A Study of Neoadjuvant FOLFIRINOX and FDR-Gemcitabine With Concurrent IMRT in Patients

• Sponsor: University of Michigan Rogel Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01661088
• Collaborator: (none)
• Enrollment: 25
• Location: 1
• Arm: 1
• Duration (Months): 99
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The investigators hypothesize that the combination of the FOLFIRINOX regimen (a combination of 5-fluorouracil, irinotecan and oxaliplatin chemotherapy) to provide maximal systemic disease control and FDR-gemcitabine chemotherapy with concurrent IMRT (Radiation therapy) to address local disease, will achieve a significant improvement R0 resection (Radiation oncology repeat surgeries) rate in borderline resectable (surgical) pancreatic cancer and enhance disease free and overall survival in this patient population.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Cancer	Drug: FOLFIRINOX; Radiation: Intensity-modulated radiotherapy (IMRT); Procedure: Surgical Exploration	Phase 2

Detailed Description

Gemcitabine has been the cornerstone of systemic therapy for pancreas cancer over this past decade. Recently, a combination of 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) was reported to have significant efficacy in advanced pancreatic cancer. Preclinical data suggests synergy between irinotecan and 5FU as well as between oxaliplatin and 5FU. Results of a phase II trial in advanced disease were reported in 2005 demonstrating a 26% confirmed response rate and median overall survival of 10.2 months. A follow-up phase III trial comparing FOLFIRINOX with gemcitabine for patients <75 years of age with advanced pancreatic cancer was presented at ASCO 2010 revealing improvement in PFS (6.4 vs 3.3 months, p=<.0001) and improved disease control rate (CR+PR+SD) (70.2% vs 50.9%, p=.0003). The most notable result was an impressive improvement in median overall survival with FOLFIRINOX compared to gemcitabine (11.1vs 6.8 months, p-value = <.0001, HR=.57). The main toxicity was grade 3/4 neutropenia (45.7% vs 18.7%, p=.0001) and increased risk of febrile neutropenia (5.4% vs 0.6%, p=.009)31.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Neoadjuvant FOLFIRINOX and FDR-Gemcitabine With Concurrent IMRT in Patients With Borderline Resectable Pancreatic Cancer
• Study Start Date: Jun 1, 2011
• Actual Primary Completion Date: Aug 10, 2017
• Actual Study Completion Date: Aug 30, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Study Treatment Patients will receive FOLFIRINOX x 6 followed by IMRT concurrent with fixed dose rate (FDR)-gemcitabine (1g/m^2) on days 1, 8, 22, 29. Intensity-modulated radiotherapy (IMRT): The prescribed dose was 50.0Gy in 2.0Gy per fraction. Patients without metastatic disease will be offered surgical exploration.

Drug: FOLFIRINOX; Starting dose levels as following: Oxaliplatin 85mg/m2 intravenously over 120 minutes on day 1. Irinotecan 180mg/m2 intravenously over 90 minutes on day 1. NOTE: patients homozygous for the UGT1A1 (TA)7 promoter allele will be treated at an initial lower dose 140mg/m2 (please see Section 6.3.a) Leucovorin 400mg/m2 intravenously over 90 minutes on day 1. 5FU 400mg/m2 as bolus intravenous injection following leucovorin on day 1. 5FU 2,400mg/m2 infused intravenously as a continuous infusion over 46 hours following the bolus 5FU, beginning on day 1.; Radiation: Intensity-modulated radiotherapy (IMRT); 50.0Gy in 2.0Gy per fraction; Procedure: Surgical Exploration; Patients without metastatic disease will be offered surgical exploration.

Outcome Measures

Primary Outcome Measures

1. The Percentage of Patients That Underwent an R0 Resection [6 months]

   To determine the frequency of achieving an R0 resection using a neoadjuvant regimen of FOLFIRINOX followed by IMRT concurrent with fixed dose rate (FDR)-gemcitabine in patients with borderline resectable pancreatic cancer. R0 resection indicates a microscopically margin-negative resection, in which no gross or microscopic tumor remains in the primary tumor bed.

Secondary Outcome Measures

1. Median Progression-free Survival Time [up to 2 years]

   To estimate progression-free survival as a function of time from study enrollment. Progression is defined as at least a 20% increase in the LD (longest diameter) of the primary lesion or the appearance of one or more new lesions

2. Median Overall Survival Time [up to 2 years]

   To estimate overall survival as a function of time from study enrollment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have cytologic or histologic confirmation of carcinoma arising in the pancreas.

• Patients must be deemed to have borderline resectable disease with no radiologic evidence of distant metastatic disease prior to registration.

• Specifically, patients must have at least one designation of borderline resectable and no designation of unresectable disease.

• Patients must have a life expectancy of at least 12 weeks, a Zubrod performance status of < 1 and be willing and medically able to undergo surgical resection.

• Patients must have adequate organ function defined as follows: absolute neutrophil count of > 1500/mm3, platelets > 100,000/mm3, serum Cr < 1.5 mg/dl, total bilirubin < 2.0 mg/dl with relief of biliary obstruction if present (PTC tube or endobiliary stent).

• Patients must be free of other active systemic malignancy, ongoing infection, or any other serious uncontrolled, concomitant systemic disorders or psychiatric condition that would interfere with the safe delivery of protocol therapy.

• Patients of reproductive potential must agree to use an effective contraceptive method during participation in this trial due to the unacceptable teratogenic toxicity of abdominal radiation and cytotoxic chemotherapy.

• Patients must be aware of the investigational nature of the therapy and provide written informed consent.

Exclusion Criteria:

• Patients with neuroendocrine tumors are excluded.

• Active systemic malignancy, ongoing infection, or any other serious uncontrolled, concomitant systemic disorders or psychiatric condition that would interfere with the safe delivery of protocol therapy.

• Patients with preexisting peripheral neuropathy > grade 2 are ineligible

• Pregnant or nursing women are ineligible.

• Patients must have no history of previous chemotherapy for pancreatic cancer or any abdominal radiation therapy.

• Patients may not have used any investigational agent within 4 weeks prior to enrollment into the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109

Sponsors and Collaborators

• University of Michigan Rogel Cancer Center

Investigators

• Principal Investigator: Mark Zalupski, MD, University of Michigan Rogel Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 14, 2016

More Information

Publications

None provided.

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT01661088
• Other Study ID Numbers: UMCC 2011.007; HUM 47389
• First Posted: Aug 9, 2012
• Last Update Posted: Nov 13, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by University of Michigan Rogel Cancer Center: Neoadjuvant FOLFIRINOX; FDR-Gemcitabine; Concurrent; IMRT; Borderline Resectable Pancreatic Cancer
• Additional relevant MeSH terms: Pancreatic Neoplasms; Folfirinox

Study Results

Participant Flow

Arm/Group Title	Study Treatment
Arm/Group Description	Patients received FOLFIRINOX x 6 followed by IMRT concurrent with fixed dose rate (FDR)-gemcitabine (1g/m^2) on days 1, 8, 22, 29. Intensity-modulated radiotherapy (IMRT): The prescribed dose was 50.0Gy in 2.0Gy per fraction. Patients without metastatic disease were offered surgical exploration.
Period Title: FOLFIRINOX
STARTED	25
COMPLETED	21
NOT COMPLETED	4
Period Title: FOLFIRINOX
STARTED	21
COMPLETED	19
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Study Treatment
Arm/Group Description	Patients received FOLFIRINOX x 6 followed by IMRT concurrent with fixed dose rate (FDR)-gemcitabine (1g/m^2) on days 1, 8, 22, 29. Intensity-modulated radiotherapy (IMRT): The prescribed dose was 50.0Gy in 2.0Gy per fraction. Patients without metastatic disease were offered surgical exploration.
Overall Participants	25
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60
Sex: Female, Male (Count of Participants)
Female	9 36%
Male	16 64%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 8%
Not Hispanic or Latino	23 92%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	The Percentage of Patients That Underwent an R0 Resection
Description	To determine the frequency of achieving an R0 resection using a neoadjuvant regimen of FOLFIRINOX followed by IMRT concurrent with fixed dose rate (FDR)-gemcitabine in patients with borderline resectable pancreatic cancer. R0 resection indicates a microscopically margin-negative resection, in which no gross or microscopic tumor remains in the primary tumor bed.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Treatment
Arm/Group Description	Patients received FOLFIRINOX x 6 followed by IMRT concurrent with fixed dose rate (FDR)-gemcitabine (1g/m^2) on days 1, 8, 22, 29. Intensity-modulated radiotherapy (IMRT): The prescribed dose was 50.0Gy in 2.0Gy per fraction. Patients without metastatic disease were offered surgical exploration.
Measure Participants	25
Number [percentage of patients]	52

2. Secondary Outcome

Title	Median Progression-free Survival Time
Description	To estimate progression-free survival as a function of time from study enrollment. Progression is defined as at least a 20% increase in the LD (longest diameter) of the primary lesion or the appearance of one or more new lesions
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Treatment
Arm/Group Description	Patients received FOLFIRINOX x 6 followed by IMRT concurrent with fixed dose rate (FDR)-gemcitabine (1g/m^2) on days 1, 8, 22, 29. Intensity-modulated radiotherapy (IMRT): The prescribed dose was 50.0Gy in 2.0Gy per fraction. Patients without metastatic disease were offered surgical exploration.
Measure Participants	25
Median (95% Confidence Interval) [months]	13.1

3. Secondary Outcome

Title	Median Overall Survival Time
Description	To estimate overall survival as a function of time from study enrollment.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Treatment
Arm/Group Description	Patients received FOLFIRINOX x 6 followed by IMRT concurrent with fixed dose rate (FDR)-gemcitabine (1g/m^2) on days 1, 8, 22, 29. Intensity-modulated radiotherapy (IMRT): The prescribed dose was 50.0Gy in 2.0Gy per fraction. Patients without metastatic disease were offered surgical exploration.
Measure Participants	25
Median (95% Confidence Interval) [months]	24.4

Adverse Events

Time Frame	30 days post treatment
Arm/Group Title	Study Treatment
Arm/Group Description	Patients received FOLFIRINOX x 6 followed by IMRT concurrent with fixed dose rate (FDR)-gemcitabine (1g/m^2) on days 1, 8, 22, 29. Intensity-modulated radiotherapy (IMRT): The prescribed dose was 50.0Gy in 2.0Gy per fraction. Patients without metastatic disease were offered surgical exploration.
All Cause Mortality
	Study Treatment
	Affected / at Risk (%)	# Events
Total	1/25 (4%)
Serious Adverse Events
	Study Treatment
	Affected / at Risk (%)	# Events
Total	6/25 (24%)
Blood and lymphatic system disorders
Febrile neutropenia	1/25 (4%)	1
Cardiac disorders
Cardiac arrest	1/25 (4%)	1
Chest pain - cardiac	1/25 (4%)	1
Gastrointestinal disorders
Esophagitis	1/25 (4%)	1
Gastrointestinal disorders - Other	1/25 (4%)	1
Lower gastrointestinal hemorrhage	1/25 (4%)	1
Nausea	2/25 (8%)	2
Vomiting	2/25 (8%)	2
Infections and infestations
Lung infection	1/25 (4%)	1
Nervous system disorders
Dysphasia	1/25 (4%)	1
Other (Not Including Serious) Adverse Events
	Study Treatment
	Affected / at Risk (%)	# Events
Total	21/25 (84%)
Blood and lymphatic system disorders
Anemia	4/25 (16%)	6
Febrile neutropenia	1/25 (4%)	1
Gastrointestinal disorders
Abdominal distension	1/25 (4%)	1
Abdominal pain	5/25 (20%)	5
Diarrhea	6/25 (24%)	6
Mucositis oral	2/25 (8%)	2
Nausea	4/25 (16%)	6
Stomach pain	1/25 (4%)	1
Vomiting	3/25 (12%)	4
General disorders
Chills	1/25 (4%)	1
Fatigue	4/25 (16%)	5
Fever	1/25 (4%)	1
Non-cardiac chest pain	1/25 (4%)	1
Hepatobiliary disorders
Bile duct stenosis	1/25 (4%)	1
Cholecystitis	1/25 (4%)	2
Infections and infestations
Abdominal infection	1/25 (4%)	1
Biliary tract infection	2/25 (8%)	3
Skin infection	1/25 (4%)	1
Urinary tract infection	1/25 (4%)	1
Investigations
Alanine aminotransferase increased	4/25 (16%)	5
Alkaline phosphatase increased	1/25 (4%)	2
Aspartate aminotransferase increased	4/25 (16%)	4
Blood bilirubin increased	1/25 (4%)	1
Lymphocyte count decreased	8/25 (32%)	14
Lymphocyte count increased	1/25 (4%)	1
Neutrophil count decreased	10/25 (40%)	15
Platelet count decreased	3/25 (12%)	5
White blood cell decreased	9/25 (36%)	10
Metabolism and nutrition disorders
Anorexia	2/25 (8%)	2
Dehydration	1/25 (4%)	1
Hyperglycemia	6/25 (24%)	10
Hypoalbuminemia	1/25 (4%)	1
Hypocalcemia	1/25 (4%)	1
Hypoglycemia	1/25 (4%)	1
Hypokalemia	1/25 (4%)	1
Hyponatremia	1/25 (4%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/25 (4%)	1
Nervous system disorders
Ataxia	1/25 (4%)	1
Dysarthria	1/25 (4%)	1
Dysgeusia	1/25 (4%)	1
Extrapyramidal disorder	1/25 (4%)	1
Paresthesia	1/25 (4%)	1
Peripheral motor neuropathy	1/25 (4%)	1
Peripheral sensory neuropathy	1/25 (4%)	1
Psychiatric disorders
Anxiety	1/25 (4%)	1
Skin and subcutaneous tissue disorders
Dry skin	1/25 (4%)	1
Vascular disorders
Hypertension	1/25 (4%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.