Inclusion Criteria:
1. Be willing and able to provide written informed consent for the study. The subject may also provide consent for Future biomedical research (FBR). However, the subject may participate in the main study without participating in FBR.
2. 18 years of age on day of signing informed consent.
3. Male and female subjects with advanced unresectable, recurrent or metastatic tumors who have received standard of care (SOC) therapy for their advanced/metastatic tumors and have no other SOC therapy available. Additionally, subjects must have received, have been intolerant to, have been ineligible for, or have declined all SOC therapies known to confer significant clinical benefit.
4. Have histologically or cytologically confirmed cancer diagnosis based on pathology report.
5. Have a predicted life expectancy of greater or equal to 3 months.
6. Have measurable disease based on RECIST 1.1.
7. Have a performance status of 0, 1 or 2 using the ECOG Performance Scale within 14 days of first dose of study drug.
8. Willing to submit a pre-treatment (archival or fresh-tissue if no archival tissue is available) and on-treatment tissue sample. Subjects in whom the treating physician deems such biopsy is clinically contraindicated will be evaluated on a case-by-case basis for enrollment pending Sponsor consultation.
Additionally, during the dose-escalation portion and if appropriate in the expansion phase of the study, the Sponsor may modify subject enrolment into various cohorts that have not begun enrolling yet such that ENPP1 and/or cGAS baseline expression level in the subject's tumor must be available and may guide enrolment eligibility for the study
9. Have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study drug (female subjects of childbearing potential who are not surgically sterilized or postmenopausal). If the urine test is positive, or cannot be confirmed as negative, a serum pregnancy test will be required.
10. Demonstrate adequate organ function: hematological, renal, hepatic, coagulation parameters and obtained within 14 days prior to the first study treatment
11. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use two highly effective contraceptive methods that result in a combined failure rate of \< 1% per year during the treatment period and for at least 120 days after the last dose of study treatment or as instructed by the package insert of the chosen co-medication.
12. For male subjects: Agree that during the period specified above, men will not father a child. Male subjects must remain abstinent (refrain from heterosexual intercourse with women of childbearing potential), must be surgically sterile (e.g., vasectomy) or use contraceptive methods that result in a failure rate of \< 1% per year during the treatment period and for at least 120 days after the last dose of study treatment.
Exclusion Criteria:
1. Use of any systemic anti-cancer therapy (including radiotherapy, chemotherapy, targeted therapy or immunotherapy) within 2 weeks prior to first dose of RBS2418 unless such therapy is being administered in combination with RBS2418 per protocol and has been approved by the Sponsor; or if subject has not recovered (i.e., Less than or equal to Grade 1 or returned to baseline level) from adverse events due to a previously administered agent; the following exceptions are allowed:
* Palliative radiotherapy for bone metastases or soft tissue lesions should be completed \> 7 days prior to baseline imaging
* Hormone-replacement therapy or oral contraceptives
* Subjects with Grade 2 neuropathy or Grade 2 alopecia
2. Subjects with evidence of rapid progression on prior therapy resulting in rapid clinical deterioration should be excluded from participation in the trial.
3. Currently participating and receiving trial therapy or has participated in a trial of an investigational agent and/or has used an investigational device within 28 days prior to Day 1.
4. Uncontrolled tumor-related pain
5. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
6. Malignancies other than indications open for enrollment within 3 years prior to Day 1, with the exception of those with negligible risk of metastasis or death treated with expected curative outcome, undergoing active surveillance or treatment-naïve for indolent tumors
7. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
8. Known hypersensitivity allergy or contraindication to any investigational product components administered as part of the combination therapy.
9. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
10. History or any evidence of interstitial lung disease
11. Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment.
12. Active HIV requiring therapy and Uncontrolled HIV\*. HIV antibody testing recommended per investigator's clinical suspicion.
13. Active hepatitis B virus (HBV; hepatitis B surface antigen reactive) or active hepatitis C virus (HCV; qualitative RNA detected)\*; such as requiring active therapy (e.g. subjects with a history of HCV are eligible as long as viral RNA is below level of detection); testing recommended per investigator's clinical suspicion.
14. Severe infections within 4 weeks prior to enrollment, including, but not limited to, hospitalization for complications of infection, bacteremia, or the presence of any active infection requiring systemic therapy.
15. Received therapeutic oral or IV antibiotics within 2 weeks prior to Day 1
16. History or current evidence of any condition, therapy, or laboratory abnormality that in the opinion of the treating investigator might confound the results of the trial or interfere with the subject's participation for the full duration of the trial.
17. Subjects with:
* A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval of \> 480 milliseconds (ms) (CTCAE Grade 1) using Fridericia's QT correction formula
* A history of additional risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
* The use of concomitant medications that are known to prolong the QT/QTc interval unless there is evidence of the lack of QT/QTc interval prolongation at baseline.
18. Subjects with gastrointestinal disorders that may affect the absorption of the drug
19. Prior allogeneic stem cell or solid organ transplant.
20. Received a live, attenuated vaccine within 28 days prior to enrollment/cohort assignment or anticipation that such a live attenuated vaccine will be required during the trial
21. Known previous or ongoing, active psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
22. Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (i.e. infectious disease) illness.
23. Pregnant or lactating or intending to become pregnant or father children within the projected duration of the trial starting with the screening visit through 120 days after the last dose of pembrolizumab and/or RBS2418.
