CTO1681 for Preventing Side Effects in Cancer Therapy

Recruiting at 6 trial locations

Overseen By Heather Nottingham, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: CytoAgents, Inc.

Must not be taking: Anticoagulants, Antiplatelets

Disqualifiers: Arrhythmia, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: 1

Duration: 2 weeks

54 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an interventional study to evaluate the use of CTO1681 in preventing or reducing CAR T-cell-induced toxicities like cytokine release syndrome (CRS). This study will enroll adult patients with DLBCL who are scheduled to receive CD19-directed CAR T-cell therapy. The first phase of the study will be open label with dose escalation. Participants will start taking CTO1681 just prior to receiving their CAR T-cell therapy and continue to take the study drug three times daily for a total of 15 days.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot be on ongoing therapeutic doses of anticoagulant therapy, antiplatelet, or fibrinolytic agents, except for low molecular weight heparin prophylaxis.

What evidence supports the effectiveness of the drug CTO1681 in preventing side effects in cancer therapy?

Research shows that similar treatments, like TRAIL/Apo2L combined with certain chemotherapy drugs, can selectively target and kill cancer cells without harming normal cells. This suggests that CTO1681, if it works similarly, might help reduce side effects by sparing healthy cells during cancer treatment. ^{1 2 3 4 5}

Is CTO1681 safe for humans?

There is no specific safety data available for CTO1681, GP1681, or similar treatments in the provided research articles. ^{6 7 8 9 10}

How does the drug in CTO1681 differ from other cancer treatments?

The drug in CTO1681 is unique because it targets inhibitor of apoptosis proteins (IAPs), which helps promote cancer cell death, unlike traditional treatments that may not specifically target these proteins. ^{11 12 13 14 15}

Research Team

Arthur Bertolino, MD, PhD, MBA

Principal Investigator

CytoAgents, Inc.

Eligibility Criteria

Adults with DLBCL who are set to receive CD19-directed CAR T-cell therapy and meet specific health criteria, such as adequate organ function and blood counts. They must not have certain heart conditions or uncontrolled bleeding disorders, be on high-dose anticoagulants, or have had recent chemotherapy.

Inclusion Criteria

My DLBCL has returned or didn't respond after my first treatment.

I meet all requirements for CAR T-cell therapy as per my hospital's rules.

I am scheduled for a specific CAR T-cell therapy for my lymphoma without taking steroids to prevent side effects.

Exclusion Criteria

I haven't had chemotherapy in the last 14 days.

I don't have major issues with absorbing food or swallowing that medication can't fix.

Grade 2 or greater electrolyte imbalance, per CTCAE v5.0: Potassium < 3.0 or > 5.5 mmol/L, Sodium < 130 or > 150 mmol/L, Calcium < 8.0 or > 11.5 mg/dL, Magnesium < 0.5 or > 1.23 mmol/L, Clinically significant ECG abnormality at Screening or Baseline (Day -1), including but not limited to, a confirmed QTcF value > 470 msec, History of clinically significant arrhythmia and/or requiring anticoagulation/antiplatelet treatment at therapeutic dose, Any clinically significant (ie, active) cardiovascular disease, including cerebral vascular accident/stroke (< 6 months before enrollment), myocardial infarction (< 6 months before enrollment) or unstable angina, and congestive heart failure ≥ New York Heart Association Classification Class III, Uncontrolled thromboembolic events or recent severe hemorrhage within the last 6 months, Known history of any bleeding disorder, Requirement for ongoing therapeutic doses of anticoagulant therapy, antiplatelet or fibrinolytic agents (low molecular weight heparin prophylaxis is allowed), Baseline systolic blood pressure <100 mmHg, History of autoimmune disease/ graft versus host disease requiring immunosuppressive therapy within the last 2 years. However, physiologic steroids (prednisone equivalent) may be given at a dose of 5 mg or less, Patients who, in the opinion of the Investigator, would be unlikely to comply with study procedures or are otherwise unsuitable for enrollment

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive CTO1681 three times daily for 15 days, starting just prior to CAR T-cell therapy

2 weeks

Multiple visits for blood samples and medical evaluations

Safety Monitoring

Participants are monitored for safety and efficacy for 43 days post-treatment

6 weeks

Regular visits for safety assessments

Follow-up

Participants are monitored for safety and tumor response for up to 6 months

6 months

Periodic visits for follow-up assessments

Treatment Details

Interventions

• CTO1681

Trial Overview CTO1681 is being tested in three different doses to see if it can prevent or lessen the severity of cytokine release syndrome (CRS) caused by CAR T-cell therapy in patients with DLBCL. The trial starts with an open-label phase where everyone gets the drug before their cell therapy.

Participant Groups

Group I: CTO1681 90 μg Total Daily Dose Experimental Treatment 1 Intervention

Participants receive 30 μg CTO1681 orally 3 times daily (total daily dose of 90 μg) for 15 days.

Group II: CTO1681 60 μg Total Daily Dose Experimental Treatment 1 Intervention

Participants receive 20 μg CTO1681 orally 3 times daily (total daily dose of 60 μg) for 15 days.

Group III: CTO1681 30 μg Total Daily Dose Experimental Treatment 1 Intervention

Participants receive 10 μg CTO1681 orally 3 times daily (total daily dose of 30 μg) for 15 days.

Who Is Running the Clinical Trial?

CytoAgents, Inc.

Lead Sponsor

Trials

1

Recruited

50+

TFS HealthScience

Collaborator

Trials

1

Recruited

50+

Findings from Research

The combination of etoposide (VP16) and TRAIL/Apo2L selectively induces apoptosis in tumor cells, such as osteosarcoma (OS) cells, without affecting normal cells, suggesting a promising strategy for targeted cancer therapy.

Other chemotherapeutic agents like ActD, DOX, and CDDP sensitize both tumor and normal cells to TRAIL/Apo2L-induced apoptosis, indicating that not all combinations maintain the desired selectivity for tumor cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective and nonselective toxicity of TRAIL/Apo2L combined with chemotherapy in human bone tumour cells vs. normal human cells. Van Valen, F., Fulda, S., Schäfer, KL., et al.[2016]

The maximum-tolerated dose (MTD) of Topotecan when combined with full-dose thoracic radiotherapy is determined to be 0.4 mg/m² per day, based on observed dose-limiting toxicities such as severe diarrhea and hematological issues.

In a study involving 24 patients with advanced thoracic malignancies, the treatment resulted in nine partial responses and significant local tumor responses, suggesting that Topotecan may enhance the effectiveness of radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of Topotecan, as a radiosensitizer, for thoracic malignancies. Forouzannia, A., Schiller, J., Berlin, J., et al.[2019]

HGS-ETR1 is a fully human antibody that specifically targets the TRAIL-R1 receptor, effectively inducing apoptosis in various tumor cells by activating both extrinsic and intrinsic apoptotic pathways.

In preclinical studies, HGS-ETR1 not only reduced tumor growth in xenograft models but also enhanced the effectiveness of standard chemotherapy agents, suggesting it could be a powerful addition to cancer treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. Pukac, L., Kanakaraj, P., Humphreys, R., et al.[2022]

The combination of ionizing radiation (IR) and the microtubule-stabilizing compound patupilone shows a promising anti-cancer effect, particularly in patupilone-sensitive non-small cell lung cancer cells, as demonstrated in tumor xenografts derived from A549 cells.

In contrast, the treatment was less effective in patupilone-resistant A549.EpoB40 cells, highlighting that the efficacy of this combined therapy is significantly influenced by the tumor microenvironment and the genetic characteristics of the cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of the microenvironment for radiosensitization by patupilone. Bley, CR., Jochum, W., Orlowski, K., et al.[2012]

Apo-2 ligand (Apo-2L)/TRAIL effectively induces apoptosis in human prostate cancer cells, particularly in PC-3 cells, through a mechanism involving caspase activation and cytochrome c release.

Treatment with paclitaxel enhances the effectiveness of Apo-2L/TRAIL by increasing the levels of death receptors DR4 and DR5, leading to significantly greater apoptosis in prostate cancer cells compared to Apo-2L/TRAIL alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pretreatment with paclitaxel enhances apo-2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of prostate cancer cells by inducing death receptors 4 and 5 protein levels. Nimmanapalli, R., Perkins, CL., Orlando, M., et al.[2015]

Ipilimumab, an anti-CTLA-4 antibody, has been shown to improve survival in patients with unresectable or metastatic melanoma, with a standard dosing of 3 mg/kg every 3 weeks for a total of 4 doses.

While ipilimumab can cause immune-related adverse events in 15% of patients, most are mild and manageable; however, high-grade events can be serious and require careful monitoring and treatment with corticosteroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab for advanced melanoma: a pharmacologic perspective. Trinh, VA., Hagen, B.[2021]

In a study of 502 patients undergoing cytotoxic chemotherapy for solid tumors, 62% experienced significant toxicities (grade 2-4), with 34% suffering from hematological issues and 20% developing infections requiring antibiotics.

Key risk factors for these toxicities included performance status ≥1, breast cancer diagnosis, low albumin levels, lymphopenia, and reduced kidney function, highlighting the need for routine monitoring of these parameters to manage and mitigate chemotherapy-related adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of current practice: management of chemotherapy-related toxicities. Lheureux, S., Clarisse, B., Launay-Vacher, V., et al.[2011]

A meta-analysis of 21 studies involving 11,144 patients revealed that anti-CTLA4 therapy significantly increases the risk of various immune-related adverse events, such as diarrhea and colitis, with a relative risk of 2.43 to 11.39 for different conditions.

In contrast, while anti-PD1 therapy also raises the risk of pruritus (itching) with a relative risk of 4.01, it does not appear to increase the risk of other immune-related adverse events, highlighting the distinct safety profiles of these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-Analysis of the Risk of Immune-Related Adverse Events With Anticytotoxic T-Lymphocyte-Associated Antigen 4 and Antiprogrammed Death 1 Therapies. Komaki, Y., Komaki, F., Yamada, A., et al.[2022]

In a study of 120 non-small-cell lung cancer patients undergoing chemotherapy, 80% experienced severe adverse drug reactions (ADRs), with 22.3% developing potentially life-threatening complications, leading to significant hospital stays and healthcare costs.

The average cost for managing toxicity per chemotherapy line was €3,366, with first-line treatments being more expensive than second-line, particularly due to ICU care associated with severe infections, highlighting the need for strategies to reduce these complications and their economic impact.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The impact of chemotherapy-induced side effects on medical care usage and cost in German hospital care--an observational analysis on non-small-cell lung cancer patients. Ihbe-Heffinger, A., Paessens, B., Berger, K., et al.[2022]

Modern multimodal tumor therapies, which include radiotherapy, chemotherapy, immunotherapy, and targeted therapies, can lead to significant acute and long-lasting side effects that negatively impact patients' quality of life and survival.

The paper highlights the need for better characterization of side effects from newly approved therapies and provides recommendations for monitoring and managing these effects in specific patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Onco-Cardiology: Consensus Paper of the German Cardiac Society, the German Society for Pediatric Cardiology and Congenital Heart Defects and the German Society for Hematology and Medical Oncology. Rassaf, T., Totzeck, M., Backs, J., et al.[2021]

LCL161, an experimental drug that targets inhibitor of apoptosis proteins to promote cancer cell death, was well tolerated at doses up to 1,800 mg in a study involving 53 patients with advanced solid tumors.

The study found that while no patients had an objective response, LCL161 showed significant pharmacodynamic activity by degrading IAP1 protein and increasing cytokine levels, suggesting it has potential for further investigation despite the absence of direct tumor responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I dose-escalation study of LCL161, an oral inhibitor of apoptosis proteins inhibitor, in patients with advanced solid tumors. Infante, JR., Dees, EC., Olszanski, AJ., et al.[2021]

DEBIO1143, an antagonist of inhibitor apoptosis proteins, was well tolerated in a first-in-man study with 31 patients, showing no maximum tolerated dose (MTD) up to 900 mg and only one dose-limiting toxicity reported at 180 mg.

The drug demonstrated pharmacodynamic effects, such as increased plasma CCL2 and decreased cIAP-1 levels, at doses greater than 80 mg, but only 17% of patients achieved stable disease, suggesting it may be more effective as an adjunct treatment rather than a standalone therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study. Hurwitz, HI., Smith, DC., Pitot, HC., et al.[2021]

The prodrug EB1627, developed from the anticancer compound CHS828, showed improved solubility and pharmacokinetic properties, allowing for intravenous administration.

In animal models, EB1627 demonstrated strong inhibitory effects on cancer growth, both on its own and when combined with the chemotherapy drug etoposide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EB1627: a soluble prodrug of the potent anticancer cyanoguanidine CHS828. Binderup, E., Björkling, F., Hjarnaa, PV., et al.[2022]

Folate-decorated nanostructured lipid carriers (FA-ETP-NLCs) effectively targeted and delivered the anticancer drug etoposide (ETP) to tumor cells that overexpress folate receptors, demonstrating a particle size of approximately 120.86 nm.

In vitro and in vivo studies showed that FA-ETP-NLCs significantly inhibited the growth of cancer cell lines and exhibited superior antitumor activity compared to other formulations, suggesting they could enhance the therapeutic efficacy of ETP while potentially reducing its toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted delivery of etoposide to cancer cells by folate-modified nanostructured lipid drug delivery system. Zhang, S., Lu, C., Zhang, X., et al.[2018]

Etoposide (ETO) induces apoptosis in HT58 human lymphoma cells within just 4 hours, indicating a rapid response to this treatment.

The study found that apoptosis is primarily regulated by phosphorylation and proteolysis involving cysteine proteases, while factors like p53 overexpression and poly(ADP-ribose) polymerase inhibition do not significantly influence the apoptotic process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of apoptosis signaling in etoposide-treated lymphoma cells. Sebestyén, A., Mihalik, R., Peták, I., et al.[2013]

References

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

Selective and nonselective toxicity of TRAIL/Apo2L combined with chemotherapy in human bone tumour cells vs. normal human cells. [2016]

2. Ireland pubmed.ncbi.nlm.nih.gov

A phase I study of Topotecan, as a radiosensitizer, for thoracic malignancies. [2019]

3. England pubmed.ncbi.nlm.nih.gov

HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. [2022]

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

Role of the microenvironment for radiosensitization by patupilone. [2012]

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

Pretreatment with paclitaxel enhances apo-2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of prostate cancer cells by inducing death receptors 4 and 5 protein levels. [2015]

6. England pubmed.ncbi.nlm.nih.gov

Ipilimumab for advanced melanoma: a pharmacologic perspective. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Evaluation of current practice: management of chemotherapy-related toxicities. [2011]

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

Meta-Analysis of the Risk of Immune-Related Adverse Events With Anticytotoxic T-Lymphocyte-Associated Antigen 4 and Antiprogrammed Death 1 Therapies. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

The impact of chemotherapy-induced side effects on medical care usage and cost in German hospital care--an observational analysis on non-small-cell lung cancer patients. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

Onco-Cardiology: Consensus Paper of the German Cardiac Society, the German Society for Pediatric Cardiology and Congenital Heart Defects and the German Society for Hematology and Medical Oncology. [2021]

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

Phase I dose-escalation study of LCL161, an oral inhibitor of apoptosis proteins inhibitor, in patients with advanced solid tumors. [2021]

12. Germany pubmed.ncbi.nlm.nih.gov

Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study. [2021]

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

EB1627: a soluble prodrug of the potent anticancer cyanoguanidine CHS828. [2022]

14. England pubmed.ncbi.nlm.nih.gov

Targeted delivery of etoposide to cancer cells by folate-modified nanostructured lipid drug delivery system. [2018]

15. Greece pubmed.ncbi.nlm.nih.gov

Modulation of apoptosis signaling in etoposide-treated lymphoma cells. [2013]