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Neoadjuvant Accelerated Short Course Radiation Therapy With Photons and Capecitabine for Resectable Pancreatic Cancer

Primary Purpose

Pancreatic Cancer

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Neoadjuvant Short-Course Photon Radiation

Capecitabine

About this trial

This is an interventional treatment trial for Pancreatic Cancer focused on measuring radiation therapy, capecitabine

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Cytologic or histologic proof of pancreatic ductal carcinoma is required prior to treatment.
No evidence of metastatic disease as determined by chest CT scan, abdominal CT scan (or MRI with gadolinium and/or manganese), and all patients must be staged with a physical exam, chest CT, and abdominal CT with intravenous contrast.
Only potentially resectable patients are eligible. Potentially resectable is defined as: a)no extrapancreatic disease, b)no evidence (on CT) of involvement of the celiac axis or superior mesenteric artery, and c)no evidence (on CT or MRI) of occlusion of the superior mesenteric vein or superior mesenteric-portal venous confluence.
18 years of age or older
ECOG Performance status of 0 or 1
Women of child bearing potential must practice adequate contraception and to refrain from breast feeding. Female patients must have a negative pregnancy test within 7 days of treatment
Lab values as specified in the protocol

Exclusion Criteria:

Patients cannot have hepatic or peritoneal metastases detected by imaging or laparoscopy prior to chemoradiation
Serious concomitant systemic disorders incompatible with the study, such as significant cardiac or pulmonary morbidity, or ongoing infection as manifested by fever
Pregnant or lactating women
Life expectancy < 3 months
Serious, uncontrolled, concurrent infection(s)
Any prior chemotherapy or radiation for treatment of the patient's pancreatic tumor
Treatment for other cancers within the last five years, except cured non-melanoma skin cancer and treated in situ cervical cancer
Clinically significant cardiac disease or myocardial infarction within the last 12 months
Other serious uncontrolled medical conditions that the investigator feels might compromise study participation
Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome
Known, existing uncontrolled coagulopathy
Unwillingness to participate or inability to comply with the protocol for the duration of the study
Any prior fluoropyrimidine therapy (unless given in an adjuvant setting and completed at least 6 months earlier)
Prior unanticipated severe reaction to fluoropyrimidine therapy, or known hypersensitivity to 5-fluorouracil or known DPD deficiency
Participation in any investigational drug study within 4 weeks preceding the start of study treatment
History of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance or oral drug intake
Major surgery, excluding laparoscopy, within 4 weeks of the start of study treatment, without complete recovery
Patients should not be on cimetidine as it can decrease the clearance of 5-FU. Another H2-blocker or proton pump inhibitor may be substituted before study entry

Sites / Locations

Brigham and Women's Hospital
Dana-Farber Cancer Institute
Massachusetts General Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Arm Label

Phase 1 Cohort 1: Photon Rad (30 Gy/12 days)+Capecitabine

Phase I Cohort 2: Photon Rad (25 Gy/11 days)+Capecitabine

Phase I Cohort 3: Photon Rad (25 Gy/5 days)+Capecitabine

All Phase I: Photon Rad+Capecitabine

Phase II: Photon Rad (MTD)+Capecitabine

Arm Description

Neoadjuvant Short-Course Photon Radiation: At dose level 1, a total dose of 30 Gy in 10 fractions (3 Gy/day) was prescribed to the 95% isodose and administered 5 days per week over 12 days. Chemotherapy: Capecitabine was given orally 825 mg/m2 BID (total 1650 mg/m2 per day) for ten consecutive weekdays, beginning on the morning of the first day of radiation therapy. Patients underwent resection of their pancreatic cancer 1-3 weeks after the completion of chemoradiation. It was recommended that patients undergoing R0 or R1 resections receive adjuvant treatment with 4-6 cycles of gemcitabine-based therapy per institutional policy, to start 4 to 10 weeks after the operation.

Neoadjuvant Short-Course Photon Radiation: At dose level 2, a total dose of 25 Gy in 5 fractions was prescribed to the 95% isodose and administered at 5 Gy per fraction over 11 days. Chemotherapy: Capecitabine was given orally 825 mg/m2 BID (total 1650 mg/m2 per day) for ten consecutive weekdays, beginning on the morning of the first day of radiation therapy. Patients underwent resection of their pancreatic cancer 1-3 weeks after the completion of chemoradiation. It was recommended that patients undergoing R0 or R1 resections receive adjuvant treatment with 4-6 cycles of gemcitabine-based therapy per institutional policy, to start 4 to 10 weeks after the operation.

Neoadjuvant Short-Course Photon Radiation: At dose level 3, a total dose of 25 Gy in 5 fractions was prescribed to the 95% isodose and administered at 5 Gy per fraction over 5 days. Chemotherapy: Capecitabine was given orally 825 mg/m2 BID (total 1650 mg/m2 per day) for ten consecutive weekdays, beginning on the morning of the first day of radiation therapy. Patients underwent resection of their pancreatic cancer 1-3 weeks after the completion of chemoradiation. It was recommended that patients undergoing R0 or R1 resections receive adjuvant treatment with 4-6 cycles of gemcitabine-based therapy per institutional policy, to start 4 to 10 weeks after the operation.

Neoadjuvant Short-Course Photon Radiation: All Phase I participants received the radiation regimen according to the established dose escalation schedule. Chemotherapy: Capecitabine was given orally 825 mg/m2 BID (total 1650 mg/m2 per day) for ten consecutive weekdays, beginning on the morning of the first day of radiation therapy. Patients underwent resection of their pancreatic cancer 1-3 weeks after the completion of chemoradiation. It was recommended that patients undergoing R0 or R1 resections receive adjuvant treatment with 4-6 cycles of gemcitabine-based therapy per institutional policy, to start 4 to 10 weeks after the operation.

Neoadjuvant Short-Course Photon Radiation: Phase II participants received the radiation regimen established in the Phase I study (MTD). Chemotherapy: Capecitabine was given orally 825 mg/m2 BID (total 1650 mg/m2 per day) for ten consecutive weekdays, beginning on the morning of the first day of radiation therapy. Patients underwent resection of their pancreatic cancer 1-3 weeks after the completion of chemoradiation. It was recommended that patients undergoing R0 or R1 resections receive adjuvant treatment with 4-6 cycles of gemcitabine-based therapy per institutional policy, to start 4 to 10 weeks after the operation.

Outcomes

Primary Outcome Measures

Neoadjuvant Short-Course Photon Radiation Therapy Maximum Tolerated Dose (MTD) [Phase I]

Neoadjuvant short-course photon radiation therapy MTD in combination with capecitabine 825 mg/m2 orally BID for ten consecutive weekdays, beginning on the morning of the first day of radiation therapy is determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If none of 3 initial patients or only 1 of 6 patients have a DLT on dose level 3 then 6 additional patients are treated at this dose. If during this expansion, the rate of DLT exceeds 30% then the next lower dose level is declared the MTD. If no DLTs are observed, the MTD is not reached.

Dose Limiting Toxicity (DLT) [Phase I]

DLT occurring within 3 weeks of the start of chemoradiation therapy was defined as: Grade 3 non-hematologic or hematologic toxicity requiring interruption of >7 days (d) of chemo or >3d chemoradiation; Grade 4 non-hematologic; Grade 4 neutropenia or thrombocytopenia; Treatment-related death; Delays in surgery >3 weeks due to treatment-related toxicity. A 30% increase in any surgical complication rate beyond those previously established rates (readmission rate: 16%; pancreatic fistula/intra-abdominal abscess/infection rate: 27%, major intra-abdominal bleeding requiring return to OR: 1.6%, delayed gastric emptying: 4.4%, and superficial wound infection rate: 8%) was also considered a DLT.

Grade 3-5 Toxicity Rate [Phase II]

All Grade 3-5 events based on CTCAEv3 related to the accelerated dose (attribution possible, probable, definite) as reported on case report forms.

Secondary Outcome Measures

Local Recurrence Rate [Phase II]

Local recurrence rate is defined as the proportion of patients with evidence of tumor recurrence within the radiation field based on RECIST criteria. Per RECIST 1.0 for target lesions, PD is at least a 20% increase in sum LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or appearance of new lesions. For non-target lesions, PD is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

Pathologic Response Rate [Phase II]

Pathologic response rate is the proportion of patients with the pathologic specimen absent any viable tumor cell. Pathological review of the pancreaticoduodenectomy specimen will be performed according to the AJCC Staging Classification, 6th edition. Initial gross evaluation and identification of resection margins will be performed jointly by the surgeon and the pathologist.

Progression-Free Survival (PFS) [Phase II]

Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. Patients alive whose disease had not progressed are censored at date of last disease evaluation

Surgical Morbidity Rate [Phase II]

The proportion of patients experienced any grade 3-4 adverse event based on CTCAEv3 related to the surgery (attribution possible, probable, definite) as reported on case report forms.

Surgical Mortality Rate [Phase II]

The proportion of patients with a death related to the surgery (CTCAEv3 attribution possible, probable, definite).

Full Information

NCT ID

NCT00889187

First Posted

April 27, 2009

Last Updated

April 12, 2018

Sponsor

Dana-Farber Cancer Institute

Collaborators

Brigham and Women's Hospital, Massachusetts General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT00889187

Brief Title

Neoadjuvant Accelerated Short Course Radiation Therapy With Photons and Capecitabine for Resectable Pancreatic Cancer

Official Title

Phase I/II Study of Neoadjuvant Accelerated Short Course Radiation Therapy With Photons and Capecitabine for Resectable Pancreatic Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

April 2018

Overall Recruitment Status

Terminated

Why Stopped

Excess toxicity was identified intraoperatively

Study Start Date

December 2009 (Actual)

Primary Completion Date

December 30, 2011 (Actual)

Study Completion Date

December 30, 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Dana-Farber Cancer Institute

Collaborators

Brigham and Women's Hospital, Massachusetts General Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this research study is to determine if it is possible to deliver high dose radiation in one week while also giving the drug capecitabine for the treatment of pancreatic cancer prior to surgery, to determine if this treatment can be given safely for the treatment of pancreatic cancer prior to surgery and, to determine if this treatment can improve the local control pancreatic cancer prior to surgery compared to historical controls of standard treatment.

Detailed Description

OBJECTIVES: Primary Phase I: To determine the feasibility and tolerability of radiation therapy for pancreatic cancer delivered with high dose external beam radiation in a one week accelerated schedule with concurrent capecitabine Phase II: To demonstrate a grade 3 or greater (any) toxicity rate of less than 20% Secondary To determine local control and recurrence patterns of pancreatic cancer relative to a standard regimen of 50.4 Gy as seen in historical controls To determine the pathologic response rate To determine the progression-free survival To determine the surgical morbidity To determine 30-day post-operative mortality after pancreatic resection

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pancreatic Cancer

Keywords

radiation therapy, capecitabine

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

10 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Phase 1 Cohort 1: Photon Rad (30 Gy/12 days)+Capecitabine

Arm Type

Experimental

Arm Description

Arm Title

Phase I Cohort 2: Photon Rad (25 Gy/11 days)+Capecitabine

Arm Type

Experimental

Arm Description

Arm Title

Phase I Cohort 3: Photon Rad (25 Gy/5 days)+Capecitabine

Arm Type

Experimental

Arm Description

Arm Title

All Phase I: Photon Rad+Capecitabine

Arm Type

Experimental

Arm Description

Arm Title

Phase II: Photon Rad (MTD)+Capecitabine

Arm Type

Experimental

Arm Description

Intervention Type

Radiation

Intervention Name(s)

Neoadjuvant Short-Course Photon Radiation

Intervention Type

Drug

Intervention Name(s)

Capecitabine

Other Intervention Name(s)

Xeloda

Primary Outcome Measure Information:

Title

Neoadjuvant Short-Course Photon Radiation Therapy Maximum Tolerated Dose (MTD) [Phase I]

Description

Time Frame

within 3 weeks of the start of chemoradiation therapy

Title

Dose Limiting Toxicity (DLT) [Phase I]

Description

Time Frame

within 3 weeks of the start of chemoradiation therapy

Title

Grade 3-5 Toxicity Rate [Phase II]

Description

All Grade 3-5 events based on CTCAEv3 related to the accelerated dose (attribution possible, probable, definite) as reported on case report forms.

Time Frame

within 3 weeks of the start of chemoradiation therapy

Secondary Outcome Measure Information:

Title

Local Recurrence Rate [Phase II]

Description

Time Frame

Disease was assessed radiologically at baseline and after treatment every 6 months for first 2 years and annually in years 3-5.

Title

Pathologic Response Rate [Phase II]

Description

Time Frame

Assessed after resection; Patients underwent resection of their pancreatic cancer up to 3 weeks after completion of chemoradiation therapy

Title

Progression-Free Survival (PFS) [Phase II]

Description

Time Frame

Disease was assessed radiologically at baseline and after treatment every 6 months for first 2 years and annually in years 3-5.

Title

Surgical Morbidity Rate [Phase II]

Description

The proportion of patients experienced any grade 3-4 adverse event based on CTCAEv3 related to the surgery (attribution possible, probable, definite) as reported on case report forms.

Time Frame

Assessed after resection; Patients underwent resection of their pancreatic cancer up to 3 weeks after completion of chemoradiation therapy

Title

Surgical Mortality Rate [Phase II]

Description

The proportion of patients with a death related to the surgery (CTCAEv3 attribution possible, probable, definite).

Time Frame

Assessed up to 30 days after resection; Patients underwent resection of their pancreatic cancer up to 3 weeks after completion of chemoradiation therapy

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Cytologic or histologic proof of pancreatic ductal carcinoma is required prior to treatment. No evidence of metastatic disease as determined by chest CT scan, abdominal CT scan (or MRI with gadolinium and/or manganese), and all patients must be staged with a physical exam, chest CT, and abdominal CT with intravenous contrast. Only potentially resectable patients are eligible. Potentially resectable is defined as: a)no extrapancreatic disease, b)no evidence (on CT) of involvement of the celiac axis or superior mesenteric artery, and c)no evidence (on CT or MRI) of occlusion of the superior mesenteric vein or superior mesenteric-portal venous confluence. 18 years of age or older ECOG Performance status of 0 or 1 Women of child bearing potential must practice adequate contraception and to refrain from breast feeding. Female patients must have a negative pregnancy test within 7 days of treatment Lab values as specified in the protocol Exclusion Criteria: Patients cannot have hepatic or peritoneal metastases detected by imaging or laparoscopy prior to chemoradiation Serious concomitant systemic disorders incompatible with the study, such as significant cardiac or pulmonary morbidity, or ongoing infection as manifested by fever Pregnant or lactating women Life expectancy < 3 months Serious, uncontrolled, concurrent infection(s) Any prior chemotherapy or radiation for treatment of the patient's pancreatic tumor Treatment for other cancers within the last five years, except cured non-melanoma skin cancer and treated in situ cervical cancer Clinically significant cardiac disease or myocardial infarction within the last 12 months Other serious uncontrolled medical conditions that the investigator feels might compromise study participation Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome Known, existing uncontrolled coagulopathy Unwillingness to participate or inability to comply with the protocol for the duration of the study Any prior fluoropyrimidine therapy (unless given in an adjuvant setting and completed at least 6 months earlier) Prior unanticipated severe reaction to fluoropyrimidine therapy, or known hypersensitivity to 5-fluorouracil or known DPD deficiency Participation in any investigational drug study within 4 weeks preceding the start of study treatment History of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance or oral drug intake Major surgery, excluding laparoscopy, within 4 weeks of the start of study treatment, without complete recovery Patients should not be on cimetidine as it can decrease the clearance of 5-FU. Another H2-blocker or proton pump inhibitor may be substituted before study entry

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Harvey Mamon, MD, PhD

Organizational Affiliation

Brigham and Women's Hospital/Dana-Farber Cancer Institute

Official's Role

Principal Investigator

Facility Information:

Facility Name

Brigham and Women's Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

Facility Name

Dana-Farber Cancer Institute

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

Facility Name

Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02214

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

24231241

Citation

Wo JY, Mamon HJ, Ferrone CR, Ryan DP, Blaszkowsky LS, Kwak EL, Tseng YD, Napolitano BN, Ancukiewicz M, Swanson RS, Lillemoe KD, Fernandez-del Castillo C, Hong TS. Phase I study of neoadjuvant accelerated short course radiation therapy with photons and capecitabine for resectable pancreatic cancer. Radiother Oncol. 2014 Jan;110(1):160-4. doi: 10.1016/j.radonc.2013.10.027. Epub 2013 Nov 11.

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Neoadjuvant Accelerated Short Course Radiation Therapy With Photons and Capecitabine for Resectable Pancreatic Cancer

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