ENB003 + Pembrolizumab for Cancer

Recruiting at 4 trial locations

Overseen By Sandra Harm, MS,MBA

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: ENB Therapeutics, Inc

Must be taking: Anti-PD1/L1

Must not be taking: Live vaccines, Immunosuppressants

Disqualifiers: Pregnancy, Active infection, Autoimmune, others

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

Compensation: Varies

Number of Visits: Unknown

137 Participants Needed

Trial Summary

What is the purpose of this trial?

First-in Human study evaluating the safety, tolerability and efficacy of ENB003 in combination with Pembrolizumab in solid tumors. The study is separated into two parts. Part A is a 3+3 dose escalation to define the recommended RP2D; this part will include metastatic melanoma, platinum resistant ovarian cancer, and pancreatic cancer patients subjects, but other solid tumors will be allowed. Once the RP2D is selected, the study will be expanded into metastatic melanoma, platinum resistant ovarian cancer, and pancreatic cancer subjects. A small number of sarcoma subjects will be included, as exploratory.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not have received certain cancer therapies or investigational agents within a specific time frame before starting the trial. It's best to discuss your current medications with the study team to ensure eligibility.

What data supports the effectiveness of the drug ENB003 + Pembrolizumab for cancer?

Pembrolizumab, a part of the treatment, has shown effectiveness in improving survival rates in various cancers, such as non-small cell lung cancer and melanoma, by helping the immune system fight cancer cells. It is also approved for treating certain types of endometrial cancer, indicating its broad potential in cancer therapy. ^{1 2 3 4 5}

What safety information is available for the cancer treatment using ENB003 and Pembrolizumab?

Pembrolizumab, also known as Keytruda, has been used in cancer treatment and is generally considered safe, but it can cause some side effects. Common side effects include fatigue, cough, nausea, and rash. Rare but serious side effects can include immune-related issues like type 1 diabetes and lung inflammation (pneumonitis). ^{1 2 6 7 8}

How is the drug combination of ENB003 and pembrolizumab different from other cancer treatments?

The combination of ENB003 and pembrolizumab is unique because it combines a novel agent, ENB003, with pembrolizumab, a PD-1 inhibitor that enhances the immune system's ability to fight cancer by blocking a pathway that tumors use to hide from immune cells. This approach may offer a new way to target cancer cells by boosting the body's natural defenses. ^{1 2 9 10 11}

Eligibility Criteria

This trial is for adults with certain solid tumors, including metastatic melanoma, platinum-resistant ovarian cancer, and pancreatic cancer. Participants must have tried some standard treatments without success and can't have had more than three prior systemic therapies. Pregnant women or those who've had severe reactions to similar drugs are excluded.

Inclusion Criteria

My pancreatic cancer has worsened despite treatment with FOLFIRINOX or a gemcitabine-based regimen.

My head or neck cancer worsened despite treatment with an anti-PD1/L1 drug.

My breast cancer is triple negative and has spread.

Exclusion Criteria

I stopped a cancer immunotherapy due to a severe side effect.

I haven't had cancer treatment or experimental drugs in the last 4 weeks.

Other Exclusions: Has previously participated in this protocol [ENB-003-101 (MK3475-951)] i.e. a subject previously enrolled in Part A cannot participate in Part B

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation (Part A)

A 7-day run-in period of ENB-003 monotherapy followed by combination therapy with pembrolizumab. Dose escalation follows a 3+3 design.

21-day cycles

Multiple visits per cycle

Dose Expansion (Part B)

Subjects receive 1 x 21-day treatment cycle of ENB-003 at the recommended phase 2 dose (RP2D) with pembrolizumab. Efficacy review by DSMB after 12-week scans.

12 weeks

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 2 years

Treatment Details

Interventions

• ENB003
• Pembrolizumab

Trial Overview The study tests ENB003 combined with Pembrolizumab on patients with solid tumors. It has two parts: Part A finds the safest dose (RP2D) through a '3+3' method; Part B expands the trial using this dose on specific cancers, including an exploratory group of sarcoma patients.

Participant Groups

Group I: ENB003 RP2D from dose escalation + Pembrolizumab Experimental Treatment 2 Interventions

The recommended phase 2 dose (RP2D) of ENB003 will be selected from the dose escalation portion of the study and administered in combination with a fixed dose of pembrolizumab (200mg)

Group II: ENB003 750 ug + Pembrolizumab Experimental Treatment 2 Interventions

750 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)

Group III: ENB003 500 ug + Pembrolizumab Experimental Treatment 2 Interventions

500 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)

Group IV: ENB003 300 ug + Pembrolizumab Experimental Treatment 2 Interventions

300 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)

Group V: ENB003 2000 ug + Pembrolizumab Experimental Treatment 2 Interventions

2000 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg). In this treatment arm, ENB003 will be administered during each 21 day cycle, as opposed to every other cycle in early arms

Group VI: ENB003 150 ug + Pembrolizumab Experimental Treatment 2 Interventions

150 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)

Group VII: ENB003 1000 ug + Pembrolizumab Experimental Treatment 2 Interventions

1000 ug ENB003 will be administered in combination with a fixed dose of pembrolizumab (200mg)

Who Is Running the Clinical Trial?

ENB Therapeutics, Inc

Lead Sponsor

Trials

1

Recruited

140+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

In a phase 3 trial involving 1019 patients with resected high-risk stage III melanoma, pembrolizumab significantly improved distant metastasis-free survival at 3.5 years, with 65.3% of patients in the pembrolizumab group remaining free of distant metastasis compared to 49.4% in the placebo group (HR 0.60).

The study also showed that pembrolizumab led to longer recurrence-free survival, with 59.8% of patients in the pembrolizumab group remaining free of recurrence compared to 41.4% in the placebo group, reinforcing its efficacy as an adjuvant therapy for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Eggermont, AMM., Blank, CU., Mandalà, M., et al.[2021]

Pembrolizumab (Keytruda) was approved by the FDA for treating metastatic non-small cell lung cancer (mNSCLC) in patients with tumors expressing PD-L1, showing significant improvements in overall survival (OS) and progression-free survival (PFS) in two major clinical trials with thousands of participants.

In the KEYNOTE-024 trial, pembrolizumab demonstrated a 40% reduction in the risk of death compared to chemotherapy, while in the KEYNOTE-010 trial, it also showed a significant survival advantage over chemotherapy in patients who had previously progressed on treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. Pai-Scherf, L., Blumenthal, GM., Li, H., et al.[2022]

Pembrolizumab (Keytruda) is approved for treating advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, specifically for patients whose disease has progressed after previous treatments.

This approval is significant for patients who are not candidates for curative surgery or radiation, providing a new therapeutic option for a challenging stage of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. Aschenbrenner, DS.[2022]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Pembrolizumab (Keytruda) effectively blocks the PD-1 pathway, enhancing T-cell activity against tumors, which supports its role in promoting tumor regression and immune rejection.

Preclinical studies in cynomolgus monkeys showed that pembrolizumab has a favorable safety profile with no significant toxicological findings, aligning with its demonstrated safety and efficacy in human clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. Hutchins, B., Starling, GC., McCoy, MA., et al.[2021]

The 400 mg dose of pembrolizumab administered every 6 weeks (Q6W) is predicted to have similar drug exposure levels as the 200 mg dose given every 3 weeks (Q3W), based on simulations from a model using data from 2993 subjects across multiple cancer trials.

Safety profiles for the 400 mg Q6W regimen are expected to be comparable to the lower doses, as predicted peak concentrations are significantly lower than the maximum clinical dose of 10 mg/kg given every 2 weeks, suggesting that efficacy and safety will be maintained across different dosing schedules.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Lala, M., Li, TR., de Alwis, DP., et al.[2021]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

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

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. [2021]

4. England pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. [2022]

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

New Approved Use for Keytruda. [2022]

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

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

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

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. [2021]

10. England pubmed.ncbi.nlm.nih.gov

A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. [2021]

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

Phase 1 dose escalation study of FGFR4 inhibitor in combination with pembrolizumab in advanced solid tumors patients. [2023]