ST-067-001 for Solid Tumors

Recruiting at6 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Simcha IL-18, Inc.

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Autoimmune disorders, Brain metastases, Cardiovascular disease, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called ST-067 on patients with certain types of cancer that have not responded to previous treatments. The goal is to find the safest and most effective dose and to see how well it works against these cancers.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are on ongoing immunosuppressive therapy or have received systemic anticancer therapy within 4 weeks of starting the trial.

What data supports the effectiveness of the treatment ST-067, Decoy-Resistant IL-18, when used with immunotherapy for advanced cancers?

Research shows that a similar treatment using a combination of IL-12 and Decoy-Resistant IL-18 can enhance the body's immune response against tumors, especially when injected directly into the tumor. This combination helps activate specific immune cells that attack cancer cells, suggesting potential effectiveness for ST-067 in advanced cancers. ^{1 2 3 4 5}

Is the combination of ST-067 (Decoy-Resistant IL-18) and immunotherapy safe for humans?

Research shows that when Decoy-Resistant IL-18 is used with IL-12 in mice, it can cause serious toxicity if given systemically, but is safer when injected directly into tumors. This suggests potential safety concerns if not administered carefully. ^{1 5 6 7 8}

What makes the drug ST-067 unique for treating advanced cancers?

ST-067, also known as Decoy-Resistant IL-18, is unique because it is engineered to resist inhibition by IL-18BP, a decoy receptor that limits the effectiveness of traditional IL-18 therapies. This allows ST-067 to enhance the immune system's ability to fight tumors by promoting the activity of specific immune cells, such as CD8+ T cells and natural killer cells, which are crucial for attacking cancer cells. ^{3 5 6 9 10}

Research Team

Jeremy Barton, MD

Principal Investigator

Simcha IL-18, Inc.

Eligibility Criteria

Adults (≥18 years) with advanced or metastatic cancer, including melanoma and lung cancer, who've progressed after standard therapy or for whom no survival-prolonging standard care is available. Participants must be able to perform light work (ECOG status of 0 or 1), have at least one measurable lesion not previously treated by biopsy or radiation, and an accessible tumor for required biopsies.

Inclusion Criteria

My cancer is one of the following types: melanoma, kidney, triple-negative breast, non-small cell lung, head and neck, or has high microsatellite instability.

My condition worsened despite standard treatments.

My tumor has not been biopsied or treated with radiation.

Exclusion Criteria

I do not have serious heart, breathing, adrenal gland, or autoimmune conditions.

I have not had radiation therapy in the past two weeks.

I do not have serious heart, lung, immune system, or adrenal gland problems.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1a Dose Escalation

Determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of ST-067, administered by subcutaneous (SC) or intravenous (IV) dosing, with or without obinutuzumab pre-treatment.

28 days per cohort

Weekly visits for dosing

Phase 1 Combination Therapy

Dose escalation in combination with pembrolizumab to determine MTD using mTPI design.

28 days per cohort

Weekly visits for ST-067, every 3 weeks for pembrolizumab

Phase 2 Expansion

Evaluate the preliminary efficacy of ST-067 administered at the RP2D in various solid tumors using a Simon 2 stage design.

8-12 weeks per assessment

Tumor response assessment every 8-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• ST-067 (Other)

Trial Overview The trial tests ST-067 as a subcutaneous injection alone and in combination with IV infusion obinutuzumab (Gazyva®) plus pembrolizumab (Keytruda). It's a multi-phase study starting with dose escalation to assess safety and preliminary effectiveness before moving on to Phase 2.

Participant Groups

Group I: Phase 2, Expansion Experimental Treatment 1 Intervention

Phase 2 will enroll patients aged 18 years or older diagnosed with the following solid tumors: melanoma, renal cell carcinoma (RCC), triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), and microsatellite instability-high (MSI-Hi) tumors at the RP2D.

Group II: Phase 1a, Dose Escalation, ST-067 SC + Obinutuzumab Pre-treatment Experimental Treatment 2 Interventions

Patients will be treated every week with ST-067 in all cohorts. The DLT period is 28 days after the initial dose of ST-067. According to the mTPI schema initially there will be 3 patients per cohort until the first DLT is observed at which point cohorts will be expanded according to the predetermined mTPI design. The starting dose for ST-067 with obinutuzumab pre-treatment will be 120µg/kg. Obinutuzumab will be administered at 1000 mg daily via IV infusion on 2 consecutive days, with the first dose given at least 7 days prior to first dose of SC ST-067.

Group III: Phase 1a, Dose Escalation Experimental Treatment 1 Intervention

In the Phase 1a monotherapy study, the starting dose of ST-067 will be 30 μg/kg, with a total of 7 dose level cohorts planned. The starting dose for the IV infusion monotherapy dosing will be 60 µg/kg. Patients will be treated every week with ST-067 in all cohorts. The DLT period is 28 days after the initial dose of ST-067. According to the mTPI schema initially there will be 3 patients per cohort until the first DLT is observed at which point cohorts will be expanded according to the predetermined mTPI design. Up to 12 patients will be treated at the RP2D.

Group IV: Phase 1 combination therapy Experimental Treatment 2 Interventions

Phase 1 dose escalation in combination with pembrolizumab will start at a dose of 30 µg/kg of ST-067 and 200 mg every 3 weeks of pembrolizumab. Patients will be treated every week with ST-067 and every three weeks with pembrolizumab. The MTD will be determined based on the mTPI design.

Who Is Running the Clinical Trial?

Simcha IL-18, Inc.

Lead Sponsor

Trials

1

Recruited

320+

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

Preclinical studies show that CD19-specific CAR-modified T cells that secrete IL-12 can effectively eliminate established tumors without the need for prior conditioning regimens, making this approach safer for patients who cannot tolerate such treatments.

The effectiveness of these modified T cells relies on both CD4(+) and CD8(+) T-cell subsets, autocrine IL-12 stimulation, and the ability to resist inhibition from T regulatory cells, suggesting a robust mechanism for enhancing anti-tumor responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Pegram, HJ., Lee, JC., Hayman, EG., et al.[2021]

The IL-18 gene-modified, C215Fab-SEA-coated tumor cell vaccine effectively stimulated the immune system, leading to significant expansion of CD4+ and CD8+ T cells in mice, indicating a strong antitumor immune response.

This vaccine provided protective immunity against tumor challenges, demonstrating its potential as an effective immunotherapy for melanoma by enhancing tumor-specific immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vaccination with IL-18 gene-modified, superantigen-coated tumor cells elicits potent antitumor immune response. Wang, Q., Yu, H., Zhang, L., et al.[2019]

In a study involving 96 mice with spontaneous metastatic lung cancer, treatment with tumor antigen-pulsed, IL-18 gene-modified dendritic cells significantly reduced lung weight and the number of metastatic nodes, indicating effective tumor suppression.

This treatment also led to longer survival times and enhanced immune responses, including increased activity of cytotoxic T cells and natural killer (NK) cells, demonstrating its potential as a powerful immunotherapy for lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of spontaneous metastatic lung cancer with tumor antigen-pulsed, interleukin-18 gene-modified dendritic cells]. Chen, J., Cao, X., Xiu, Q.[2012]

Using dendritic cells modified with a recombinant adenovirus encoding interleukin-18 (rAd/IL-18) significantly enhances the generation and activation of tumor-specific cytotoxic T lymphocytes (CTLs), which are crucial for effective cancer treatment.

The study demonstrated that these engineered dendritic cells not only improve the maturation of CTLs but also increase their ability to kill breast cancer cells expressing the MAGE-A3 antigen, suggesting a promising approach to boost the efficacy of adoptive cell transfer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human dendritic cells engineered to secrete interleukin-18 activate MAGE-A3-specific cytotoxic T lymphocytes in vitro. Fan, X., Ye, M., Xue, B., et al.[2012]

The combination of mRNA constructs encoding IL12 and decoy-resistant IL18 (DR-18) shows strong antitumor effects by inducing significant IFNγ release and enhancing the activation of CD8+ T cells, which are crucial for effective immune responses against tumors.

When administered intratumorally in mice, this combination not only targets the treated tumor but also delays the growth of distant tumors, especially when combined with anti-PD-1 antibody treatment, suggesting a promising strategy for immunotherapy in cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intratumoral Gene Transfer of mRNAs Encoding IL12 in Combination with Decoy-Resistant IL18 Improves Local and Systemic Antitumor Immunity. Cirella, A., Bolaños, E., Di Trani, CA., et al.[2023]

The study identifies IL-18BP as a significant barrier to the effectiveness of IL-18 in cancer therapy, as it is frequently upregulated in various tumors and limits IL-18's anti-tumor activity.

An engineered 'decoy-resistant' IL-18 (DR-18) was developed, which showed potent anti-tumor effects in mouse models by enhancing CD8+ T cell function and natural killer cell activity, suggesting a promising new approach for immunotherapy against resistant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Zhou, T., Damsky, W., Weizman, OE., et al.[2022]

The novel PD-L1 B-cell peptide vaccine (PDL1-Vaxx) has shown strong immunogenicity and the ability to inhibit tumor growth in various animal models, demonstrating its potential as a safe checkpoint inhibitor vaccine.

When combined with the HER-2 vaccine (B-Vaxx), PDL1-Vaxx exhibited synergistic effects in tumor inhibition, suggesting that combining immuno-oncology agents could enhance treatment efficacy for cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A newly discovered PD-L1 B-cell epitope peptide vaccine (PDL1-Vaxx) exhibits potent immune responses and effective anti-tumor immunity in multiple syngeneic mice models and (synergizes) in combination with a dual HER-2 B-cell vaccine (B-Vaxx). Guo, L., Overholser, J., Darby, H., et al.[2022]

The BNT162b2 vaccine demonstrated a high efficacy in solid cancer patients undergoing systemic chemotherapy, with 98.4% of participants showing a positive antibody response three months after the second dose.

The vaccine was found to be safe, as none of the 63 patients required postponement or discontinuation of their chemotherapy due to adverse reactions from the vaccination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Prospective Study Regarding the Efficacy and Safety of the BNT162b2 Vaccine in Patients With Solid Malignancies Undergoing Systemic Chemotherapy. Yamasaki, E., Shimamoto, F., Nishikawa, H., et al.[2022]

Therapeutic cancer vaccines effectively stimulate the immune system to target and destroy cancer cells, leading to long-term remissions in some patients with advanced disease.

Various types of cancer vaccines, including inactivated tumor cells and heat shock protein vaccines, have been developed and tested in clinical trials, showing promise in enhancing the body's immune response against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic cancer vaccines. Morris, LF., Ribas, A.[2007]

Therapeutic cancer vaccines aim to treat established tumors by inducing strong immune responses, particularly through the use of antigen-presenting cells like dendritic cells, which can be enhanced by transfecting them with tumor antigens.

Recent studies show that using tumor cells expressing anti-CD137 single-chain Fv fragments can effectively engage immune cells to destroy tumors, even those with low immunogenicity, suggesting a promising direction for future cancer vaccine development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic vaccination with tumor cells that engage CD137. Hellstrom, KE., Hellstrom, I.[2018]

References

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

Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

Vaccination with IL-18 gene-modified, superantigen-coated tumor cells elicits potent antitumor immune response. [2019]

3. China pubmed.ncbi.nlm.nih.gov

[Treatment of spontaneous metastatic lung cancer with tumor antigen-pulsed, interleukin-18 gene-modified dendritic cells]. [2012]

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

Human dendritic cells engineered to secrete interleukin-18 activate MAGE-A3-specific cytotoxic T lymphocytes in vitro. [2012]

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

Intratumoral Gene Transfer of mRNAs Encoding IL12 in Combination with Decoy-Resistant IL18 Improves Local and Systemic Antitumor Immunity. [2023]

6. England pubmed.ncbi.nlm.nih.gov

IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. [2022]

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

A newly discovered PD-L1 B-cell epitope peptide vaccine (PDL1-Vaxx) exhibits potent immune responses and effective anti-tumor immunity in multiple syngeneic mice models and (synergizes) in combination with a dual HER-2 B-cell vaccine (B-Vaxx). [2022]

8. Greece pubmed.ncbi.nlm.nih.gov

A Prospective Study Regarding the Efficacy and Safety of the BNT162b2 Vaccine in Patients With Solid Malignancies Undergoing Systemic Chemotherapy. [2022]

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

Therapeutic cancer vaccines. [2007]

10. Germany pubmed.ncbi.nlm.nih.gov

Therapeutic vaccination with tumor cells that engage CD137. [2018]