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

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ClinicalTrials.gov Identifier: NCT03340974
Recruitment Status : Recruiting
First Posted : November 14, 2017
Last Update Posted : April 23, 2018
Sponsor:
Collaborator:
M.D. Anderson Cancer Center
Information provided by (Responsible Party):
Galera Therapeutics, Inc.

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 GC4419 or placebo to patients who have been diagnosed with locally advanced pancreatic cancer.

Condition or disease Intervention/treatment Phase
Pancreatic Cancer Stereotactic Body Radiation Therapy Drug: GC4419 Drug: Placebo Radiation: Stereotactic Radiation Therapy (SBRT) Phase 1 Phase 2

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 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 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 but no later than 60 minutes following the end 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

Objectives:

Primary:

• To determine the Maximum Tolerated Dose (MTD) of Stereotactic Body Radiation Therapy (SBRT) when given in combination with placebo or GC4419

Secondary:

  • To evaluate Progression-free survival (PFS) at MTD for patients treated with SBRT given in combination with placebo or GC4419
  • To evaluate Overall Response Rate (ORR) including stable disease, partial/ complete response at 90 days for patients treated with SBRT given in combination with placebo or GC4419
  • To evaluate tumor resectability after SBRT in combination with placebo or GC4419
  • To evaluate the R0 Resection Rate and Pathologic Complete Response Rate (pCR) for patients who eventually undergo surgical resection
  • To compare acute toxicity rate at 90 days for patients treated at the SBRT MTD in combination with placebo or GC4419
  • To compare efficacy rates at 90 days for patients treated at the SBRT MTD with placebo or GC4419

Exploratory:

  • To evaluate patient reported outcomes for patients treated with SBRT in combination with placebo or GC4419
  • To compare genomic changes based on whole exome sequencing, and transcriptome sequencing from pre and post SBRT core biopsy samples.
  • To compare pathologic changes pre and post SBRT based on core biopsy samples
  • To compare differences in immune infiltrate pre and post SBRT using IHC for immune activation, exhaustion and proliferation phenotypes, deep T cell sequencing from core biopsy specimens and multi parametric flow cytometry (MPFC) from cytology brushings
  • To compare changes in circulating tumor cells (CTC's), circulating tumor DNA (ctDNA) and circulating immune cells (MPFC) pre and post SBRT

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: An Adaptive Phase I/II Dose Escalation Trial of Stereotactic Body Radiation Therapy in Combination With Radiomodulating Agent GC4419 in Locally Advanced Pancreatic Adenocarcinoma
Actual Study Start Date : February 12, 2018
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : June 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A: SBRT + GC4419 Drug: GC4419
90 mg GC4419 per day daily (60 min IV infusion, to complete within 60 minutes prior to SBRT), concurrent with daily fractions of SBRT to assigned dose level, administered Monday - Friday over one week.

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

Placebo Comparator: Arm B: SBRT + Placebo Drug: Placebo
Placebo daily (60 min IV infusion, to complete within 60 minutes prior to SBRT), concurrent with daily fractions of SBRT to assigned dose level, administered Monday - Friday over one week.

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




Primary Outcome Measures :
  1. CTCAE grade 3 or 4 gastro-intestinal (GI) toxicities or deaths [ Time Frame: Within 90 days from the start of therapy ]
    Number of CTCAE grade 3 or 4 gastro-intestinal (GI) toxicities or deaths

  2. Radiographic stable disease (SD) based on RECIST criteria [ Time Frame: Evaluated at day 90 from the start of therapy ]
    Radiographic stable disease (SD) or better based on RECIST criteria, compared to baseline imaging of the same type



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Cytologic or biopsy confirmed adenocarcinoma of the pancreatic head, body or tail
  2. Locally advanced, unresectable pancreatic cancer as determined by a pancreaticobiliary surgeon as part of a multidisciplinary discussion at MDACC, including triphasic CT demonstrating tumor abutment of the superior mesenteric artery (SMA) or celiac axis, superior mesenteric vein (SMV) or portal vein (PV) involvement which is not resectable without vascular reconstruction.
  3. Pancreatic tumor size ≤ 5cm
  4. No evidence of distant metastasis either prior to or after induction chemotherapy.
  5. Completion of at least 3 months, but no more than 7 months of standard induction chemotherapy for LAPC, which should consist of either FOLFIRINOX or gemcitabine and nab-paclitaxel, preferably with a washout period no longer than 8 weeks.
  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 ≥ 100,000/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 in the patient's primary language (English or Spanish). If patient is not sufficiently fluent in either English or Spanish to understand consent, they will not be eligible for the study.

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. Direct invasion of the duodenum by the primary tumor
  6. Residual or ongoing ≥ Grade 3 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03340974


Contacts
Contact: Melissa Brookes 610-725-1500 mbrookes@galeratx.com
Contact: Jon Holmlund, MD jholmlund@galeratx.com

Locations
United States, Texas
The University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Denise Erdman    713-792-3583      
Sponsors and Collaborators
Galera Therapeutics, Inc.
M.D. Anderson Cancer Center
Investigators
Study Chair: Jon Holmlund, MD Galera Therapeutics, Inc.

Responsible Party: Galera Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT03340974     History of Changes
Other Study ID Numbers: GTI-4419-101
First Posted: November 14, 2017    Key Record Dates
Last Update Posted: April 23, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Galera Therapeutics, Inc.:
Super Oxide Dismutase

Additional relevant MeSH terms:
Pancreatic Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases