This is a randomized phase II neoadjuvant study comparing neoadjuvant therapy with PD-1
inhibitor Dostarlimab (TSR-042) to the PD-1/TIM-3 inhibitor combination Dostarlimab
(TSR-042)/TSR-022 in patients with resectable regionally advanced or oligometastatic
melanoma.
Patients with stage III B/C/D or oligometastatic stage IV A melanoma with lymph node (LN)
and/or in-transit and/or oligometastatic disease who have yet to undergo definitive surgery
are eligible to enroll.
Suitable patients will be identified pre-operatively. Patients will undergo screening
evaluation consisting of systemic/CNS staging scans, tumor biopsy, blood studies to confirm
suitability. Subjects will receive neoadjuvant therapy (Dostarlimab (TSR-042) or Dostarlimab
(TSR-042)/TSR-022 combination for 6 weeks prior to planned surgery (pre-operative phase).
Surgery will occur 1-4 weeks after completion of pre-operative therapy. After recovery from
surgery subjects will receive Dostarlimab (TSR-042) (Post-Operative phase) for approximately
48 weeks; for a total of 54 weeks of study drug(s) administration in total.
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
- 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 (resectability
determination/deemed resectable at baseline to be eligible), includes: 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
- 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
Exclusion Criteria:
- Patients with uveal and/or mucosal melanoma histology are excluded (Patients with
melanoma of unknown histology are permitted to enroll after discussion with Principal
Investigator)
- Is currently participating in or has participated in a study of an investigational
agent or using an investigational device within 4 weeks of the first dose of
treatment.
- Is receiving systemic immunosuppression with either corticosteroids (>10mg daily
prednisone equivalent) or other immunosuppressive medications) for active autoimmune
disease: history of active autoimmune disease requiring systemic treatment within the
past 3 months or a documented history of clinically severe autoimmune disease, or a
syndrome that requires systemic steroids (>10mg daily prednisone or equivalent) or
systemic immunosuppressive agents
- ≥ CTCAE grade 3 immune-related AE (irAE) experienced with prior immunotherapy (except,
non-clinically significant lab abnormalities (elevations in lipase, amylase not
associated with clinically significant disease etc.) even if ≥ CTCAE grade 3 may
enroll if resolved at this time, or, development of autoimmune disorders of Grade ≤ 3
may enroll if the disorder has resolved to Grade ≤ 1)
- received prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
baseline) from adverse events due to a previously administered agent (except ≤ Grade 2
neuropathy)
- autoimmune disorders of Grade 4 while on prior immunotherapy
- active (i.e., symptomatic or growing) central nervous system (CNS) and/or
leptomeningeal metastases (CNS lesions that are treated and deemed stable (repeat
imaging study done at least 2 weeks prior to first dose of study treatment) are NOT
permitted to enroll even if other inclusion criteria are met and patients are
neurologically asymptomatic)
- 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.
