TORL-4-500 for Advanced Cancer

Recruiting at 10 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new treatment called TORL-4-500, an experimental therapy, to determine its safety and effectiveness for individuals with advanced cancer, specifically those with metastatic solid tumors. The study will assess the body's tolerance to the treatment and its potential to shrink tumors. Suitable candidates include those with a measurable solid tumor who have been living with advanced cancer. Participants should also be in generally good health aside from their cancer. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

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.

Is there any evidence suggesting that TORL-4-500 is likely to be safe for humans?

Research shows that TORL-4-500 is a new treatment being tested for advanced cancer. As this is its first trial in humans, detailed safety results are not yet available. The main goal is to determine its safety and tolerability for patients. The study will monitor any side effects or dosage-related issues.

As an early-phase study, it seeks to understand the treatment's effects on humans for the first time. Although human data is limited, the trial is designed to carefully monitor and manage any safety concerns. If the treatment showed promise in lab or animal tests, this trial will help assess its safety for broader human use. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about TORL-4-500 because it offers a novel approach to treating advanced cancer. Unlike many current treatments that target cancer cells generally, TORL-4-500 works by specifically targeting a unique pathway involved in cancer cell growth and survival. This targeted method could potentially lead to more effective treatment outcomes with fewer side effects. Additionally, TORL-4-500 is administered intravenously once every three weeks, which might provide a more convenient dosing schedule compared to some existing therapies that require more frequent administration.

What evidence suggests that TORL-4-500 might be an effective treatment for advanced cancer?

Research shows that TORL-4-500 could help treat advanced cancer. Studies have found that it works well in lab tests by specifically targeting certain cancer cells called DLK1 positive cells. These tests suggest that TORL-4-500 might shrink tumors in some cancer types. The treatment is an antibody-drug conjugate, combining an antibody with a drug to directly attack and kill cancer cells. Although research in humans remains in the early stages, these initial results offer hope for people with advanced cancer. Participants in this trial will receive TORL-4-500 as a monotherapy, administered intravenously once every three weeks. ^{2 3 6 7 8}

Who Is on the Research Team?

Caroline Labib, PharmD

Principal Investigator

TORL Biotherapeutics, LLC

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06005740

NCT06005740 | A Phase 1, First in Human Study of TORL- ... This first-in-human study will evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of TORL-4-500 in patients with advanced cancer. For ...

2. researchgate.net researchgate.net/publication/379199791_Abstract_1896_Therapeutic_potential_of_TORL-4-500_an_antibody-drug_conjugate_directed_against_delta_like_non-canonical_notch_ligand_1_DLK1

Therapeutic potential of TORL-4-500, an antibody-drug ... TORL-4-500 exhibited selective efficacy in cell line xenograft models of DLK1 positive human cancers. ... advanced cancer and is currently ongoing (NCT06005740).

3. uclahealth.org uclahealth.org/clinical-trials/phase-1-first-human-study-torl-4-500-patients-with-advanced

A Phase 1, First in Human Study of TORL-4-500 in Patients ... This first-in-human study will evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of TORL-4-500 in patients with advanced cancer.

4. globenewswire.com globenewswire.com/news-release/2025/09/25/3156585/0/en/Advanced-Liver-Cancer-Clinical-Trial-Pipeline-Shows-Potential-with-Active-Contributions-from-50-Key-Companies-DelveInsight.html

Advanced Liver Cancer Clinical Trial Pipeline Shows In June 2024, AbelZeta Pharma, Inc. announced preliminary safety and efficacy results from its first-time in human investigator-initiated trial ...

5. delta.larvol.com delta.larvol.com/Products/?ProductId=b6940f3d-a2c9-4c44-bbfc-726146c2e707

TORL-4-500 / TORL Biotherap A phase I, first in human study of TORL-4-500 in patients with advanced cancer (ESMO 2024) - P1 | "This study is currently open with patients enrolling in ...

6. mayo.edu mayo.edu/research/clinical-trials/cls-20575573

First in Human Study of TORL-4-500 in Participants With ... About this study. The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of TORL-4-500 ...

7. annalsofoncology.org annalsofoncology.org/article/S0923-7534(24)02272-5/fulltext

687TiP A phase I, first in human study of TORL-4-500 in ... TORL-4-500-001 is a two-part first in human study to characterize the safety, tolerability, and dose-limiting toxicities (DLT)

8. cancer.gov cancer.gov/clinicaltrials/NCI-2024-00046

A Phase 1, First in Human Study of TORL-4-500 in Patients ... This first-in-human study will evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of TORL-4-500 in patients with advanced cancer.