TTI-101 + Radiotherapy for Pancreatic Cancer

Overseen By Alex Fonder

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Colorado, Denver

Must not be taking: Herbal medications

Disqualifiers: Pregnancy, Cardiac issues, CNS metastases, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for certain types of pancreatic cancer. Researchers aim to determine if TTI-101, an experimental drug, is safe and well-tolerated when combined with focused radiation therapy. It targets individuals with a specific type of pancreatic cancer that is difficult to remove surgically or is locally advanced. Those who have recently completed a round of chemotherapy and have pancreatic adenocarcinoma without requiring artery reconstruction might be suitable candidates. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Do I need to stop taking my current medications for this trial?

The trial does not specify if you need to stop taking your current medications, but you must stop using herbal medications 7 days before the first dose. Senna and flaxseed are allowed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that TTI-101, a new treatment being tested, is generally safe for people. Studies have found that most patients tolerate this drug well, with few experiencing serious side effects. An independent safety board reviewed the data and found no major safety issues with TTI-101. This is encouraging for those considering joining a trial with this treatment.

In these trials, TTI-101 is used with Stereotactic Body Radiation Therapy (SBRT), a precise type of radiation therapy. The goal of this combination is to effectively treat pancreatic cancer. Although the trials are still in the early stages, the safety results so far are promising for potential participants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for pancreatic cancer?

Unlike the standard treatments for pancreatic cancer, which often include chemotherapy and radiation, TTI-101 offers a novel approach by specifically targeting and inhibiting a protein known as STAT3. This protein plays a critical role in cancer cell survival and proliferation, making its inhibition a promising strategy for tackling tumor growth. Researchers are excited about TTI-101 because it not only directly targets cancer cells but also works in combination with stereotactic body radiotherapy (SBRT) to potentially enhance the overall treatment effectiveness, potentially leading to better outcomes for patients.

What evidence suggests that TTI-101 combined with radiotherapy could be effective for pancreatic cancer?

Research has shown that TTI-101, a new treatment under study in this trial, has yielded promising results in early studies. In patients with advanced cancers, including pancreatic cancer models, TTI-101 helped shrink tumors and was well-tolerated. One study found that 54% of patients with various solid tumors experienced significant benefits. TTI-101 targets a protein called STAT3, which plays a crucial role in cancer cell growth. This trial will evaluate TTI-101 in combination with radiotherapy for pancreatic cancer. Although specific results for its use with radiotherapy in pancreatic cancer aren't available yet, these initial findings are encouraging. ^{1 2 4 6 7}

Who Is on the Research Team?

David Binder, MD, PhD

Principal Investigator

University of Colorado, Denver

Are You a Good Fit for This Trial?

This trial is for adults with borderline resectable pancreatic cancer who've had chemotherapy. They must be able to swallow pills, have certain blood cell counts and organ function levels, not be pregnant or breastfeeding, agree to use contraception, and can't have other serious health issues or recent major surgery.

Inclusion Criteria

Stated willingness to comply with all study procedures and be available for the duration of the study.

My blood clotting time is normal or managed with medication.

I have a specific type of pancreatic cancer that is almost operable.

Exclusion Criteria

I have been symptom-free from COVID-19 for at least 2 weeks.

I have serious heart problems, including recent heart attack or severe heart failure.

I have had episodes of brain confusion due to liver problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Participants receive TTI-101 in combination with Stereotactic Body Radiation Therapy (SBRT) to determine the recommended phase 2 dose (RP2D) using a 3 + 3 dose-escalation design.

6 months

Phase 2 Treatment

An additional 12 patients are treated at RP2D in combination with SBRT to evaluate safety, tolerability, and efficacy.

2 years

Follow-up

Participants are monitored for progression-free survival and objective response rate.

2 years

What Are the Treatments Tested in This Trial?

Interventions

• TTI-101

Trial Overview The trial tests TTI-101 combined with Stereotactic Body Radiation Therapy (SBRT) in treating pancreatic ductal adenocarcinoma. It aims to assess the safety and effectiveness of this combination therapy in patients whose condition allows for potential surgical removal of the tumor.

How Is the Trial Designed?

Group I: Phase II Experimental Treatment 1 Intervention

An additional 12 patients will be enrolled in phase 2 so that total of 18 patients are treated at RP2D in phase 2 (the 6 patients treated at RP2D in phase 1 will be rolled over to phase 2) of TTI-101 in combination with SBRT.

Group II: Phase I Experimental Treatment 1 Intervention

During Phase 1, up to 2 dose levels of TTI-101 with SBRT will be tested using a 3 + 3 dose-escalation design to determine the RP2D. Up to 3 participants may be enrolled with either 0/3 or 1/3 DLT in order to more fully evaluate the safety and tolerability at a given dose level. Therefore, a minimum of 9 patients (3 at dose 0, and 6 at dose 1) and maximum 18 (6 patients at each dose level) will be enrolled in the phase 1.

TTI-101 is already approved in United States for the following indications:

Approved in United States as TTI-101 for:

• Orphan Drug designation for Idiopathic Pulmonary Fibrosis and Hepatocellular Carcinoma

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Tvardi Therapeutics, Incorporated

Industry Sponsor

Trials

5

Recruited

360+

Published Research Related to This Trial

In a review of fourteen studies on DNA repair inhibitors combined with radiotherapy for pancreatic ductal adenocarcinoma (PDAC), in vitro experiments showed a significant increase in cell killing by a factor of 1.35, indicating strong potential for radiosensitization.

While 86% of in vitro studies demonstrated effective radiosensitization, only 60% of in vivo studies showed similar effects, suggesting that while the approach is promising, further research is needed to confirm efficacy in living organisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting DNA repair in combination with radiotherapy in pancreatic cancer: A systematic review of preclinical studies. Waissi, W., Paix, A., Nicol, A., et al.[2020]

In a study of 497 patients with locally advanced pancreatic cancer, those receiving a higher radiotherapy dose (≥61Gy) experienced significantly improved overall survival (OS), progression-free survival (PFS), and local failure-free rate (LFFR) compared to those receiving lower doses (<61Gy).

Importantly, the increased dose did not lead to higher rates of severe toxicity, suggesting that dose-escalated chemoradiotherapy can be a safe and effective treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Chung, SY., Chang, JS., Lee, BM., et al.[2022]

In a review of clinical data from 20 institutions, increasing the radiation dose for treating unresectable pancreatic cancer did not show a clear improvement in overall survival, but it did enhance tumor response, which is important for patient quality of life.

The study proposes a new dose escalation trial using a fractionation scheme of 2.25 Gy per fraction up to a total of 69.75 Gy, aiming to improve treatment outcomes for patients with advanced pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SU-E-T-256: Radiation Dose Responses for Chemoradiation Therapy of Pancreatic Cancer: An Analysis of Compiled Clinical Data Using Biophysical Models. Moraru, I., Tai, A., Erickson, B., et al.[2019]

The TT-LAP trial is investigating a novel triple-modal treatment combining proton beam therapy, hyperthermia, and chemotherapy (gemcitabine plus nab-paclitaxel) for patients with locally advanced pancreatic cancer, aiming to improve safety and efficacy compared to traditional treatments.

This phase I/II clinical trial will assess the 2-year survival rate and other outcomes in 30 patients, marking the first evaluation of this combined approach for this challenging cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triple modal treatment comprising with proton beam radiation, hyperthermia, and gemcitabine/nab-paclitaxel for locally advanced pancreatic cancer: a phase I/II study protocol (TT-LAP trial). Shimomura, O., Endo, M., Makishima, H., et al.[2023]

Computed tomography (CT) guided radioactive 125I seed implantation (CTRISI) significantly reduced pain levels in 37 patients with advanced pancreatic cancer, as measured by the Numerical Rating Scale (NRS), with improvements noted at 1 week, 1 month, and 2 months post-implantation.

Patients also experienced a significant decrease in their daily hydroxycodone dosage after 1 week and 1 month following the procedure, indicating effective pain management without serious complications, although the reduction in pain relief was not sustained at the 2-month mark.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Computed Tomography-guided 125I Radioactive Seed Implantation Therapy for Pancreatic Cancer Pain. Fan, T., Zhou, JY.[2021]

Patients with pancreatic cancer often have advanced disease that cannot be surgically removed, leading to high local recurrence rates and low long-term survival when treated with surgery alone.

Adjuvant chemoradiation is supported for patients with resected pancreatic cancer, while radiation combined with chemotherapy offers modest benefits for those with locally unresectable disease, highlighting the need for improved treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of radiation therapy in the management of the patient with pancreatic cancer. Abrams, RA.[2005]

In a study of 68 pancreatic cancer patients undergoing hypofractionated radiotherapy, dosimetric parameters, particularly the absolute volume of the duodenum receiving radiation (aV45), were identified as significant predictors of gastrointestinal (GI) toxicity, with 18 patients experiencing grade II and 2 patients grade III toxicity.

To minimize the risk of GI toxicity during treatment, it is crucial to reduce the irradiated volume of the duodenum, as an aV45 of 0.5 cm³ was found to be the optimal threshold for predicting higher grades of toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictive dosimetric parameters for gastrointestinal toxicity with hypofractioned radiotherapy in pancreatic adenocarcinoma. Liu, X., Ren, G., Li, L., et al.[2020]

In a phase I trial involving 37 patients with advanced pancreatic cancer, the maximum-tolerated radiation dose concurrent with full-dose gemcitabine was determined to be 36 Gy, as higher doses (42 Gy) resulted in significant acute and late gastrointestinal toxicities.

The study suggests that while the highest radiation dose tested was not safe, the lower dose of 36 Gy is recommended for further investigation in a phase II trial due to better tolerance and promising survival data.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer. McGinn, CJ., Zalupski, MM., Shureiqi, I., et al.[2022]

In a meta-analysis of 830 patients with locally advanced unresectable pancreatic cancer, adding radiotherapy to chemotherapy did not improve overall survival or progression-free survival in randomized controlled trials, and it was associated with increased severe gastrointestinal adverse events.

Observational studies suggested a potential benefit of radiotherapy on survival outcomes, but these results may be influenced by differences in patient characteristics, highlighting the need for further research to identify which patients might truly benefit from radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemoradiotherapy versus chemotherapy for locally advanced unresectable pancreatic cancer: A systematic review and meta-analysis. Ng, IW., Soon, YY., Chen, D., et al.[2019]

In a study of 31 patients with pancreatic cancer receiving palliative radiotherapy, 57% reported less pain and improved symptoms after one month, indicating the treatment's effectiveness in symptom management.

Overall, 89% of patients showed improvement in general symptoms according to the FACT-General scale, demonstrating that radiotherapy can significantly enhance the quality of life for those suffering from pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical assessment of palliative radiotherapy for pancreatic cancer. Tian, Q., Zhang, F., Wang, Y.[2022]

In the RTOG trial 9704, patients with pancreatic cancer who had a CA 19-9 serum level of ≥90 U/mL experienced significantly worse overall survival, with a median survival of only 10 months compared to 21 months for those with levels <90 U/mL.

Patients with pancreatic head tumors treated with gemcitabine and a CA 19-9 level <90 U/mL showed improved survival outcomes, with a median survival of 24 months and a 5-year survival rate of 34%, which is better than the results from the CONKO-001 trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five year results of US intergroup/RTOG 9704 with postoperative CA 19-9 ≤90 U/mL and comparison to the CONKO-001 trial. Berger, AC., Winter, K., Hoffman, JP., et al.[2022]

In a study of 67 patients with endometrial cancer, those receiving proton beam therapy (PT) reported significantly less diarrhea during and after treatment compared to those receiving intensity-modulated radiation therapy (IMRT), suggesting PT may be a safer option for gastrointestinal side effects.

Patients treated with IMRT experienced higher rates of grade 3+ gastrointestinal toxicity, including loss of bowel control, indicating that PT could potentially lead to better patient-reported outcomes in terms of gastrointestinal health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Proton Beam Therapy Compared With Intensity-Modulated Radiation Therapy for Uterine Cancer. Anderson, JD., Voss, MM., Laughlin, BS., et al.[2023]

In a study of 13 patients with unresectable pancreatic cancer, accelerated radiochemotherapy (ART) led to a nominal reduction in exocrine function, but not all patients experienced pathological changes, indicating that ART may not significantly impair pancreatic function in the early period after treatment.

Despite some patients showing reduced exocrine function, there was no significant change in endocrine function or the development of diabetes, suggesting that pancreatic enzyme preparations could help maintain nutritional status during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accelerated radiochemotherapy in pancreatic cancer is not necessarily related to a pathologic pancreatic function decline in the early period. Horst, E., Seidel, M., Micke, O., et al.[2019]

Citations

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Novel STAT3 Inhibitor TT1-101 Is Safe and Shows ... TTI-101 showed clinically meaningful antitumor activity in advanced metastatic HCC and other solid tumors, with a clinical benefit rate of 54%.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06141031

Study Details | NCT06141031 | Phase I/IB Trial of ... Phase 1: Determine the safety of delivering Stereotactic Body Radiation Therapy in combination with TTI-101 in borderline resectable pancreatic cancer by ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11911802/

Phase I Trial of TTI-101, a First-in-Class Oral Inhibitor of ... All eight patients demonstrated a decrease in the H-score at the follow-up biopsy (approximately 6 weeks after initiating treatment), with a median decrease of ...

4. nature.com nature.com/articles/s41388-020-01626-z

Targeting STAT3 by a small molecule suppresses ... In animal models of pancreatic cancer, N4 was well tolerated, suppressed tumor growth and metastasis, and significantly prolonged survival of ...

5. withpower.com withpower.com/trial/tti-101-radiotherapy-for-pancreatic-cancer-3da66

TTI-101 + Radiotherapy for Pancreatic Cancer The available research does not provide specific data on the effectiveness of TTI-101 combined with radiotherapy for pancreatic cancer. Instead, it ...

6. medchemexpress.com medchemexpress.com/C188-9.html?srsltid=AfmBOoq2dEb1Ojqbrj6PuQ7N_izxSYuE1-DAFcY9vporUCwNpSvtnc_b

C188-9 (TTI-101) | STAT3 Inhibitor Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system, leading to preservation of muscle mass in cancer cachexia.

7. researchgate.net researchgate.net/publication/378132721_Discovery_of_the_Highly_Selective_and_Potent_STAT3_Inhibitor_for_Pancreatic_Cancer_Treatment

(PDF) Discovery of the Highly Selective and Potent STAT3 ... Discovery of the Highly Selective and Potent STAT3 Inhibitor for Pancreatic Cancer Treatment. February 2024; ACS Central Science 10(3). DOI:10.1021/acscentsci.