XTX301 for Solid Tumors

Recruiting at 11 trial locations

Overseen By Xilio Medical Affairs

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Xilio Development, Inc.

Must not be taking: Immunosuppressants, IL-12 therapy

Disqualifiers: Liver metastasis, CNS malignancy, Autoimmune, others

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

Compensation: Varies

Number of Visits: Unknown

358 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a first-in-human, multicenter, Phase 1/2, open-label study designed to evaluate the safety and tolerability of XTX301 as monotherapy in patients with advanced solid tumors.

Do I need to stop my current medications for the XTX301 trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that ongoing medical castration must be maintained for prostate cancer patients, suggesting some treatments may continue. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug XTX301 for solid tumors?

Research shows that XTX301, a modified form of Interleukin-12 (IL-12), can effectively activate immune responses in tumors without causing significant side effects, as demonstrated in animal studies. This drug is designed to be activated specifically in the tumor environment, which helps reduce the toxicity typically associated with IL-12 treatments. ^{1 2 3 4 5}

Is XTX301 safe for humans?

XTX301, a modified form of Interleukin-12 (IL-12), has shown promise in preclinical studies by reducing tumor growth without causing significant side effects in animal models. In a study with non-human primates, XTX301 was tolerated well at doses higher than those effective in mice, suggesting it may be safer than traditional IL-12 treatments. ^{1 6 7 8 9}

What makes the drug XTX301 unique for treating solid tumors?

XTX301 is unique because it is a tumor-activated form of interleukin-12 (IL-12) that is designed to be activated specifically within the tumor environment, reducing the systemic toxicity typically associated with IL-12 treatments. This targeted activation allows for potent anti-tumor activity while minimizing side effects, making it a promising option for solid tumor treatment. ^{1 2 4 10 11}

Eligibility Criteria

This trial is for adults with advanced solid tumors like melanoma, lung, breast, and prostate cancer that have not responded to standard treatments. Participants must be in a stable condition (ECOG 0-2), have good organ function, and be able to provide tumor tissue samples. People with liver metastasis, active brain cancers or infections like hepatitis B/C, recent transplants or severe immune-related reactions from past immunotherapies cannot join.

Inclusion Criteria

I can take care of myself and perform daily activities.

My organs are working well.

My cancer is advanced or has spread, and standard treatments haven't worked or aren't suitable.

Exclusion Criteria

I have an active hepatitis B or C infection.

I have previously been treated with IL-12 therapy.

I do not have an active brain tumor or cancer spread to my brain or its coverings.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment - Dose Escalation

XTX301 monotherapy administered in ascending doses to assess safety, tolerability, and determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D)

8-12 weeks

Phase 1 Treatment - Pharmacodynamics Expansion

Evaluation of XTX301 in patients with selected advanced solid tumors to further characterize the pharmacodynamics profile

8-12 weeks

Phase 2 Treatment - Disease-Specific Cohorts

Further evaluation of safety and antitumor activity/efficacy of XTX301 in disease-specific expansion cohorts

16-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• XTX301

Trial Overview XTX301 is being tested as a solo treatment for various advanced solid tumors. This first-in-human study aims to see how safe it is and what effects it has on patients who've run out of standard treatment options. It involves taking biopsies before and after starting the drug to closely monitor its impact.

Participant Groups

Group I: Phase 2 - XTX301 Monotherapy Dose Expansion in Disease-Specific Cohorts Experimental Treatment 1 Intervention

Phase 2 will further evaluate the safety and antitumor activity/efficacy of XTX301 monotherapy in disease-specific expansion cohorts of patients with select tumors, namely: * Cohort 2A: head and neck squamous cell carcinoma (HNSCC) * Cohort 2B: melanoma * Cohort 2C: non-small cell lung cancer (NSCLC) * Cohort 2D: ovarian cancer * Cohort 2E: castrate-resistant prostate cancer (CRPC) * Cohort 2F: triple-negative breast cancer (TNBC)

Group II: Phase 1 - XTX301 Monotherapy Dose Escalation and Pharmacodynamics Expansion Experimental Treatment 1 Intervention

Part 1A Dose Escalation of XTX301 administered in ascending doses to patients with advanced solid tumors to assess the safety and tolerability and determine/define MTD and/or the highest recommended Phase 2 dose (RP2D). Part 1B Evaluation of XTX301 in patients with selected advanced solid tumors to further characterize the pharmacodynamics profile of XTX301.

Who Is Running the Clinical Trial?

Xilio Development, Inc.

Lead Sponsor

Trials

3

Recruited

680+

Findings from Research

XTX301 is a novel tumor-activated form of IL12 that shows significant antitumor activity in mouse models without causing systemic toxicity, suggesting a safer alternative to traditional IL12 administration.

In a nonhuman primate study, XTX301 was well-tolerated at doses higher than those effective in mice, indicating its potential for effective cancer treatment with a wider safety margin, and it is currently being tested in a phase I clinical trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

XTX301, a tumor-activated Interleukin-12 has the potential to widen the therapeutic index of IL-12 treatment for solid tumors as evidenced by pre-clinical studies. Patel, E., Malkova, NV., Crowe, D., et al.[2023]

A high-capacity adenoviral vector delivering interleukin-12 (IL-12) significantly reduced tumor burden and improved overall survival in a model of pediatric osteosarcoma, demonstrating its potential as a therapeutic intervention.

The treatment not only eradicated tumors but also induced long-term immunological memory in survivors, suggesting that it could provide lasting protection against tumor recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Local administration of IL-12 with an HC vector results in local and metastatic tumor control in pediatric osteosarcoma. Zalacain, M., Bunuales, M., Marrodan, L., et al.[2021]

The IL-12 family cytokines, including IL-12, IL-23, IL-27, IL-35, and IL-39, play crucial roles in regulating immune responses in cancer, with IL-12 acting as an effector cytokine that enhances anti-tumor immunity by activating cytotoxic T and NK cells.

While IL-12 promotes anti-tumor effects, other family members like IL-23 and IL-27 can have dual roles, potentially aiding tumor growth, and IL-35 primarily inhibits effector T cells, suggesting that these cytokines could be targeted for immunomodulatory therapies in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-12 Family Cytokines in Cancer and Immunotherapy. Mirlekar, B., Pylayeva-Gupta, Y.[2021]

mWTX-330, a novel INDUKINE molecule, shows promising antitumor activity in mice by selectively activating immune cells within tumors while minimizing systemic toxicity, making it a safer option for cancer immunotherapy.

The effectiveness of mWTX-330 relies on its ability to be processed by tumor-specific proteases, enhancing the immune response through mechanisms like increasing polyfunctional CD8+ T cells and reducing exhausted T cells, which are crucial for effective cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

mWTX-330, an IL-12 INDUKINE Molecule, Activates and Reshapes Tumor-Infiltrating CD8+ T and NK Cells to Generate Antitumor Immunity. Nirschl, CJ., Brodkin, HR., Domonkos, C., et al.[2023]

Interleukin-12 (IL-12) has shown strong potential to boost antitumor immune responses, but its initial clinical use faced challenges due to a poor benefit-toxicity ratio.

Localized delivery methods for IL-12, such as electroporation of plasmid DNA and combination with checkpoint inhibitors, have improved its therapeutic effectiveness and safety, showing promising results in early-phase clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel strategies exploiting interleukin-12 in cancer immunotherapy. Cirella, A., Luri-Rey, C., Di Trani, CA., et al.[2022]

Interleukin-12 (IL-12) has shown strong antitumor effects in preclinical models, but its systemic delivery in early clinical trials led to significant toxicities, limiting its use in humans.

Recent advancements in localized delivery systems for IL-12, such as immunocytokine fusions and polymeric nanoparticles, have demonstrated promising antitumor immunity with fewer side effects, suggesting a potential resurgence in IL-12-based cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Localized Interleukin-12 for Cancer Immunotherapy. Nguyen, KG., Vrabel, MR., Mantooth, SM., et al.[2021]

The novel immunocytokine NHS-IL12, which combines IL-12 with a tumor-targeting antibody, shows a longer plasma half-life and selective targeting to tumors, making it a potentially safer and more effective cancer treatment compared to standard recombinant IL-12.

NHS-IL12 demonstrated superior anti-tumor effects in murine models, primarily through CD8+ T cell activation, and when combined with other therapies like vaccines or chemotherapy, it produced even greater anti-tumor responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The immunocytokine NHS-IL12 as a potential cancer therapeutic. Fallon, J., Tighe, R., Kradjian, G., et al.[2021]

Human lung tumor biopsies can be successfully implanted into SCID mice, maintaining their viability and tumor microenvironment characteristics for at least 3 months, allowing for the study of tumor dynamics in a controlled setting.

Inflammatory cells within these tumor xenografts can suppress tumor growth through the production of interleukin-12 (IL-12), and this effect can be enhanced by delivering IL-12 using biodegradable microspheres, highlighting the potential for targeted cytokine therapies in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human inflammatory cells within the tumor microenvironment of lung tumor xenografts mediate tumor growth suppression in situ that depends on and is augmented by interleukin-12. Sugiyama, Y., Kato, M., Chen, FA., et al.[2019]

A novel therapeutic system using membrane-anchored IL-12 (aIL-12) delivered by tumor-specific T cells showed increased antitumor efficacy while maintaining low systemic exposure to IL-12, minimizing potential toxicity.

In both murine and human tumor models, the NFAT-inducible aIL-12 construct improved antitumor responses without causing detectable levels of IL-12 in serum or weight loss, indicating a safer and more effective approach to cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced efficacy and limited systemic cytokine exposure with membrane-anchored interleukin-12 T-cell therapy in murine tumor models. Zhang, L., Davies, JS., Serna, C., et al.[2020]

Lentiviral transduction of human sarcoma cells to produce interleukin-12 (IL-12) allows for localized delivery of this cytokine, enhancing both innate and adaptive immune responses without the systemic toxicities associated with traditional IL-12 administration.

In murine models, IL-12 expressing sarcomas not only restricted tumor growth but also triggered a specific immune response, indicating that this method could be a promising approach for treating sarcomas through autologous reintroduction of modified tumor cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sarcoma IL-12 overexpression facilitates NK cell immunomodulation. Rademacher, MJ., Cruz, A., Faber, M., et al.[2021]

In a phase 1 trial involving 31 patients with recurrent high-grade glioma, the hIL-12 gene therapy showed acceptable safety and tolerability, with dose-related increases in hIL-12 and interferon-γ observed, indicating a potential immunological antitumor effect.

Patients receiving a 20 mg dose of the oral activator veledimex (VDX) had a median overall survival of 12.7 months, while concurrent high doses of corticosteroids negatively impacted survival outcomes, highlighting the importance of managing steroid use in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: Results of a phase 1 trial. Chiocca, EA., Yu, JS., Lukas, RV., et al.[2023]

References

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

XTX301, a tumor-activated Interleukin-12 has the potential to widen the therapeutic index of IL-12 treatment for solid tumors as evidenced by pre-clinical studies. [2023]

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

Local administration of IL-12 with an HC vector results in local and metastatic tumor control in pediatric osteosarcoma. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

IL-12 Family Cytokines in Cancer and Immunotherapy. [2021]

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

mWTX-330, an IL-12 INDUKINE Molecule, Activates and Reshapes Tumor-Infiltrating CD8+ T and NK Cells to Generate Antitumor Immunity. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Novel strategies exploiting interleukin-12 in cancer immunotherapy. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Localized Interleukin-12 for Cancer Immunotherapy. [2021]

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

The immunocytokine NHS-IL12 as a potential cancer therapeutic. [2021]

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

Human inflammatory cells within the tumor microenvironment of lung tumor xenografts mediate tumor growth suppression in situ that depends on and is augmented by interleukin-12. [2019]

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

Enhanced efficacy and limited systemic cytokine exposure with membrane-anchored interleukin-12 T-cell therapy in murine tumor models. [2020]

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

Sarcoma IL-12 overexpression facilitates NK cell immunomodulation. [2021]

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

Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: Results of a phase 1 trial. [2023]