Pilot Dose Escalation Trial of Stereotactic Body Radiation Therapy (SBRT) in Combination With GC4419 in Pancreatic Cancer

NCT ID: NCT03340974

Last Updated: 2023-12-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-02-12
• Study Completion Date: 2021-05-26

Brief Summary

The purpose of the phase I/II clinical study is to determine the best dose of fractionated stereotactic radiation therapy (SBRT) given either with Avasopasem manganese (GC4419) or placebo to patients who have been diagnosed with locally advanced pancreatic cancer.

Detailed Description

This is a parallel arm adaptive design phase I-II dose-finding study to determine the optimal dose of fractionated stereotactic radiation therapy (SBRT), given either with the radiomodulating agent Avasopasem manganese (GC4419) or placebo for treatment of locally advanced pancreatic cancer. Dose-finding will be done using the sequentially adaptive phase I-II Late onset Efficacy-Toxicity (LO-ET) trade-off-based design [1-3].

A maximum of 48 patients will be randomized 1:1 to Arm A or Arm B. Patients in Arm A will receive Avasopasem manganese (GC4419) in combination with their assigned SBRT dose, and patients in Arm B will receive Placebo (PBO) with their assigned SBRT dose. The randomization will be restricted so that the sample size within each arm is exactly 24 patients.

GC4419/placebo will be given intravenously in a one hour infusion. SBRT must be initiated as soon as possible upon completion of the GC4419/placebo infusion.

GC4419/placebo will be given beginning on the first day of radiation and continuing daily, concurrent M-F throughout the administration of SBRT

Conditions

Pancreatic Cancer; Stereotactic Body Radiation Therapy

Keywords

Avasopasem manganese

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

GC4419 90mg +50 Gy SBRT

Avasopasem manganese (GC4419) +SBRT

Group Type: EXPERIMENTAL

GC4419

Intervention Type: DRUG

90 mg Avasopasem (GC4419) per day daily (60 min IV infusion, prior to SBRT), concurrent with daily fractions of SBRT to assigned dose level

Stereotactic Radiation Therapy (SBRT) 50 Gy

Intervention Type: RADIATION

Dose-finding will be done using the sequentially adaptive phase I-II Late onset Efficacy-Toxicity (LO-ET) trade-off-based design.

GC4419 90 mg + 55 Gy SBRT

Avasopasem manganese (GC4419) +SBRT

Group Type: EXPERIMENTAL

GC4419

Intervention Type: DRUG

90 mg Avasopasem (GC4419) per day daily (60 min IV infusion, prior to SBRT), concurrent with daily fractions of SBRT to assigned dose level

Stereotactic Radiation Therapy (SBRT) 55 Gy

Intervention Type: RADIATION

Dose-finding will be done using the sequentially adaptive phase I-II Late onset Efficacy-Toxicity (LO-ET) trade-off-based design.

Placebo + 50 Gy SBRT

Placebo +SBRT

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo daily (60 min IV infusion, prior to SBRT), concurrent with daily fractions of SBRT to assigned dose level

Stereotactic Radiation Therapy (SBRT) 50 Gy

Intervention Type: RADIATION

Dose-finding will be done using the sequentially adaptive phase I-II Late onset Efficacy-Toxicity (LO-ET) trade-off-based design.

Placebo + 55 Gy SBRT

Placebo + SBRT

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo daily (60 min IV infusion, prior to SBRT), concurrent with daily fractions of SBRT to assigned dose level

Stereotactic Radiation Therapy (SBRT) 55 Gy

Intervention Type: RADIATION

Dose-finding will be done using the sequentially adaptive phase I-II Late onset Efficacy-Toxicity (LO-ET) trade-off-based design.

Interventions

GC4419

90 mg Avasopasem (GC4419) per day daily (60 min IV infusion, prior to SBRT), concurrent with daily fractions of SBRT to assigned dose level

Intervention Type: DRUG

Placebo

Placebo daily (60 min IV infusion, prior to SBRT), concurrent with daily fractions of SBRT to assigned dose level

Intervention Type: DRUG

Stereotactic Radiation Therapy (SBRT) 50 Gy

Dose-finding will be done using the sequentially adaptive phase I-II Late onset Efficacy-Toxicity (LO-ET) trade-off-based design.

Intervention Type: RADIATION

Stereotactic Radiation Therapy (SBRT) 55 Gy

Dose-finding will be done using the sequentially adaptive phase I-II Late onset Efficacy-Toxicity (LO-ET) trade-off-based design.

Intervention Type: RADIATION

Other Intervention Names

Avasopasem manganese

Eligibility Criteria

Inclusion Criteria

1. Cytologic or biopsy confirmed adenocarcinoma of the pancreatic head, body or tail

2. Disease that is appropriate for SBRT by virtue of being:

a. Locally advanced and technicallyunresectable, as determined by a pancreaticobiliary surgeon as part of a multidisciplinary review at the investigative site, including multi-phasic CT demonstrating: i.Greater than 180 degree tumor involvement of the superior mesenteric artery ii. Greater than 180 degree tumor involvement of the celiac axis, including major branches of the celiac axis that render it unresectable (e.g. common hepatic artery).

iii. Tumor involvement of the first branch of the SMA that is not surgically reconstructible iv. Long segment involvement of the superior mesenteric vein/portal vein or hepatic artery that is not surgically reconstructible b. Potentially resectable, but patient is judged not a candidate for surgery, after multidisciplinary review at the investigative site; c. Potentially resectable, but the patients refuses surgery and is considered an acceptable candidate for SBRT after multidisciplinary review at the investigative site; d. "Borderline" resectable, as determined by multidisciplinary review, including absence of distant lymphadenopathy and the primary tumor characterized by one of more of the following: i. A tumor-vessel interface (TVI) with the mesenteric vein (SMV) or portal vein (PV) measuring ≥180° of the circumference of either vein's wall or short-segment occlusion of either vein with a normal vein above or below the obstruction amenable to reconstruction; ii. Any TVI with the common hepatic artery (CHA) with normal artery proximal and distal to the TVI amenable to reconstruction; iii. A TVI with the superior mesenteric artery (SMA) measuring <180° of the circumference of the vessel wall

3. Pancreatic tumor size and limited bowel involvement by tumor must be judged acceptable for SBRT at the discretion of the treating investigator

4. No evidence of distant metastasis either prior to or after induction chemotherapy.

5. Completion of at least 3 months of standard induction chemotherapy for LAPC, which should consist of either FOLFIRINOX, gemcitabine or nab-paclitaxel or another standard combination of induction chemotherapy agents

6. Patient must have metal stent in place if duodenal stent is required. If patient has plastic stent, this must be replaced prior to radiation.

7. Ability to understand and follow the breathing instructions involved in the respiratory gating procedure or to tolerate compression sufficient to reduce fiducial motion to <= 5mm.

8. Age 18 years or older

9. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (0, 1 or 2)

10. Adequate hematologic function as indicated by i. Absolute neutrophil counts (ANC) ≥ 1,500/mm3 ii. Hemoglobin (Hgb) ≥ 8.0 g/dL iii. Platelet count ≥ 75,000/mm3

11. Adequate renal and liver function as indicated by:

i. Creatinine ≤ 1.5 x upper-normal limit (ULN) ii. Total bilirubin ≤ 1.5 x upper-normal limit (ULN) iii. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN iv. Alkaline phosphatase ≤ 2.5 x ULN

12. Properly obtained written informed consent

Exclusion Criteria

1. Prior radiation therapy to the abdomen that would overlap with treatment field

2. Prior surgical resection of pancreatic tumor

3. Receiving any approved or investigational anti-cancer agent other than those provided for in this study

4. Uncontrolled or active gastric or duodenal ulcer disease within 30 days of enrollment

5. Visible invasion of tumor into the lumen of the bowel or stomach on endoscopy (Note: Radiological infiltration into bowel is allowed, unless deemed clinically unsafe.)

6. Residual or ongoing ≥ Grade 3 non-hematologic toxicity from chemotherapy

7. Contraindication to IV contrast

8. Concurrent participation in another interventional clinical trial or use of another investigational agent within 30 days of study entry Note: Patients who are participating in non-interventional clinical trials (e.g., QOL, imaging, observational, follow-up studies, etc.) are eligible, regardless of the timing of participation.

9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, renal failure, cardiac arrhythmia, or psychiatric illness that would limit compliance with treatment

10. Second primary malignancy within the last 5 years, unless treated definitively and with low risk of recurrence in the judgment of the treating investigator

11. Known history of HIV or active hepatitis B/C (patients who have been vaccinated for hepatitis B and do not have a history of infection are eligible)

12. Female patients who are pregnant or breastfeeding

13. Women of child-bearing potential who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period and for 30 days after the last dose of GC4419. This includes any woman who has experienced menarche but has not undergone successful surgical sterilization or is not postmenopausal (defined as amenorrhea for at least 12 consecutive months, or women on hormone replacement therapy with serum FSH levels greater than 35 mIU/mL. A negative urine or serum pregnancy test must be obtained within 14 days prior to the start of study therapy in all women of child-bearing potential.

14. Male subjects who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period and for up to 90 days after the last dose of GC4419 are excluded.

15. Requirement for concurrent treatment with nitrates or other drugs that may, in the judgment of the treating investigator, create a risk for a precipitous decrease in blood pressure.

16. Medical history that includes any condition, or requires the use of concomitant medications which, in the investigator's judgment, are associated with or create a risk of increased carotid sinus sensitivity, symptomatic bradycardia, or syncopal episodes.

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

Sponsors

M.D. Anderson Cancer Center

OTHER

Sponsor Role: collaborator

Galera Therapeutics, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Gene Kennedy, MD

Role: STUDY_CHAIR

Galera Therapeutics

Locations

Moffitt Cancer Center

Tampa, Florida, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Atlantic Health System / Morristown Medical Center

Morristown, New Jersey, United States

Duke University Medical Center

Durham, North Carolina, United States

UT Southwestern Medical Center

Dallas, Texas, United States

The University of Texas MD Anderson Cancer Center

Houston, Texas, United States

Countries

United States

References

Hoffe S, Frakes JM, Aguilera TA, Czito B, Palta M, Brookes M, Schweizer C, Colbert L, Moningi S, Bhutani MS, Pant S, Tzeng CW, Tidwell RS, Thall P, Yuan Y, Moser EC, Holmlund J, Herman J, Taniguchi CM. Randomized, Double-Blinded, Placebo-controlled Multicenter Adaptive Phase 1-2 Trial of GC 4419, a Dismutase Mimetic, in Combination with High Dose Stereotactic Body Radiation Therapy (SBRT) in Locally Advanced Pancreatic Cancer (PC). Int J Radiat Oncol Biol Phys. 2020 Dec 1;108(5):1399-1400. doi: 10.1016/j.ijrobp.2020.09.022. Epub 2020 Nov 18. No abstract available.

Reference Type: RESULT

PMID: 33427657 (View on PubMed)

Taniguchi CM, Frakes JM, Aguilera TA, Palta M, Czito B, Bhutani MS, Colbert LE, Abi Jaoude J, Bernard V, Pant S, Tzeng CD, Kim DW, Malafa M, Costello J, Mathew G, Rebueno N, Koay EJ, Das P, Ludmir EB, Katz MHG, Wolff RA, Beddar S, Sawakuchi GO, Moningi S, Slack Tidwell RS, Yuan Y, Thall PF, Beardsley RA, Holmlund J, Herman JM, Hoffe SE. Stereotactic body radiotherapy with or without selective dismutase mimetic in pancreatic adenocarcinoma: an adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial. Lancet Oncol. 2023 Dec;24(12):1387-1398. doi: 10.1016/S1470-2045(23)00478-3.

Reference Type: DERIVED

PMID: 38039992 (View on PubMed)

Sishc BJ, Ding L, Nam TK, Heer CD, Rodman SN, Schoenfeld JD, Fath MA, Saha D, Pulliam CF, Langen B, Beardsley RA, Riley DP, Keene JL, Spitz DR, Story MD. Avasopasem manganese synergizes with hypofractionated radiation to ablate tumors through the generation of hydrogen peroxide. Sci Transl Med. 2021 May 12;13(593):eabb3768. doi: 10.1126/scitranslmed.abb3768.

Reference Type: DERIVED

PMID: 33980575 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

GTI-4419-101

Identifier Type: -

Identifier Source: org_study_id