TORL-1-23 for Advanced Cancer

(TRIO049 Trial)

Recruiting at 18 trial locations

Overseen By Ibrahim Qazi

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: TORL Biotherapeutics, LLC

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: Unknown

Duration: 28 days

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called TORL-1-23 to determine its safety and effectiveness for people with advanced cancer. The study examines the drug's impact on tumors and how the body processes it. Participants will receive the treatment in two phases: initially to determine the right dose, followed by an assessment of its broader effects. Suitable candidates for this trial have advanced, measurable solid tumors and good organ function. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

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.

Is there any evidence suggesting that TORL-1-23 is likely to be safe for humans?

Research shows that TORL-1-23 is generally safe for people with advanced cancer. Researchers have tested it on patients with difficult-to-treat solid tumors, including those unresponsive to certain treatments like some ovarian cancers. Studies have found that TORL-1-23 has a manageable safety profile. While some side effects may occur, they are usually not severe and can be managed with proper care. The treatment has also shown promising results in shrinking tumors, suggesting that it not only can be tolerated by patients but may also help in fighting the cancer. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for advanced cancer, which often involve chemotherapy or targeted therapies, TORL-1-23 acts on a unique mechanism by specifically targeting tumor cells while minimizing harm to healthy cells. Researchers are particularly excited about its potential to offer fewer side effects than traditional therapies, which can be quite harsh on the body. Additionally, TORL-1-23's innovative approach could lead to more effective outcomes in resistant cancer types, offering new hope for patients who haven't benefited from existing treatments.

What evidence suggests that TORL-1-23 might be an effective treatment for advanced cancer?

Research shows that TORL-1-23 has promising results for treating some advanced cancers. In earlier studies, patients with advanced solid tumors that are CLDN6-positive, such as ovarian cancer, had up to a 50% chance of tumor shrinkage at certain doses. Specifically, half of the patients experienced a reduction in cancer size. The treatment was generally well-tolerated, indicating a favorable safety profile. This trial will further investigate TORL-1-23, which could be effective for patients with advanced cancer, especially those with CLDN6-positive tumors. ^{1 2 3 6 7}

Who Is on the Research Team?

Hatem Dokainish

Principal Investigator

TORL Biotherapeutics, LLC

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• TORL-1-23

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

The phase I trial involving 67 patients found that the oral TORC1/2 inhibitor TAK-228, when combined with paclitaxel, showed a safety profile similar to other TORC inhibitors, with common side effects including neutropenia and diarrhea.

TAK-228 demonstrated promising preliminary antitumor activity, with 14 out of 54 evaluable patients achieving either a partial response or stable disease lasting at least 6 months, supporting further research into its use with other treatments.

NCBI (Pubmed)

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. Burris, HA., Kurkjian, CD., Hart, L., et al.[2022]

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]

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]

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]

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]

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]

The study identified TXNIP and TORC1/2 signaling as key drivers of peritoneal metastasis (PM) in ovarian cancer, suggesting that targeting these pathways could lead to new therapies.

Inhibition of TORC1/2 using the drug TAK228 was shown to prevent PM in both in vitro and in vivo models, indicating its potential as a treatment strategy for this serious complication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Loss of TXNIP enhances peritoneal metastasis and can be abrogated by dual TORC1/2 inhibition. Spaeth-Cook, D., Burch, M., Belton, R., et al.[2019]

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]

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]

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]

Citations

1. onclive.com onclive.com/view/torl-1-23-is-tolerable-active-in-heavily-pretreated-cldn6-advanced-ovarian-cancer-other-solid-tumors

TORL-1-23 Is Tolerable, Active in Heavily Pretreated ... TORL-1-23 showed promising efficacy in CLDN6-positive advanced solid tumors, with the highest ORR of 50% at 2.4 mg/kg in ovarian cancer patients ...

2. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT05103683

NCT05103683 | First in Human Study of TORL-1-23 ... This first-in-human study will evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of TORL-1-23 in patients with advanced cancer.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06690775

CATALINA-2: A Clinical Study of TORL-1-23 in Platinum- ... A Phase 2 study to evaluate the safety and efficacy of TORL-1-23 in patients with advanced ovarian cancer. ... efficacy outcome measures of TORL-1-23 per RECIST ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.3082

Initial results of dose finding in a first-in-human phase 1 ... Conclusions: TORL-1-23 has a favorable safety/tolerability profile and PK characteristics with preliminary antitumor activity in pts with ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1048891X24113941

PR062/#686 First-in-human phase 1 study of torl-1–23, a ... In participants with heavily-pretreated CLDN6-expressing ovarian cancer, the novel TORL-1–23 ADC shows a favorable safety/tolerability profile and encouraging ...

6. prnewswire.com prnewswire.com/news-releases/torl-biotherapeutics-presents-updated-phase-1-results-of-novel-claudin-6-targeted-antibody-drug-conjugate-torl-1-23-at-the-2024-european-society-of-medical-oncology-congress-302248489.html

TORL BioTherapeutics Presents Updated Phase 1 Results ... TORL-1-23 Demonstrates Clinically Meaningful, Durable and Confirmed Responses with a Generally Manageable Safety Profile in Patients with ...

7. clinicaltrial.be clinicaltrial.be/en/details/37374?per_page=20&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

First in Human Study of TORL-1-23 in Participants With Ad... Secondary outcomes 20 · Objective Response Rate (ORR) · Duration of Response (DOR) · Progression Free Survival (PFS) · Time to Response (TTR) · 1 ...