TTI-101 + Radiotherapy for Pancreatic Cancer

Overseen By Kayla Vondran

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

Trial Summary

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.

What data supports the idea that TTI-101 + Radiotherapy for Pancreatic Cancer is an effective treatment?

The available research does not provide specific data on the effectiveness of TTI-101 combined with radiotherapy for pancreatic cancer. Instead, it discusses other treatments and strategies, such as combining chemotherapy with radiotherapy or using targeted therapies with radiotherapy. These studies suggest that combining different treatments can improve outcomes for pancreatic cancer patients, but there is no direct evidence for TTI-101 in the provided information. ^{1 2 3 4 5}

What safety data is available for TTI-101 and radiotherapy in pancreatic cancer treatment?

The provided research abstracts do not directly mention TTI-101, C-188-9, or any of its variants in combination with radiotherapy for pancreatic cancer. The studies focus on radiotherapy techniques and their associated toxicities, such as gastrointestinal toxicity, in pancreatic cancer treatment. However, they do not provide specific safety data for TTI-101 or its combinations. Further research specifically involving TTI-101 would be needed to determine its safety profile in this context. ^{6 7 8 9 10}

Is the drug TTI-101 a promising treatment for pancreatic cancer?

TTI-101, when combined with radiotherapy, could be promising for treating pancreatic cancer because radiotherapy has shown benefits in managing the disease, especially when surgery isn't an option. Combining it with a new drug like TTI-101 might improve outcomes. ^{8 10 11 12 13}

What is the purpose of this trial?

To evaluate the safety and tolerability of TTI-101 given in combination with Stereotactic Body Radiation Therapy (SBRT) in borderline resectable and locally advanced pancreatic ductal adenocarcinoma.

Research Team

David Binder, MD, PhD

Principal Investigator

University of Colorado, Denver

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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 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 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 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 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 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 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]

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 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]

References

1. England 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). [2023]

2. Australia pubmed.ncbi.nlm.nih.gov

Chemoradiotherapy versus chemotherapy for locally advanced unresectable pancreatic cancer: A systematic review and meta-analysis. [2019]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Targeting DNA repair in combination with radiotherapy in pancreatic cancer: A systematic review of preclinical studies. [2020]

4. France pubmed.ncbi.nlm.nih.gov

Clinical assessment of palliative radiotherapy for pancreatic cancer. [2022]

5. United States 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. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Predictive dosimetric parameters for gastrointestinal toxicity with hypofractioned radiotherapy in pancreatic adenocarcinoma. [2020]

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

Outcomes of Proton Beam Therapy Compared With Intensity-Modulated Radiation Therapy for Uterine Cancer. [2023]

8. Ireland pubmed.ncbi.nlm.nih.gov

Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. [2022]

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

Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer. [2022]

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

Accelerated radiochemotherapy in pancreatic cancer is not necessarily related to a pathologic pancreatic function decline in the early period. [2019]

11. Pakistan pubmed.ncbi.nlm.nih.gov

Computed Tomography-guided 125I Radioactive Seed Implantation Therapy for Pancreatic Cancer Pain. [2021]

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

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

13. United States 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. [2019]