A Phase 1, Open-label, Multicenter, Dose-escalation and Cohort Expansion Study of OKN4395, a Triple Antagonist of EP2, EP4, and DP1 Prostanoid Receptors, as Monotherapy and in Combination With Pembrolizumab, in Patients With Advanced Solid Tumors
The purpose of this study is to investigate the study drug, OKN4395, administered alone and in combination with pembrolizumab. The overall objectives of this study are to determine the safety and tolerability (degree to which side effects of a drug can be tolerated) of OKN4395 alone and in combination with pembrolizumab, OKN4395 and metabolites (broken-down substances) of OKN4395 levels in the blood, and antitumor activity of OKN4395 alone and in combination with pembrolizumab. This study will be split into 2 parts. Part 1a will look at multiple doses of OKN4395 either alone (monotherapy) or with pembrolizumab (combination therapy) administered on day 1 of each 21-day cycle in patients with solid tumors until the participant has disease progression or discontinues for any reason. The dose of OKN4395 will be increased, after each group of 3 or more participants completes their first 3 weeks of treatment and their data is evaluated for safety, with a planned dose range from 10 mg twice a day to 450 mg twice a day through 13 dose levels. Part 1a also includes a parallel substudy (Substudy 1) consisting of at least 12 participants, aiming to test the effect of food and stomach acid on the levels of OKN4395 in the blood as well as its tolerability. Part 1b will evaluate OKN4395 alone and in combination with pembrolizumab administered on day 1 of each 21-day cycle in patients with selected cancer types. Part 1b will comprise 4 cohorts: Cohort 1 in sarcoma (OKN4395 alone), Cohort 2 in non-small cell lung cancer (NSCLC), Cohort 3 in colorectal cancer, and Cohort 4 in gastric cancer (GC), with cohorts 2 to 4 in combination with pembrolizumab. The overall study will enrol approximately 146 participants with up to 54 participants to receive OKN4395 alone and 12 participants to receive OKN4395 in combination with pembrolizumab in Part 1a, and 80 participants in Part 1b split: 20 on monotherapy and 60 on combination therapy. The study will be conducted in the US, Australia, UK and in the EU.
• Histologically or cytologically confirmed disease, locally advanced or metastatic:
• For Phase 1a:
• Solid tumor with a COX2-associated immunosuppressive pathway, for which standard treatment 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 authorized treatment options should be exhausted
⁃ Cohort 1: Sarcoma (fibrous sarcoma \[myxofibrosarcoma or solitary fibrous tumor\], dedifferentiated liposarcoma, undifferentiated pleomorphic sarcoma or pleomorphic sarcoma, or leiomyosarcoma), that is either refractory to or progressing on standard of care, with no more than 3 prior lines of systemic therapy. Patients with a solitary fibrous tumor can be included in the study without prior treatment if, in the investigator's opinion, it is in the participant's best interest and no established standard of care exists or is available.
⁃ Cohort 2: NSCLC (squamous or adenomatous without EGFR/ALK mutations), with disease progression on a PD-(L)1 CPI regimen, and no more than 3 prior lines of systemic therapy. When known, PD-L1 status should be provided.
⁃ Cohort 3: CRC (Microsatellite stable or Microsatellite instability - low), and no 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 maintenance of a first-line CPI + chemotherapy regimen, after chemotherapy cessation.
• ECOG performance status of 0 or 1.
• 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 \[not worsened to Grade \>2 for \>3 months prior to screening\]).
• One or more new or growing tumor lesions amenable to a safe biopsy (at baseline, a suitable archival specimen obtained when not undergoing treatment and within 1 year \[Phase 1a\], or within 90 days and after the last administration of the previous systemic therapy \[Phase 1b\] is suitable). In addition (where applicable) an archival tumor biopsy collected before the start of the first-line treatment in the metastatic setting is requested (but optional).
• At least one target lesion measurable by RECIST 1.1 as noted by local investigators/radiologists.
• The ability to swallow and retain OKN4395 as an oral medication without significant gastrointestinal abnormalities that might alter absorption.
• The willingness and ability to comply with the evaluation, randomizations and requirements of the protocol. For Substudy 1, the ability to comply with the evaluation requirements includes the absence of any condition known to affect upper gastrointestinal motility, absorption, and pH.
• Adequate hematologic, renal, and hepatic function (based on local laboratory assessments):
∙ Hematological variables: absolute neutrophil counts ≥1.5 × 109 /L, platelet counts ≥75 × 109 /L, and hemoglobin ≥8 g/dL
‣ Renal variables: creatinine clearance ≥ 60 mL/min1 by Du Bois \& Du Bois formula
‣ Hepatic variables: total serum bilirubin ≤1.5 × ULN, AST and ALT ≤3 × ULN, and ALP ≤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)
‣ Serum albumin ≥30 g/L