OKN4395 + Pembrolizumab for Solid Tumors

(INVOKE Trial)

Recruiting at 3 trial locations

Overseen By Epkin

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Epkin

Must not be taking: PPIs, H2 antagonists, Steroids, NSAIDs

Disqualifiers: CNS metastasis, Active infection, COPD, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 42

166 Participants Needed

Trial Summary

What is the purpose of this trial?

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 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 cancer types. Part 1b will comprise 5 cohorts: Cohort 1 in sarcoma (OKN4395 alone), Cohort 2 pancreatic adenocarcinoma (OKN4395 alone), Cohort 3 in non-small cell lung cancer (NSCLC), Cohort 4 in colorectal cancer, and Cohort 5 in head \& neck squamous cell carcinoma (HNSCC), with cohorts 3 to 5 in combination with pembrolizumab. The monotherapy expansion Cohort 1 will also be used to explore the effect of food on the levels of OKN4395 in the blood. Similarly, Cohort 2 will be used to explore the effect of gastric pH 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, Australia, UK and in the EU.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, certain medications like systemic steroids, NSAIDs, and drugs affecting gastrointestinal pH or specific enzymes must be stopped before starting the trial. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug OKN4395 + Pembrolizumab for solid tumors?

Research shows that pembrolizumab, one of the drugs in this treatment, has been effective in treating various cancers like advanced melanoma and non-small-cell lung cancer by helping the immune system attack cancer cells. ^{1 2 3 4 5}

Is the combination of OKN4395 and Pembrolizumab safe for humans?

Pembrolizumab has been studied in various cancers like ovarian, lung, and bone cancer, showing a safety profile that is generally acceptable, but it can have side effects like fatigue, rash, and diarrhea. However, specific safety data for the combination of OKN4395 and Pembrolizumab is not available in the provided research. ^{1 2 4 6 7}

What makes the drug OKN4395 + Pembrolizumab unique for treating solid tumors?

This treatment combines OKN4395 with pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells. Pembrolizumab is already used for various cancers, but combining it with OKN4395 may enhance its effectiveness, especially in tumors that are less responsive to immunotherapy alone. ^{1 3 8 9 10}

Eligibility Criteria

This trial is for patients with various solid tumors, including lung cancer and mesothelioma. Participants must have a type of tumor that the study targets and be willing to undergo treatment cycles every 21 days. Specific eligibility details are not provided but typically include factors like age, health status, and prior treatments.

Inclusion Criteria

At least one target lesion measurable by RECIST 1.1

My cancer is confirmed and has spread or is advanced.

My solid tumor cannot be treated with standard options.

Exclusion Criteria

My cancer has spread to my brain.

I do not have active hepatitis B, C, or HIV.

Known H. pylori infection without proof of eradication

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-escalation Treatment

Participants receive multiple doses of OKN4395 either alone or with pembrolizumab, with dose escalation based on safety evaluations

21-day cycles, up to 27 months

Visits every 21 days

Cohort Expansion Treatment

Evaluation of OKN4395 alone and in combination with pembrolizumab in specific cancer cohorts

21-day cycles, up to 27 months

Visits every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• OKN4395
• Pembrolizumab

Trial Overview The trial tests OKN4395 alone or combined with pembrolizumab in treating solid tumors. It's split into two parts: Part 1a explores multiple doses; Part 1b focuses on selected cancers. Doses range from 10 mg to 450 mg twice daily over several levels.

Participant Groups

Group I: Phase 1b Cohort 5: HNSCC Experimental Treatment 2 Interventions

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

Group II: Phase 1b Cohort 4: Colorectal Cancer Experimental Treatment 2 Interventions

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

Group III: Phase 1b Cohort 3: NSCLC Experimental Treatment 2 Interventions

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

Group IV: Phase 1b Cohort 2: Pancreas Gastric pH Effect (without H2RA) Experimental Treatment 1 Intervention

No co-administered H2RA (H2 receptor antagonist; famotidine) first dose, and OBD/MTD (mono) dose of OKN4395 as monotherapy for the remainder of treatment.

Group V: Phase 1b Cohort 2: Pancreas Gastric pH Effect (with H2RA) Experimental Treatment 2 Interventions

Co-administered H2RA (H2 receptor antagonist; famotidine) first dose, and OBD/MTD (mono) dose of OKN4395 as monotherapy for the remainder of treatment.

Group VI: Phase 1b Cohort 1: Sarcoma Food Effect (Fed) Experimental Treatment 2 Interventions

Fed first dose, and OBD/MTD (mono) dose of OKN4395 as monotherapy for the remainder of treatment.

Group VII: Phase 1b Cohort 1: Sarcoma Food Effect (Fasted) Experimental Treatment 2 Interventions

Fasted first dose, and OBD/MTD (mono) dose of OKN4395 as monotherapy for the remainder of treatment.

Group VIII: Monotherapy Dose Escalation Phase (Phase 1a) Experimental Treatment 1 Intervention

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

Group IX: Combination Dose Confirmation Phase (Phase 1a) Experimental Treatment 2 Interventions

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.

Who Is Running the Clinical Trial?

Epkin

Lead Sponsor

Trials

1

Recruited

170+

Precision For Medicine

Industry Sponsor

Trials

6

Recruited

640+

Findings from Research

In a phase Ib trial involving 26 patients with advanced PD-L1-positive ovarian cancer, pembrolizumab demonstrated a confirmed objective response rate of 11.5%, indicating some level of antitumor activity, with 1 complete response and 2 partial responses observed.

The treatment was generally well-tolerated, with 73.1% of patients experiencing treatment-related adverse events, but no deaths or treatment discontinuations due to these events, suggesting that pembrolizumab has a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. Varga, A., Piha-Paul, S., Ott, PA., et al.[2019]

Pembrolizumab combined with adjuvant chemotherapy significantly improves one-year survival rates, overall response rates, and progression-free survival in patients with advanced non-small cell lung cancer (NSCLC), based on a meta-analysis of 14 studies.

This treatment not only enhances efficacy but also reduces the incidence of adverse drug reactions, indicating a favorable safety profile, although further validation through larger randomized controlled trials is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Efficacy and Safety Analysis of PD-1/PD-L1 Inhibitor vs. Chemotherapy in the Treatment of Advanced Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. Guo, WW., Zhang, TW., Wang, BL., et al.[2023]

A systematic review of four trials involving 3425 patients found that lower doses of pembrolizumab (2 mg/kg every 3 weeks) are equally effective as higher doses (10 mg/kg) in treating advanced melanoma and non-small-cell lung cancer (NSCLC).

The safety profile of pembrolizumab was similar across different doses, suggesting that the lower dose may be sufficient for routine treatment without compromising efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review. Abdel-Rahman, O.[2018]

A 68-year-old patient with stage IV lung adenocarcinoma showed an unexpected positive response to paclitaxel after failing treatment with pembrolizumab, an anti-PD-1 immunotherapy.

The patient experienced a response duration of over fourteen months with paclitaxel, suggesting that combining or sequencing chemotherapy with immunotherapy may enhance treatment effectiveness in certain cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prolonged response with paclitaxel after immunotherapy by pembrolizumab in lung cancer]. Zapata, E., Mennecier, B., Leduc, C., et al.[2017]

In a study of 655 patients with advanced melanoma, pembrolizumab showed an overall objective response rate of 33%, indicating its efficacy in treating this type of cancer.

The median overall survival for patients receiving pembrolizumab was 23 months, with a 12-month survival rate of 66%, while 14% of patients experienced severe treatment-related adverse events, highlighting its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. Ribas, A., Hamid, O., Daud, A., et al.[2022]

In a real-life study of 108 patients with advanced non-small cell lung cancer (NSCLC) and a PD-L1 tumor proportion score of ≥50%, pembrolizumab showed a median progression-free survival of 10.1 months, similar to results from the KEYNOTE-024 trial.

The treatment was generally well-tolerated, with only 8% of patients experiencing grade 3 adverse events, and no severe (grade 4 or 5) adverse events reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line pembrolizumab for non-small cell lung cancer patients with PD-L1 ≥50% in a multicenter real-life cohort: The PEMBREIZH study. Amrane, K., Geier, M., Corre, R., et al.[2021]

In a phase 2 trial involving 12 patients with advanced osteosarcoma, pembrolizumab showed no clinical benefit at 18 weeks, with all patients experiencing disease progression and a median overall survival of only 6.6 months.

Despite the lack of significant antitumor activity, pembrolizumab was well-tolerated, with no treatment-related deaths or severe adverse events, suggesting it may be safe for use in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in advanced osteosarcoma: results of a single-arm, open-label, phase 2 trial. Boye, K., Longhi, A., Guren, T., et al.[2022]

In a study of 1,026 treatment-naïve patients with metastatic non-small-cell lung cancer (NSCLC) and PD-L1 expression of ≥50%, pembrolizumab showed an objective response rate of 44.5%, with median progression-free survival of 7.9 months and overall survival of 17.2 months.

Higher PD-L1 expression (≥90%) was linked to better treatment outcomes, while factors like poor performance status and the presence of bone or liver metastases were associated with worse clinical outcomes, indicating the importance of patient selection for pembrolizumab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ≥ 50. Cortellini, A., Tiseo, M., Banna, GL., et al.[2020]

In a study involving 173 patients with advanced melanoma who had not responded to previous treatments, pembrolizumab showed an overall response rate of 26% at both 2 mg/kg and 10 mg/kg doses, indicating its potential effectiveness in this challenging patient population.

The treatment was well tolerated with no drug-related deaths, and the safety profiles were similar across both doses, with fatigue, pruritus, and rash being the most common side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Robert, C., Ribas, A., Wolchok, JD., et al.[2022]

Pembrolizumab is an effective monoclonal antibody that targets the PD-1 immune checkpoint, helping to restore T cell anti-tumor responses, and is administered at a dose of 200 mg every 3 weeks until disease progression or for up to 24 months.

It has received approval for treating various cancers, including melanomas and non-small cell lung cancers, particularly in tumors that are hypermutated or express PD-L1, but ongoing research aims to expand its use to less immunogenic tumor types through combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical utility of pembrolizumab in the management of advanced solid tumors: an evidence-based review on the emerging new data. du Rusquec, P., de Calbiac, O., Robert, M., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Clinical Efficacy and Safety Analysis of PD-1/PD-L1 Inhibitor vs. Chemotherapy in the Treatment of Advanced Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review. [2018]

4. France pubmed.ncbi.nlm.nih.gov

[Prolonged response with paclitaxel after immunotherapy by pembrolizumab in lung cancer]. [2017]

5. United States pubmed.ncbi.nlm.nih.gov

Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

First-line pembrolizumab for non-small cell lung cancer patients with PD-L1 ≥50% in a multicenter real-life cohort: The PEMBREIZH study. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

Pembrolizumab in advanced osteosarcoma: results of a single-arm, open-label, phase 2 trial. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ≥ 50. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. [2022]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Clinical utility of pembrolizumab in the management of advanced solid tumors: an evidence-based review on the emerging new data. [2023]