Details

Details

Title A First-in-Human Single Ascending Dose Study of TRX518 in Subjects with Unresectable Stage III or Stage IV Malignant Melanoma or other Solid Tumor Malignancies

IRB GITR1Y13

CC 13-1109

Hospital Main Campus

Disease Melanoma, Solid Tumors

Drug TRX518

Description

Description

Primary Objective
  • Determine safety and tolerability, PK, and PD profiles of TRX518.
  • Define a maximum single dose at which there are tolerable side effects and/or maximum PK/PD parameter changes Occur (maximum tolerated dose MTD; Section 9.7).
Secondary Objectives
  • Evaluate the effect of TRX518 on lymphoid cell subset number and function.
  • Assess TRX518 immunogenicity.
  • Evaluate the effect of TRX518 on long-term safety at Months 6, 12, 18, and 24.
Exploratory Objectives
  • Document tumor response.
  • Evaluate the effect of TRX518 on generation of autoimmune phenomena as assessed by serologic markers and clinical monitoring.
  • Determine whether TRX518 can induce antibodies to NY-ESO-1 in subjects who are seronegative but have NY-ESO-1+ tumors or increase antibody titers in anti-NY-ESO-1 seropositive subjects.
  • Evaluate humoral and cellular responses to NY-ESO-1 and other tumor-specific antigens.
Inclusion Criteria

Inclusion Criteria

  1. Informed Consent form signed by the subject.
  2. Males and females 18 years or older at the time of dose initiation.
  3. Histologically confirmed unresectable Stage III or Stage IV malignant melanoma, or other Solid Tumor Malignancies with at least 1 measurable lesion
  4. Failed to respond to or relapsed following standard treatment, declined or was not eligible for standard treatment
  5. Expected survival of at least 12 weeks after dosing.
  6. Karnofsky Performance Status ≥ 70 in the 7 day baseline period immediately prior to dosing.
  7. Evidence of adequate organ function by standard laboratory tests:
    1. Cr < 1.5 X upper limit of normal (ULN).
    2. Total and direct Bil (T-Bil or D-Bil) ≤ 1.5 X ULN (prior diagnosis or past history consistent with Gilberts syndrome may be an exception).
    3. AST and ALT ≤ 2.5 X ULN.
    4. Plts > 100,000/μL
    5. Hgb ≥ 9.0 g/dL
    6. Neutrophil count ≥ 1000/mm3
    7. Lymphocyte count ≥ 800/mm3
  8. 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. Examples of adequate methods of contraception include abstinence, intrauterine device, hormonal contraception, use of spermicide and a condom by sexual partner, or partner with a vasectomy. Adequate contraception must be used from the beginning of the screening period until at least 8 weeks after the last dose of TRX518. Male subjects with partners of childbearing potential must use a barrier method of contraception from the day of the first dose of TRX518 until at least 8 weeks after the last dose.
  9. The Investigator must judge all pre-dose vital signs, physical examination, laboratory, or any other safety variables to be within normal limits or abnormalities to be clinically insignificant.
Exclusion Criteria

Exclusion Criteria

  1. Evidence of progression of central nervous system (CNS) metastases or symptomatic CNS metastases within 35 days prior to dosing.
  2. Ocular melanoma which has not metastasized (eye lesions of other cancer types are acceptable), or presence of a non-solid tumor (e.g. lymphoma, leukemia and myeloma).
  3. A history of any major surgery within 6 weeks prior to dosing.
  4. Any history of antitumor therapy (standard or experimental chemotherapeutic, radiation or surgical therapy) completed within 30 days prior to dosing, with the exception of palliative ablation of lesion(s) as long as measurable disease lesion(s) remain for evaluation of exploratory endpoints. Refer to # 11 for instructions regarding inclusion criteria relating to other anti-human GITR monoclonal antibody (mAb) or immunomodulatory therapies.
  5. 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 (i.e., rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, etc.) except for vitiligo and autoimmune thyroiditis.
  6. Clinically significant heart disease, defined as NYHA Class III or IV.
  7. A suspected allergy or sensitivity to TRX518 or excipients based upon known allergies to compounds of a similar class, or which in the opinion of the Principal Investigator suggests an increased potential for an adverse hypersensitivity to TRX518.
  8. Any significant systemic infection within 4 weeks before dosing.
  9. Pregnancy or breast feeding.
  10. A diagnosis of HIV, hepatitis B, hepatitis C, or any current laboratory findings or clinical signs and symptoms that suggest these conditions.
  11. Treatment with any other anti-human GITR monoclonal antibody (mAb) or immunomodulatory therapy 42 days prior to dosing (30 days for Interleukin-2 & Interferon-α, 7 days for Topical Imiquimod)
  12. Unresolved immune- related adverse events following prior biological therapy
  13. Use of any investigational drugs within 30 days prior to dosing.
  14. Plans to donate blood or plasma within 90 days post dosing.
  15. Any condition that requires or is likely to require treatment with systemic corticosteroids within the Core Study Period (Weeks 1-18).