A Phase 1, First-in-human Study of OKN4395 and Pembrolizumab in Patients With Solid Tumors

Inclusion Criteria:

1. Histologically or cytologically confirmed disease, locally advanced or metastatic: For Phase 1a: Solid tumor with a COX2-associated immunosuppressive pathway, for which standardtreatment options are not available, no longer effective, refused or not tolerated. For Phase 1b: For all cohorts, in the opinion of the investigator, all appropriate authorizedtreatment options should be exhausted

• Cohort 1: Sarcoma (fibrous sarcoma [myxofibrosarcoma or solitary fibroustumor], dedifferentiated liposarcoma, undifferentiated pleomorphic sarcoma orpleomorphic sarcoma, or leiomyosarcoma), that is either refractory to orprogressing on standard of care, with no more than 3 prior lines of systemictherapy. Patients with a solitary fibrous tumor can be included in the studywithout prior treatment if, in the investigator's opinion, it is in theparticipant's best interest and no established standard of care exists or isavailable.

• Cohort 2: NSCLC (squamous or adenomatous without EGFR/ALK mutations), withdisease progression on a PD-(L)1 CPI regimen, and no more than 3 prior lines ofsystemic therapy. When known, PD-L1 status should be provided.

• Cohort 3: CRC (Microsatellite stable or Microsatellite instability - low), andno more than 4 prior lines of systemic therapy.

• Cohort 4: GC (gastric and gastro-esophageal junction adenocarcinoma),HER2-negative, planned to or currently receiving CPI monotherapy as maintenanceof a first-line CPI + chemotherapy regimen, after chemotherapy cessation.

2. ECOG performance status of 0 or 1.

3. Recovery from any medically relevant AE/irAE from previous treatment regimen (defined as recovery to Grade ≤1 level per CTCAE v 5.0 before Screening, or chronic,stable, Grade 2 AEs [not worsened to Grade >2 for >3 months prior to screening]).

4. One or more new or growing tumor lesions amenable to a safe biopsy (at baseline, asuitable archival specimen obtained when not undergoing treatment and within 1 year [Phase 1a], or within 90 days and after the last administration of the previoussystemic therapy [Phase 1b] is suitable). In addition (where applicable) an archivaltumor biopsy collected before the start of the first-line treatment in themetastatic setting is requested (but optional).

5. At least one target lesion measurable by RECIST 1.1 as noted by localinvestigators/radiologists.

6. The ability to swallow and retain OKN4395 as an oral medication without significantgastrointestinal abnormalities that might alter absorption.

7. The willingness and ability to comply with the evaluation, randomizations andrequirements of the protocol. For Substudy 1, the ability to comply with theevaluation requirements includes the absence of any condition known to affect uppergastrointestinal motility, absorption, and pH.

8. Adequate hematologic, renal, and hepatic function (based on local laboratoryassessments):

9. Hematological variables: absolute neutrophil counts ≥1.5 × 109 /L, plateletcounts ≥75 × 109 /L, and hemoglobin ≥8 g/dL

10. Renal variables: creatinine clearance ≥ 60 mL/min1 by Du Bois & Du Bois formula

11. Hepatic variables: total serum bilirubin ≤1.5 × ULN, AST and ALT ≤3 × ULN, andALP ≤2.5 × ULN; except for hyperbilirubinemia of Gilbert's syndrome (participants with Gilbert's syndrome can be included if total serum bilirubin ≤5× ULN and direct bilirubin ≤1.5 x ULN)

12. Serum albumin ≥30 g/L

Exclusion Criteria:

1. Except for the current regimen in Cohort 4, ongoing or recent anticancer therapywithin the following timeframe prior to first dose of study drug:

2. Chemotherapy, ADCs, or other antibodies < 21 days

3. Immunotherapy or cellular therapy < 28 days

4. Radiation therapy (palliative radiation for bone pain <48 hours; stereotacticor small field brain irradiation <7 days; all other radiation therapy <14 days)

5. TKI or any other anticancer therapy < 5 half-lives or < 7 days, whichever islonger

6. Central nervous system metastasis (radiologically progressive, or clinicallysymptomatic, or requiring immunosuppressive therapies [including low dosesteroids]).

7. Any active infection (bacterial, viral, fungal) requiring IV systemic therapy.

8. Unstable COPD defined as frequent or severe exacerbations per investigatordiscretion.

9. Known history of or active HBV (HBsAg reactive and/or HBV DNA detected) or HCV (HCVRNA detected) infection.

10. HIV infection with CD4 lymphocyte count <350 cells/μL at time of Screening, orfailure to achieve and maintain virologic suppression defined as confirmed HIV RNAlevel < 50 or lower limit of detection by the local available assay at time ofScreening and for at least 12 weeks prior to Screening.

11. Known history of bleeding disorders, INR ≥1.5 × ULN at screening (or INR and/or aPTTwithin therapeutic range if on anticoagulation therapy), or a history ofgastrointestinal bleeding (inflammatory, ulcerative, or diverticular) within thelast 2 years.

12. Known H. pylori infection without proof of eradication at least 2 months prior toscreening.

13. Systemic treatment with any drug known to impact gastrointestinal pH within 7 days (PPIs) or 12 hours (H2 antagonists) of first dose of OKN4395 (unless adapted afterSubstudy 1). Where said treatments have been used for more than 2 weeks prior todiscontinuation, discontinuation should occur at least 21 days before first dose ofOKN4395.

14. Acute treatment with any systemic steroid therapy (>10 mg prednisone equivalent), orany corticosteroid medication within 14 days of first dose of OKN4395 for anycondition.

15. For participants planned to receive combination therapy: Ongoing and history ofactive autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressivedrugs). Any replacement therapy (i.e. thyroxine, insulin, or physiologiccorticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) isnot considered a form of systemic treatment and is allowed. Participants withhyperthyroidism or hypothyroidism but that are stable on hormone replacement arealso allowed.

16. Systemic treatment with NSAIDs, COX2 inhibitors, or synthetic prostaglandins within 5 half-lives prior to the first dose of OKN4395 (acetylsalicylic acid ≤ 160 mg/day,or 325 mg ≤ 3 times/week is permitted).

17. Systemic treatment with strong inhibitors/inducers of CYP and UGT enzymes within 14days of first dose of OKN4395.

18. QTcF interval of > 450 ms based on mean of the central triplicate readings.

19. Known hypersensitivity to any excipients of the OKN4395 formulation or pembrolizumab (for combination cohorts).

20. Pregnant or lactating women. Women of childbearing potential must have a negativeserum pregnancy test at screening and have a negative a urine dipstick pregnancytest prior to the initiation of study treatment (can be done on C1-D1 visit).

21. Evidence of any other active malignancy requiring systemic therapy within the 2years prior to Screening. (Exceptions: non-melanoma skin cancer, in situ melanoma,in situ cervical cancer, ductal carcinoma in situ of the breast, or localized andpresumed cured prostate cancer; participants on long-term anti-hormonal therapy fora prior malignancy are allowed if the malignancy has not been active within theprior 2 years).

22. History or current evidence of any condition, surgical or medical therapy, orlaboratory abnormalities that might confound the results of the study, make studydrug administration hazardous, interfere with the participant's involvement for thefull duration of the study, or make it difficult to monitor AEs such that, in theopinion of the treating physician, it is not in the best interest of the participantto participate