Neoplasms

Symptoms and General Pathology

All Conditions

Skin and Connective Tissue Diseases

Nervous System Diseases

Rare Diseases

Neoplasm Metastasis

Melanoma

Melanoma, Cutaneous Malignant

Brain Neoplasms

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

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Ocular Melanoma

Neuroendocrine Tumor

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Immune Checkpoint Inhibitors

Pembrolizumab

Immunomodulating Agents

Nivolumab

Ipilimumab

Immunoglobulins

Antineoplastic Agents, Immunological

Patients receive standard of care pembrolizumab and undergo 3-5 fractions SRS. Patients also undergo TTFields over 8 hours daily using NovoTTF-100M device until intra-cranial progression or until end of immunotherapy treatments at the discretion of the treating physician in the absence of disease progression or unacceptable toxicity.

Patients receive standard of care nivolumab and ipilimumab and undergo 3-5 fractions SRS. Patients also undergo TTFields over 8 hours daily using NovoTTF-100M device until intra-cranial progression or until end of immunotherapy treatments at the discretion of the treating physician in the absence of disease progression or unacceptable toxicity.

Stereotactic Radiosurgery

Tumor Treating Fields Therapy

Mohammad Khan, MD, PhD

Allyson K. Anderson

Mohammad K. Khan, MD, PhD

Mohammad K Khan, MD, PhD

This phase I trial finds out the side effects and possible benefits of stereotactic radiosurgery and immune checkpoint inhibitors with NovoTTF-100M for the treating of melanoma that has spread to the brain (brain metastases). Stereotactic radiosurgery is a type of external radiation therapy that uses special equipment to position the patient and precisely give a single large dose of radiation to a tumor. It is used to treat brain tumors and other brain disorders that cannot be treated by regular surgery. Immunotherapy with monoclonal antibodies, such as pembrolizumab, nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. NovoTTF-100M is a portable battery operated device which produces tumor treating fields in the body by means of surface electrodes placed on the skin. Tumor treating fields are low intensity, intermediate frequency electric fields that pulse through the skin to disrupt cancer cells' ability to divide. Giving stereotactic radiosurgery and immune checkpoint inhibitors with NovoTTF-100M may work better than stereotactic radiosurgery and immune checkpoint inhibitors.

PRIMARY OBJECTIVE:

I. To determine the safety of combining tumor treating fields therapy (TTFields) to the two therapeutic backbones (stereotactic radiosurgery \[SRS\]+pembrolizumab and SRS+dual-checkpoint).

SECONDARY OBJECTIVES:

I. To evaluate skin toxicity (grade 1 \& 2 skin \> 20% and grade 3 \& 4 toxicity above 2% at 4-6 weeks and 3 months). (Skin AES include Dermatitis, Erosions, Infections, Ulceration).

II. Control of the treated lesion in the brain with SRS+ immune checkpoint inhibitors (ICI) (i.e. local control), development of additional sites of disease in the brain that were not initially treated with SRS (i.e. anywhere intra-cranial failure), intra-cranial progression free survival (local control of the area that received SRS and anywhere intra-cranial failure), extra-cranial disease response (overall progression free survival), and overall survival.

III. To evaluate treatment response at un-irradiated and extra-cranial sites (i.e. the abscopal effect) with all three arms.

IV. To compare differences in potential serological and immune biomarkers, pretreatment, during treatment, and post treatment.

V. Symptomatic radionecrosis rates at 3 and 6 months.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I: Patients receive standard of care pembrolizumab and undergo 3-5 fractions SRS. Patients also undergo TTFields over 8 hours daily using NovoTTF-100M device until intra-cranial progression or until end of immunotherapy treatments at the discretion of the treating physician in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive standard of care nivolumab and ipilimumab and undergo 3-5 fractions SRS. Patients also undergo TTFields over 8 hours daily using NovoTTF-100M device until intra-cranial progression or until end of immunotherapy treatments at the discretion of the treating physician in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 28 days.

Stereotactic Radiosurgery and Immune Checkpoint Inhibitors With NovoTTF-100M for the Treatment of Melanoma Brain Metastases

Safety and Efficacy of SRS and Immune Checkpoint Inhibitors (ICI) Concurrent With NovoTTF-100M in Melanoma Brain Metastases

Will be analyzed separately for arms 1 and 2. Radiation Therapy Oncology Group Grade 3 CNS toxicity will be measured using RTOG grade 3 CNS toxicity and reported as percentage of patients developing grad 3 CNS toxicity. Higher score means more patients developing toxicity. Lower score means less patients developing toxicity.

As measured by Common Terminology Criteria for Adverse Events (CTCAE) 5.0, will be reported using frequencies and percentages. Skin toxicity will be analyzed separately for arms 1 and 2.

As measured by CTCAE 5.0, will be reported using frequencies and percentages. Alopecia will be analyzed separately for arms 1 and 2.

Will be defined as the time without evidence of tumor progression from time of stereotactic radiosurgery (SRS). Local control will be estimated using the Kaplan-Meier method. A 95% confidence interval for 6-month and 12-month local control will be estimated using the Greenwood formula. Local control will be analyzed separately for arms 1 and 2.

Will be defined as the time without evidence of tumor progression from time of SRS. Intracranial control will be estimated using the Kaplan-Meier method. A 95% confidence interval for 6-month and 12-month intracranial control will be estimated using the Greenwood formula. Intracranial control will be analyzed separately for arms 1 and 2.

PFS will be estimated using the Kaplan-Meier method, and a 95% confidence interval for median PFS will be estimated using the Brookmeyer-Crowley approach. PFS will be analyzed separately for arms 1 and 2.

OS will be estimated using the Kaplan-Meier method, and a 95% confidence interval for median OS will be estimated using the Brookmeyer-Crowley approach. OS will be analyzed separately for arms 1 and 2.

National Cancer Institute (NCI)

NovoCure Ltd.

Emory University

Principal Investigator

Acral Lentiginous Melanoma

Patients receive encorafenib PO QD on days 1-28, binimetinib PO BID on days 1-28, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients receive nivolumab IV on day 1 of all cycles and ipilimumab IV over 30 minutes on day 1 of cycles 1-4. Cycles repeat every 21 days for 4 cycles and then every 28 days in the absence of disease progression or unacceptable toxicity.

Binimetinib

Encorafenib

Catrina Mireles

Dana Sparks

Site Public Contact

Maya Khalil

Furhan Yunus

Charles W. Drescher

Nicholas DiBella

Jay W. Carlson

Lisa Bailey

Bartosz Chmielowski

Charles H. Redfern

Theresa M. Medina

Sajeve S. Thomas

Zeynep Eroglu

John M. Schallenkamp

Maria T. Grosse-Perdekamp

Bryan A. Faller

This phase II trial compares the effect of encorafenib, binimetinib, and nivolumab versus ipilimumab and nivolumab in treating patients with BRAF- V600 mutant melanoma that has spread to the brain (brain metastases). Encorafenib and binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Ipilimumab and nivolumab are monoclonal antibodies that may interfere with the ability of tumor cells to grow and spread. This trial aims to find out which approach is more effective in shrinking and controlling brain metastases from melanoma.

PRIMARY OBJECTIVE:

I. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 between participants randomized to the triplet combination of encorafenib + binimetinib + nivolumab versus the doublet combination of ipilimumab + nivolumab among participants with BRAF-V600 mutant melanoma that has metastasized to the brain.

SECONDARY OBJECTIVES:

I. To estimate the overall survival (OS) of participants in each treatment arm. II. To estimate the objective response rate (ORR) (confirmed and unconfirmed, complete and partial responses) per RECIST 1.1 in each treatment arm.

III. To estimate the intracranial response rate (ICRR), defined as confirmed and unconfirmed complete and partial response per modified RECIST for brain metastases (mRECIST).

IV. To evaluate the duration of response, per RECIST 1.1 and the duration of ICRR per mRECIST, and per Response Assessment in Neuro-Oncology (RANO)-Brain Metastases (BM) (and immunotherapy \[i\]RANO) in each treatment arm.

V. To evaluate the toxicity profile of each treatment arm. VI. To evaluate current and emerging radiographic response criteria (modified RECIST 1.1, modified RANO-BM and iRANO) by a retrospective blinded independent centralized review (BICR) of banked images.

BANKING OBJECTIVE:

I. To bank tumor tissue, cerebral spinal fluid (CSF), stool and blood samples for future correlative studies.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, binimetinib PO twice daily (BID) on days 1-28, and nivolumab intravenously (IV) on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive nivolumab IV on day 1 of all cycles and ipilimumab IV over 30 minutes on day 1 of cycles 1-4. Cycles repeat every 21 days for 4 cycles and then every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 2 years, and then annually until 3 years after randomization.

A Study to Compare the Administration of Encorafenib + Binimetinib + Nivolumab Versus Ipilimumab + Nivolumab in BRAF-V600 Mutant Melanoma With Brain Metastases

A Randomized Phase 2 Trial of Encorafenib + Binimetinib + Nivolumab vs Ipilimumab + Nivolumab in BRAF-V600 Mutant Melanoma With Brain Metastases

Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Will be assessed by Immunotherapy Response Assessment Criteria for Intracranial Metastases (RANO-BM). Will construct Kaplan-Meier plots and estimate the median OS and construct 95% Brookmeyer-Crowley Confidence intervals.

The ICRR is defined as the best response when applying modified (m)RECIST criteria. Will compare intracranial response based on assessments per mRECIST, RANO-BM and immunotherapy (i)RANO criteria based on a review of the banked images. For each of these methods, the best response to treatment will be summarized by treatment arm, the percent agreement between each pair of methods will be reported along with a 95% confidence interval, and a p-value based on a two-sided McNemar's test will be calculated.

SWOG Cancer Research Network

Mouth and Tooth Diseases

Infections

Stomatitis

Virus Diseases

Vesicular Stomatitis

Intraocular Melanoma

Anti-Infective Agents

Interferons

Interferon-beta

Antiviral Agents

Immunologic Factors

Patients receive recombinant vesicular stomatitis virus-expressing interferon-beta and tyrosinase related protein 1 IT and IV over 30-60 minutes 2-4 hours later on day 1.

Patients receive recombinant vesicular stomatitis virus-expressing interferon-beta and tyrosinase related protein 1 IT and IV over 30-60 minutes 2-4 hours later on day 1. Cycle 1 continues for 28 days, with subsequent cycles repeating every 21 days in the absence of disease progression or unacceptable toxicity.

Recombinant Vesicular Stomatitis Virus-expressing Interferon-beta and Tyrosinase Related Protein 1

Roxana S. Dronca, M.D.

This phase I trial studies the side effects and best dose of a modified virus called VSV-IFNbetaTYRP1 in treating patients with stage III-IV melanoma. The vesicular stomatitis virus (VSV) has been altered to include two extra genes: human interferon beta (hIFNbeta), which may protect normal healthy cells from becoming infected with the virus, and TYRP1, which is expressed mainly in melanocytes (specialized skin cell that produces the protective skin-darkening pigment melanin) and melanoma tumor cells, and may trigger a strong immune response to kill the melanoma tumor cells.

PRIMARY OBJECTIVE:

I. To determine the safety profile and maximum tolerated dose (MTD) of recombinant vesicular stomatitis virus-expressing interferon-beta and tyrosinase related protein 1 (VSV-IFNbeta-TYRP1) therapy when administered by intravenous (IV) and intratumoral (IT) injection in patients with previously treated metastatic melanoma.

SECONDARY OBJECTIVE:

I. To gather preliminary data on tumor response rate and progression-free survival time of VSV-IFNbeta-TYRP1 intravenous and intratumoral therapy among patients with metastatic malignant melanoma.

CORRELATIVE OBJECTIVES:

I. To determine the pharmacokinetic (PK) profile of VSV-IFNbeta-TYRP1 in patients by measurement of viremia in the blood using reverse transcriptase polymerase chain reaction (RT-PCR) for VSV-N ribonucleic acid (RNA).

II. To characterize the pharmacodynamics (PD) of VSV-IFNbeta-TYRP1 by measuring serum interferon-beta.

III. To determine if there is viral shedding (mouthwash, buccal swab, and urine) before and after viral treatment at different time points.

IV. Assess fresh pre- and post-treatment tumor biopsy samples for viral RNA, viral protein by immunohistochemistry (IHC), infectious virus recovery, infiltrating immune cells.

V. Assess transcriptome of fresh pre- and post-treatment tumor biopsy samples. VI. Assess exome of fresh peripheral blood lymphocytes (PBL) and fresh tumor samples pre-VSV treatment for neoantigen profiling.

VII. Assess changes in cytokine levels and immune cell profile in peripheral blood and tumor samples, pre and post viral treatment.

VIII. Assess if there is an increase in the amount of VSV and melanoma antigen, specifically TYRP1, reactive IFN-gamma secreting T cells by intracellular staining intracellular cytokine (ICS) and enzyme-linked immunosorbent spot (ELISpot) assays.

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 groups.

GROUP A: Patients receive recombinant vesicular stomatitis virus-expressing interferon-beta and tyrosinase related protein 1 intratumorally (IT) and intravenously (IV) over 30-60 minutes 2-4 hours later on day 1.

GROUP B: Patients receive recombinant vesicular stomatitis virus-expressing interferon-beta and tyrosinase related protein 1 IT and IV over 30-60 minutes 2-4 hours later on day 1. Cycle 1 continues for 28 days, with subsequent cycles repeating every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients in Group A are followed up at 42 days. Patients in Group B are followed up at 28 days, every 3 months until progressive disease, and then every 6 months for a maximum of 5 years after study registration.

Modified Virus VSV-IFNbetaTYRP1 in Treating Patients With Stage III-IV Melanoma

Phase I Trial to Evaluate the Safety and Efficacy of Intratumoral and Intravenous Injection of Vesicular Stomatitis Virus Expressing Human Interferon Beta and Tyrosinase Related Protein 1 (VSV-IFNb-TYRP1) in Patients With Metastatic Ocular Melanoma and Previously Treated Patients With Unresectable Stage III/IV Cutaneous Melanoma

The maximum tolerated dose is defined as the highest dose level among those tested where at most 1 out of 6 patients develops a dose-limiting toxicity (DLT) prior to the start of their second cycle of treatment and the next highest dose level is such that 2 of the 3 to 6 patients treated at this dose level develop a DLT prior to the start of their second cycle of treatment.

Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed by dose level to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

A tumor response is defined as either a complete response or partial response on two consecutive evaluations at least 6 weeks apart. Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population (overall and by dose level).

The distribution of survival time will be estimated using the method of Kaplan-Meier.

Mayo Clinic

Respiratory Tract (Lung and Bronchial) Diseases

Carcinoma

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Meningeal Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Patients receive nivolumab IT over 5 minutes on day 1 of every cycle. Beginning in cycle 2, patients also receive nivolumab IV over 30 minutes on day 1 (4 hours after the IT dose). Cycles repeat every 14 days for 18 cycles and then every 28 days (cycles 19 and beyond) in the absence of disease progression or unacceptable toxicity. Patients will have CSF and blood specimen collection on days 1, 2, 8 of each cycle and end of treatment. Patients undergo CT or PET at baseline, cycle 5 and then every 8 weeks. Patients undergo MRI at baseline, cycles 3, 5, and then every 8 weeks.

Biospecimen Collection

Computed Tomography

Undergo lumbar puncture for cerebrospinal fluid collection

Lumbar Puncture

Magnetic Resonance Imaging

Positron Emission Tomography

Isabella C Glitza, MD

This phase I/Ib trial studies the side effects and best dose of intrathecal nivolumab, and how well it works in combination with intravenous nivolumab in treating patients with leptomeningeal disease. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

PRIMARY OBJECTIVE:

I. To determine the safety and/or recommended dose of intrathecal (IT) nivolumab in combination with systemic nivolumab treatment in melanoma and lung cancer with leptomeningeal disease (LMD).

SECONDARY OBJECTIVE:

I. To assess overall survival with combined intrathecal and systemic administration of nivolumab in this patient population.

EXPLORATORY OBJECTIVES:

I. Compare the immunological effects of this treatment on immune cells in the cerebrospinal fluid (CSF) to those observed in the peripheral blood and in non-LMD tumors.

II. Evaluation of predictors (clinical, molecular, and/or immune) of the efficacy and safety of this regimen.

III. To assess the effect of nivolumab on subsequent treatment. IV. To compare levels of nivolumab in the CSF and peripheral blood.

OUTLINE: This is a phase I, dose-escalation study followed by a phase Ib study.

Patients receive nivolumab IT over 5 minutes on day 1 of every cycle. Beginning in cycle 2, patients also receive nivolumab intravenously (IV) over 30 minutes on day 1 (4 hours after the IT dose). Cycles repeat every 14 days for 18 cycles and then every 28 days (cycles 19 and beyond) in the absence of disease progression or unacceptable toxicity. Patients will have CSF and blood specimen collection on days 1, 2, 8 of each cycle and end of treatment. Patients undergo computed tomography (CT) or positron emission tomography (PET) at baseline, cycle 5 and then every 8 weeks. Patients undergo magnetic resonance imaging (MRI) at baseline, cycles 3, 5, and then every 8 weeks.

After completion of study treatment, patients are followed up within 4 weeks and then every 12 weeks thereafter.

Intravenous and Intrathecal Nivolumab in Treating Patients With Leptomeningeal Disease

Phase I/Ib Study of Concurrent Intravenous and Intrathecal Nivolumab for Melanoma and Lung Cancer Patients With Leptomeningeal Disease (LMD)

Safety and tolerability of treatment will be assessed by vital signs, laboratory assessments, adverse events, and serious adverse events for the safety population. Adverse events will be graded by the Common Terminology Criteria for Adverse Events version 4.0. Categorical measures will be summarized using frequencies and percentages while continuous variables will be summarized using mean, standard deviation, median, minimum, and maximum.

The Bayesian modified toxicity probability interval method will be used to find the recommended dose.

The Kaplan-Meier method will be used to estimate the distribution of OS from the start of study treatment, and Cox proportional hazard regression will be used to assess the relationship between OS and various covariates of interest, including but not limited to patient demographics, tumor characteristics, disease characteristics, and the expression of biomarkers.

M.D. Anderson Cancer Center

Recurrence

Disease Attributes

Interferon-alpha

Interferon alpha-2

INDUCTION THERAPY: Patients receive high-dose recombinant interferon alfa-2B intravenously (IV) over 20 minutes on days 1-5. Treatment repeats weekly for 4 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 3 weeks for a total of 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive high-dose recombinant interferon alfa-2B subcutaneously (SC) on days 1, 3, and 5. Treatment repeats every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 12 weeks for 3 years in the absence of disease progression or unacceptable toxicity.

Patients undergo CT scan, PET scan, MRI and blood sample collection throughout the study.

Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 52 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, PET scan, MRI and blood sample collection throughout the study.

Quality-of-Life Assessment

Recombinant Interferon Alfa-2b

Sapna Patel

This randomized phase III trial studies how well pembrolizumab works compared with the current standard of care, physician/patient choice of either high-dose recombinant interferon alfa-2B or ipilimumab, in treating patients with stage III-IV melanoma that has been removed by surgery but is likely to come back or spread. High-dose recombinant interferon alfa-2B may help shrink or slow the growth of melanoma. Immunotherapy with monoclonal antibodies, such as ipilimumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether pembrolizumab is more effective than the current standard of care in treating patients with melanoma.

PRIMARY OBJECTIVES:

I. To compare overall survival (OS) of patients with resected stage III and IV melanoma treated with physician/patient choice of either high dose interferon recombinant interferon alfa-2b (alfa-2b) or ipilimumab versus MK-3475 (pembrolizumab).

II. Among patients who are PD-L1 positive, to compare OS of patients with resected stage III and IV melanoma treated with physician/patient choice of either high dose interferon alfa-2b or ipilimumab versus MK-3475 (pembrolizumab).

III. To compare relapse-free survival (RFS) of patients with resected stage III and IV melanoma treated with physician/patient choice of either high dose interferon alfa-2b or ipilimumab to MK-3475 (pembrolizumab).

SECONDARY OBJECTIVES:

I. To estimate OS and RFS for patients who are PD-L1 negative or PD-L1 indeterminate in this population.

II. To compare OS and RFS of patients between the two arms within PD-L1 positive and negative subgroups and to look at the interaction between PD-L1 (positive versus negative) and treatment arm.

III. To assess the safety and tolerability of the regimens.

ADDITIONAL OBJECTIVES:

I. To bank tissue and whole blood in anticipation of future correlative studies in this patient population.

II. To evaluate PD-L1 expression through immunohistochemistry assay. III. To evaluate the effect of treatment-related side effects that may have an impact on the health-related domains of quality of life (QOL) using the Functional Assessment of Cancer Therapy (FACT)-Biological Response Modifiers (BRM), European Quality of Life Five Dimension Three Level Scale (EQ-5D-3L), and Functional Assessment of Chronic Illness Therapy Diarrhea (FACIT-D) between patients treated with physician/patient choice of either high-dose interferon alfa-2b or ipilimumab and MK-3475 (pembrolizumab).

IV. Pharmacokinetic (PK) and anti-drug antibody (ADA) testing will be performed on all patients receiving MK-3475 (pembrolizumab).

TRANSLATIONAL OBJECTIVES RELATED TO T-CELL RECEPTOR BETA CHAIN SEQUENCING:

I. To evaluate the association between TCR beta variable gene (TRBV) haplotype and grade 3-4 immune-related adverse events (irAEs) among stage III melanoma patients treated with adjuvant ipilimumab or pembrolizumab.

II. To describe the TRBV haplotype distribution among this cohort of patients studied.

TRANSLATIONAL MEDICINAL OBJECTIVE RELATED TO ASSOCIATION OF CIRCULATING TUMOR DNA (ctDNA) WITH RELAPSE-FREE SURVIVAL IN HIGH-RISK, RESECTED MELANOMA PATIENTS.

I. To evaluate associations between pretreatment ctDNA (present versus absent) and relapse within 2 years of randomization in a case-control analysis across treatment arms.

II. To evaluate associations between pretreatment ctDNA (present versus absent) and relapse within 2 years of randomization in a case-control analysis across treatment arms.

III. To evaluate associations between pretreatment ctDNA and relapse within 2 years of randomization in a case-control analysis within each treatment arm (after treatment arm data are unblinded to investigators).

IV. To evaluate associations between "early-on treatment" ctDNA levels and relapse within 2 years of randomization.

V. To describe ctDNA levels at end of therapy and time of relapse.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I:

INDUCTION THERAPY: Patients receive high-dose recombinant interferon alfa-2B intravenously (IV) over 20 minutes on days 1-5. Treatment repeats weekly for 4 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 3 weeks for a total of 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive high-dose recombinant interferon alfa-2B subcutaneously (SC) on days 1, 3, and 5. Treatment repeats every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 12 weeks for 3 years in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 52 weeks in the absence of disease progression or unacceptable toxicity.

Patients undergo computed tomography (CT) scan, positron emission tomography (PET) scan, magnetic resonance imaging (MRI) and blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 30 days, 6 and 12 weeks, every 3 months for 2 years, every 6 months for 3 years, and then every 12 months for 5 years.

Physician/Patient Choice of Either High-Dose Recombinant Interferon Alfa-2B or Ipilimumab, Versus Pembrolizumab in Treating Patients With Stage III-IV High Risk Melanoma That Has Been Removed by Surgery

A Phase III Randomized Trial Comparing Physician/Patient Choice of Either High Dose Interferon or Ipilimumab to MK-3475 (Pembrolizumab) in Patients With High Risk Resected Melanoma

From date of randomization to date of death due to any cause. Patients last known to be alive were censored at date of last contact. OS estimates will be calculated using the method of Kaplan-Meier. Comparison between arms will be performed using a stratified log-rank test in the intent-to-treat population.

From date of randomization to date of first documentation of disease recurrence (relapse) or death due to any cause. On study disease assessments by imaging were to be performed every 12 weeks until 2 years from randomization, and then every 6 months until 5 years from randomization. Patients last known to be alive and relapse-free were censored at date of last contact. RFS estimates will be calculated using the method of Kaplan-Meier. Comparison between arms will be performed using a stratified log-rank test in the intent-to-treat population.

From date of randomization to date of death due to any cause. Patients last known to be alive were censored at date of last contact. OS estimates will be calculated using the method of Kaplan-Meier. Comparison between arms will be performed using a stratified log-rank test in the intent-to-treat population among those patients with PD-L1 positive tumors.

PD-L1 expression was evaluated by immunohistochemistry (IHC) assay on archival or fresh tumor tissue using the 22C3 antibody and was scored on a scale of 0 to 5 (with higher numbers reflecting a higher level of PD-L1 expression); a score of 2 or higher (staining on greater than 1% of cells) was considered to indicate PD-L1 positivity.

From date of randomization to date of first documentation of disease recurrence (relapse) or death due to any cause. On study disease assessments by imaging were to be performed every 12 weeks until 2 years from randomization, and then every 6 months until 5 years from randomization. Patients last known to be alive and relapse-free were censored at date of last contact. RFS estimates will be calculated using the method of Kaplan-Meier. Comparison between arms will be performed using a stratified log-rank test in the intent-to-treat population among those patients with PD-L1 positive tumors.

PD-L1 expression was evaluated by immunohistochemistry (IHC) assay on archival or fresh tumor tissue using the 22C3 antibody and was scored on a scale of 0 to 5 (with higher numbers reflecting a higher level of PD-L1 expression); a score of 2 or higher (staining on greater than 1% of cells) was considered to indicate PD-L1 positivity.

From date of randomization to date of death due to any cause. Patients last known to be alive will be censored at date of last contact. OS estimates will be calculated using the method of Kaplan-Meier. Cox regression models will be used to estimate hazard ratios and calculate confidence intervals to compare treatment arms in the PD-L1 negative subgroup. In addition Cox regression models for OS will be used to estimate interaction terms between PD-L1 status and treatment arm.

PD-L1 expression was evaluated by immunohistochemistry (IHC) assay on archival or fresh tumor tissue using the 22C3 antibody and was scored on a scale of 0 to 5 (with higher numbers reflecting a higher level of PD-L1 expression); a score of 0-1 (staining on ≤ 1% of cells) was considered to indicate PD-L1 negative status.

From date of randomization to date of first documentation of disease recurrence (relapse) or death due to any cause. On study disease assessments by imaging were to be performed every 12 weeks until 2 years from randomization, and then every 6 months until 5 years from randomization. Patients last known to be alive and relapse-free were censored at date of last contact. RFS estimates will be calculated using the method of Kaplan-Meier. Cox regression models will be used to estimate hazard ratios and calculate confidence intervals to compare treatment arms in the PD-L1 negative subgroup. In addition Cox regression models for RFS will be used to estimate interaction terms between PD-L1 status and treatment arm.

PD-L1 expression was evaluated by IHC assay on archival or fresh tumor tissue using the 22C3 antibody and was scored on a scale of 0 to 5; a score of 2 or higher was considered to indicate PD-L1 positivity. a score of 0-1 was considered to indicate PD-L1 negative status.

The proportion of patients experiencing a particular adverse event (AE), as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (CTCAE version 5.0 beginning April 1, 2018), for each treatment regimen using the number of patients who received at least one dose of that regimen as the denominator. AEs are AE proportions will be estimated along with a 95% confidence intervals.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Stereotactic Radiosurgery and Immune Checkpoint Inhibitors With NovoTTF-100M for the Treatment of Melanoma Brain Metastases	NCT05341349	Clinical Stage ... Melanoma of Unk... Metastatic Mali... Metastatic Mela... Metastatic Muco... Metastatic Ocul... Pathologic Stag...	Ipilimumab Nivolumab Pembrolizumab Stereotactic Ra... Tumor Treating ...	22 Years -	Emory University
A Study to Compare the Administration of Encorafenib + Binimetinib + Nivolumab Versus Ipilimumab + Nivolumab in BRAF-V600 Mutant Melanoma With Brain Metastases	NCT04511013	Acral Lentigino... Clinical Stage ... Metastatic Cuta... Metastatic Mali... Metastatic Mela... Metastatic Muco... Pathologic Stag...	Binimetinib Encorafenib Ipilimumab Nivolumab	18 Years -	SWOG Cancer Research Network
Modified Virus VSV-IFNbetaTYRP1 in Treating Patients With Stage III-IV Melanoma	NCT03865212	Clinical Stage ... Clinical Stage ... Metastatic Chor... Metastatic Mela... Metastatic Muco... Metastatic Uvea... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Pathologic Stag... Unresectable Me...	Recombinant Ves...	18 Years -	Mayo Clinic
Intravenous and Intrathecal Nivolumab in Treating Patients With Leptomeningeal Disease	NCT03025256	Acral Lentigino... Central Nervous... Clinical Stage ... Leptomeningeal ... Melanocytoma Metastatic Lung... Metastatic Mela... Metastatic Muco... Metastatic Uvea... Stage IV Lung C...	Biospecimen Col... Computed Tomogr... Lumbar Puncture Magnetic Resona... Nivolumab Positron Emissi...	18 Years -	M.D. Anderson Cancer Center
Stereotactic Radiosurgery and Immune Checkpoint Inhibitors With NovoTTF-100M for the Treatment of Melanoma Brain Metastases	NCT05341349	Clinical Stage ... Melanoma of Unk... Metastatic Mali... Metastatic Mela... Metastatic Muco... Metastatic Ocul... Pathologic Stag...	Ipilimumab Nivolumab Pembrolizumab Stereotactic Ra... Tumor Treating ...	22 Years -	Emory University
Physician/Patient Choice of Either High-Dose Recombinant Interferon Alfa-2B or Ipilimumab, Versus Pembrolizumab in Treating Patients With Stage III-IV High Risk Melanoma That Has Been Removed by Surgery	NCT02506153	Clinical Stage ... Clinical Stage ... Metastatic Cuta... Metastatic Muco... Metastatic Non-... Non-Cutaneous M... Recurrent Cutan... Recurrent Mucos... Recurrent Non-C...	Biospecimen Col... Computed Tomogr... Ipilimumab Magnetic Resona... Pembrolizumab Positron Emissi... Quality-of-Life... Recombinant Int...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for metastatic mucosal melanoma