ENB003 + Pembrolizumab for Cancer

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of a new drug combination, ENB003 (an experimental treatment) and pembrolizumab, for individuals with certain types of advanced cancers. It aims to assess how well this combination works against tumors such as melanoma, ovarian, and pancreatic cancers, among others. The trial will begin by determining the optimal dose and then test that dose in broader groups. Participants should have specific cancer types that have not responded well to prior treatments and have progressed after previous therapy. Those with these cancers, who have seen them worsen despite treatment, might be suitable candidates for this study. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to be among the first to benefit from this innovative approach.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of ENB003 and pembrolizumab is generally safe for patients. Studies have found promising results with few serious side effects. For instance, one study found that patients with various solid tumors, such as ovarian cancer, did not experience severe side effects when treated with this combination.

Early findings also suggest that this treatment is safe and may be effective against tumors. Notably, pembrolizumab, one of the drugs in this combination, has already received FDA approval for treating other cancers, which reassures about its safety.

In summary, current research supports the safety of ENB003 combined with pembrolizumab. However, as with any new treatment, risks remain, and ongoing studies are crucial to confirm these early results. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ENB003 combined with Pembrolizumab for cancer treatment because it introduces a novel mechanism of action. Unlike traditional cancer treatments that primarily target cancer cells directly, ENB003 enhances the immune system's ability to fight cancer by inhibiting a protein called ENTPDase2, which is involved in suppressing immune responses. This could potentially lead to a more robust and sustained attack on the cancer by the body's own immune system. Additionally, the trial explores various dosing levels and schedules, including a unique regimen where ENB003 is administered every 21 days, providing insights into optimizing the treatment's effectiveness. This approach has the potential to improve outcomes for patients who may not respond to current standards of care.

What evidence suggests that this trial's treatments could be effective for solid tumors?

Research has shown that combining ENB003 with Pembrolizumab yields promising results for treating certain solid tumors. In patients with resistant ovarian cancer, this combination halted cancer growth in 50% of cases. Furthermore, 60% of patients experienced no cancer progression for at least 8 months, a significant improvement compared to about 20% with Pembrolizumab alone. The trial will test various dosages of ENB003 with a fixed dose of Pembrolizumab to determine the most effective regimen. These early results suggest that this combination might be effective for hard-to-treat cancers such as ovarian, melanoma, and pancreatic cancers. Reports indicate that the treatment is safe and well-tolerated by patients. ^{1 2 4 6 7}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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, 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]

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 (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]

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]

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, 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]

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]

Citations

1. enbpharma.com enbpharma.com/enb-therapeutics-presents-top-line-results-from-phase-1b-enbolden-101-study-in-platinum-refractory-resistant-ovarian-cancer-at-sitc-2023/

Resistant Ovarian Cancer at SITC 2023 “These data, demonstrate that ENB-003 in combination with KEYTRUDA is safe, with encouraging signs of clinical activity and support the ...

2. clin.larvol.com clin.larvol.com/trial-detail/NCT04205227

ENB003 Plus Pembrolizumab Phase 1b/2a in Solid Tumors The data demonstrated that the treatment regimen was safe and well tolerated. The objective response rate (ORR) and disease control rate (DCR- patients ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04205227

ENB003 Plus Pembrolizumab Phase 1b/2a in Solid Tumors First-in Human study evaluating the safety, tolerability and efficacy of ENB003 in combination with Pembrolizumab in solid tumors.

4. onclive.com onclive.com/view/enb-003-plus-pembrolizumab-elicits-safety-activity-in-ovarian-cancer-and-other-advanced-refractory-solid-tumors

ENB-003 Plus Pembrolizumab Elicits Safety, Activity in ... Regarding efficacy, patients treated with the combination (n = 16) experienced a DCR of 50%. A total of 7 patients achieved SD, and 8 patients ...

5. targetedonc.com targetedonc.com/view/enb-003-data-shows-promise-in-platinum-resistant-ovarian-cancer

ENB-003 Data Shows Promise in Platinum-Resistant ... Moreover, progression-free survival (PFS) at 8 months was 60%, compared with a historical PFS of approximately 20% at 6 months with single-agent ...

6. enbpharma.com enbpharma.com/wp-content/uploads/2020/11/SITC-POSTER-2020-V2-1.pdf

Phase 1/2 study using ENB-003, a first-in-class selective ... The combination of ENB-003 and pembrolizumab is well tolerated thus far and is demonstrating promising early signals of anti-tumor efficacy. The best ...

7. jitc.bmj.com jitc.bmj.com/content/8/Suppl_3/A480.2

803 Phase 1/2 study using ENB-003, a first-in-class ... Part 1 of this study seeks to evaluate the safety and tolerability of ENB-003 in combination with pembrolizumab in refractory advanced ETBR+ ...