Phase I/IB Trial of Radiotherapy in Combination With TTI-101 in Borderline Resectable and Locally Advanced Pancreatic Ductal Adenocarcinoma

NCT ID: NCT06141031

Last Updated: 2025-07-08

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-01-16
• Study Completion Date: 2028-09-30

Brief Summary

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.

Conditions

Pancreatic Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Phase I

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.

Group Type: EXPERIMENTAL

TTI-101

Intervention Type: DRUG

TTI-101 is an orally bioavailable, small-molecule inhibitor of Signal Transducer and Activator of Transcription 3 (STAT3), a transcription factor whose upregulation and activation governs many hallmarks of cancer, inflammation, and fibrosis.

Phase II

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 Type: EXPERIMENTAL

TTI-101

Intervention Type: DRUG

TTI-101 is an orally bioavailable, small-molecule inhibitor of Signal Transducer and Activator of Transcription 3 (STAT3), a transcription factor whose upregulation and activation governs many hallmarks of cancer, inflammation, and fibrosis.

Interventions

TTI-101

TTI-101 is an orally bioavailable, small-molecule inhibitor of Signal Transducer and Activator of Transcription 3 (STAT3), a transcription factor whose upregulation and activation governs many hallmarks of cancer, inflammation, and fibrosis.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Patients must have pathologically confirmed pancreatic adenocarcinoma with borderline resectable or locally advanced PDAC as defined by NCCN guidelines, with no expected arterial resection-reconstruction.

2. Borderline resectable patients only: Completion of inducation chemotherpy within 1-3 weeks of study treatment start. Patients that exceed this window should complete an additional cycle of induction chemotherapy prior to initiation of study treatment, per provider discretion.

3. Age ≥ 18 years at time of study entry.

4. Provision to sign and date the consent form.

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

6. Ability to swallow tablets by mouth.

7. ECOG performance status ≤2 or KPS ≥60%

8. Absolute neutrophil count ≥ 1,000/mcL

9. Platelets ≥ 70,000/mcL

10. Hemoglobin ≥ 9 g/dL, patients may be transfused to meet this criterion

11. Serum albumin ≥ 2.8 g/dL

12. Total Bilirubin ≤ 2mg/dL

13. AST(SGOT)/ALT(SGPT)/ALP ≤ 3 x institutional upper limit of normal (IULN)

14. Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL >40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:

Males:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) / 72 x serum creatinine (mg/dL)

Females:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 / 72 x serum creatinine (mg/dL)

15. INR ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or PTT is within therapeutic range of intended use of anticoagulants

16. aPTT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or PTT is within therapeutic range of intended use of anticoagulants

17. Sexually active women of childbearing potential (defined in section 7.1) and men must agree to use at least 1 highly effective method of contraception (defined in section 7.1) from screening and for at least 30 days after administration of the last dose of the study treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.

Exclusion Criteria

1. Pregnant or breastfeeding. Patients must have a negative serum or urine pregnancy test within 5 days of study treatment.

2. Previous treatment of the current malignancy with a STAT inhibitor.

3. Herbal preparations are not allowed throughout the study. These herbal medications include but are not limited to St. John's wort, kava, ephedra (Ma Huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Participants should stop using herbal medications 7 days prior to the first dose of study treatment.

a. Senna and flaxseed are permitted

4. Is not fully recovered from all COVID-19-related symptoms for 2 weeks prior to Cycle 1 Day 1, if previously tested positive for COVID-19.

5. Ongoing toxicity (except alopecia) due to a prior therapy, unless returned to baseline or Grade 1 or less.

6. Has had major surgery within 3 weeks prior to starting IP or has not recovered from major side effects due to surgery.

7. Significantly impaired cardiac function such as unstable angina pectoris, symptomatic congestive heart failure with New York Heart Association Class III or IV, myocardial infarction within the last 12 months prior to study entry; serious arrhythmia (including QTc prolongation of >470 ms and/or pacemaker) or prior diagnosis of congenital long QT syndrome.

8. Pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Participants with indwelling catheters for control of effusions or ascites are allowed.

9. History of cerebrovascular accident or stroke within the previous 2 years.

10. History of hepatic encephalopathy.

11. Uncontrolled or symptomatic hypercalcemia (ionized calcium >1.5 mmol/L, calcium >12 mg/dL, or corrected serum calcium >ULN).

12. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).

13. History of Grade 3 or 4 allergic reactions attributed to compounds of similar chemical or biologic composition as TTI-101 (hydroxyl-naphthalene sulfonamides).

14. Known active metastases in the central nervous system (unless stable by brain imaging studies for at least 1 month without evidence of cerebral edema and no requirements for corticosteroids or anticonvulsants).

15. History of malabsorption, or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the IP.

16. Participants with chronic HBV infection, unless screening viral load <500 IU/mL on stable doses of antiviral therapy. Note: Participants with chronic HCV infection are allowed to enroll into the study but do not have a defined maximum viral load requirement for study entry. Participants with both HBV and HCV infection are excluded unless they have negative HCV RNA.

17. History of malignancy other than PDAC within 3 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (eg, 5-year overall survival [OS] rate >90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.

18. Has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate participation in the clinical study, or compromise compliance with the protocol such as:

• Chronic pancreatitis.
• Active untreated or uncontrolled fungal, bacterial, or viral infections (including COVID-19), sepsis, etc.
• Acute and chronic, active infectious disorders including viral and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy.

19. Prior treatment for pancreatic cancer in the past 2 years and outside of the induction chemotherapy received for the current diagnosis.

20. Measurable distant metastases on re-staging imaging post chemotherapy. tCurrently receiving any other investigational agents or has participated in a study of an investigational agent or using an investigational device overlapping with study treatments within 3-6 months preceding diagnosis at the discretion of the PI.

21. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to TTI-101.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Tvardi Therapeutics, Incorporated

INDUSTRY

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David Binder, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Colorado, Denver

Locations

University of Colorado

Aurora, Colorado, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Alex Fonder

Role: CONTACT

alex.fonder@cuanschutz.edu

1-303-724-5046

Facility Contacts

Alex Fonder

Role: primary

alex.fonder@cuanschutz.edu

1-303-724-5046

Other Identifiers

NCI-2023-10168

Identifier Type: OTHER

Identifier Source: secondary_id

22-0734.cc

Identifier Type: -

Identifier Source: org_study_id