Trial of TRX518 (Anti-GITR mAb) in Stage III or IV Malignant Melanoma or Other Solid Tumors (TRX518-001)

• 1. Adverse events (Safety) [ Time Frame: 18 weeks ] [ Designated as safety issue: Yes ]
  Any adverse change in health or side effect from the initiation of the study drug dose through completion or premature withdrawal.
• 2. Pharmacokinetics (PK) [ Time Frame: 18 weeks ] [ Designated as safety issue: No ]
  Observations of the distribution, duration of effects and chemical changes of TRX518 in the body and the effects and routes of the body's elimination of TRX518.
• 3. Pharmacodynamics (PD) [ Time Frame: 18 weeks ] [ Designated as safety issue: No ]
  Observation of the effects of TRX518 on the body and immune system.

TRX518-001 is an open label, non-randomized single group assignment, Phase 1 single dose escalation study in adults with biopsy proven unresectable Stage III or Stage IV melanoma or other solid tumor malignancies. The study objectives are to determine the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of TRX518 and to define the maximum tolerated dose at which there are tolerable side effects and/or maximum PK/PD parameter changes.

Subjects will be assigned to a cohort in the order screening is completed. Dose will depend upon the cohort in which a subject is enrolled and cohorts will be dosed consecutively by ascending dose.

MSKCC Study #10-147

The following visits are required:

• Screening visit: 1 to 2 appointments will be conducted to determine eligibility. All or most requirements can be determined from the patient's medical records.
• Baseline visit: within 7 days of the planned study dosing day a baseline physical exam, blood tests and electrocardiogram will be obtained.
• Dosing visit: 1 outpatient visit where TRX518 will be given IV over 1 hour followed by 4 hours of observation and some repeat blood tests.
• Follow up visits: 5 outpatient visits following dosing at 1, 8 and 15 days and 3, 6, 12, and 18 weeks post dosing
• Long term follow-up: 4 brief assessments by medical record review and/or telephone contact at 6, 12, 18, and 24 months post dosing.
• The core study duration is 18 weeks. The follow-up study duration is 24 months.

Inclusion Criteria:

• 18 years or older at the time of dose initiation.
• Unresectable Stage III or Stage IV biopsy proven malignant melanoma or other solid tumor malignancies, with at least 1 measurable lesion, who have failed to respond to or relapsed following standard treatment or who have declined to pursue standard treatment, in otherwise stable health (as confirmed by medical history, physical examination, ECG, and screening laboratory tests).
• Expected survival of at least 12 weeks after dosing.
• Karnofsky Performance Status ≥70 in the 7 day baseline period immediately prior to dosing.
• Evidence of adequate organ function by standard laboratory tests.
• All female subjects of child bearing age must be either surgically sterile, postmenopausal for at least 1 year, or using an acceptable method of contraception. Adequate contraception for both male and female subjects must be used from the beginning of the screening period until at least 8 weeks after the last dose of TRX518.

Exclusion Criteria:

• Evidence of progression of central nervous system (CNS) metastases or symptomatic CNS metastases within 30 days prior to dosing.
• Ocular melanoma.
• Any major surgery within 6 weeks prior to dosing.
• Any history of antitumor therapy (standard or experimental) completed within 30 days prior to dosing.
• Any concomitant serious physical illness other than cancer (i.e., immune deficiency disease, bleeding disorder, etc.) within 1 year prior to dosing. Specifically, no history of autoimmune disease.
• Clinically significant heart disease, defined as NYHA Class III or IV.