Neoplasms

Skin and Connective Tissue Diseases

All Conditions

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

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Interferons

Interferon-alpha

Interferon alpha-2

Antiviral Agents

Immunologic Factors

Patients receive recombinant interferon alfa-2b SC thrice weekly. Treatment continues for 11 months in the absence of disease progression or unacceptable toxicity.

recombinant interferon alfa-2b

Blood for use in correlative studies approximately 30 ml 30 x 106 peripheral blood mononuclear cell (PBMCs) will be drawn on day 1 every other week during the first 12 weeks just prior to treatment and at 1 and 4 hours post therapy.

laboratory biomarker analysis

William Carson, MD

This pilot clinical trial studies recombinant interferon alfa-2b in treating patients with melanoma. Recombinant interferon alfa-2b may interfere with the growth of tumor cells and slow the growth of melanoma

PRIMARY OBJECTIVES:

I. To determine whether selection of the optimal IFN-alpha-2b (recombinant interferon alfa-2b) dose can be made using signal transduction data.

SECONDARY OBJECTIVES:

I. To determine the tolerability of adjuvant IFN-alpha-2b administered at an optimized dose in terms of the toxicities that are observed and the ability of patients to receive a full year of therapy.

II. The transcription of a panel of IFN-alpha-induced genes previously identified by microarray analysis will be determined by Real-Time reverse transcriptase-polymerase chain reaction (RT PCR) in order that the correlation between signal transducer and activator of transcription 1 (STAT1) phosphorylation and IFN-alpha gene regulation can be evaluated.

III. Microarray analysis of patient peripheral blood mononuclear cells (PBMCs) will be used to evaluate the effect of dose-reduction on IFN-alpha gene expression.

IV. In order to define the clinical role of tumor sensitivity to IFN-alpha, patient tumor biopsies taken prior to the administration of IFN-alpha will be systematically evaluated for cellular levels of janus kinase (Jak)-STAT signaling intermediates.

OUTLINE:

Patients receive recombinant interferon alfa-2b subcutaneously (SC) thrice weekly. Treatment continues for 11 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months for 2 years.

Recombinant Interferon Alfa-2b in Treating Patients With Melanoma

Pilot Study of IFN-alpha-2b Dose Reduction With Dose Optimization

Mean and 95% confidence interval will be summarized for phospho-STAT1 at a lower dose and the standard dose. The phospho-STAT1 will also be compared between the dose levels.

Determine the tolerability of adjuvant IFN-α-2b administered at an optimized dose in terms of the toxicities that are observed and the ability of patients to receive a full year of therapy.

Levels of p-STAT1 in PBMCs were analyzed just prior to IFN-a-2b administration to determine levels that remained stable or increased over the course of dose reduction.

Evaluated using microarray analysis of patient PBMCs. Compared using the Wilcoxon signed rank test for the dose 10MU/m2

Evaluated using microarray analysis of patient PBMCs. Compared using the Wilcoxon signed rank test for the dose 4MU/m2

Evaluated using microarray analysis of patient PBMCs. Compared between doses using the Wilcoxon signed rank test.

Define the clinical role of tumor sensitivity to IFN-α, patient tumor biopsies taken prior to the administration of IFN-α will be systematically evaluated for cellular levels of Jak-STAT signaling intermediates.

Schering-Plough

William Carson

Principal Investigator

Patients receive recombinant interferon alfa-2b SC thrice weekly. Treatment continues for 11 months in the absence of disease progression or unacceptable toxicity.

recombinant interferon alfa-2b: Given SC

laboratory biomarker analysis: Blood for use in correlative studies approximately 30 ml 30 x 106 peripheral blood mononuclear cell (PBMCs) will be drawn on day 1 every other week during the first 12 weeks just prior to treatment and at 1 and 4 hours post therapy.

Treatment (Interferon Therapy)

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

United States

Region of Enrollment

Dose I (10 MU/m2)

Dose II (4 MU/m2)

Level of Activated STAT1(Phospho-STAT1)

Number of Patients With Adverse Events

Percentage of Patients With Correlation Between STAT1 Phosphorylation and Interferon Alfa Gene Regulation

SOCS1-1 hour post 10MU-

OAS1-1 hour post 10MU-

CXCL10-1 hour post 10MU

CD69-1 hour post 10MU

Effect of Dose-reduction on Expression of Interferon Alfa Stimulated Genes

SOCS1-1 hour post 4MU

OAS1-1 hour post 4MU

CXCL10-1 hour post 4MU

CD69-1 hour post 4MU

Effect of Dose-reduction on Interferon Alfa Gene Expression

SOCS1- 4 hour post-10MU

OAS1-4 hour post -10MU

CXCL10-4 hour post- 10MU

CD69-4 hour post- 10MU

Effect of Dose-reduction on Interferon Alfa Gene Expression Through Marker CD69

SOCS1-4 hour post 4MU-

OAS1-4 hour post 4MU

CXCL10-4 hour post 4MU

CD69-4 hour post 4MU

Effect of Dose-reduction on Interferon Alfa Gene Expression at Dose Level 4MU

Data was not collected and analyzed for outcome measure

Clinical Role of Tumor Sensitivity to Recombinant Interferon Alfa-2b Using Cellular Levels of Jak-STAT Signaling Intermediates

Overall Study

Atezolizumab

Vemurafenib

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Protein Kinase Inhibitors

Enzyme Inhibitors

Arm A BRAF mutated patients. Over a period of 6 weeks (1) + (2):

1. Vemurafenib 960 mg bid p.o. from week 1 to week 6.
2. Cobimetinib 60 mg qd p.o. from week 1 to week 3 and week 5 to week 6. Week 4 off.

After surgery and a second screening period (up to six weeks): Atezolizumab 1200 mg IV for 52 weeks

Arm B BRAF mutated patients. Over a period of 6 weeks (1) + (2) + (3):

1. Vemurafenib 720 mg bid p.o. from week 1 to week 6.
2. Cobimetinib 60 mg qd p.o. from week 1 to week 3 and from week 5 to week 6. Week 4 off.
3. Atezolizumab 840 mg IV for 2 cycles (day 1 of week 4 and day 1 of week 7).

After surgery and a second screening period (up to six weeks): Atezolizumab 1200 mg IV for 52 weeks

Arm C BRAF WT patients. Over a period of six weeks (1) + (2):

1. Cobimetinib 60 mg qd p.o. from week 1 to week 3 and from week 5 to week 6,
2. Atezolizumab 840 mg IV for 2 cycles (day 1 of week 1 and day 1 of week 4).

After surgery and a second screening period (up to six weeks): Atezolizumab 1200 mg IV for 52 weeks

Cobimetinib 60 mg qd p.o. from week 1 to week 3 and week 5 to week 6. Week 4 off.

Cobimetinib 20 MG Oral Tablet

960 (arm A) /720 (arm B) mg bid p.o. from week 1 to week 6.

Vemurafenib 240 Mg Oral Capsule

840 mg IV for 2 cycles for Arm B and C. After surgery in all arms 1200 mg IV for 52 weeks

Atezolizumab 1200 MG in 20 ML Injection

Paolo Ascierto

Neoadjuvant plus adjuvant treatment with target therapy and immunotherapy given in combination or sequence may have an anti-tumour activity and may reduce the risk of relapse in patients with high-risk resectable melanoma (stage III B / C / D and oligometastatic stage IV).

Melanoma represents a considerable health burden and an ongoing area of unmet need in oncology. Despite melanoma accounts for only 1% of diagnosed skin cancers, it is the cause of most skin cancer-related deaths. Until recently, limited effective treatment options were available to patients with advanced melanoma. Historically, response rates to conventional chemotherapy and immunomodulation therapy (interleukin-2 or interferon-γ) have been reported at approximately 5-19%.

Adjuvant immune checkpoint blockade (ICB) and target therapy improve outcomes of patients with high-risk resectable melanoma. It has recently been demonstrated that treatment with neoadjuvant and adjuvant targeted therapy (dabrafenib and trametinib) is associated with a high pathologic complete response (pCR) rate and improved outcomes over surgery alone. However, treatment with ICB has not been well studied in the neoadjuvant setting, despite preclinical studies suggesting that neoadjuvant administration of ICB is associated with improved survival and enhanced anti-tumour immune responses compared to the same therapy administered in the adjuvant setting.

The advantage of neoadjuvant trials is the availability of blood and tumour tissue samples before and after systemic therapy for the conduct of novel mechanistic and biomarker studies in the circulation and the tumour microenvironment.

Prospective neoadjuvant clinical trials with targeted (dabrafenib/trametinib combo) or immunotherapeutic agents (nivolumab alone or nivolumab/ipilimumab combo) and combinations are now running in a subgroup of highrisk melanoma patients with pooled overall promising preliminary results of high rates of pathologic complete responses (pCRs, 30-50%) and early data of positive correlation between pCR and relapse-free survival. Based on the available results to date, we aim to conduct a randomized, noncomparative phase II trial to define the role of neoadjuvant plus adjuvant target and immunotherapy, given in combination or sequence, in patients with high risk surgically resectable melanoma.This approach has the potential to define whether neoadjuvant treatment has antitumour activity and whether it reduces the risk of relapse after surgery.

The study will be conducted according to an open-label, randomized, not comparative phase II design. Three arms for a total of 88 patients will be considered.

BRAF mutated patients will be randomized in two arms: Arm A and Arm B (27 patients per arm). BRAF WT patients will be included in Arm C (34 patients).

Combination or Sequence of Vemurafenib, Cobimetinib, and Atezolizumab in High-risk, Resectable Melanoma

"NEOadjuvant Plus Adjuvant Therapy With Combination or Sequence of Vemurafenib, cobImetinib, and atezolizuMab in Patients With High-risk, Surgically Resectable BRAF Mutated and Wild-type Melanoma"

Defined as the lack of all signs of cancer in tissue samples removed during surgery

Defined as the time from randomisation to recurrence event or last follow-up

Defined as the time from the date of randomisation to the date of death due to any cause

Defined as the sum of pathologic complete responses (pCRs), near pathologic complete responses near pCRs) and pathologic partial responses (pPRs).

All AEs, Grade 3 to 4 AEs, serious adverse events (SAEs), deaths, AEs of special interest (AESIs), and AEs leading to treatment discontinuation or withdrawal from the study

Immunoscore, Circulating cytokines and chemokines profiling, Metabolomic profiling,Tumour mutational burden, Myeloid-derived suppressors cells, immune cell subtypes expression and lymphocyte activation, Additional analysis of protein levels (i.e. CCR5), DNA mutations, and/or mRNA analysis

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Recombinant Interferon Alfa-2b in Treating Patients With Melanoma	NCT01460875	Stage IA Skin M... Stage IB Skin M... Stage IIA Skin ... Stage IIB Skin ... Stage IIC Skin ... Stage IIIA Skin... Stage IIIB Skin... Stage IIIC Skin... Stage IV Skin M...	recombinant int... laboratory biom...	12 Years -	Ohio State University Comprehensive Cancer Center
Combination or Sequence of Vemurafenib, Cobimetinib, and Atezolizumab in High-risk, Resectable Melanoma	NCT04722575	Melanoma	Cobimetinib 20 ... Vemurafenib 240... Atezolizumab 12...	18 Years -	Fondazione Melanoma Onlus
Combination or Sequence of Vemurafenib, Cobimetinib, and Atezolizumab in High-risk, Resectable Melanoma	NCT04722575	Melanoma	Cobimetinib 20 ... Vemurafenib 240... Atezolizumab 12...	18 Years -	Fondazione Melanoma Onlus

Spots Global Cancer Trial Database for high risk melanoma