Radiotherapy in Combination With TTI-101 in Borderline Resectable and Locally Advanced Pancreatic Ductal Adenocarcinoma

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

The survival rate for patients with pancreatic cancer remains at a dismal 10% or less at 5 years, and although trials integrating stereotactic body radiation therapy (SBRT) alone have shown improvement in local control, initial invigoration of immune response, and relief of symptom burden, SBRT has not demonstrated any improvement in survival. Preclinical research has established that STAT3 inhibition given concurrently with SBRT and in the maintenance phase acts as a synergistic agent that enhances the pro-inflammatory effects of SBRT while reducing its undesired effects (including fibrosis and immunosuppression). This study exploits the window of opportunity post-chemotherapy to advance the hypothesis that the addition of STAT3 inhibition in combination with SBRT will be safe and will enhance 2-year progression-free survival.

Study Overview

• Status: Recruiting
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: TTI-101; Radiation: Stereotactic body radiation therapy

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Sana Karam, M.D., Ph.D.; Phone Number: 314-273-3240; Email: sanadkaram@wustl.edu

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Completed
      • University of Colorado
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School Of Medicine
      • Sub-Investigator: Olivia Aranha, M.D., Ph.D.
      • Sub-Investigator: Kian-Huat Lim, M.D.
      • Sub-Investigator: Patrick Grierson, M.D., Ph.D.
      • Sub-Investigator: Dominic Sanford, M.D.
      • Sub-Investigator: Rama Suresh, M.D.
      • Sub-Investigator: Caron Rigden, M.D.
      • Sub-Investigator: Moh'd Khushman, M.D.
      • Sub-Investigator: Roheena Panni, M.D.
      • Sub-Investigator: Nikolaos Andreatos, M.D.
      • Sub-Investigator: Ramon Jin, M.D., Ph.D.
      • Sub-Investigator: Michael Waters, M.D., Ph.D.
      • Sub-Investigator: Chunjie Li, M.D., Ph.D.
      • Contact: Sana Karam, M.D., Ph.D.; Phone Number: 314-273-3240; Email: sanadkaram@wustl.edu
      • Principal Investigator: Sana Karam, M.D., Ph.D.
      • Sub-Investigator: Joseph Harms, Ph.D., DABR
      • Sub-Investigator: Trang Nguyen, M.D.
      • Sub-Investigator: Mark Sundermeyer, M.D.
      • Sub-Investigator: Ben Tan, M.D.
      • Sub-Investigator: Junxiao Hu, Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Pathologically confirmed pancreatic adenocarcinoma that is borderline resectable or locally advanced as defined by NCCN guidelines, with no expected arterial resection/reconstruction.
• Patients who are borderline resectable must have completed standard of care induction chemotherapy between 1 and 3 weeks prior to planned start of TTI-101 + SBRT. Patients who exceed this window may be considered for enrollment if they complete an additional cycle of induction chemotherapy prior to initiation of study treatment (per provider discretion). The amount of induction chemotherapy cycles allowed will be left to the discretion of the treating medical oncologist. There is no timing restriction for patients with locally advanced disease.
• At least 18 years of age.
• ECOG performance status ≤ 2

• Adequate bone marrow and organ function as defined below:

  • Absolute neutrophil count ≥ 1.0 K/cumm
  • Platelets ≥ 70 K/cumm
  • Hemoglobin ≥ 9.0 g/dL (patients may be transfused to meet this criterion)
  • Total bilirubin ≤ 2 mg/dL
  • AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
  • Serum albumin ≥ 2.8 g/dL
  • Ionized calcium ≤ 1.5 mmol/L, calcium ≤ 12 mg/dL, or corrected serum calcium ≤ IULN)
  • Measured creatinine clearance > 40 mL/min or calculated creatinine clearance > 40 mL/min by Cockcroft-Gault or by 24-hour urine collection for determination of creatinine clearance (calculations in protocol).
• Able to swallow pills.
• INR and aPTT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy (in which case INR and PTT must be within therapeutic range of intended use of anticoagulants)
• The effects of TTI-101 on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use at least 1 highly effective method of contraception from screening through the duration of study participation, and for 30 days after last dose of TTI-101. Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform the treating physician immediately.
• Agreement to adhere to Lifestyle Considerations throughout study duration.
• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria:

• Prior treatment for pancreatic cancer in the past 2 years (outside of the induction chemotherapy received for the current diagnosis).
• Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial.
• Currently 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 months preceding study entry at the discretion of the PI.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to TTI-101 or other agents used in the study.
• Uncontrolled intercurrent illness including but not limited to: ongoing or active infection (fungal, bacterial, or viral (including COVID-19)), sepsis, 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), and chronic pancreatitis. Patients with a recent COVID-19 diagnosis must have fully recovered from all COVID-19 symptoms for 2 weeks prior to the start of study treatment.
• Significantly impaired cardiac function such as symptomatic congestive heart failure with NYHA Class III or IV, unstable angina pectoris, myocardial infarction within the last 12 months prior to study entry, serious cardiac arrhythmia (including QTc prolongation of > 470 ms and/or pacemaker), or prior diagnosis of congenital long QT syndrome.
• Ongoing toxicity due to induction chemotherapy, unless returned to baseline or grade 1 or less (except alopecia and labs noted in inclusion criterion #5).
• Has had major surgery within 3 weeks prior to starting TTI-101 or has not recovered from major side effects due to surgery.
• Presence of pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequent). Participants with indwelling catheters for control of effusions or ascites are allowed.
• History of cerebrovascular accident or stroke within the previous 2 years.
• History of hepatic encephalopathy.
• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
• History of malabsorption or other chronic gastrointestinal disease or condition that may hamper compliance or absorption of TTI-101.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum or urine pregnancy test within 5 days of study entry.
• HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.
• Evidence of chronic hepatitis B virus (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load on suppressive therapy are eligible. HBV testing not required in the absence of known history of infection.
• History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing not required in the absence of known history of infection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TTI-101 + SBRT Dose Level 0 (original starting dose); Treatment consists of TTI-101 by mouth twice daily at 400 mg and SBRT (5 fractions of 6.6 Gy each) over the course of 3 weeks.; After combination therapy is concluded, patients who entered the study as locally advanced will receive up to 10 additional weeks of TTI-101 monotherapy (until a tumor biopsy that will occur between Weeks 9 and 13). After discontinuation of TTI-101, patients will receive SOC chemotherapy as part of their routine care (not dictated by study participation).; Patients who entered the study as borderline resectable will be assessed following the initial 3 weeks of treatment. If they have reverted to resectable, they will undergo surgery, followed by optional adjuvant chemotherapy at the discretion of their treating team. If they are unresectable, they will follow the path of the locally advanced patients (up to 10 weeks of TTI-101 monotherapy, followed by disease assessment, followed by SOC chemotherapy).	Drug: TTI-101; Given at the assigned dose assigned in the protocol.; Radiation: Stereotactic body radiation therapy; Given at the assigned dose and fractions assigned in the protocol.; Other Names: SBRT
Experimental: TTI-101 + SBRT Dose Level -1 (WUSM starting dose); Treatment consists of TTI-101 by mouth twice daily at 200 mg & SBRT (3 fractions of 6 Gy each, approximately every other day) over the course of 3 weeks.; After combination therapy is concluded, patients who entered the study as locally advanced will receive up to 10 additional weeks of TTI-101 monotherapy (until a tumor biopsy that will occur between Weeks 9 and 13 if possible). After discontinuation of TTI-101, patients will receive SOC chemotherapy as part of their routine care (not dictated by study participation).; Patients who entered the study as borderline resectable will be assessed following the initial 3 weeks of treatment. If they have reverted to resectable, they will undergo surgery, followed by optional adjuvant chemotherapy at the discretion of their treating team. If they are unresectable, they will follow the path of the locally advanced patients (up to 10 weeks of TTI-101 monotherapy, followed by disease assessment, followed by SOC chemotherapy).	Drug: TTI-101; Given at the assigned dose assigned in the protocol.; Radiation: Stereotactic body radiation therapy; Given at the assigned dose and fractions assigned in the protocol.; Other Names: SBRT
Experimental: TTI-101 + SBRT Dose Level -2; Treatment consists of TTI-101 by mouth twice daily at 200 mg and SBRT (1 fraction of 12 Gy each) over the course of 3 weeks.; After combination therapy is concluded, patients who entered the study as locally advanced will receive up to 10 additional weeks of TTI-101 monotherapy (until a tumor biopsy that will occur between Weeks 9 and 13 if possible). After discontinuation of TTI-101, patients will receive SOC chemotherapy as part of their routine care (not dictated by study participation).; Patients who entered the study as borderline resectable will be assessed following the initial 3 weeks of treatment. If they have reverted to resectable, they will undergo surgery, followed by optional adjuvant chemotherapy at the discretion of their treating team. If they are unresectable, they will follow the path of the locally advanced patients (up to 10 weeks of TTI-101 monotherapy, followed by disease assessment, followed by SOC chemotherapy).	Drug: TTI-101; Given at the assigned dose assigned in the protocol.; Radiation: Stereotactic body radiation therapy; Given at the assigned dose and fractions assigned in the protocol.; Other Names: SBRT
Experimental: TTI-101 + SBRT Expansion Phase; Treatment consists of TTI-101 by mouth twice daily at the RP2D dose and SBRT (at the RP2D dose and timing) over the course of 3 weeks.; After combination therapy is concluded, patients who entered the study as locally advanced will receive up to 10 additional weeks of TTI-101 monotherapy (until a tumor biopsy that will occur between Weeks 9 and 13 if possible). After discontinuation of TTI-101, patients will receive SOC chemotherapy as part of their routine care (not dictated by study participation).; Patients who entered the study as borderline resectable will be assessed following the initial 3 weeks of treatment. If they have reverted to resectable, they will undergo surgery, followed by optional adjuvant chemotherapy at the discretion of their treating team. If they are unresectable, they will follow the path of the locally advanced patients (up to 10 weeks of TTI-101 monotherapy, followed by disease assessment, followed by SOC chemotherapy).	Drug: TTI-101; Given at the assigned dose assigned in the protocol.; Radiation: Stereotactic body radiation therapy; Given at the assigned dose and fractions assigned in the protocol.; Other Names: SBRT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of TTI-101 and SBRT	The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity during the dose-limiting toxicity (DLT) evaluation period.; The final determination of the RP2D will be based on an overall evaluation of the totality of the available data observed in phase IB.	Through completion of follow-up (estimated to be 2 years and 3 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	PFS is defined as the time from treatment initiation to documented disease progression or death from any cause. The 2-year PFS probability will be reported as a descriptive summary measure.	2 years
Overall survival (OS)	OS is defined as the time from treatment initiation to death from any cause. The 2-year OS probability will be reported as a descriptive summary measure.	2 years
Pathologic response rate	Pathologic response rate among patients who receive neoadjuvant TTI-101 in combination with SBRT and subsequently undergo surgical resection (including pCR and/or major pathologic response).; Pathologic complete response (pCR) is defined as the absence of any vital tumor tissue in the sampled pancreatic resection specimen.; Major pathologic response is defined as ≤ 10% residual viable tumor cells remaining in the surgical specimen after treatment.	At the time of surgery (estimated to be 5 weeks)
R0 resection rate among patients who undergo surgical resection	R0 resection is defined as microscopic tumor clearance in the pancreatic resection specimen.	At the time of surgery (estimated to be 5 weeks)
Frequency of adverse events	Graded according to NCI CTCAE v 5.0.	From start of treatment through 90 days after last dose of TTI-101 (estimated to be 6 months)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Tvardi Therapeutics, Incorporated; The V Foundation
• Investigators: Principal Investigator: Sana Karam, M.D., Ph.D., Washington University School Of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): January 16, 2024
• Primary Completion (Estimated): June 30, 2029
• Study Completion (Estimated): June 30, 2029

Study Registration Dates

• First Submitted: November 8, 2023
• First Submitted That Met QC Criteria: November 14, 2023
• First Posted (Actual): November 21, 2023

Study Record Updates

• Last Update Posted (Actual): May 27, 2026
• Last Update Submitted That Met QC Criteria: May 22, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: borderline resectable; locally advanced
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Investigative Techniques; Therapeutics; Surgical Procedures, Operative; Radiotherapy; Stereotaxic Techniques; Neurosurgical Procedures; Radiosurgery; C188-9 compound
• Other Study ID Numbers: 202602103; NCI-2023-10168 (Other Identifier: CTRP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No