Ensayos clínicos

Study closed to enrollment

Inclusion Criteria:

• Unresectable Stage III or Stage IV melanoma.
• Patients must have measurable disease, defined as lesions that can be accurately measure in in 2 perpendicular diameters with at least one diameter > 20mm and the other >10mm on conventional CT or MRI or 10mm x 10 mm by spiral CT.
• No systemic treatment in the previous 28 days.
• Age ≥18 years. Because no dosing or adverse event data are currently available on the use of ipilimumab or indoximod in patients <18 years of age, children are excluded from this study.
• ECOG performance status ≤2 (Karnofsky ≥60% )
• Patient has adequate bone marrow and organ function as defined by the following laboratory values :
• Absolute Neutrophil Count (ANC) ≥ 1.0 x 109/L
• Platelets ≥ 100 x 109/L
• Hemoglobin ≥ 9.0 g/dL
• INR ≤ 2 x ULN
• Potassium, calcium, magnesium ≤ Grade 1 per CTCAE
• Serum Creatinine ≤ 1.5 x ULN
• Serum Bilirubin, amylase and lipase ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, total bilirubin ≤ 3 x ULN, with direct bilirubin ≤ 1.5 x ULN)
• AST and ALT ≤ 3 x ULN (or ≤ 5.0 x ULN if hepatic metastases are present)
• Serum Albumin ≥ 3 g/dL
• Patients must have normal pituitary function as defined below:
• free T4, TSH within normal institutional limits
• ACTH within normal institutional limits
• Patients with known brain metastases will only be eligible after their tumors have been treated with definitive resection and/or radiotherapy and they are neurologically stable for at least 1 month off steroids.
• The effects of indoximod on the developing human fetus are unknown. For this reason and because indoximod may affect maternal immune tolerance of the fetus, sexually active women of child-bearing potential must agree to use two forms of contraception (hormonal and barrier method of birth control or abstinence) prior to study entry and for the duration of study participation. Use of contraception or abstinence should continue for a minimum of 1 month after completion of the study. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should discontinue the study drug and inform her treating physician immediately. A pregnancy test is required prior to study enrollment and monthly while on treatment with indoximod for all women of child-bearing potential. Also men should be discouraged from fathering children while on treatment.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Patients who have had molecular targeted therapy (including vemurafenib) or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
• Patients who have had prior therapy with immune checkpoint inhibition or or indoximod are excluded from the trial. Pre-treatment with other immune modulators is allowed in the phase 1 component of the study only. For the Phase II component, patients are excluded if they have had prior therapy with or immune-stimulating agents including interleukin-2, interferons, CTLA-4 or PD1 antagonists, CD40 or CD137 agonist, or cancer therapeutic vaccines in any prior line for metastatic disease. Interferons used in the adjuvant setting are allowed (Phase 1 or 2 component).
• Patients with known active, uncontrolled brain metastases should be excluded from this clinical trial.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ipilimumab or tryptophan containing substances. This would include L-tryptophan or 5-hydroxy-tryptophan supplements. Also patients with a history of known hypersensitivity reactions to mouse or humanized monoclonal antibodies are excluded.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (especially toxoplasmosis, which could potentially be worsened by indoximod (Divanovic et al., 2012)), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because indoximod is an immunoregulatory agent with the potential for abortifacient effects due to fetal rejection by the maternal immune system. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with indoximod, breastfeeding should be discontinued if the mother is treated with indoximod.
• Known HIV-positive patients and those with other acquired/inherited immunodeficiencies are ineligible due the possibility of affecting the response to indoximod, and the higher risk of active opportunistic infections.
• Any other cancer, unless the patient has been disease-free for ≥5 years (except treated and cured basal-cell or squamous-cell skin cancer, superficial bladder cancer, or treated carcinoma in situ of the cervix, breast, or bladder and treated localized prostate cancer with undetectable PSA for 2 years).
• Patients with laboratory evidence of pancreatitis are excluded.
• Patients with autoimmune disease (e.g., psoriasis, extensive atopic dermatitis, asthma, IBD, M.S., uveitis, vasculitis), chronic inflammatory condition, or any condition requiring concurrent use of any systemic immunosuppressants or steroids for any reason are excluded from the study. Patients with isolated vitiligo remain eligible. Any patient with an allo-transplant of any kind would be excluded as well, including xenograft heart valve. Mild, intermittent asthma requiring only occasional beta-agonist inhaler use or mild localized eczema will not be excluded.
• Chronic use of immune-suppressive drugs (ie, systemic corticosteroids used in the management of cancer or non-cancer related illnesses, eg, COPD).
• Patients who are receiving any other investigational agent.