and Ipilimumab Therapy	NCT03719131	Cutaneous Melan... Cutaneous Melan... Stage III Melan... Stage IIIA Skin... Stage IIIB Skin... Stage IIIC Skin... Stage IV Skin M... Unresectable Me...	Nivolumab Rituximab and H... Ipilimumab	18 Years -	Emory University
pDNA Intralesional Cancer Vaccine for Cutaneous Melanoma	NCT03655756	Cutaneous Melan... Cutaneous Melan...	IFx-Hu2.0	18 Years -	TuHURA Biosciences, Inc.

Spots Global Cancer Trial Database for cutaneous melanoma, stage iv