A Study of OR502, a Monoclonal Antibody Targeting LILRB2, Alone and in Combination With Anticancer Agents

Inclusion Criteria:

1. Informed consent signed by the subject prior to conducting study-specificprocedures.

2. Male or female subjects ≥ 18 years of age.

3. Histological diagnosis as follows:

4. Parts A and B (Cohorts A1, A2, and B1): subjects must have a histologicaldiagnosis of any type of carcinoma, sarcoma, or melanoma with progressivemetastatic disease, or progressive locally advanced disease not amenable tolocal therapy with curative intent.

5. Part B (Expansion Cohorts B2-B3): subjects must have a histological diagnosisof the relevant tumor type (CSCC or PROC) with advanced/metastatic disease notamenable to local therapy with curative intent.

6. Prior therapies: a. Part A (dose-escalation) and Cohort B1 (monotherapy expansion) i. Subjects musthave experienced progressive disease (PD) on an established standard systemicanti-cancer therapy for a given tumor type or have been intolerant to such therapy,or in the opinion of the Investigator have been considered ineligible for aparticular form of standard therapy on medical grounds. Subjects must have noavailable proven curative or life prolonging therapies. b. Cohorts B4 and B5 (mini-expansion cohorts) i. Subjects must have received aPD-(L)1 inhibitor-based therapy, either alone or in combination with otheranti-cancer agents, for at least 12 weeks. If subjects have received other lines ofimmunotherapy, including PD-(L)1-based therapy, they must have demonstrated clinicalbenefit on each prior immunotherapy. Subjects may also have received additionalanti-cancer therapies after failure of a PD-(L)1 inhibitor, but 2nd line subjectsare preferred. c. Cohorts B2 and B3 (dose-expansion) i. Cohort B2 subjects (CSCC) must havereceived a PD-(L)1 inhibitor. Subjects may not have received an additionalimmunotherapy. ii. Cohort B3 subjects (PROC) must have received platinum-based therapy andexperienced disease progression on or within 6 months of completion of such therapy.Subjects may have received prior anti-PD-1 therapy. Subjects may have receivedadditional therapies after failure of platinum-based therapy.

7. Subjects must have measurable disease per RECIST v1.1.

8. People of childbearing potential, if not postmenopausal (defined as no menses for atleast 12 continuous months prior to study entry) or surgically sterile, must bewilling to practice at least one of the highly effective methods of birth controldescribed in Section 4.3 for at least a menstrual cycle (or partner's menstrualcycle, for male subjects) before and for 4 months after study medicationadministration.

9. Resolution of prior clinically significant therapy-related AEs (excluding alopeciaand ≤ Grade 2 peripheral neuropathy) to ≤ Grade 1 per NCI-CTCAE version 5.0, and notreatment for these AEs for at least 2 weeks prior to the time of enrollment.Electrolyte and hormonal supplementation may be used to treat these AEs provided thesubject is stable on these supplements.

10. Minimum of 2 weeks since the last dose of other hormone therapy and 3 weeks sincethe last dose of other systemic cancer therapy or radiotherapy (> 4 weeks in case ofnitrosoureas or radio-immuno conjugate therapy). Adjuvant hormonal therapy (e.g.,tamoxifen) is allowed provided the original tumor diagnosis was more than 3 yearsbefore the first dose of study medication. Subjects with prostate cancer on stabledoses of anti-hormone treatment may remain on therapy for this trial.

11. Subjects must have adequate organ function.

12. Biopsy specimens:

13. All subjects must be able to supply an archival tumor tissue specimen. If anarchival specimen is not available, subjects may remain eligible with approvalof the medical monitor.

14. Subjects in Cohort B1 must consent to pre- and on-treatment biopsies. Tissueobtained for the biopsy must not be previously irradiated. No systemicanti-neoplastic therapy may be received by the subject between the time of thebiopsy and the first administration of study medication.

15. Subjects in all other cohorts will be asked to consent to pre- and on-treatmentbiopsies for biomarker analysis of the acquired tissue. These biopsies areoptional and not required for study participation. Tissue obtained for thebiopsy must not be previously irradiated. No systemic anti-neoplastic therapymay be received by the subject between the time of the biopsy and the firstadministration of study medication.

16. Subject is able and willing to comply with the protocol and the restrictions andassessments therein.

17. As required by local regulations or law, subjects must fulfill the obligation ofaffiliation or beneficiary of a social security or similar scheme.

Exclusion Criteria:

1. Subject previously had a severe hypersensitivity reaction to treatment with anothermonoclonal antibody (mAb).

2. Life expectancy < 12 weeks.

3. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) >

5. Prior organ or stem cell transplant.

6. Subjects with symptomatic ascites or pleural effusion. Subjects who are clinicallystable for at least 2 weeks following treatment for these conditions (includingtherapeutic thoraco- or paracentesis) are eligible.

7. Subject has a known active central nervous system (CNS) primary tumor or metastasesand/or carcinomatous meningitis. Subjects with previously treated brain metastasesmay participate provided they are clinically stable for at least 4 weeks prior tostudy entry, have no radiological evidence of new or enlarging brain metastases, andare off steroids or on a stable dose up to an equivalent of prednisone 10 mg/day forat least 15 days prior to first dose of study medication. Subjects who have symptomsconsistent with CNS metastasis must have a negative magnetic resonance imaging (MRI)scan during the screening period.

8. Subject has a known history of a hematologic malignancy, malignant primary braintumor, or another malignant primary solid tumor (other than that under study),unless the subject has undergone potentially curative therapy with no evidence ofrecurrent disease for at least 3 years before the start of treatment.

9. Subjects with a known history of AJCC Stage 1 cancer that has undergonepotentially curative therapy with no evidence of recurrent disease for at least 1 year before the start of treatment may be eligible at the Investigator'sdiscretion after consultation with the Sponsor.

10. Subjects who underwent successful definitive resection of basal cell carcinomaof the skin, superficial bladder cancer, squamous cell carcinoma of the skin,in situ cervical cancer, or other in situ cancers at any time before the startof treatment, and have no evidence of recurrent disease, are eligible.

11. Recent or ongoing serious infection including the following:

12. Any uncontrolled Grade 3 or higher (per NCI-CTCAE version 5.0) viral,bacterial, or fungal infection within 2 weeks prior to the first dose of OR502.Routine antimicrobial prophylaxis is allowed.

13. Uncontrolled infection with human immunodeficiency virus (HIV). Subjects onstable highly active antiretroviral therapy (HAART) with undetectable viralload and normal CD4 counts for at least 6 months prior to study entry areeligible. Serological testing for HIV at screening is not required.

14. Known to be positive for hepatitis B virus (HBV) surface antigen, or any otherpositive test for hepatitis B indicating acute or chronic infection. Subjectswho are or have received anti-HBV therapy and have undetectable HBV DNA for atleast 6 months prior to study entry are eligible. Serological testing forhepatitis B at screening is not required.

15. Known active hepatitis C as determined by positive serology and confirmed bypolymerase chain reaction (PCR). Subjects on or having received anti-retroviraltherapy are eligible provided they are virus-free by PCR for at least 6 monthsprior to study entry. Serological testing for hepatitis C at screening is notrequired.

16. Known active or latent tuberculosis (testing at screening is not required).

17. Autoimmune disease or inflammatory condition requiring systemic anti-inflammatorytherapy with exceptions as noted in Exclusion Criterion 10. Subjects on hormonereplacement therapy for autoimmune-induced endocrinopathies are eligible.

18. Use of systemic corticosteroids within 15 days or other immunosuppressive drugswithin 30 days prior to start of the study, with the exception of corticosteroids asreplacement therapy up to an equivalent of prednisone 10 mg/day, which are allowed.

19. QTc interval ≥ 470 msec by electrocardiogram (ECG).

20. Subject has received an investigational product or been treated with aninvestigational device within 30 days prior to first administration of studymedication.

21. Subject has received a live vaccine within 30 days prior to first administration ofstudy medication.

22. For Cohorts A2, B1, B2, and B3 only:

23. Known hypersensitivity to cemiplimab or any of its excipients orcontraindicated to cemiplimab per approved local labeling.

24. Interstitial lung disease.

25. Prior pneumonitis requiring systemic corticosteroid therapy.

26. Receiving immunosuppressive therapy, with exceptions as noted in ExclusionCriterion 10.

27. A history of severe immune-related adverse reactions from treatment withipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiringcorticosteroid treatment (> 10 mg/day prednisone or equivalent) for more than 12 weeks.

28. Concurrent therapy with anti-cancer or anti-neoplastic drugs, with the exception ofadjuvant hormonal therapy, which is allowed as outlined in Inclusion Criterion 8.

29. History or clinical evidence of any surgical or medical condition that theInvestigator judges as likely to interfere with the results of the study or pose anadditional risk in participating, e.g., rapidly progressive or uncontrolled diseaseinvolving a major organ system-vascular, cardiac, pulmonary, gastrointestinal,gynecologic, hematologic, neurologic, neoplastic, renal, endocrine, autoimmune or animmunodeficiency, or clinically significant active psychiatric or abuse disorders.

30. Subjects who, at the time of signing informed consent, had a recent history (withinthe last year) of chronic substance abuse.

31. Subject is pregnant or breastfeeding or expecting to conceive or father childrenwithin the projected duration of the study.

32. Vulnerable persons: subjects under judicial safeguard, subjects deprived of theirliberty by judicial or administrative decision, subjects under psychiatric carewithout their consent, subjects admitted to a health or social institution forpurposes other than research, adults subject to a measure of legal protection (guardianship or curatorship), and subjects unable to express their consent.