TORL-3-600 for Advanced Cancer

Recruiting at 7 trial locations

Overseen By Brandon Sookdeo

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: TORL Biotherapeutics, LLC

Must not be taking: Chemotherapy, Biologics

Disqualifiers: Brain metastases, Cardiac disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 63 days

70 Participants Needed

Trial Summary

What is the purpose of this trial?

This first-in-human study will evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of TORL-3-600 in patients with advanced cancer

Do I have to stop taking my current medications for 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 treatment within 14 days for small molecules and 28 days for biologics before starting the trial.

What data supports the effectiveness of the drug TORL-3-600 for advanced cancer?

Research on similar drugs that inhibit TORC1/2, like TAK-228 and PQR620, shows they can reduce tumor growth and enhance the effects of other cancer treatments. These findings suggest that TORL-3-600, if it works similarly, might also be effective in treating advanced cancers. ^{1 2 3 4 5}

What safety data exists for molecular target anticancer drugs like TORL-3-600?

Molecular target anticancer drugs, which may include treatments like TORL-3-600, have been shown to significantly increase the risk of serious adverse events (SAEs) and fatal adverse events (FAEs) compared to placebo. The overall incidence of SAEs was about 27%, and FAEs was about 2.3%, indicating a need for careful monitoring to prevent these events. ^{6 7 8 9 10}

What makes the drug TORL-3-600 unique for treating advanced cancer?

TORL-3-600 is unique because it is a dual inhibitor of TORC1 and TORC2, which are part of a signaling pathway often involved in cancer growth. This dual inhibition approach is different from some existing treatments that target only one part of the pathway, potentially offering a more comprehensive way to slow down or stop cancer progression. ^{1 3 4 11 12}

Research Team

Stephen Letrent, PharmD, PhD

Principal Investigator

TORL Biotherapeutics, LLC

Eligibility Criteria

This trial is for adults with advanced solid tumors, measurable disease, good performance status (able to carry out daily activities), and proper organ function. It's not for those who've had recent cancer treatments, have serious health issues or infections, a history of certain blood disorders or another cancer within the last 3 years (except some skin cancers and low-risk cases). Pregnant or breastfeeding women and individuals with significant heart disease or active brain metastases are also excluded.

Inclusion Criteria

My organs are working well.

Measurable disease, per RECIST v1.1

I am fully active or can carry out light work.

Exclusion Criteria

I do not have any serious, uncontrolled illnesses or infections.

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

I have not taken any cancer treatments recently before starting TORL-3-600.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive TORL-3-600 to evaluate safety, tolerability, pharmacokinetics, and antitumor activity

63 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 2 years

Treatment Details

Interventions

• TORL-3-600

Trial Overview The study tests TORL-3-600 in patients with advanced cancers to assess its safety, how well it's tolerated by the body, how the body processes it (pharmacokinetics), and its effectiveness against tumors. As this is a first-in-human study, participants will be among the first to receive this experimental treatment.

Participant Groups

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

TORL-3-600

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

TORL-3-600

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

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]

In elderly patients, using two low-dose mTOR inhibitors that specifically target TORC1 resulted in a reduction in infection rates, suggesting a potential benefit in enhancing immune function.

This approach highlights the therapeutic potential of mTOR inhibitors in improving health outcomes for older adults, particularly in reducing susceptibility to infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Harnessing TORC to boost the horsepower of aging immune systems. Clark, RA.[2019]

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]

PQR620, a new dual TORC1/2 inhibitor, demonstrated significant anti-tumor activity in 56 lymphoma cell lines, with a median IC50 value of 250 nM after 72 hours, indicating its potential effectiveness against lymphoma.

When combined with the BCL2 inhibitor venetoclax, PQR620 showed increased cytotoxicity, suggesting that this combination therapy could enhance treatment outcomes for lymphoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Novel TORC1/2 Kinase Inhibitor PQR620 Has Anti-Tumor Activity in Lymphomas as a Single Agent and in Combination with Venetoclax. Tarantelli, C., Gaudio, E., Hillmann, P., et al.[2023]

Active-site TOR inhibitors (asTORi) provide a more effective treatment option for leukemia, lymphoma, and myeloma by inhibiting both TORC1 and TORC2 complexes, unlike traditional rapamycin and its analogs that only partially inhibit TORC1.

Preclinical studies indicate that asTORi demonstrate greater efficacy and tolerability compared to rapalogs in specific types of blood cancers, suggesting they could be a promising avenue for further research in treating various hematologic malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Target of rapamycin signaling in leukemia and lymphoma. Vu, C., Fruman, DA.[2022]

A meta-analysis of 53 Phase II/III/IV trials involving nearly 20,000 patients revealed that molecular target anticancer drugs significantly increase the risk of serious adverse events (SAEs) by 57% and fatal adverse events (FAEs) by 51% compared to placebo.

The overall incidence rates for SAEs and FAEs were found to be 26.9% and 2.3%, respectively, highlighting the need for careful monitoring and preventive measures for patients receiving these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of serious adverse event and fatal adverse event with molecular target anticancer drugs in cancer patients: A meta-analysis. Wang, Z., Yang, X., Wang, J., et al.[2020]

Out of 236 Individual Case Safety Reports (ICSRs) analyzed, only 18 (7.6%) were classified as off-label cases, indicating a low incidence of off-label use of antineoplastic drugs in pediatric patients, primarily related to therapeutic indications.

Among the off-label cases, 29 adverse drug reactions (ADRs) were reported, with common reactions including diarrhea and neutropenia, suggesting that while off-label use is limited, it can still lead to significant safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Anticancer Agents Used in Children: A Focus on Their Off-Label Use Through Data From the Spontaneous Reporting System. Mascolo, A., Scavone, C., Bertini, M., et al.[2022]

A total of 409 adverse events (AEs) were reported in the FDA-FAERS database and 253 in the Eudra-Vigilance database, indicating that darolutamide is generally safe in real-life settings, with fatigue being the most common side effect.

In a registry study, serious AEs occurred in 24.8% of patients treated with darolutamide, highlighting the importance of monitoring for potential serious effects, although the overall safety profile remains encouraging for clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events related to darolutamide treatment: analysis of "real life" data from EudraVigilance and the Food and Drug Administration database entries. Tema, G., Lombardo, R., Cicione, A., et al.[2023]

A review of 81 clinical trials involving over 45,000 patients revealed that the reporting of adverse events (AEs) for targeted therapies and immunotherapies is often inadequate, particularly regarding recurrent/late toxicities and the duration of AEs.

The study highlights that more than 90% of trials failed to adequately report the timing and occurrence of all-grade AEs, indicating a need for improved transparency and detail in AE reporting in future oncology trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Review of adverse events reporting in clinical trials leading to approval of targeted therapy and immunotherapy. Bossi, P., Botta, L., Bironzo, P., et al.[2020]

The combination of sorafenib, gemcitabine, and capecitabine is tolerable for patients with advanced renal cell carcinoma, with a recommended phase II dose established to minimize side effects like hand-foot syndrome.

Out of 15 patients treated, 29% showed a partial response to the therapy, and the median progression-free survival was 7.5 months, indicating potential effectiveness of this treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of sorafenib plus gemcitabine and capecitabine for patients with advanced renal cell carcinoma: New York Cancer Consortium Trial NCI 6981. Tagawa, ST., Milowsky, MI., Jeske, S., et al.[2022]

In a phase II study involving 35 men with advanced castration-resistant prostate cancer (mCRPC), everolimus did not produce any significant prostate-specific antigen (PSA) responses, leading to the conclusion that it has no clinical utility as a single agent for this condition.

While everolimus showed predictable low-grade toxicities, such as mucositis and fatigue, it failed to demonstrate meaningful clinical benefits, as indicated by a median progression-free survival of only 3.6 months and an increase in tumor proliferation markers despite inhibition of downstream mTOR targets.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 clinical trial of TORC1 inhibition with everolimus in men with metastatic castration-resistant prostate cancer. George, DJ., Halabi, S., Healy, P., et al.[2021]

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]

References

1. 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]

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

Harnessing TORC to boost the horsepower of aging immune systems. [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. Switzerland pubmed.ncbi.nlm.nih.gov

The Novel TORC1/2 Kinase Inhibitor PQR620 Has Anti-Tumor Activity in Lymphomas as a Single Agent and in Combination with Venetoclax. [2023]

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

Target of rapamycin signaling in leukemia and lymphoma. [2022]

6. India pubmed.ncbi.nlm.nih.gov

Risk of serious adverse event and fatal adverse event with molecular target anticancer drugs in cancer patients: A meta-analysis. [2020]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Safety of Anticancer Agents Used in Children: A Focus on Their Off-Label Use Through Data From the Spontaneous Reporting System. [2022]

8. Italy pubmed.ncbi.nlm.nih.gov

Adverse events related to darolutamide treatment: analysis of "real life" data from EudraVigilance and the Food and Drug Administration database entries. [2023]

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

Systematic Review of adverse events reporting in clinical trials leading to approval of targeted therapy and immunotherapy. [2020]

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

A phase I trial of sorafenib plus gemcitabine and capecitabine for patients with advanced renal cell carcinoma: New York Cancer Consortium Trial NCI 6981. [2022]

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

Phase 2 clinical trial of TORC1 inhibition with everolimus in men with metastatic castration-resistant prostate cancer. [2021]

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

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