Neoplasms

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Melanoma

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

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Neuroepithelioma

All Drugs and Chemicals

Anti-Infective Agents

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Antibodies

Antibodies, Monoclonal

Immunoglobulins

Endothelial Growth Factors

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Interferons

Tyrosine Kinase Inhibitors

Antiviral Agents

Interferon-alpha

Interferon-alfa-1b

Tyrosine

Recombinant human interferon α1b administered 600μg every other day. Toripalimab administered 240mg intravenously every three weeks. Anlotinib hydrochloride given 12mg or 10mg or 8mg orally (Daily for two weeks continuously, followed by one week of rest). A recommended phase II dose (RP2D) of anlotinib hydrochloride will be determined.

Recombinant human interferon α1b is a protein with potent antiviral, antiproliferative and immunomodulatory properties.

Recombinant human interferon α1b

Toripalimab is a recombinant, humanized programmed death receptor (PD-1) monoclonal antibody that binds to PD- and prevents binding of PD-1 with programed death ligands 1 (PD-L1) and PD-L2. It can function to activate cytotoxic T lymphocytes and inhibit tumor growth.

Toripalimab

Anlotinib hydrochloride is a novel oral tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR) and c-kit.

Anlotinib hydrochloride

Guannan Zhu, M.D.;Ph.D

The purpose of this study is to evaluate the efficacy and safety of recombinant human interferon-α1b (IFN-α1b) combined with toripalimab and anlotinib hydrochloride in patients with unresectable advanced melanoma. This study consists of 2 phases（ Ib / II）. Phase Ib will determine the recommended phase Ⅱ dose for anlotinib hydrochloride. Phase II will evaluate the efficacy and safety of the triple combination regimens.

This is a single-arm, single-center Phase Ib/II trial to evaluate the efficacy and safety of the combination of recombinant human interferon α1b plus toripalimab and anlotinib hydrochloride in patients with unresectable Stage IIIc, Stage IIId, and Stage IV melanoma(AJCC 8th). Phase I is to evaluate the dose-limiting toxicities (DLT) and determine the recommended Phase II dose (RP2D) of anlotinib hydrochloride in patients with unresectable advanced melanoma receiving recombinant human interferon α1b 600ug QOD plus toripalimab 240mg Q3W. Anlotinib hydrochloride will be given in a dose descending manner(12mg- 10mg- 8mg). In the phase II study, 30 Phase II will enroll 30 patients. The primary endpoint in the II phase is objective response rate (ORR) and progression-free survival (PFS). The second endpoint is disease control rate (DCR), clinical benefit rate (CBR), duration of response (DOR), and overall survival(OS). The safety profile of this combined IFN-α1b/ toripalimab/anlotinib hydrochloride regimen will be monitored during both phases. Specifically, phase Ib will evaluate dose-limiting toxicities(DLT). Phase II will evaluate the numbers and severity of toxicity per the Criteria for Adverse Events version 5 (CTCAEv) including but not limited to all adverse events (AE).

Interferon-α1b Combined With Toripalimab and Anlotinib Hydrochloride in Advanced Unresectable Melanoma

Interferon-α1b (IFN-α1b) Combined With Toripalimab and Anlotinib Hydrochloride in Patients With Advanced Unresectable Melanoma

RP2D of anlotinib hydrochloride will be depended according to the dose-limiting toxicities of anlotinib hydrochloride

proportion of patients with a complete response or partial response to treatment

time from enrollment to progression or death

the percentage of patients who have achieved complete response, partial response and stable disease to the therapeutic intervention

time from response to progression/death (the earlier event)

The median and 3 year OS rate of patients with unresectable advanced melanoma treated with the combination regimen of interferon-α1b, toripalimab, and anlotinib hydrochloride

the proportion of patients with a complete or partial response or with stable disease at Week 24

Xijing Hospital

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Stage 1: Neoadjuvant stage (Week 1-9, 3 cycles)

Stage 2: Surgical period (2 weeks, ±7 days after the last dose of neoadjuvant therapy) After multidisciplinary MDT team evaluation, the primary lesion and metastasis were resected in the corresponding departments.

Stage 3: Postoperative adjuvant period (3 weeks ±7 days -45 weeks, 15 cycles) γδ T cells administered intravenously every three weeks. Recombinant human interferon α1b administered 300μg every other day.

Stage 1: Neoadjuvant stage (Week 1-9, 3 cycles)

Stage 2: Surgical period (2 weeks, ±7 days after the last dose of neoadjuvant therapy) After multidisciplinary MDT team evaluation, the primary lesion and metastasis were resected in the corresponding departments.

Stage 3: Postoperative adjuvant period (3 weeks ±7 days -45 weeks, 15 cycles) γδ T cells administered intravenously every three weeks.Pembrolizumab administered 200mg intravenously every three weeks.

Cells will be extracted from a healthy donor by apheresis, followed by ex-vivo expansion and activation. The ex-vivo expanded γδT cells from donors will be adoptively transfused.

Ex-vivo expanded allogeneic γδ T cells

Pembrolizumab is a recombinant, humanized programmed death receptor (PD-1) monoclonal antibody that binds to PD- and prevents binding of PD-1 with programed death ligands 1 (PD-L1) and PD-L2. It can function to activate cytotoxic T lymphocytes and inhibit tumor growth.

GuanNan Zhu, M.D.;Ph.D

The purpose of this study is to evaluate the efficacy and safety of allogeneic γδ T cells combined with recombinant human interferon-α1b (IFN-α1b) or PD-1 monoclonal antibody in neoadjuvant treatment of patients with Stage III-IV resectable melanoma.

This is a double-arm, single-center, randomized, open label Phase I clinical trial to evaluate the efficacy and safety of the combination of ex-vivo expanded allogeneic γδ T cells plus recombinant human interferon α1b or PD-1 monoclonal antibody in patients with Stage III-IV resectable melanoma(AJCC 8th). We randomly assigned patients with stage III-IV melanoma that was amenable to surgical resection to three doses of neoadjuvant γδT cells plus IFN-α1b or γδT cells plus pembrolizumab , surgery, and 15 doses of adjuvant γδT cells plus IFN-α1b or γδT cells plus pembrolizumab. The primary endpoints are pathological response rate after 3 cycles of treatment, including: complete pathological response rate (pCR), major pathological response rate (MPR), partial pathological response rate (pPR); preoperative imaging response rate (RECIST v1.1) was evaluated, including complete response (CR), partial response (PR), stable disease (SD), and disease progression (PD); and proportion of patients who do not need surgery due to remission. The second endpoints are event-free survival (EFS), relapse free survival (RFS), and overall survival (OS, 3 years after surgery). The safety profile of the combined γδT cells/IFN-α1b regimen and γδT cells/ pembrolizumab regimen will be monitored, we will evaluate the numbers and severity of toxicity per the Criteria for Adverse Events version 5 (CTCAEv) including but not limited to all adverse events (AE), incidence of surgery-related adverse events, and proportion of inoperable patients (due to disease progression or treatment-related adverse events).

Allogeneic Gammadelta T Cells Combined With Interferon-α1b or PD-1 Monoclonal Antibody in Stage III-IV Amenable to Surgical Resection Melanoma

Efficacy and Safety of Allogeneic γδ T Cells (γδ T Cells) Combined With Interferon-alpha1b (IFN-α1b) or PD-1 Monoclonal Antibody in Neoadjuvant Treatment of Stage III-IV Resectable Melanoma

Investigators will measure the rate of pCR after surgery.

Investigators will measure the rate of mPR after surgery.

Investigators will measure the rate of pPR after surgery.

ORR will be measured after neoadjuvant therapy (for participants who have measurable disease per RECIST 1.1 at start of neoadjuvant therapy).

EFS is defined as time from randomization to melanoma progression (irresectable stage III or stage IV disease), melanoma recurrence, treatment-related death, or melanoma-related death, whichever occurs first. Occurrence of a new primary melanoma during treatment/follow-up is also regarded as an event. Presurgical resectable progression to stage III disease is not defined as an event, even as death to another reason than melanoma or the study treatment.

RFS is defined as time from surgery until disease relapse.

The 3 years after surgery OS rate of patients with γδ T cells plus IFN-α1B or γδ T cells plus pembrolizumab，From date of enrollment until the date of death from any cause.

Therapy-related adverse events will be recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Interferon-α1b Combined With Toripalimab and Anlotinib Hydrochloride in Advanced Unresectable Melanoma	NCT05539118	Melanoma	Recombinant hum... Toripalimab Anlotinib hydro...	18 Years - 75 Years	Xijing Hospital
Interferon-α1b Combined With Toripalimab and Anlotinib Hydrochloride in Advanced Unresectable Melanoma	NCT05539118	Melanoma	Recombinant hum... Toripalimab Anlotinib hydro...	18 Years - 75 Years	Xijing Hospital
Allogeneic Gammadelta T Cells Combined With Interferon-α1b or PD-1 Monoclonal Antibody in Stage III-IV Amenable to Surgical Resection Melanoma	NCT06212388	Melanoma	Ex-vivo expande... Recombinant hum... Pembrolizumab	18 Years - 75 Years	Xijing Hospital

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