Details
Description
Inclusion Criteria
Exclusion Criteria
Details
Title A Two Part, Phase 1, Multicenter, Open-label Study of TRX518 in Adults with Advanced Solid Tumors
IRB GITR 1Y15
CC 101506C
Hospital Main Campus
Phase Phase 1
Disease Solid Tumors
Drug TRX518
Description
Primary Objective:- Characterize the safety and tolerability of multi-dose TRX518 monotherapy in adult patients with recurrent or refractory advanced solid tumors.
- Characterize the pharmacokinetics (PK) of multi-dose TRX518 monotherapy in adult patients with recurrent or refractory advanced solid tumors;
- Evaluate adult patients with recurrent or refractory advanced tumors treated with multi-dose TRX518 monotherapy for any evidence of antitumor activity (objective response rate [ORR], progression free survival [PFS], duration of response [DoR] and overall survival [OS]);
- Evaluate the effect of multi-dose TRX518 monotherapy on lymphoid cell subset number and function.
- Evaluate the effect of multi-dose TRX518 monotherapy on generation of autoimmune phenomena as assessed by serologic markers and clinical monitoring;
- Evaluate humoral and cellular responses;
- Assess pharmacodynamics utilizing surrogate biomarkers;
- Evaluate the effect of multi-dose TRX518 monotherapy on tumor immunohistology and biomarkers of interest and/or infiltrating immune cells and their presence or absence correlated with observed clinical outcomes.
Inclusion Criteria
- Histologically documented metastatic or locally advanced, incurable solid malignancy.
- Tumor tissue for mandatory pre-treatment evaluation (fresh biopsy during Screening preferred; archived specimen may be acceptable with prior approval from Medical Monitor) and lesion accessible for required post-treatment biopsy (C1D21 +/- 7 days).
- Has one or more tumors measurable on radiographic imaging.
- Ambulatory and ≥18 years of age.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1. Patients with an ECOG PS score of 2 may be entered upon the review and approval of the Medical Monitor.
- Life expectancy of at least 12 weeks.
- Disease-free of active second/secondary or prior malignancies for ≥2 years, with the exception of currently treated basal cell or squamous cell carcinoma of the skin or carcinoma in-situ of the cervix or breast.
- Acceptable liver function:
- Bilirubin ≤1.5 x upper limit of normal (ULN);
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤2.5 x ULN. (If liver metastases are present, then ≤5 x ULN is allowed.)
- Acceptable renal function:
- If serum creatinine abnormal for age, calculated creatinine clearance ≥50 mL/min using the Cockcroft and Gault Method.
- Acceptable hematologic status:
- Granulocyte count ≥1.5 x 109/L;
- Absolute lymphocyte count ≥0.8 x 109/L;
- Hemoglobin ≥9 g/dL (transfusion permitted within 7 days of study entry);
- Platelet count ≥100 x 109/L.
- Acceptable coagulation status:
- Prothrombin time (PT)/partial thromboplastin time (PTT) ≤1.2 x ULN (unless receiving anticoagulation therapy, if receiving anticoagulation therapy, eligibility will be based upon international normalized ratio [INR], see 11[b][i]);
- INR ≤1.6 (unless receiving anticoagulation therapy)
- If receiving anticoagulation therapy: INR ≤3.0 and no active bleeding, (i.e., no bleeding within 14 days prior to first dose of study therapy).
- Women of child bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) from 1 month prior to their first dose of study drug through 4 months after their last dose of study drug. Should a woman or female partner of a man become pregnant or suspect she is pregnant while participating in the study, he or she should inform the Investigator immediately.
- Reliable and willing to be available for the duration of the study and willing to follow study procedures.
- Provide written informed consent prior to any study-specific procedures.
Exclusion Criteria
- Hematologic malignancies or multiple myeloma.
- New York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, or unstable arrhythmia.
- Cardiac function:
- Known ejection fraction of <50% by gated radionuclide study (e.g., multi-gated acquisition scan);
- Fridericia-corrected QT interval (QTcF) >470 msec (female) or >450 msec (male), or history of congenital long QT syndrome;
- Any electrocardiogram (ECG) abnormality, including pericarditis, that, in the Investigator's opinion, would preclude safe participation in the study.
- Active, uncontrolled bacterial, viral, or fungal infections within 7 days of study entry requiring systemic therapy.
- Any concomitant serious physical illness other than cancer (e.g., immune deficiency disease, bleeding disorder) within 1 year prior to dosing.
- Specifically, subjects with active autoimmune disease or history of known or suspected autoimmune disease, with the exception of subjects with isolated vitiligo, resolved childhood asthma/atopy, psoriasis not requiring systemic treatment and controlled thyroid disorders..
- Unresolved immune related AEs following prior biological therapy.
- Known clinically important respiratory impairment.
- Known to be human immunodeficiency virus (HIV) positive or have hepatitis B surface antigen (HBSAg) or hepatitis C antibodies (HCAb) unless HCV RNA undetected/negative.
- History of major organ transplant (i.e., heart, lungs, liver, and kidney).
- History of an allogeneic bone marrow transplant.
- History of an autologous bone marrow transplant within 90 days of study entry.
- Symptomatic central nervous system (CNS) malignancy or metastasis. Patients with treated CNS metastases are eligible, provided their disease is radiographically stable, asymptomatic, and they are not currently receiving corticosteroids and/or anticonvulsants. Radiation must have been completed at least 14 days prior to study entry. Screening of asymptomatic patients without a history of CNS metastases is not required.
- Serious nonmalignant disease that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor.
- Pregnant or nursing women.
- Treatment with any other anti-human GITR monoclonal antibody (mAb).
- Treatment with another immunomodulatory therapy within 42 days prior to study entry (>30 days for interleukin-2 and interferon-α, 7 days for topical imiquimod).
- Treatment with surgery or chemotherapy within 21 days prior to study entry (42 days for nitrosoureas or mitomycin C).
- Currently receiving any other investigational agent or received an investigational agent within 30 days or 5 half-lives prior to study entry, whichever is longer.
- A suspected allergy or sensitivity to TRX518 or excipients based upon known allergies to compounds of a similar class or that, in the Investigator's opinion, suggests an increased potential for an adverse hypersensitivity to TRX518.
- Significant allergy to a biological pharmaceutical therapy that, in the Investigator's opinion, poses an increased risk to the patient.
- Concurrent systemic corticosteroids.
- Unwillingness or inability to comply with procedures required in this protocol.
- Psychiatric illness/social situations that would limit compliance with study requirements.
- Active substance abuse.