Immune dynamics and biomarkers of anti-tumor response in BMS-986340 (anti-CCR8) and nivolumab (anti-PD-1) co-treatment of metastatic tumors

Prior treatment

• other invasive malignancy within 2 years prior to entry into the study, except for those treated with surgical therapy only
• discontinuation of previous immunotherapy due to severe immune-related adverse events
• anticancer treatment within the last 14 days before the start of trial treatment, for example chemotherapy, radiotherapy, immunotherapy
• steroid therapy with prednisone equivalent > 10 mg daily.

Other illness

• active autoimmune diseases
• active diverticular disease of active and/or uncontrolled inflammatory bowel disease (IBD).
• mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study.
• any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive the planned therapy, or interfere with the interpretation of study results
• known primary immunodeficiency or active HIV.
• known active or chronic viral hepatitis indicated by positive test for hepatitis B surface antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV RNA).

Lab values

• clinically significant cardiovascular disease within 6 months prior to enrollment (or randomization), including: o prior events including myocardial infarction, pericardial effusion, and myocarditis. o prior cardiac arrhythmia including atrial fibrillation and atrial flutter or requiring concurrent use of drugs or biologics with pro-arrhythmic potential. o NYHA Class II or greater heart failure. o QTc prolongation > 470 millisecond or other significant ECG abnormality noted within 14 days of treatment. o uncontrolled hypertension, hypertensive crisis, history of hypertensive encephalopathy or history of posterior reversible encephalopathy syndrome (PRES). o unstable angina.
• known pregnancy or a positive serum or urine pregnancy test at screening (for any participant in whom WOCBP status cannot be fully excluded by documented medical history).

Other

• untreated and/or unstable central nervous system (CNS) metastases and/or leptomeningeal metastases

• male and female patients ≥ 18 years old
• Life expectancy > 12 weeks
• Normal bone marrow and organ function (Neutrophils ≥ 1500/mm3; Platelets ≥ 100x103/mm3; Hemoglobin ≥ 9.0 g/dL)
• Serum creatinine ≤ 1.5 x the upper limit of normal (ULN) or creatinine clearance (CrCl)≥ 40 mL/min (using the Cockcroft-Gault formula)
• Aspartate aminotransferase (AST) ≤ 2 x ULN; Alanine aminotransferase (ALT) ≤ 2 x ULN; Bilirubin≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL); INR ≤ 1.5 x ULN; PTT ≤ 1.5 x ULN
• At least one lesion accessible for safe core needle biopsy (excluding bone lesions)
• Patients must agree to have fresh tumor biopsy and healthy skin punch biopsy at a pre-treatment before therapy administration at C1D1, C2D1 and C3D1, ;
• Patients must agree to have a tumor-draining lymph node core biopsy, when accessible and technically feasible, at C2D1 and C3D1.
• Patients must agree to have, if possible, safe and technically feasible a fresh tumor biopsy, healthy skin punch biopsy and eventually a tumor-draining lymph node core biopsy at C5D1.
• Patients must agree, if possible, safe and technically feasible to have a fresh tumor biopsy taken at progression..
• Participants must have a tumor that can be biopsied at an acceptable clinical risk as judged by the investigator to be eligible. An unsuccessful fresh tumor biopsy at screening, before C1D1, will not exclude participants from receiving study treatment. A repeat biopsy at screening or on-treatment from the same or an alternative site will be required if clinically feasible (at the discretion of the investigator) if the initial attempt was unsuccessful in obtaining adequate tissue. Only one repeat attempt may be performed at each time point, if clinically feasible.
• ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
• women participants must have documented proof that they are not of childbearing potential;or women of child bearing potential (WOCBP) (See Note 1 below for definition of WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) within 24 hours prior to the start of study treatment. WOCBP must agree to have pregnancy test collected on Day 1 of each cycle. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. WOCBP must agree to follow instructions for methods of contraception that are highly effective (with a failure rate of <1% per year), as described in Appendix 1, during the treatment period and for at least 3 months after the last monotherapy treatment or for at least 6 months after the last dose of study treatment if receiving combination treatment and must agree not to donate eggs (ova, oocytes) for the purpose of reproduction for the same time period. Women who are not of childbearing potential are exempt from contraceptive requirements
• male participants receiving both monotherapy and combination therapy should maintain their usual practice with regard to contraception (if any); however, no specific contraceptive measures are required
• Histologically confirmed diagnosis of NSCLC or gastric cancer or MSS CRC or pancreatic adenocarcinoma
• participants will be expected to have received all available standard of care therapies (including an available PD-(L)1 inhibitor if known to be effective in the tumor type considered) and have no approved or otherwise effective treatment options remaining and must have failed at least one prior standard systemic therapy line and have no available approved treatment option with a meaningful expected clinical benefit, as judged by the treating physician in consideration of current treatment guidelines. For PD-(L)1-refractory NSCLC and gastric cancer cohorts: patients must have failed ≥1 prior PD-(L)1-containing regimen. For MSS CRC and pancreatic adenocarcinoma cohorts: patients must have failed ≥1 prior line of standard chemotherapy (e.g., FOLFOX/FOLFIRI ± targeted agents for CRC; gemcitabine/nab-paclitaxel for PDAC), patients must be immunotherapy naïve and have no further standard options with demonstrated survival benefit
• participants must have experienced radiographically documented progressive disease on or after the most recent therapy
• measurable disease per RECIST 1.1
• ECOG performance status ≤ 1 or Karnofsky performance status of ≥ 70.