ONC-392 + Pembrolizumab for Non-Small Cell Lung Cancer

(PRESERVE-001 Trial)

Recruiting at 41 trial locations

Overseen By Martin Devenport, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: OncoC4, Inc.

Must not be taking: Chronic steroids

Disqualifiers: Active brain metastasis, Active infection, others

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

Compensation: Varies

Number of Visits: 42

733 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for advanced or metastatic non-small cell lung cancer and other solid tumors. It tests ONC-392, a special antibody, both alone and with pembrolizumab, a medication already used in cancer treatment. The trial aims to determine the safest dose and assess its effectiveness. People with non-small cell lung cancer that has progressed, especially those unresponsive to previous treatments, might be suitable candidates. As a Phase 1 and Phase 2 trial, this research seeks to understand how the treatment works in people and measure its effectiveness in an initial group, offering participants a chance to contribute to groundbreaking cancer treatment advancements.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) of 21 days for cancer therapeutic drugs and 28 days for antibody drugs. If you are on chronic systemic steroid therapy at doses greater than 10 mg/day, you may not be eligible to participate.

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

A previous study found that ONC-392 at a dose of 10 mg/kg was safe and well-tolerated when used alone. Patients, particularly those with difficult-to-treat non-small cell lung cancer (NSCLC), showed promising results. When combined with pembrolizumab, researchers continued to monitor safety closely. Pembrolizumab, already approved for other cancers, provides some confidence in its safety.

This trial remains in the early stages, with researchers primarily focused on determining safe dosage levels. However, existing research on ONC-392 alone and with pembrolizumab suggests a positive safety outlook. Participants will be carefully monitored for any side effects as the study progresses. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ONC-392 combined with pembrolizumab for non-small cell lung cancer (NSCLC) because it targets the immune system differently from standard treatments. Most current therapies, like chemotherapy and traditional immunotherapies, focus on attacking cancer cells directly or boosting the immune response broadly. However, ONC-392 is designed to enhance the body's natural immune checkpoints more precisely, potentially leading to a more effective and controlled attack on cancer cells. This targeted approach could be especially beneficial for patients with PD-1 resistant cancers, offering new hope where existing treatments might fall short.

What evidence suggests that this trial's treatments could be effective for non-small cell lung cancer?

Research has shown that ONC-392, a new treatment, may help treat non-small cell lung cancer (NSCLC). This drug aids the immune system in attacking cancer cells by blocking a protein that usually prevents immune cells from attacking. In this trial, some participants will receive ONC-392 as a single agent, which has proven effective on its own, especially for patients whose cancer no longer responds to other treatments. Other participants will receive ONC-392 combined with pembrolizumab, another cancer drug. This combination has shown promising results in enhancing the immune system's ability to fight cancer. These early findings suggest that this combination might effectively treat advanced NSCLC. ^{1 2 3 5 6}

Who Is on the Research Team?

Tianhong Li

Principal Investigator

University of California, Davis

Are You a Good Fit for This Trial?

Adults over 18 with certain advanced solid tumors or NSCLC, who have measurable disease and are in good physical condition. They must not be on high-dose steroids, pregnant, breastfeeding, or have brain metastases. Participants need functioning organs and agree to use contraception.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

I have an advanced cancer type that is treated with Pembrolizumab.

I am a woman who can have children and my pregnancy test is negative.

Exclusion Criteria

I am on long-term steroid treatment with doses over 10 mg/day.

I have active brain or spinal cord cancer symptoms.

Patients who have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-Finding Phase I (Part A)

ONC-392 is administered as a single agent to determine the recommended Phase II dose for monotherapy

21 days

Every 21 days (Q3W)

Combination Therapy Phase (Part B)

ONC-392 is administered in combination with pembrolizumab to determine the recommended Phase II dose for combination therapy

21 days

Every 21 days (Q3W)

Expansion Cohorts (Part C)

Further assessment of safety and efficacy of ONC-392 in various cancer cohorts

Varies by cohort

Phase II Study (Part D)

ONC-392 monotherapy in recurrent and/or metastatic adenoid cystic carcinoma

1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• ONC-392
• Pembrolizumab

Trial Overview The trial is testing ONC-392 alone and combined with Pembrolizumab in patients with various cancers including NSCLC. It's a first-in-human study assessing safety, how the body processes the drug (pharmacokinetics), and effectiveness.

How Is the Trial Designed?

Group I: ONC-392 in combination with pembrolizumab Experimental Treatment 2 Interventions

The Part B1 study will test ONC-392 intravenous (IV) infusion, Q3W, in combination with fixed dose of pembrolizumab. The dose for pembrolizumab will be fixed at 200mg/cycle dosed every 21 days (Q3W). The Part B1 will start at one level below RP2D-M dose for ONC-392 and 200mg of pembrolizumab. When 2 DLTs occur before 6 patients are enrolled, the ONC-392 dose will be decreased to the next dose level until ≤ 1/6 patients treated at that dose develops a DLT. This dose level will be designated RP2D-C. In Part C, the expansion cohorts Arm D to G will assess the safety and efficacy of ONC-392 in different dose levels and Pembrolizumab combination therapy in non small cell lung cancer, and metastatic melanoma.

Group II: ONC-392 and docetaxel Experimental Treatment 2 Interventions

Part E Arm O will test ONC-392 in combination with docetaxel, IV infusion, Q3W, in PD-1 resistant NSCLC patients.

Group III: ONC-392 Treatment as single agent Experimental Treatment 1 Intervention

The Part A study will test ONC-392 intravenous (IV) infusion up to five predefined dose levels from 0.1 mg/kg to 10 mg/kg ONC-392 as monotherapy every 21 days (Q3W). The Part A study will determine the maximal tolerable dose (MTD) and the recommended Phase 2 dose in monotherapy (RP2D-M). In Part C, Arms A-C, I-N monotherapy expansion cohorts will further assess the safety and efficacy of ONC-392 in different dose levels as monotherapy in pancreatic cancer, triple negative breast cancer, non small cell lung cancer with driver mutations, PD-1 resistant non small cell lung cancer, PD-1 resistant melanoma, head and neck cancer, ovarian cancer, renal cell carcinoma and other solid tumors. Part D is a Phase II study on recurrent and/or metastatic adenoid cystic carcinoma.

Who Is Running the Clinical Trial?

OncoC4, Inc.

Lead Sponsor

Trials

8

Recruited

1,800+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

Pembrolizumab is a safe and effective immune checkpoint inhibitor that targets the PD-1 receptor, currently approved for treating advanced melanoma and metastatic non-small cell lung cancer (NSCLC).

Ongoing studies are exploring the potential of pembrolizumab in combination with other treatments for lung cancer and other cancer types, while also investigating biomarkers that may predict patient response to this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer. Dang, TO., Ogunniyi, A., Barbee, MS., et al.[2020]

Single-agent pembrolizumab, an immune checkpoint inhibitor, significantly improved the patient's condition with marked responses in lung, brain, and pancreatic tumors after just three cycles, despite severe immune-mediated toxicities leading to treatment discontinuation.

Molecular analysis revealed that the lung and pancreatic tumors were clonal, sharing mutations in PIK3CA, NF1, and TP53, which may have contributed to the favorable immune response observed, as indicated by a strong immuno-oncology expression score.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of the tumor immune-microenvironment of adenocarcinoma of lung with a metastatic lesion in the pancreas treated successfully with first-line, single-agent pembrolizumab. Saltman, DL., Nielsen, TJ., Salina, D., et al.[2023]

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 study of 3,877 patients with advanced non-small-cell lung cancer (NSCLC) receiving pembrolizumab monotherapy, those who met eligibility criteria had significantly better overall survival (OS) compared to ineligible patients, with median OS of 16.3 months for eligible patients versus 8.2 months for ineligible patients.

The findings suggest that using an augmented population approach, which combines eligible and unknown patients, can enhance the analysis of real-world data, showing similar survival profiles and characteristics among these groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Augmenting Real-World Data Through Modeling Key Clinical Trial Eligibility Criteria: An Example of Patients With Non-small-Cell Lung Cancer Treated With Pembrolizumab. Jemielita, T., Li, XN., Burke, T., et al.[2021]

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]

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]

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) has been approved by the FDA for treating high-risk, non-muscle invasive bladder cancer (NMIBC) in patients who are unresponsive to BCG therapy and are either ineligible for or have opted not to undergo cystectomy.

This approval specifically targets patients with carcinoma in situ (CIS) with or without papillary tumors, highlighting its role as a treatment option for those with limited surgical options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approves Pembrolizumab for BCG-Unresponsive NMIBC. Wright, KM.[2021]

In a study of 566 patients with metastatic non-small cell lung cancer (NSCLC) treated with first-line pembrolizumab, the median overall survival was 19.6 months, with 3-year survival rates of 36.2%, indicating promising long-term outcomes in a real-world setting.

The study found that 38.6% of patients experienced a real-world tumor response, with the most common reasons for discontinuation of treatment being disease progression and therapy-related adverse effects, highlighting the treatment's efficacy and safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Real-World Outcomes of First-Line Pembrolizumab Monotherapy for Metastatic Non-Small Cell Lung Cancer With ≥50% Expression of Programmed Cell Death-Ligand 1. Velcheti, V., Hu, X., Yang, L., et al.[2022]

In the KEYNOTE-024 study involving 305 patients with untreated advanced non-small-cell lung cancer, pembrolizumab significantly improved overall survival (OS) compared to platinum-based chemotherapy, with a median OS of 30.0 months versus 14.2 months for chemotherapy.

Pembrolizumab also had a better safety profile, with fewer treatment-related severe adverse events (31.2% for pembrolizumab vs. 53.3% for chemotherapy), indicating it is a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. Reck, M., Rodríguez-Abreu, D., Robinson, AG., 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05671510

NCT05671510 | ONC-392 Versus Docetaxel in Metastatic ... The study will test whether gotistobart, in comparison with chemotherapy agent docetaxel, could prolong the life for NSCLC patients.

2. investors.biontech.de investors.biontech.de/news-releases/news-release-details/biontech-and-oncoc4-initiate-pivotal-phase-3-trial-bnt316onc-392

BioNTech and OncoC4 Initiate Pivotal Phase 3 Trial of ... BioNTech and OncoC4 initiate pivotal Phase 3 trial of BNT316/ONC-392 program in metastatic NSCLC. 29 June 2023

3. oncoc4.com oncoc4.com/press-releases/oncoc4-to-present-global-pivotal-phase-3-trial-design-for-next-generation-ctla-4-antibody-gotistobart-monotherapy-being-co-developed-with-biontech-in-nsclc-at-the-iaslc-2025-world-conference-on-lung-c/

OncoC4 to Present Global Pivotal Phase 3 Trial Design ... PRESERVE-003 is evaluating gotistobart vs. docetaxel in patients with squamous non-small cell lung cancer (sqNSCLC) who have progressed on ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04140526

NCT04140526 | Safety, PK and Efficacy of ONC-392 in ... In Part C, the expansion cohorts Arm D to G will assess the safety and efficacy of ONC-392 in different dose levels and Pembrolizumab combination therapy in non ...

5. graphite.ucsd.edu graphite.ucsd.edu/2025/05/04/onc-392-bnt-316gotistobart-a-new-promising-drug-for-cancer-patients/

ONC-392/BNT-316(Gotistobart) – a New Promising Drug ... Gotistobart is a new drug developed from cloning an antibody that exists within the body that targets the CTLA-4 that regulates and restricts T-Cell activation.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.9024

Safety and clinical activity of target-preserving anti-CTLA-4 ... Overall, ONC-392 monotherapy with 10 mg/kg is safe and tolerable. Onc-392 monotherapy has showed encouraging anti-tumor activity in IO-resistant NSCLC.