Neoadjuvant PD-1 Inhibitor Dostarlimab (TSR-042) vs. Combination of Tim-3 Inhibitor Cobolimab (TSR-022) and PD-1 Inhibitor Dostarlimab (TSR-042) in Melanoma

Inclusion Criteria

• •written informed consent for the study
• •≥ 18 years of age
• •histologically or cytologically confirmed diagnosis of cutaneous or unknown primary melanoma (excluding uveal/choroidal and mucosal melanoma; although acral melanoma is included) belonging to one of the following AJCC 8th edition TNM stages:
• •1. Tx or T1-4 AND
• •2. N1b, or N1c, or N2b, or N2c, or N3b, or N3c AND/OR
• •3. M1a or M1b
• •Patients are eligible for this trial either at presentation for primary melanoma with concurrent regional nodal and/or in-transit metastasis and/or oligometastasis; AND/OR at the time of clinical detected nodal and/or in-transit and/or oligometastatic recurrence; and may belong to any of the following groups:
• •Primary melanoma with clinically apparent regional lymph node metastases; Clinically detected recurrent melanoma at the proximal regional lymph node(s) basin; Clinically detected primary melanoma involving multiple regional nodal groups; Clinical detected nodal melanoma (if single site) arising from an unknown primary; In-transit and/or satellite metastases with or without regional lymph node involvement; Distant skin and/or in-transit and/or satellite metastases with or without regional lymph node involvement; Oligometastatic lung disease with or without regional lymph node involved permitted if deemed resectable at baseline NOTE: Determination of resectability must be made at baseline to be eligible for this neoadjuvant study.
• •measurable disease based on RECIST 1.1
• •must provide tumor tissue from a newly obtained core, punch, incisional or excisional tumor biopsy
• •0 or 1 on the ECOG Performance Scale
• •Demonstrate adequate organ function on screening labs obtained within 14 days of registration
• •negative serum pregnancy test (females of childbearing potential)
• •females of non-childbearing potential must be ≥45 years of age and has not had menses for \>1 year; if amenorrhoeic for \<2 years without history of a hysterectomy and oophorectomy must have an FSH value in the postmenopausal range; post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation (documented hysterectomy or oophorectomy)
• •male subjects should agree to use an adequate method of contraception
• •known additional malignancy that is progressing or requires active treatment (except, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy)
• •invasive cancer diagnosed and treated less than 2 years prior to current presentation (other indolent malignancies that are not progressing and/or deemed to require active therapy are not exclusionary)
• •evidence of interstitial lung disease or active, non-infectious pneumonitis
• •active infection requiring systemic therapy
• •history or current evidence of any condition, therapy, or laboratory abnormality determined to be significant, in the opinion of the treating investigator
• •known psychiatric or substance abuse disorders that would interfere with study compliance
• •is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial
• •had a live vaccine within 30 days of initiating protocol therapy
• •received prior therapy with an IDO inhibitor, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 and/or combination (including nivolumab, pembrolizumab or ipilimumab/nivolumab). Prior treatment with ipilimumab or interferon alfa is allowed.
• •history of allergic or hypersensitivity reaction to components or excipients of Dostarlimab (TSR-042) and TSR-022, interferon alfa or ipilimumab
• •known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
• •known history of or screening test that is positive for hepatitis B virus (HBV; eg, HBsAg reactive or HBV DNA detected) or hepatitis C virus (HCV; HCV antibody positive and/or HCV RNA quantitative is detected). Hepatitis C antibody - positive subjects who received and completed treatment for hepatitis C that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable. Hepatitis B positive subjects who received and completed treatment for hepatitis B that was intended to eradicate the virus may participate if hepatitis B DNA levels are undetectable.