Phase I Clinical Trial of Tremelimumab Plus MEDI3617 in Patients With Unresectable Stage III or Stage IV Melanoma

Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study.

Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier;

Received any prior monoclonal antibody against CTLA-4;

Any prior ≥ Grade 3 immune-related adverse event (irAE) while receiving immunotherapy or any unresolved irAE at time of study entry

Participants with a history of hypersensitivity to compounds of similar biologic composition to tremelimumab or any constituent of the product;

The last dose of prior systemic therapy (e.g. chemotherapy, targeted therapy etc) or radiation therapy (with the exception of palliative radiotherapy) was received less than 14 days prior to the first day of treatment;

Concurrent enrollment in another clinical study or receipt of an investigational product within the last 4 weeks (participation in the survival follow-up period of a study is not an exclusion criterion);

Currently receiving systemic corticosteroids or other immunosuppressive medications or has a medical condition that requires the chronic use of corticosteroids. Note: inhaled and topical steroids are permitted;

Subjects should not be vaccinated with live attenuated vaccines within one month prior to starting tremelimumab treatment;

Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results;

Active, untreated central nervous system (CNS) metastasis (subjects with brain metastases who are identified at screening may be rescreened after the lesion\[s\] have been appropriately treated and subjects are off corticosteroids);

Any serious uncontrolled medical disorder or active infection that would impair the subject's ability to receive investigational product, such as conditions associated with frequent diarrhea;

History of of chronic inflammatory or autoimmune disease (eg, Addison's disease, multiple sclerosis, Graves' disease, Hashimoto's thyroiditis, rheumatoid arthritis, hypophysitis, uveitis, etc) with symptomatic disease within the last 3 years. Note: Active vitiligo or alopecia or a history of vitiligo or alopecia will not be a basis for exclusion;

Active or history of inflammatory bowel disease (eg, colitis, Crohn's), irritable bowel disease, celiac disease or other serious gastrointestinal chronic conditions associated with diarrhea. Active or history of systemic lupus erythematosis or Wegener's granulomatosis;

History of sarcoidosis syndrome;

Active history of diverticulitis. Note that diverticulosis is permitted;

History of other malignancy unless the subject has been disease-free for at least 3 years. Non-invasive cancer history (such as carcinoma in situ \[CIS\] that has been resected) is allowed;

Unresolved toxicities from prior anticancer therapy that have not resolved to CTCAE, version 4.0, Grade ≤ 1 or baseline, with the exception of alopecia and laboratory values listed in 3.1.8;

Any condition that would prohibit the understanding or rendering of information and consent and compliance with the requirements of this protocol;

Prior treatment with angiopoietin inhibitors, or inhibitors of Tie1 or Tie2 including, but not limited to, AMG386, CVX-060, XL880, and XL820;

Current necessity for full-dose anticoagulation with warfarin or its equivalent (i.e. unfractionated and/or low molecular weight heparin);

Symptomatic peripheral vascular disease;

Known bleeding diathesis or coagulopathy;

Significant known vascular disease (e.g aortic aneurysm, aortic dissection);

Pulmonary hemorrhage or gross hemoptysis (bright red blood of ≥ ½ teaspoon per episode) within 6 months prior to enrollment;

Serious non-healing wound, ulcer, or bone fracture within 6 months prior to enrollment;

Major surgical procedure or significant traumatic injury within 28 days prior to study enrollment;

Pregnant women are excluded from this study because tremelimumab and MEDI3617 are monoclonal antibodies with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with because tremelimumab and MEDI3617, breastfeeding should be discontinued if the mother is treated with tremelimumab and MEDI3617. These potential risks may also apply to other agents used in this study.

Patients with grade 2 or higher peripheral neuropathy will be excluded in the dose-escalation phase of the protocol

What this study is about