TORL-4-500 for Advanced Cancer

Recruiting at 9 trial locations

Overseen By Caroline Labib, PharmD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: TORL Biotherapeutics, LLC

Must not be taking: Chemotherapy, Biologics

Disqualifiers: Brain metastases, Cardiac disease, MDS, others

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

Compensation: Varies

Number of Visits: 6

70 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial requires that you have not received any chemotherapeutic, investigational, or other therapies for cancer within 14 days for small molecule drugs and 28 days for biologic drugs before starting the trial. It does not specify other medications, so you may need to discuss with the trial team.

What data supports the effectiveness of the drug TORL-4-500 for advanced cancer?

The JUPITER-06 trial showed that toripalimab, an immune checkpoint inhibitor, combined with chemotherapy improved survival in patients with advanced esophageal cancer, suggesting that similar treatments may be effective for other advanced cancers. ^{1 2 3 4 5}

What safety data exists for TORL-4-500 or similar treatments in humans?

The safety profiles of drugs for advanced melanoma, including targeted therapies, show common side effects like skin issues and endocrine disorders. Serious adverse effects can occur with cancer therapies, sometimes requiring intensive care. It's important to have healthcare professionals manage these complications. ^{6 7 8 9 10}

What makes the drug TORL-4-500 unique for advanced cancer treatment?

The drug TORL-4-500 is unique because it may offer a novel approach to treating advanced cancer by potentially targeting specific pathways or mechanisms that are not addressed by current standard treatments, such as CDK 4/6 inhibitors or m-TOR inhibitors, which are commonly used in hormone receptor-positive, HER2-negative breast cancer. This could provide new options for patients who have developed resistance to existing therapies. ^{11 12 13 14 15}

What is the purpose of this trial?

This first-in-human study will evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of TORL-4-500 in patients with advanced cancer. For Part 1, any advanced or metastatic solid tumor malignancy will be evaluated including, for example, adrenocortical carcinoma (ACC).

Research Team

Caroline Labib, PharmD

Principal Investigator

TORL Biotherapeutics, LLC

Eligibility Criteria

This trial is for adults with advanced solid tumors, including liver cancer, who have measurable disease and are in good physical condition (ECOG 0-1). They must have proper organ function and not be recovering from severe side effects of previous treatments. People with brain metastases, significant heart issues, recent cancer therapies, uncontrolled diseases or infections, a history of certain blood disorders or another cancer within the last three years cannot join.

Inclusion Criteria

I am fully active or can carry out light work.

My organs are working well.

My cancer is in an advanced stage and not just in one place.

Exclusion Criteria

I have a history of serious heart problems.

I had cancer before, but it's been a while.

I have not had cancer treatment within the specified time before starting TORL-4-500.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment - Part 1

Monotherapy Dose Finding with TORL-4-500 administered intravenously once every 3 weeks

9 weeks

3 visits (in-person)

Treatment - Part 2

Expansion as Monotherapy with TORL-4-500 administered intravenously once every 3 weeks

9 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 2 years

Treatment Details

Interventions

• TORL-4-500

Trial Overview The study tests TORL-4-500 to see how safe it is and how well it works against advanced cancers. It will also look at how the body processes the drug. This is an early-phase trial designed to gather initial data on this new potential treatment's effects on people with serious forms of cancer.

Participant Groups

Group I: Monotherapy Dose Dose Finding - Part 1 Experimental Treatment 1 Intervention

TORL-4-500 iv once every 3 weeks

Group II: Expansion as Monotherapy - Part 2 Experimental Treatment 1 Intervention

TORL-4-500 iv once every 3 weeks

Who Is Running the Clinical Trial?

TORL Biotherapeutics, LLC

Lead Sponsor

Trials

6

Recruited

600+

Translational Research in Oncology

Collaborator

Trials

22

Recruited

6,700+

Findings from Research

APTO-253, a drug tested in a Phase I study with 32 patients suffering from advanced solid tumors, was found to be well tolerated, with fatigue being the most common side effect, occurring in over 10% of participants.

At the recommended Phase 2 dose of 229 mg/m², APTO-253 showed evidence of antitumor activity, achieving stable disease in 24% of patients, indicating potential effectiveness in treating advanced solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of APTO-253 HCl, an inducer of KLF4, in patients with advanced or metastatic solid tumors. Cercek, A., Wheler, J., Murray, PE., et al.[2021]

The study is investigating the safety and efficacy of combining toripalimab (an immune checkpoint inhibitor) with chemotherapy and radiotherapy in patients with unresectable stage IV esophageal squamous cell carcinoma, aiming to improve survival outcomes.

The trial will measure key outcomes such as progression-free survival and overall survival rates, with a focus on patient safety and quality of life, indicating a comprehensive approach to evaluating the treatment's effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toripalimab in Combination With Induction Chemotherapy and Subsequent Chemoradiation as First-Line Treatment in Patients With Advanced/Metastatic Esophageal Carcinoma: Protocol for a Single-Arm, Prospective, Open-Label, Phase II Clinical Trial (TR-EAT). Wu, L., Wang, Y., Li, B., et al.[2022]

The phase III JUPITER-6 trial demonstrated that toripalimab combined with chemotherapy significantly improves progression-free survival and overall survival in previously untreated patients with advanced esophageal squamous cell carcinoma.

These results highlight the importance of immune checkpoint inhibitors, like toripalimab, as essential components in the first-line treatment strategy for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JUPITER-06 establishes immune checkpoint inhibitors as essential first-line drugs for the treatment of advanced esophageal squamous cell carcinoma. Yamamoto, S., Kato, K.[2022]

SALL4 is highly expressed in serous ovarian carcinoma (SOC) tissues and cell lines, and its expression is linked to worse clinical outcomes, including advanced disease stage and lower survival rates, based on analysis of 91 SOC tissue samples.

Manipulating SALL4 levels affects the invasive and proliferative abilities of ovarian cancer cells, suggesting that SALL4 could serve as a potential therapeutic target and prognostic marker for SOC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SALL4 is a marker of poor prognosis in serous ovarian carcinoma promoting invasion and metastasis. Yang, M., Xie, X., Ding, Y.[2019]

The combination of tivantinib and sorafenib was found to be safe and tolerable in 87 patients with advanced solid tumors, with the most common side effects being rash, diarrhea, and anorexia, but no unexpected toxicities were reported.

Preliminary results showed a 12% overall response rate, with higher efficacy in specific cancers: 26% in melanoma, 15% in renal cell carcinoma, and 10% in hepatocellular carcinoma, indicating potential therapeutic benefits for these tumor types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 trial of tivantinib in combination with sorafenib in adult patients with advanced solid tumors. Puzanov, I., Sosman, J., Santoro, A., et al.[2021]

Vemurafenib, an oral BRAF kinase inhibitor, has been shown to be a safe and tolerable treatment for patients with metastatic melanoma harboring BRAFV600 mutations, with a median follow-up of 32.2 months in a study involving 3219 patients.

The most common adverse events included arthralgia, alopecia, and hyperkeratosis, and while patients with longer durations of response experienced more severe adverse events, no new safety concerns emerged over the two-year treatment period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label, multicentre safety study of vemurafenib in 3219 patients with BRAFV600 mutation-positive metastatic melanoma: 2-year follow-up data and long-term responders' analysis. Blank, CU., Larkin, J., Arance, AM., et al.[2022]

Emerging cancer therapies, such as monoclonal antibodies and immune effector cell therapies, can lead to serious adverse effects like cytokine release syndrome, which is the most common toxicity and can necessitate ICU admission.

Management of these toxicities often requires a multidisciplinary approach and may involve supportive care, corticosteroids, and immune suppressants, highlighting the need for standardized treatment protocols to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Critical Care Management of Toxicities Associated With Targeted Agents and Immunotherapies for Cancer. Gutierrez, C., McEvoy, C., Munshi, L., et al.[2021]

A comprehensive analysis of 25,900 adverse event reports from 2008 to 2018 revealed that the safety profiles of drug classes for advanced melanoma treatment have diversified, with specific adverse reactions linked to different therapies.

Targeted therapies were commonly associated with skin and retinal disorders, while immunotherapies led to endocrine dysfunctions and less common issues like neuropsychiatric disorders, highlighting the need for improved management strategies by healthcare professionals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of drugs for advanced melanoma: A report based on 2008-2018 US Food and Drug Administration Data. Casarotto, E., Noize, P., Létinier, L., et al.[2021]

A safety analysis of ubrogepant and rimegepant, based on 2010 and 3691 adverse event reports respectively, identified 10 and 25 significant safety signals, indicating potential risks associated with these medications.

The adverse events reported were primarily related to psychiatric, neurological, gastrointestinal, skin, vascular, and infectious issues, highlighting the need for further research to confirm these safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ubrogepant and rimegepant: signal detection using spontaneous reports of adverse events from the Food and Drug Administration Adverse Event Reporting System. Battini, V., Carnovale, C., Clementi, E., et al.[2023]

Immune checkpoint antibodies targeting the PD-1/PD-L1 pathway have shown significant antitumor activity and have been approved for use as single-agent therapies in metastatic malignant melanoma and nonsmall-cell lung cancer.

Understanding the toxicities associated with PD-1/PD-L1 blockade and having effective management strategies is crucial for maximizing both the safety and efficacy of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Naidoo, J., Page, DB., Li, BT., et al.[2023]

Estrogen receptor-positive breast cancer, which makes up 70% of all breast cancers, often develops resistance to endocrine treatments, particularly due to mutations in the estrogen receptor that can occur under treatment pressure from aromatase inhibitors.

New orally available nonsteroidal selective estrogen receptor degraders (SERDs) are showing promise in early clinical trials for overcoming endocrine resistance, with the potential for effective treatment even in the presence of receptor mutations, but further studies are needed to confirm their efficacy in larger populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective oestrogen receptor degraders in breast cancer: a review and perspectives. Gombos, A.[2020]

CDK 4/6 inhibitors have significantly improved outcomes for patients with advanced luminal breast cancer, changing the treatment landscape and leading to ongoing studies to use these agents in earlier stages of the disease.

Combining endocrine therapy with targeted agents like CDK 4/6 inhibitors may enhance treatment effectiveness, especially for patients at higher risk of relapse, as seen in trials like ADAPTCYCLE that aim to reduce chemotherapy use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined endocrine and targeted therapy in luminal breast cancer. Goldner, M., Pandolfi, N., Maciel, D., et al.[2022]

CDK4/6 inhibitors combined with endocrine therapy significantly improve survival rates in advanced hormone receptor-positive, HER2-negative breast cancer, but there is limited data on treatment options after disease progression with these inhibitors.

Resistance to CDK4/6 inhibitors often involves mutations in PIK3CA and ESR1, with PIK3CA mutations being actionable due to the recent approval of targeted therapies like alpelisib, highlighting the importance of genomic sequencing for guiding further treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Practical Treatment Strategies and Future Directions After Progression While Receiving CDK4/6 Inhibition and Endocrine Therapy in Advanced HR+/HER2- Breast Cancer. Sammons, S., Shastry, M., Dent, S., et al.[2021]

Hormone therapy is the preferred treatment for hormone-receptor positive (HR+) and HER2-negative advanced breast cancer, with recent guidelines recommending the use of combination therapies involving targeted drugs and aromatase inhibitors (AI) or selective estrogen receptor down-regulators (SERD).

CDK4/6 inhibitors are effective in halting tumor growth by blocking cell cycle progression in HR+ tumors and are now considered standard first-line therapy when combined with AIs, while other combinations like Everolimus plus AI are recommended for second-line treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of hormone-receptor positive human epidermal receptor 2 negative advanced or metastatic breast cancers. Ngan, RKC.[2020]

Recent advancements in endocrine therapy for hormone receptor-positive, HER2-negative metastatic breast cancer have introduced new drug combinations, such as cyclin-dependent kinase 4/6 inhibitors (palbociclib and ribociclib) and mTOR inhibitors (everolimus), which help overcome resistance to traditional antiestrogen treatments.

These novel therapies have significantly improved the quality of life and tumor control for many patients, allowing them to live for several years despite the disease being considered incurable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metastatic breast cancer: Endocrine therapy landscape reshaped. Salkeni, MA., Hall, SJ.[2020]

References

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

Phase 1 study of APTO-253 HCl, an inducer of KLF4, in patients with advanced or metastatic solid tumors. [2021]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Toripalimab in Combination With Induction Chemotherapy and Subsequent Chemoradiation as First-Line Treatment in Patients With Advanced/Metastatic Esophageal Carcinoma: Protocol for a Single-Arm, Prospective, Open-Label, Phase II Clinical Trial (TR-EAT). [2022]

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

JUPITER-06 establishes immune checkpoint inhibitors as essential first-line drugs for the treatment of advanced esophageal squamous cell carcinoma. [2022]

4. Greece pubmed.ncbi.nlm.nih.gov

SALL4 is a marker of poor prognosis in serous ovarian carcinoma promoting invasion and metastasis. [2019]

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

Phase 1 trial of tivantinib in combination with sorafenib in adult patients with advanced solid tumors. [2021]

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

Open-label, multicentre safety study of vemurafenib in 3219 patients with BRAFV600 mutation-positive metastatic melanoma: 2-year follow-up data and long-term responders' analysis. [2022]

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

Critical Care Management of Toxicities Associated With Targeted Agents and Immunotherapies for Cancer. [2021]

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

Safety profile of drugs for advanced melanoma: A report based on 2008-2018 US Food and Drug Administration Data. [2021]

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

Ubrogepant and rimegepant: signal detection using spontaneous reports of adverse events from the Food and Drug Administration Adverse Event Reporting System. [2023]

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

Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. [2023]

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

Selective oestrogen receptor degraders in breast cancer: a review and perspectives. [2020]

12. England pubmed.ncbi.nlm.nih.gov

Combined endocrine and targeted therapy in luminal breast cancer. [2022]

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

Practical Treatment Strategies and Future Directions After Progression While Receiving CDK4/6 Inhibition and Endocrine Therapy in Advanced HR+/HER2- Breast Cancer. [2021]

14. China pubmed.ncbi.nlm.nih.gov

Management of hormone-receptor positive human epidermal receptor 2 negative advanced or metastatic breast cancers. [2020]

15. Germany pubmed.ncbi.nlm.nih.gov

Metastatic breast cancer: Endocrine therapy landscape reshaped. [2020]