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

All Drugs and Chemicals

Antineoplastic Agents

Amino Acids

Antibodies

Antibodies, Monoclonal

Immune Checkpoint Inhibitors

Nivolumab

Ipilimumab

Immunoglobulins

Antineoplastic Agents, Immunological

Tyrosine

Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg IV every 3 weeks + Cabozantinib 40 mg PO daily for 4 cycles followed by Nivolumab 480 mg IV every 4 weeks + Cabozantinib 40 mg PO daily for up to 24 months.

Ipilimumab is a fully human IgG1 kappa monoclonal antibody that binds the co-inhibitory receptor CTLA-4. Antibody binding prevents interaction with the CTLA-4 ligands CD80 and CD86. Blockade of CTLA-4 results in increased T cell activation and proliferation. Ipilimumab was the first immune checkpoint inhibitor to receive FDA approval as a cancer therapy. Treatment of patients with advanced metastatic melanoma with ipilimumab monotherapy resulted in improved overall survival. Subsequent clinical trials with ipilimumab alone and in combination with anti-PD-1 antibodies have demonstrated impressive clinical activity in patients with melanoma, renal cell carcinoma, non-small cell lung cancer and other cancers. Side effects of ipilimumab result from autoimmune attack on healthy tissues. Side effects may include dermatitis, colitis, hepatitis, hypophysitis, pneumonitis, endocrinopathies, nephritis, arthritis, neuropathies and others.

Nivolumab is a fully human IgG4 kappa monoclonal antibody that binds the co-inhibitory receptor PD-1. Nivolumab binding to PD-1 blocks interaction with the PD-1 ligands PD-L1 and PD-L2. PD-1 blockade can lead to reinvigoration of exhausted T cells and prevent T cell exhaustion of newly activated T cells. Nivolumab has been shown to have excellent clinical efficacy in treating a wide range of cancers as monotherapy and in combination with ipilimumab.

Cabozantinib is a potent small molecule inhibitor of multiple receptor tyrosine kinases. Cabozantinib inhibits VEGFR2, MER, KIT, and MET at single digit nanomolar IC50 concentrations. Other kinases including ROS1, RET, FLT3, RON, AXL, and TIE2 are also inhibited with nanomolar concentrations of cabozantinib. Cabozantinib has been shown to have clinical activity in a variety of solid tumors and has been approved by the FDA for treatment of medullary thyroid cancer, renal cell carcinoma and hepatocellular carcinoma.

Cabozantinib

Matthew Taylor, MD

The primary objective of this clinical trial is to evaluate the clinical efficacy and progression free survival of the triplet combination of ipilimumab + nivolumab + cabozantinib in patients with anti-PD-1/PD-L1 refractory metastatic cutaneous melanoma.

This is a phase II, single arm, single institution clinical trial. Eligible adults with anti-PD-1 refractory, unresectable/metastatic cutaneous melanoma will be treated with the triplet combination of ipilimumab 1 mg/kg + nivolumab 3 mg/kg every 3 weeks for 4 cycles in addition to cabozantinib 40 mg/day. For cycles 5+, treatment will consist of nivolumab 480 mg IV every 4 weeks in combination with cabozantinib 40 mg/day. The total duration of therapy will be 24 months or until either disease progression or the occurrence of unacceptable drug-related toxicity. Regular tumor assessments should be performed to determine if PD is present.

Study of Ipilimumab, Nivolumab, and Cabozantinib in Patients With Cutaneous Melanoma

A Phase II, Single-Arm Clinical Trial Evaluating the Triplet Combination of Ipilimumab, Nivolumab, and Cabozantinib in Patients With Anti-PD-1(L1) Refractory Cutaneous Melanoma

Progression free survival will be defined as the time between the date of enrollment and the first date of documented progression (per iRECIST), as determined by the investigator, or death due to any cause, whichever occurs first.

Number of patients who reported incidence of grade ≥3 treatment related adverse events.

Bristol-Myers Squibb

Exelixis

Providence Health & Services

Spots Global Cancer Trial Database for refractory cutaneous melanoma