TORL-1-23 for Ovarian Cancer

Recruiting at 19 trial locations

Overseen By Ibrahim Qazi, PharmD

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: TORL Biotherapeutics, LLC

Must not be taking: CYP3A4 inducers, P-glycoprotein inhibitors

Disqualifiers: Brain metastases, Cardiac disease, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 24 months

230 Participants Needed

Trial Summary

What is the purpose of this trial?

A Phase 2 study to evaluate the safety and efficacy of TORL-1-23 in patients with advanced ovarian cancer.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are taking drugs that strongly affect certain liver enzymes (CYP3A4) or P-glycoprotein. It's best to discuss your current medications with the study team.

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

Research on similar drugs, like TAK228, shows that dual TORC1/2 inhibitors can help prevent the spread of ovarian cancer cells and improve outcomes when combined with standard chemotherapy. This suggests that TORL-1-23, if it works similarly, might also be effective in treating ovarian cancer. ^{1 2 3 4 5}

What safety data exists for the treatment TORL-1-23 (TAK228) in humans?

TAK228, also known as TORL-1-23, was evaluated in a phase I trial for safety in patients with advanced solid tumors, showing it was generally safe when combined with paclitaxel, with or without trastuzumab. ^{1 4 6 7 8}

How is the drug TORL-1-23 different from other ovarian cancer treatments?

TORL-1-23 is unique because it is a dual TORC1/2 inhibitor, which targets specific signaling pathways involved in cancer cell growth and survival. This approach is different from standard chemotherapy, as it aims to prevent peritoneal metastasis (spread of cancer within the abdominal cavity) by inhibiting these pathways, potentially offering a new option for patients with chemotherapy-resistant ovarian cancer. ^{1 2 3 9 10}

Eligibility Criteria

This trial is for women aged 18 or older with advanced ovarian, peritoneal, or fallopian tube cancer that's resistant to platinum-based therapy. They must have had a complete or partial response to initial treatment but showed progression within 3-6 months after the last dose if only one line of therapy was received. For multiple lines of therapy, progression should be within 6 months post-treatment.

Inclusion Criteria

Participants of childbearing potential must have a negative serum pregnancy test within 72 hours before starting study drug treatment

Participants must agree to use a highly effective birth control method from the time of the first study drug treatment through 7 months after the last study drug treatment, or be of nonchildbearing potential

Participants must agree not to donate eggs from the first study drug treatment through 7 months after the last study drug treatment

Exclusion Criteria

I have a history of serious heart problems.

I do not have any severe medical conditions that make me a high risk.

Any condition that interferes with ability to participate in the study, causes undue risk, or complicates the interpretation of safety data

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive TORL-1-23 on Day 1 and pegfilgrastim on Day 4 of each 21-day cycle

24 months

1 visit every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term follow-up

Participants are monitored for overall survival and progression-free survival

16 months

Treatment Details

Interventions

• TORL-1-23

Trial Overview The CATALINA-2 study tests TORL-1-23's safety and effectiveness in treating advanced ovarian cancer that hasn't responded well to platinum-based treatments. Pegfilgrastim is also used; it helps reduce infection risk by increasing white blood cells.

Participant Groups

Group I: Cohort 3 Experimental Treatment 2 Interventions

Participants will receive TORL-1-23 on Day 1 of each 21-day cycle. Additionally, pegfilgrastim will be administered on Day 4 of each 21-day cycle.

Group II: Cohort 2 Experimental Treatment 2 Interventions

Participants will receive TORL-1-23 on Day 1 of each 21-day cycle. Additionally, pegfilgrastim will be administered on Day 4 of each 21-day cycle.

Group III: Cohort 1 Experimental Treatment 2 Interventions

Participants will receive TORL-1-23 on Day 1 of each 21-day cycle. Additionally, pegfilgrastim will be administered on Day 4 of each 21-day cycle.

Who Is Running the Clinical Trial?

TORL Biotherapeutics, LLC

Lead Sponsor

Trials

6

Recruited

600+

European Network of Gynaecological Oncological Trial Groups (ENGOT)

Collaborator

Trials

41

Recruited

19,200+

Findings from Research

The DICE trial is investigating the effectiveness of TAK228, a dual TORC1/2 inhibitor, combined with weekly paclitaxel chemotherapy in 124 women with platinum-resistant ovarian cancer, aiming to improve progression-free survival (PFS) and overall survival (OS).

The trial will also assess safety and quality of life, ensuring that the addition of TAK228 does not lead to significantly worse adverse events compared to standard treatment, with recruitment ongoing since September 2018.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statistical analysis plan for the Dual mTorc Inhibition in advanCed/recurrent Epithelial ovarian, fallopian tube or primary peritoneal cancer (of clear cell, endometrioid and high-grade serous type, and carcinosarcoma) trial (DICE). de la Rosa, CN., Krell, J., Day, E., et al.[2023]

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]

In a phase I trial involving patients with advanced solid tumors, the combination of the dual m-TORC1/2 inhibitor vistusertib with weekly paclitaxel showed promising efficacy, particularly in high-grade serous ovarian cancer (HGSOC), with a response rate of 52% and a median progression-free survival of 5.8 months.

The treatment was generally well-tolerated, although dose-limiting toxicities such as fatigue and mucositis were observed, leading to adjustments in dosing schedules to improve tolerability, especially in squamous non-small-cell lung cancer (SqNSCLC) patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer. Basu, B., Krebs, MG., Sundar, R., et al.[2023]

In a study involving 58 transgenic mice with ovarian cancer, treatment with the mTOR inhibitor RAD001 (Everolimus) significantly delayed tumor development and reduced tumor burden by approximately 84%.

RAD001 treatment also decreased the formation of ascites and peritoneal dissemination, with only 21% of treated mice developing these conditions compared to 74% in the placebo group, suggesting its potential as a chemopreventive strategy for women at high risk of ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RAD001 (Everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer. Mabuchi, S., Altomare, DA., Connolly, DC., et al.[2021]

Optimal surgical debulking to achieve no residual disease (R0) significantly improves survival rates in patients with epithelial ovarian cancer, which is crucial given its high mortality rate.

The SOLO-1 trial demonstrated that olaparib, a maintenance therapy, significantly reduces the risk of disease progression by 70% in patients with advanced ovarian cancer who have BRCA mutations, highlighting its efficacy in targeted treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multimodal Treatment of Primary Advanced Ovarian Cancer. Friedrich, M., Friedrich, D., Kraft, C., et al.[2021]

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]

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]

In the phase III SOLO1 trial, maintenance treatment with olaparib significantly improved progression-free survival in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation, with 260 patients receiving olaparib compared to 131 on placebo.

The most common adverse events associated with olaparib, such as anemia and nausea, occurred early (within 3 months) but were manageable, with only a small number of patients needing to discontinue treatment, indicating a predictable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability of maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA mutation in the randomized phase III SOLO1 trial. Colombo, N., Moore, K., Scambia, G., et al.[2022]

A study involving whole-exome sequencing of 158 patients from 140 families with a history of ovarian cancer identified two new potential risk genes, ANKRD11 and POLE, which may contribute to moderate ovarian cancer risk.

In vitro experiments revealed that a mutation in the ANKRD11 gene significantly reduced protein expression, suggesting a mechanism by which it may act as a tumor suppressor, highlighting its potential role in understanding ovarian cancer etiology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Whole-exome sequencing of ovarian cancer families uncovers putative predisposition genes. Zhu, Q., Zhang, J., Chen, Y., et al.[2022]

The study established a transgenic mouse model that mimics ovarian carcinosarcoma, revealing that mutations in K-ras and deletion of p53 in ovarian surface epithelium lead to the development of high-grade, poorly differentiated tumors that are highly metastatic.

K-rasG12D mutation was shown to significantly enhance cell proliferation, migration, and invasion in ovarian cancer cell lines, suggesting its critical role in the progression of ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KRAS mutation coupled with p53 loss is sufficient to induce ovarian carcinosarcomas in mice. Tang, FH., Hsieh, TH., Hsu, CY., et al.[2022]

References

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

Statistical analysis plan for the Dual mTorc Inhibition in advanCed/recurrent Epithelial ovarian, fallopian tube or primary peritoneal cancer (of clear cell, endometrioid and high-grade serous type, and carcinosarcoma) trial (DICE). [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. England pubmed.ncbi.nlm.nih.gov

Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer. [2023]

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

RAD001 (Everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer. [2021]

5. Greece pubmed.ncbi.nlm.nih.gov

Multimodal Treatment of Primary Advanced Ovarian Cancer. [2021]

6. 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]

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

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

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

Tolerability of maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA mutation in the randomized phase III SOLO1 trial. [2022]

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

Whole-exome sequencing of ovarian cancer families uncovers putative predisposition genes. [2022]

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

KRAS mutation coupled with p53 loss is sufficient to induce ovarian carcinosarcomas in mice. [2022]