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Trial of Carbon Ion Versus Photon Radiotherapy for Locally Advanced, Unresectable Pancreatic Cancer (CIPHER)

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ClinicalTrials.gov Identifier: NCT03536182
Recruitment Status : Not yet recruiting
First Posted : May 24, 2018
Last Update Posted : January 7, 2019
Sponsor:
Information provided by (Responsible Party):
University of Texas Southwestern Medical Center

Brief Summary:
To determine if carbon ion radiotherapy improves overall survival versus photon therapy in patients with locally advanced, unresectable pancreatic cancer

Condition or disease Intervention/treatment Phase
Locally Advanced Pancreatic Adenocarcinoma Radiation: Carbon ion radiotherapy Radiation: Photon radiotherapy Drug: Gemcitabine Drug: nab-paclitaxel Phase 3

Detailed Description:

A significant percentage of patients with incurable pancreatic cancer die with predominantly local disease. Conventional chemoradiotherapy (i.e. using photon therapy) leads to inadequate locoregional control rates, despite concurrent chemotherapy and modern radiation techniques. Carbon ion radiation therapy holds the promise of a novel biological mechanism for eradicating local-only disease (heavy ion therapy), and preliminary data are extremely encouraging. Thus, evaluating the comparative effectiveness of a novel and more potent radiotherapy modality in this known radioresistant, lethal disease is a natural question.

This is a randomized phase III trial comparing photon-based (IMRT) and carbon-ion based (CIRT) chemoradiotherapy treatments. Patients will be randomized in a 2:1 ratio (CIRT:IMRT) to one of the following two treatment arms following non-progressive disease during induction chemotherapy:

  • Carbon ion-based irradiation (CIRT). Patients will be treated with carbon ion irradiation plus concurrent gemcitabine chemotherapy. This chemoradiation course is followed by treatment with gemcitabine and nab-paclitaxel chemotherapy.
  • Photon-based irradiation (IMRT). Patients will be treated with x-ray irradiation (IMRT) plus concurrent gemcitabine chemotherapy. This chemoradiation course is followed by treatment with gemcitabine and nab-paclitaxel chemotherapy.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 103 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients will be randomized in a 2:1 ratio (Carbon Ion Radiation Therapy : Conventional Photon Radiation Therapy)
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: CIPHER: A Prospective, Multi-Center Randomized Phase 3 Trial of Carbon Ion Versus Conventional Radiation Therapy for Locally Advanced, Unresectable Pancreatic Cancer
Estimated Study Start Date : February 1, 2019
Estimated Primary Completion Date : July 1, 2021
Estimated Study Completion Date : July 1, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Arm A: Carbon ion radiotherapy

Arm A (Carbon ion radiotherapy in Japan): 55.2 GyE in 4.6 GyE per fraction in 12 fractions delivered 4 days a week.

Arm A (Carbon ion radiotherapy using the LEM [European] model): The dose calculation algorithms used in Japan and Europe (local effect model, LEM) are different, so the total dose must be modified to ensure consistency 8. Patients treated in Europe should receive 59.4 GyE in 4.95 GyE per fraction in 12 fractions delivered 4 days a week.

Concurrent gemcitabine at 1000 mg/m2 will be delivered during weeks 1-3 of CIRT in Japan and Italy.

Patients treated in Italy and Japan will be treated with 4 cycles of gemcitabine + nab-Paclitaxel following chemoradiotherapy.

Radiation: Carbon ion radiotherapy

Japan: 55.2 GyE in 4.6 GyE per fraction in 12 fractions delivered 4 days a week.

European: 59.4 GyE in 4.95 GyE per fraction in 12 fractions delivered 4 days a week

Other Name: CIRT

Drug: Gemcitabine
Concurrent gemcitabine at 1000 mg/m2 will be delivered during weeks 1-3 of CIRT. 1000 mg/m2 weekly, three on/one off for 4 cycles following chemoradiotherapy
Other Name: Gemzar

Drug: nab-paclitaxel
125 mg/m2 weekly, three on/one off for 4 cycles following chemoradiotherapy
Other Name: Abraxane

Active Comparator: Arm B: Photon radiotherapy

Arm B (Photon radiotherapy): 50.4 Gy in 1.8 Gy per fraction in 28 fractions delivered 5 days a week.

Concurrent gemcitabine at 600 mg/m2 will be delivered during weeks 1-5 of IMRT

Patients treated in United States will be treated with 4 cycles of gemcitabine + nab-Paclitaxel following chemoradiotherapy.

Patients treated in China and Korea will receive 4 cycles of gemcitabine alone, with the exception of para-aortic node positive patients in Korea, who will also receive gemcitabine+nab-Paclitaxel.

Radiation: Photon radiotherapy
50.4 Gy in 1.8 Gy per fraction in 28 fractions delivered 5 days a week.
Other Name: IMRT

Drug: Gemcitabine
Concurrent gemcitabine at 600 mg/m2 will be delivered during weeks 1-5 of IMRT. 1000 mg/m2 weekly, three on/one off for 4 cycles following chemoradiotherapy
Other Name: Gemazr

Drug: nab-paclitaxel
125 mg/m2 weekly, three on/one off for 4 cycles following chemoradiotherapy
Other Name: Abraxane




Primary Outcome Measures :
  1. 2 year overall survival [ Time Frame: 2 years ]
    Overall survival outcomes will be estimated using the Kaplan-Meier approach and compared between the arms using the log-rank test. The Cox proportional hazard regression model will be used to determine hazard ratios and 95% confidence intervals for the treatment difference in overall survival. Unadjusted ratios and ratios adjusted for stratification variables and other covariates of interest will be computed.


Secondary Outcome Measures :
  1. Progression-free survival [ Time Frame: 3 years ]

    Progression-free survival outcomes will be estimated using the Kaplan-Meier approach and compared between the arms using the stratified log-rank test. The Cox proportional hazard regression model will be used to determine hazard ratios and 95% confidence intervals for the treatment difference in overall survival. Unadjusted ratios and ratios adjusted for stratification variables and other covariates of interest will be computed.

    Locoregional progression will be defined as a 20% increase in the sum of diameters of the measureable primary tumor and/or distinct lymph node masses, comparing to the baseline scan. In addition to this 20% increase, the sum should also be at least 5 mm as an absolute increase and progression must be shown on at least two sequential scans.


  2. Patterns-of-failure [ Time Frame: 3 years ]
    The cumulative incidence of locoregional and distant failure will be estimated using cumulative incidence statistics, with death serving as the competing risk. A comparison of these endpoints will be performed using Gray's test.

  3. Quality-of-life [ Time Frame: 6 months ]
    Patient-reported functional status will be assessed with the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep). Trial Outcome Indices (TOI) also will be utilized to measure the summed functional well-being, physical well-being, and the additional concerns (hepatobiliary) subscales of the FACT-Hep. A 7-point deterioration in the FACT-Hep TOI between pre-treatment and at 6 months post treatment will be considered clinically significant.

  4. Number and severity of treatment-related Adverse Events [ Time Frame: 3 years ]
    Only adverse events assessed to be definitely, probably, or possibly related to protocol treatment will be considered. Adverse events will be graded by a numerical score according to the defined NCI Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03)


Other Outcome Measures:
  1. Quality-adjusted survival time [ Time Frame: 3 years ]
    The quality-adjusted survival time estimates need to account for the presence of censoring. Due to the induced informative censoring problem, the ordinary survival method (e.g., Kaplan-Meier estimator) cannot be applied in this case. Accordingly, the investigators will use the inverse-probability weighted method of Zhao and Tsiatis to carry out the survival time analysis to estimate quality adjusted survival time, data from EQ-5D will first be translated into utility measures. These measures are obtained at discrete time points, so they will be interpolated into the time intervals between the visits. The quality-adjusted survival time is just an integration of the utility measures over a patient's survival time, or until the time limit similar as the cost calculation, whichever occurs earlier



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Ages Eligible for Study:   18 Years to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. All patients must be willing and capable to provide informed consent within the 30 days prior to registration to participate in the protocol.
  2. Histological and/or cytological diagnosis of pancreas adenocarcinoma must be done at any point prior to registration
  3. Unresectable by radiographic or exploration within 30 days of registration
  4. Age ≥ 18 years.
  5. Distance from the pancreas tumor edge to the bowel and stomach > 3 mm (in both the prone and supine positions)
  6. Tumor does not exceed 15 cm in greatest dimension
  7. No evidence for metastatic disease as assessed by CT imaging of the chest, abdomen and pelvis OR by PET-CT within the 30 days prior to registration.
  8. Zubrod performance status of 0-1, within 30 days prior to registration.
  9. CMP and CBC with differential obtained within 14 days prior to registration (may be taken after stent placement), with adequate hematologic variables as defined by:

    Absolute neutrophil count > 1500 cells/mm3 Creatinine <1.5 mg/dL Hemoglobin >8.0 g/dL AST and ALT < 2.5 X ULN Bilirubin < 1.5 times the ULN (after stent placement, if necessary)

  10. Patients must complete all required pretreatment evaluations
  11. Able to travel to a foreign country within approximately 2 weeks of randomization (for patients enrolled at UTSW)?
  12. Women of childbearing potential and male participants must agree to use an effective method of contraception.

A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

  • Has not undergone a hysterectomy or bilateral oophorectomy; or
  • Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

Exclusion Criteria:

  1. Subjects receiving other investigational agents.
  2. History of allergic reactions attributed to compounds of similar chemical or biologic composition to gemcitabine or nab-paclitaxel or other agents used in study.
  3. Subjects who are pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
  4. Prior treatment for pancreatic cancer preceding registration
  5. Prior radiation to the upper abdomen
  6. Placement of a metal stent for relief of biliary obstruction (metal stents may be placed following completion of radiation therapy).
  7. Body weight >100 kg
  8. Active inflammatory bowel disease or active gastric/duodenal ulcer
  9. Metal implants in the upper abdomen
  10. Expected medical intolerance of radiotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.
  11. History of HIV or hepatitis B or C

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): NCT03536182


Contacts
Contact: David Sher, MD 214-645-7607 david.sher@utsouthwestern.edu
Contact: Sarmistha Sen 214-645-1477 sarmistha.sen@utsouthwestern.edu

Locations
United States, Texas
University of Texas Southwestern Medical Center Not yet recruiting
Dallas, Texas, United States, 75390
Contact: David Sher, MD    214-645-7607    david.sher@utsouthwestern.edu   
Contact: Sarmistha Sen       sarmistha.sen@utsouthwestern.edu   
Sponsors and Collaborators
University of Texas Southwestern Medical Center
Investigators
Principal Investigator: David Sher, MD University of Texas Southwestern Medical Center

Responsible Party: University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT03536182     History of Changes
Other Study ID Numbers: STU 022016-002
First Posted: May 24, 2018    Key Record Dates
Last Update Posted: January 7, 2019
Last Verified: January 2019

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
Pediatric Postmarket Surveillance of a Device Product: No

Additional relevant MeSH terms:
Adenocarcinoma
Pancreatic Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Paclitaxel
Gemcitabine
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs