Brief Summary
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 bloodthe red bodily fluid that transports oxygen and other nutrients around the body, 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 dosethe amount of medication taken of OKN4395 will be increased, after each group of 3 or more patients 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 1b will evaluate OKN4395 alone and in combination with pembrolizumab administered on day 1 of each 21-day cycle in patients with selected cancera disease where abnormal cells split without control and spread to other nearby body tissue and/or organs types. Part 1b will comprise 4 cohorts: cohort 1 in sarcomacancer arising from bones and/or soft tissue (OKN4395 alone), cohort 2 in non-small cell lung cancer (NSCLC), cohort 3 in mesothelioma, and cohort 4 in head & neck squamous cell carcinomacancer arising from tissues that line organs (HNSCC), with cohorts 2 to 4 in combination with pembrolizumab. The monotherapy expansion cohort (Cohort 1) will also be used to choose the optimal dose for further development and to explore the effect of food on the levels of OKN4395 in the blood. The overall study will enrol approximately 166 participants with up to 54 participants to receive OKN4395 alone and 12 participants to receive OKN4395 in combination with pembrolizumab in Part 1a, and 100 participants in Part 1b split: 40 on monotherapy and 60 on combination therapy. The study will be conducted in the US, in the UK and in the EU.
Intervention / Treatment
- Drug: OKN4395
- Combination Product: Pembrolizumab
- Other: Fastingto withhold from food and drink for a certain period of time; fasting time will be different for every procedure/treatment
- Other: Fed
Inclusion Criteria:
- Histologically or cytologically confirmed disease, locally advancedat a late stage, far along or metastatic:
For Phase 1a:
Solid tumor for which standard treatment options are not available, no longer effective, refused or not tolerated.
For Phase 1b:
- Cohort 1: Sarcoma (fibrous sarcoma [myxofibrosarcoma or solitary fibrous tumor], dedifferentiated liposarcoma, undifferentiated pleomorphicmany forms; cells that have different size, shape etc. sarcoma or pleomorphic sarcoma), 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: Squamous NSCLC, with previous platinum-based chemotherapya cancer treatment that uses drugs to kill or slow the growth of cancer cells, while minimising damage to healthy cells and a previous PD-(L)1 CPI regimen (unless not eligible/unwilling to receive such therapies), and no more than 2 prior lines of systemic therapy. When known, PD-L1 status should be provided.
- Cohort 3: Malignantcancerous, may grow and spread to other areas of the body Mesothelioma, with previous platinum-based chemotherapy and a previous PD-(L)1 CPI regimen (unless not eligible/unwilling to receive such therapies), and no more than 2 prior lines of systemic therapy. When known, PD-L1 status should be provided.
- Cohort 4: HNSCC (oral cavity, oropharynx, larynx, hypopharynx), with a previous regimen containing a PD-(L)1 CPI (unless not eligible/unwilling to receive such therapies), and no more than 3
- ECOG performance status of 0 or 1.
- Recovery from any medically relevant AE/irAE from previous treatment regimen (defined as recovery to Gradea description of how abnormal cancer cells and tissue look under a microscope when compared to healthy cells ≤1 level per CTCAE v 5.0 before Screeningtesting for cancer or conditions that can lead to cancer before symptoms appear, also known as cancer screening, or chronica long-lasting disease that changes slowly over time, 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 biopsyremoval of a section of tissue to analyse for cancer cells (at baseline, a suitable archival specimena sample for investigating (e.g. blood, stools, urine, sputum etc.) 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 food effect evaluation randomization and requirements (Phase 1b Cohort 1 only).
- 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
- 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