Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

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

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

X4P-001 100 mg capsules, administered orally, continuous daily dosing

X4P-001

Pembrolizumab 2 mg/kg, administered by IV infusion every 3 weeks

Lu Gan, MD, PhD

The goals of this protocol are 1) to investigate the safety and tolerability of X4P-001 in combination with Keytruda® (pembrolizumab) in patients with advanced melanoma, and 2) to assess serial biopsies of melanoma tumor lesions obtained throughout the study for inflammatory and tumor cell infiltrates. After completion of study treatment, participants with resectable disease will undergo surgery, unresectable participants may continue on pembrolizumab as standard of care.

X4P-001 is an orally bioavailable CXCR4 antagonist that has demonstrated activity in various tumor models. CXCR4 (C-X-C chemokine receptor type 4) is the receptor for CXCL12 (C-X-C chemokine ligand type 12). CXCL12 has potent chemotactic activity for lymphocytes and MDSCs (myeloid-derived suppressor cells), and is important in homing of hematopoietic stem cells to the bone marrow. CXCR4 is also expressed and active on multiple types of human cancers, including melanoma, ccRCC, and ovarian cancer. Additionally, increased expression of CXCR4 on tumor cells has been associated with significantly decreased overall participant survival.

In animal cancer models, interference with CXCR4 function has been demonstrated to disrupt the tumor microenvironment (TME) and unmask the tumor to immune attack by multiple mechanisms, including:

* Decreasing the infiltration of MDSCs
* Increasing the ratio of CD8+ T cells to Treg cells
* Eliminating tumor re-vascularization

Pembrolizumab is a humanized IgG4 kappa monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is currently approved for the treatment of unresectable or metastatic melanoma. Analysis of tumor samples before and during treatment in an earlier study demonstrated that a clinical response was associated with an increase in the density of CD8+ T cells in the tumor parenchyma (center), while disease progression was associated with persistent low levels of those cells. In an autochthonous murine model of pancreatic adenocarcinoma, persistent tumor growth despite administration of anti-PD-L1 was similarly associated with failure of tumor-specific cytotoxic T cells to enter the TME despite their presence in the peripheral circulation. This immunosuppressed phenotype was associated with CXCL12 production by cancer-associated fibroblasts. Moreover, administration of a CXCR4 antagonist (AMD3100) induced rapid T-cell accumulation among the cancer cells and, in combination with anti-PD-L1, synergistically decreased tumor growth.

Based on these observations, the hypothesis is that effective CXCR4 antagonism by X4P-001 would be of potential benefit in participants with advanced melanoma and other cancers by multiple mechanisms, resulting in increased anti-tumor immune attack.

X4P-001 and Pembrolizumab in Patients With Advanced Melanoma

A Phase 1b Trial of X4P-001 Alone and With Pembrolizumab in Patients With Advanced Melanoma

X4 Pharmaceuticals

Angiogenesis Inhibitors

AMG 780 will be administered by IV infusion every 2 weeks

AMG 780

This is a first in human, open-label, sequential dose escalation and expansion study of AMG 780 in up to 62 subjects with advanced solid tumors. The dose escalation part of the study is aimed at evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of AMG 780. The dose expansion will consist of up to 20 subjects and the dose level of AMG 780 will be dependent upon emerging safety and PK data from the dose escalation part of the study.

A Phase 1 Dose Escalation Study of AMG 780 in Adult Subjects With Advanced Solid Tumors

A Phase 1, First-in-Human Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AMG 780 in Adult Subjects With Advanced Solid Tumors

Amgen

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
X4P-001 and Pembrolizumab in Patients With Advanced Melanoma	NCT02823405	Melanoma	X4P-001 Pembrolizumab	18 Years -	X4 Pharmaceuticals
A Phase 1 Dose Escalation Study of AMG 780 in Adult Subjects With Advanced Solid Tumors	NCT01137552	Advanced Solid ...	AMG 780	18 Years -	Amgen

Spots Global Cancer Trial Database for advance malignancy