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

NCT06789172 | Recruiting Phase 1 FDA Drug

• 1 other identifier: OKN-4395-121
• Study Type: interventional
• Target: 146
• Locations: 3 countries
• Sites: 10

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 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.

Conditions

Solid Tumours; Sarcoma; HNSCC; Non Small Cell Lung Cancer; NSCLC; Colorectal Cancer (CRC); Myxofibrosarcoma (MFS); Solitary Fibrous Tumors; Dedifferentiated Liposarcoma; Undifferentiated Pleomorphic Sarcoma (UPS); Leiomyosarcoma; Leiomyosarcoma (LMS); Gastric Cancer (GC); Gastric Cancer Adenocarcinoma Metastatic; Gastric / Gastroesophageal Junction Adenocarcinoma

Outcome Measures

Primary Outcomes (9)

• Incidence of DLTs in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab. (Phase 1a)

  DLTs = dose-limiting toxicities

  From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months

• Incidence and severity of TEAEs in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1a)

  TEAEs = treatment-emergent adverse events

  From enrolment of the first participant to the end of Phase 1a; up to 27 months

• Incidence and severity of SAEs in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1a)

  SAEs = serious adverse events

  From enrolment of the first participant to the end of Phase 1a; up to 27 months

• Incidence of dose interruptions, dose reductions, and dose intensities in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1a)

  From enrolment of the first participant to the end of Phase 1a; up to 27 months

• Incidence and severity of clinically relevant ECG abnormalities in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1a)

  ECG = electrocardiogram

  From enrolment of the first participant to the end of Phase 1a; up to 27 months

• Incidence and severity of laboratory abnormalities in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1a)

  Graded where appropriate with the CTCAE v5.0.

  From enrolment of the first participant to the end of Phase 1a; up to 27 months

• Incidence and severity of clinically relevant changes in vital signs in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1a)

  From enrolment of the first participant to the end of Phase 1a; up to 27 months

• To assess the overall response rate in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1b Cohorts 1-3)

  From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b

• To assess the progression-free survival in participants treated with OKN4395 in combination with pembrolizumab in selected cancer types. (Phase 1b Cohort 4)

  From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b

Secondary Outcomes (29)

• To assess the overall response rate in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1a)

  From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months

• To assess the disease control rate at >=12 weeks in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1a)

  From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months

• To assess the duration of response in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1a)

  From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months

• To assess the progression-free survival in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1a)

  From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months

• To assess the time to treatment failure in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1a)

  From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months

Study Arms (7)

Monotherapy Dose Escalation Phase (Phase 1a)

EXPERIMENTAL

The Monotherapy Escalation Phase will include increasing doses of OKN4395 alone in patients with solid tumors with a COX2-associated immunosuppressive pathway.

Drug: OKN4395

Combination Dose Confirmation Phase (Phase 1a)

EXPERIMENTAL

The Combination Dose Confirmation Phase will include increasing or decreasing doses of OKN4395 in combination with pembrolizumab in patients with solid tumors with a COX2-associated immunosuppressive pathway. The first dose level used will be 1 level below the identified OBD/MTD for monotherapy. Subsequent dose levels tested will either be increased or decreased in response to observed toxicity.

Drug: OKN4395; Combination Product: Pembrolizumab

Phase 1a Substudy 1

EXPERIMENTAL

Participants will receive 3 doses of OKN4395 in a fasted, fed, and high gastric pH state (once each) with a washout period inbetween. Each state and dose will occur within the first 8 days of treatment (C1 D1-D8). The sequence of these predose conditions will be randomized. After C1 D8, participants will receive OKN4395 as monotherapy twice per day, in line with the dose escalation portion of the study, for the remainder of treatment. The high pH state is achieved through co-administration of the H2 receptor antagonist, famotidine, administered 2 hours before OKN4395 at a dose of 20mg intravenously.

Drug: OKN4395; Other: Fasting; Other: Fed; Drug: H2 Receptor Antagonist

Phase 1b Cohort 1: Sarcoma

EXPERIMENTAL

OKN4395 (OBD/MTD monotherapy dose)

Drug: OKN4395

Phase 1b Cohort 2: Non-Small Cell Lung Cancer

EXPERIMENTAL

OKN4395 (OBD/MTD combination dose) in combination with pembrolizumab

Drug: OKN4395; Combination Product: Pembrolizumab

Phase 1b Cohort 3: Colorectal Cancer

EXPERIMENTAL

OKN4395 (OBD/MTD combination dose) in combination with pembrolizumab

Drug: OKN4395; Combination Product: Pembrolizumab

Phase 1b Cohort 4: Gastric Cancer

EXPERIMENTAL

OKN4395 (OBD/MTD combination dose) in combination with pembrolizumab

Drug: OKN4395; Combination Product: Pembrolizumab

Interventions

H2 Receptor Antagonist DRUG

Famotidine 20 mg IV (as a slow push over 2 minutes) administered 3 hours prior to OKN4395

Also known as: Famotidine, H2RA

Phase 1a Substudy 1

OKN4395 DRUG

OKN4395 oral dosing twice per day

Combination Dose Confirmation Phase (Phase 1a); Monotherapy Dose Escalation Phase (Phase 1a); Phase 1a Substudy 1; Phase 1b Cohort 1: Sarcoma; Phase 1b Cohort 2: Non-Small Cell Lung Cancer; Phase 1b Cohort 3: Colorectal Cancer; Phase 1b Cohort 4: Gastric Cancer

Pembrolizumab COMBINATION_PRODUCT

200 mg IV every 3 weeks

Combination Dose Confirmation Phase (Phase 1a); Phase 1b Cohort 2: Non-Small Cell Lung Cancer; Phase 1b Cohort 3: Colorectal Cancer; Phase 1b Cohort 4: Gastric Cancer

Fasting OTHER

Fasting before first dose of OKN4395

Phase 1a Substudy 1

Fed OTHER

Food provided to patient before first OKN4395 dose

Phase 1a Substudy 1

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Except for the current regimen in Cohort 4, ongoing or recent anticancer therapy within the following timeframe prior to first dose of study drug:
• Chemotherapy, ADCs, or other antibodies \< 21 days
• Immunotherapy or cellular therapy \< 28 days
• Radiation therapy (palliative radiation for bone pain \<48 hours; stereotactic or small field brain irradiation \<7 days; all other radiation therapy \<14 days)
• TKI or any other anticancer therapy \< 5 half-lives or \< 7 days, whichever is longer
• Central nervous system metastasis (radiologically progressive, or clinically symptomatic, or requiring immunosuppressive therapies \[including low dose steroids\]).
• Any active infection (bacterial, viral, fungal) requiring IV systemic therapy.
• Unstable COPD defined as frequent or severe exacerbations per investigator discretion.
• Known history of or active HBV (HBsAg reactive and/or HBV DNA detected) or HCV (HCV RNA detected) infection.
• HIV infection with CD4 lymphocyte count \<350 cells/μL at time of Screening, or failure to achieve and maintain virologic suppression defined as confirmed HIV RNA level \< 50 or lower limit of detection by the local available assay at time of Screening and for at least 12 weeks prior to Screening.
• Known history of bleeding disorders, INR ≥1.5 × ULN at screening (or INR and/or aPTT within therapeutic range if on anticoagulation therapy), or a history of gastrointestinal bleeding (inflammatory, ulcerative, or diverticular) within the last 2 years.
• Known H. pylori infection without proof of eradication at least 2 months prior to screening.
• 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 after Substudy 1). Where said treatments have been used for more than 2 weeks prior to discontinuation, discontinuation should occur at least 21 days before first dose of OKN4395.
• Acute treatment with any systemic steroid therapy (\>10 mg prednisone equivalent), or any corticosteroid medication within 14 days of first dose of OKN4395 for any condition.
• For participants planned to receive combination therapy: Ongoing and history of 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). Any replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed. Participants with hyperthyroidism or hypothyroidism but that are stable on hormone replacement are also allowed.

Sponsors & Collaborators

• Epkin: lead
• Precision For Medicine: collaborator

Study Sites (10)

Precision NextGen Oncology and Research Center

Beverly Hills, California, 90212, United States

RECRUITING

Sarcoma Oncology Center

Santa Monica, California, 90403, United States

RECRUITING

MD Anderson Cancer Center

Houston, Texas, 77030, United States

RECRUITING

Chris O'Brien Lifehouse

Sydney, New South Wales, Australia

RECRUITING

Linear Clinical Research

Perth, Western Australia, 6009, Australia

RECRUITING

The Beatson

Glasgow, United Kingdom

RECRUITING

Leicester Royal Infirmary

Leicester, LE1 5WW, United Kingdom

RECRUITING

University College London Hospital

London, United Kingdom

RECRUITING

The Christie

Manchester, United Kingdom

RECRUITING

Churchill Hospital

Oxford, United Kingdom

RECRUITING

Related Publications (2)

• Stephane Champiat et al. Updated design of INVOKE: A phase 1 study of OKN4395, a first-in-class EP2/EP4/DP1 triple prostanoid receptor antagonist, in patients with advanced solid tumors.. J Clin Oncol 44, TPS2681-TPS2681(2026). DOI:10.1200/JCO.2026.44.16_suppl.TPS2681

  BACKGROUND

• Neal Shiv Chawla et al. INVOKE: A phase 1 study of OKN4395, a first-in-class EP2/EP4/DP1 triple prostanoid receptor antagonist, in patients with advanced solid tumors.. J Clin Oncol 43, TPS2683-TPS2683(2025). DOI:10.1200/JCO.2025.43.16_suppl.TPS2683

  BACKGROUND

Related Links

• Information about the INVOKE trial
• Information for participants in the INVOKE trial

MeSH Terms

Conditions

Sarcoma; Squamous Cell Carcinoma of Head and Neck; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Dermatofibrosarcoma; Solitary Fibrous Tumors; Liposarcoma; Histiocytoma, Malignant Fibrous; Leiomyosarcoma; Stomach Neoplasms

Interventions

pembrolizumab; Angptl4 protein, mouse; Histamine H2 Antagonists; Famotidine

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Neoplasms by Site; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Fibrosarcoma; Neoplasms, Fibrous Tissue; Neoplasms, Connective Tissue; Neoplasms, Adipose Tissue; Histiocytoma; Neoplasms, Muscle Tissue; Stomach Diseases

Intervention Hierarchy (Ancestors)

Histamine Antagonists; Histamine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Physiological Effects of Drugs; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Central Study Contacts

Epkin

CONTACT

+33 787922617; clinicaltrials@owkin.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 13, 2025
• First Posted: January 23, 2025
• Study Start: January 23, 2025
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): September 1, 2028
• Last Updated: June 11, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share

Locations

GB (5); US (3); AU (2)