TORL-1-23 for Advanced Cancer

(TRIO049 Trial)

Recruiting at 12 trial locations

Overseen By Ibrahim Qazi

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: TORL Biotherapeutics, LLC

Disqualifiers: Brain metastases, Cardiac disease, MDS, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial will test a new drug called TORL-1-23 in patients with advanced cancer to see if it is safe and effective. Researchers will study how the drug behaves in the body and its ability to fight cancer.

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 must not have received any cancer treatments within 14 days for small molecule therapies and 28 days for biologic therapies before starting the trial.

What data supports the effectiveness of the drug TORL-1-23 for advanced cancer?

Research on similar drugs, like TAK-228 and Palomid 529, which also inhibit TORC1/2, shows they can reduce tumor growth and prevent cancer spread in various models. This suggests that TORL-1-23 might work similarly in treating advanced cancer. ^{1 2 3 4 5}

Is TORL-1-23 safe for humans?

Toremifene, which may be similar to TORL-1-23, has been studied in patients with advanced breast cancer and was generally well-tolerated with mild side effects. In combination with other treatments, it did not significantly increase adverse effects. ^{6 7 8 9 10}

What makes the drug TORL-1-23 unique for treating advanced cancer?

TORL-1-23 is unique because it targets mutant p53 proteins, which are often found in many cancers and contribute to tumor growth and resistance to treatment. This drug aims to reactivate these mutant proteins, potentially offering a new approach for cancers that are difficult to treat with existing therapies. ^{11 12 13 14 15}

Research Team

Hatem Dokainish

Principal Investigator

TORL Biotherapeutics, LLC

Eligibility Criteria

This trial is for adults with advanced solid tumors, including specific cancers like non-small cell lung cancer and ovarian cancer. Participants must have measurable disease, be relatively fit (ECOG status 0-1), and their organs must function well. They can't join if they have serious brain metastases, unresolved side effects from past treatments, recent other cancer therapies, severe health issues unrelated to the tumor, certain blood disorders or another recent cancer.

Inclusion Criteria

Measurable disease, per RECIST v1.1

My organs are functioning well.

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

Exclusion Criteria

I am not pregnant or breastfeeding.

I still experience side effects from past treatments, except for hair loss or acceptable lab results.

I have a history of serious heart problems.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive TORL-1-23 to evaluate safety, tolerability, pharmacokinetics, and antitumor activity

28 days

Multiple visits for dose escalation and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 2 years

Extension

Participants may continue to receive treatment as part of an open-label extension

Long-term

Treatment Details

Interventions

• TORL-1-23 (Other)

Trial Overview The study is testing TORL-1-23's safety and effectiveness in treating advanced cancers. It's a first-in-human study which means it's the first time this drug is being given to people. Researchers will look at how patients tolerate the drug, its behavior in the body (pharmacokinetics), and whether it shrinks tumors.

Participant Groups

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

TORL-1-23

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

TORL-1-23

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

A novel biomarker, TOR1B, has been identified as a significant predictor of bone metastasis in breast cancer patients, with high expression levels found in those with metastasis (p < 0.05).

TOR1B expression levels can help distinguish prognosis in estrogen receptor (ER) and progesterone receptor (PR) positive patients, where lower levels are associated with delayed bone metastasis (HR, 0.28; 95% CI 0.094-0.84).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TOR1B: a predictor of bone metastasis in breast cancer patients. Nguyen, MN., Akter, S., Akhter, H., et al.[2023]

Palomid 529 (P529), a TORC1/TORC2 inhibitor, effectively reduces cell proliferation and induces apoptosis in hormone-refractory prostate cancer (HRPC) cells, especially in those lacking the PTEN gene, indicating its potential as a targeted therapy.

Combining P529 with conventional chemotherapy drugs like docetaxel and cisplatin shows strong synergistic effects, leading to increased complete responses and reduced tumor progression in in vivo models, suggesting a promising new treatment strategy for HRPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The TORC1/TORC2 inhibitor, Palomid 529, reduces tumor growth and sensitizes to docetaxel and cisplatin in aggressive and hormone-refractory prostate cancer cells. Gravina, GL., Marampon, F., Petini, F., et al.[2022]

AZD2014, an oral m-TORC 1/2 inhibitor, was found to have a maximum tolerated dose (MTD) of 50 mg taken twice daily, with manageable side effects such as fatigue and mucositis in a study involving 56 patients.

At the MTD, AZD2014 demonstrated pharmacologically relevant drug levels and showed promising clinical responses, including partial responses in patients with specific mutations in pancreatic and breast cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014. Basu, B., Dean, E., Puglisi, M., et al.[2022]

Toremifene (TOR) effectively inhibits the growth of human lung adenocarcinoma cells (A549) and enhances the effectiveness of cisplatin (DDP) when used together, particularly at concentrations of 5 micromol/L or higher.

The combination of TOR and DDP increases the expression of p21, suggesting a mechanism of action that enhances the antitumor activity during specific phases of the cell cycle (S, G2, and M phases).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Synergistic effect of toremifene and cisplatin on human lung cancer cell line A549]. Zhang, X., Li, Q., Han, Y., et al.[2013]

A 47-year-old woman with advanced breast cancer and liver metastases showed a partial response to high-dose TOR treatment after previous therapies failed, indicating its potential efficacy in difficult cases.

Following the administration of TOR, the patient's liver dysfunction improved, suggesting that TOR may also have a beneficial effect on liver function in patients with metastatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A case of advanced breast cancer with multiple liver metastases resistant to chemotherapy responding to high-dose toremifene]. Matsumoto, C., Ishikawa, T., Momiyama, N., et al.[2018]

In a study involving 14 hormone receptor negative metastatic breast cancer patients, the combination of paclitaxel (PTX) and toremifene (TOR) showed a significant improvement in clinical benefit rate and time to progression compared to PTX alone.

Adding TOR to the PTX regimen did not significantly increase adverse events, suggesting that this combination therapy is both effective and safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The combined effect of paclitaxel and toremifene therapy for metastatic breast cancer]. Sakurai, K., Matsuo, S., Enomoto, K., et al.[2015]

In a study of 18 patients with advanced or recurrent breast cancer, high-dose toremifene (HD-TOR) showed a clinical benefit rate of 56%, indicating it can be an effective treatment option, especially for those who have previously received aromatase inhibitors.

The treatment was well-tolerated with mild adverse events, and patients experienced a median progression-free survival of 5.5 months, suggesting HD-TOR could be a viable second-line therapy for AI-resistant breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A study of the efficacy of high-dose toremifene in advanced and recurrent breast cancer]. Tokura, H., Fujisaki, M., Takahashi, T., et al.[2013]

In a study of 217 postmenopausal women with advanced breast cancer, toremifene (TOR) showed a higher response rate of 64% compared to 52% for tamoxifen (TAM), indicating that TOR may be more effective as a treatment option.

Toremifene was associated with a lower incidence of undesirable side effects compared to tamoxifen, suggesting it is a safer alternative for patients with estrogen receptor-positive advanced breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III randomized trial of toremifene vs tamoxifen in hormonodependant advanced breast cancer. Milla-Santos, A., Milla, L., Rallo, L., et al.[2019]

APR-246, currently in a phase II clinical trial for high-grade serous ovarian cancer, shows promise in reactivating mutant p53 and modulating redox activity in breast cancer cell lines, with effects on gene expression that vary by cell line.

The study identified six genes consistently upregulated by APR-246 across multiple cell lines, suggesting they could serve as new biomarkers for monitoring treatment response in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Mutant p53-Targeting Compound APR-246 Induces ROS-Modulating Genes in Breast Cancer Cells. Synnott, NC., Madden, SF., Bykov, VJN., et al.[2020]

Mutated p53 proteins, found in nearly 40% of human tumors, not only lose their tumor-suppressing abilities but also promote cancer progression and resistance to treatment, leading to worse outcomes for patients.

Recent mouse models show that tumors with stabilized mutant p53 proteins rely on these proteins for their growth and spread, suggesting that targeting these proteins could be a promising strategy for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gain-of-Function (GOF) Mutant p53 as Actionable Therapeutic Target. Schulz-Heddergott, R., Moll, UM.[2020]

Mutant p53 (mtp53) promotes cancer growth through the WASP-interacting protein (WIP), which is crucial for the proliferation of cancer stem cell-like cells in glioblastoma and breast cancer.

Knocking down WIP in mtp53-expressing cells significantly reduces their growth and CSC-like markers, indicating that targeting WIP could be a potential therapeutic strategy against cancers driven by mutant p53.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mutant p53 oncogenic functions in cancer stem cells are regulated by WIP through YAP/TAZ. Escoll, M., Gargini, R., Cuadrado, A., et al.[2021]

In a phase Ib/II clinical trial of APR-246 combined with chemotherapy for metastatic esophageal cancer, TP53 mutation status was found to be an unreliable predictor of response to the treatment, suggesting that other factors should be considered for patient selection.

The study identified SLC7A11 expression as a superior biomarker for predicting sensitivity to APR-246, indicating that it should be used to better stratify patients in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SLC7A11 Is a Superior Determinant of APR-246 (Eprenetapopt) Response than TP53 Mutation Status. Fujihara, KM., Corrales Benitez, M., Cabalag, CS., et al.[2022]

The study created novel humanized mutant p53 knock-in mice with the R248Q and G245S mutations, revealing that R248Q significantly accelerates tumor onset and reduces survival compared to p53-null mice, indicating a strong oncogenic gain of function.

In contrast, G245S did not affect tumor latency or survival, suggesting that not all p53 mutations have the same biological impact, which aligns with observations in Li-Fraumeni patients showing differing outcomes based on specific p53 mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis. Hanel, W., Marchenko, N., Xu, S., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

TOR1B: a predictor of bone metastasis in breast cancer patients. [2023]

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

Loss of TXNIP enhances peritoneal metastasis and can be abrogated by dual TORC1/2 inhibition. [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies. [2022]

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

The TORC1/TORC2 inhibitor, Palomid 529, reduces tumor growth and sensitizes to docetaxel and cisplatin in aggressive and hormone-refractory prostate cancer cells. [2022]

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

First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014. [2022]

6. China pubmed.ncbi.nlm.nih.gov

[Synergistic effect of toremifene and cisplatin on human lung cancer cell line A549]. [2013]

7. Japan pubmed.ncbi.nlm.nih.gov

[A case of advanced breast cancer with multiple liver metastases resistant to chemotherapy responding to high-dose toremifene]. [2018]

8. Japan pubmed.ncbi.nlm.nih.gov

[The combined effect of paclitaxel and toremifene therapy for metastatic breast cancer]. [2015]

9. Japan pubmed.ncbi.nlm.nih.gov

[A study of the efficacy of high-dose toremifene in advanced and recurrent breast cancer]. [2013]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Phase III randomized trial of toremifene vs tamoxifen in hormonodependant advanced breast cancer. [2019]

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

The Mutant p53-Targeting Compound APR-246 Induces ROS-Modulating Genes in Breast Cancer Cells. [2020]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Gain-of-Function (GOF) Mutant p53 as Actionable Therapeutic Target. [2020]

13. England pubmed.ncbi.nlm.nih.gov

Mutant p53 oncogenic functions in cancer stem cells are regulated by WIP through YAP/TAZ. [2021]

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

SLC7A11 Is a Superior Determinant of APR-246 (Eprenetapopt) Response than TP53 Mutation Status. [2022]

15. England pubmed.ncbi.nlm.nih.gov

Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis. [2021]