A Trial of Gemcitabine, Infusional 5-Fluorouracil and Cisplatin for Advanced Pancreatic and Biliary Cancers

• Sponsor: University of Michigan Rogel Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01661114
• Collaborator: (none)
• Enrollment: 39
• Location: 1
• Arm: 1
• Duration (Months): 56
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

Multi-agent chemotherapy has value for patients with advanced pancreatic-biliary cancers leading to responses in a substantial minority and increasing survival. The use of the FOLFIRINOX regimen is limited by its' intensity and toxicity. Previous protocol and clinical experience within the University of Michigan Pancreatic Program leads to an expectation of tolerance and efficacy of the proposed regimen. Advantages of the proposed regimen relative to FOLFIRINOX include:

1. Substitution of gemcitabine for irinotecan. Single agent activity of gemcitabine is at least as good as irinotecan (probably better, especially when delivered by FDR [fixed-dose rate] infusion) and gemcitabine is much better tolerated with less diarrhea, nausea/emesis, myelosuppression and alopecia.

2. Deletion of leucovorin infusion and 5FU bolus injection will lessen myelosuppression, mucositis and diarrhea.

3. Substitution of cisplatin for oxaliplatin will reduce cost of therapy and avoid cold aggravated dysesthesia.

Presuming evidence of efficacy and confirmation of tolerance with the proposed regimen, the investigators believe this treatment may be more widely applicable to pancreatic-biliary cancer patients, including those with advanced disease as well as being considered for use in locally advanced and neo- and adjuvant settings.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Cancer; Biliary Cancer	Drug: Gemcitabine; Drug: 5-FU; Drug: Cisplatin	Phase 2

Detailed Description

Gemcitabine combined with 5FU may enhance the activity of 5-FU in vivo. Gemcitabine is an inhibitor of ribonucleotide reductase, an enzyme needed for synthesis of deoxynucleotides, and 5-FU interferes with dTTP synthesis by inhibition of thymidylate synthase (TS). It is likely that concomitant administration of gemcitabine and 5FU results in increased cytotoxicity by reducing intracellular dTTP thru two different mechanisms, thereby inhibiting DNA replication and repair. Platinum compounds lead to cell death by forming DNA adducts and causing double strand breaks. By inhibiting DNA synthesis and repair, both gemcitabine and 5-FU potentiate the activity of cisplatin. These interactions underlie the clinical synergism that has been observed with platinum/5FU and platinum/gemcitabine combinations.

Study Design

• Study Type: Interventional
• Actual Enrollment: 39 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Trial of Gemcitabine, Infusional 5-Fluorouracil and Cisplatin for Advanced Pancreatic and Biliary Cancers
• Study Start Date: Jul 1, 2011
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Mar 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Gemcitabine, 5-FU and Cisplatin 4 cycles - Gemcitabine, 5-FU and Cisplatin (2 months)-Continue treatment until progression of disease or intolerable toxicity	Drug: Gemcitabine; Drug: 5-FU; Other Names: 5-Fluorouracil ; Drug: Cisplatin

Outcome Measures

Primary Outcome Measures

1. The Percentage of Untreated and Previously Treated Patients That Had a Partial Response to Treatment [28 days]

   The primary objective of this clinical trial is to estimate the response rate to treatment with the triplet chemotherapy regimen of gemcitabine, infusional 5-FU, and cisplatin, in untreated and previously treated advanced pancreatic and biliary cancer patients. Partial Response (PR) is defined as At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures

1. Median Overall Survival of Previously Treated and Previously Untreated Patients [1 year]

   To assess the overall survival following treatment with gemcitabine, 5-FU and cisplatin.

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 histologic or cytologic diagnosis of pancreatic adenocarcinoma or biliary tract cancer (intrahepatic or extrahepatic cholangiocarcinoma or gallbladder carcinoma).

• Patients must have clinical/radiologic evidence of metastatic disease.

• Previous systemic therapy for metastatic disease limited to one cytotoxic chemotherapy regimen not containing cisplatin. Previous therapy for metastatic disease might have included gemcitabine or infusional 5-FU but not both agents.

• ECOG (Eastern Cooperative Oncology Group) performance status < 1 (A measure of quality of life where 0 represents asymptomatic and 5 represents death).

• Patients must have adequate bone marrow (absolute neutrophil count >1,500/mm3, platelet count >100,000/mm3) and renal function (serum creatinine < 1.25 x ULN).

• Patients must have at least one measurable lesion per RECIST criteria.

• Patients must be free of serious concomitant medical disorders incompatible with study participation including active infection requiring systemic therapy.

• Previous malignancies are permitted provided that they have been treated with curative intent and patient is without evidence of active systemic disease.

• Patients must be informed of the investigational nature of this study and provide written informed consent prior to receiving protocol treatment.

Exclusion Criteria:

• Patients with pre-existing peripheral neuropathy > grade 2 are ineligible.

• Previous systemic therapy for metastatic disease limited to one cytotoxic chemotherapy regimen not containing cisplatin.

• Previous therapy for metastatic disease might have included gemcitabine or infusional 5-FU but not both agents.

• Serious concomitant medical disorders incompatible with study participation including active infection requiring systemic therapy.

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)

None provided.

More Information

Publications

• Colucci et al., 2002, Louvet et al., 2005, Berlin et al., 2002, Cunningham et al., 2009, Heinemann et al., 2008, Valle et al., 2010

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT01661114
• Other Study ID Numbers: UMCC 2011.036; HUM 49518
• First Posted: Aug 9, 2012
• Last Update Posted: Oct 19, 2016
• Last Verified: Sep 1, 2016

• Keywords provided by University of Michigan Rogel Cancer Center: Gemcitabine, Infusional 5-Fluorouracil,Cisplatin; Advanced Pancreatic and Biliary Cancers; untreated & previously treated pancreatic & biliary cancer.
• Additional relevant MeSH terms: Biliary Tract Neoplasms; Gemcitabine; Fluorouracil

Study Results

Participant Flow

Arm/Group Title	Gemcitabine, 5-FU and Cisplatin
Arm/Group Description	4 cycles - Gemcitabine, 5-FU and Cisplatin (2 months)-Continue treatment until progression of disease or intolerable toxicity
Period Title: Overall Study
STARTED	39
COMPLETED	39
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Gemcitabine, 5-FU and Cisplatin
Arm/Group Description	4 cycles - Gemcitabine, 5-FU and Cisplatin (2 months)-Continue treatment until progression of disease or intolerable toxicity
Overall Participants	39
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	61
Sex: Female, Male (Count of Participants)
Female	16 41%
Male	23 59%

Outcome Measures

1. Primary Outcome

Title	The Percentage of Untreated and Previously Treated Patients That Had a Partial Response to Treatment
Description	The primary objective of this clinical trial is to estimate the response rate to treatment with the triplet chemotherapy regimen of gemcitabine, infusional 5-FU, and cisplatin, in untreated and previously treated advanced pancreatic and biliary cancer patients. Partial Response (PR) is defined as At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

Patients with metastatic adenocarcinoma of the pancreas or biliary tract, previously untreated or having received one cytotoxic regimen for advanced disease.

Arm/Group Title	Gemcitabine, 5-FU and Cisplatin
Arm/Group Description	4 cycles - Gemcitabine, 5-FU and Cisplatin (2 months)-Continue treatment until progression of disease or intolerable toxicity
Measure Participants	39
Untreated	40
Received Previous Treatment	7.1

2. Secondary Outcome

Title	Median Overall Survival of Previously Treated and Previously Untreated Patients
Description	To assess the overall survival following treatment with gemcitabine, 5-FU and cisplatin.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Patients with metastatic adenocarcinoma of the pancreas or biliary tract, previously untreated or having received one cytotoxic regimen for advanced disease.

Arm/Group Title	Gemcitabine, 5-FU and Cisplatin
Arm/Group Description	4 cycles - Gemcitabine, 5-FU and Cisplatin (2 months)-Continue treatment until progression of disease or intolerable toxicity
Measure Participants	39
Previously Untreated	10.3
Previously Treated	4.9

Adverse Events

Arm/Group Title	Gemcitabine, 5-FU and Cisplatin
Arm/Group Description	4 cycles - Gemcitabine, 5-FU and Cisplatin (2 months)-Continue treatment until progression of disease or intolerable toxicity
All Cause Mortality
	Gemcitabine, 5-FU and Cisplatin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Gemcitabine, 5-FU and Cisplatin
	Affected / at Risk (%)	# Events
Total	10/39 (25.6%)
Gastrointestinal disorders
Anal Ulcer	1/39 (2.6%)	1
Duodenal obstruction	1/39 (2.6%)	1
Duodenal ulcer	1/39 (2.6%)	1
Gastrointestinal disorders - Other	1/39 (2.6%)	1
Lower gastrointestinal hemorrhage	1/39 (2.6%)	1
Nausea	2/39 (5.1%)	2
Vomiting	1/39 (2.6%)	1
General disorders
Chills	1/39 (2.6%)	1
Fatigue	1/39 (2.6%)	1
Fever	2/39 (5.1%)	2
Infections and infestations
Infections and infestations - Other	2/39 (5.1%)	2
Joint infection	1/39 (2.6%)	1
Upper respiratory infection	1/39 (2.6%)	1
Injury, poisoning and procedural complications
Hip fracture	1/39 (2.6%)	1
Spinal fracture	1/39 (2.6%)	1
Nervous system disorders
Intracranial hemorrhage	1/39 (2.6%)	1
Syncope	2/39 (5.1%)	2
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/39 (2.6%)	1
Other (Not Including Serious) Adverse Events
	Gemcitabine, 5-FU and Cisplatin
	Affected / at Risk (%)	# Events
Total	39/39 (100%)
Blood and lymphatic system disorders
Anemia	36/39 (92.3%)	49
Cardiac disorders
Palpitations	1/39 (2.6%)	1
Supraventricular tachycardia	1/39 (2.6%)	2
Ear and labyrinth disorders
Ear and labyrinth disorders - Other	1/39 (2.6%)	1
Hearing impaired	1/39 (2.6%)	1
Eye disorders
Blurred vision	3/39 (7.7%)	3
Eye pain	1/39 (2.6%)	1
Gastrointestinal disorders
Abdominal distension	1/39 (2.6%)	1
Abdominal pain	8/39 (20.5%)	9
Anal ulcer	1/39 (2.6%)	1
Bloating	1/39 (2.6%)	1
Cheilitis	1/39 (2.6%)	1
Constipation	12/39 (30.8%)	14
Diarrhea	13/39 (33.3%)	18
Dry mouth	3/39 (7.7%)	3
Duodenal obstruction	2/39 (5.1%)	2
Duodenal ulcer	1/39 (2.6%)	1
Dyspepsia	1/39 (2.6%)	1
Dysphagia	1/39 (2.6%)	1
Enterocolitis	1/39 (2.6%)	1
Flatulence	3/39 (7.7%)	3
Gastroesophageal reflux disease	1/39 (2.6%)	1
Gastrointestinal disorders - Other	1/39 (2.6%)	1
Lower gastrointestinal hemorrhage	1/39 (2.6%)	1
Mucositis oral	6/39 (15.4%)	6
Nausea	24/39 (61.5%)	38
Oral dysesthesia	1/39 (2.6%)	1
Oral pain	1/39 (2.6%)	1
Pancreatitis	1/39 (2.6%)	1
Vomiting	15/39 (38.5%)	23
General disorders
Chills	3/39 (7.7%)	4
Edema face	1/39 (2.6%)	1
Edema limbs	4/39 (10.3%)	4
Facial pain	1/39 (2.6%)	1
Fatigue	26/39 (66.7%)	36
Fever	9/39 (23.1%)	10
Flu like symptoms	1/39 (2.6%)	1
Localized edema	1/39 (2.6%)	1
Neck edema	3/39 (7.7%)	3
Non-cardiac chest pain	3/39 (7.7%)	4
Pain	4/39 (10.3%)	4
Infections and infestations
Appendicitis	1/39 (2.6%)	1
Eye infection	1/39 (2.6%)	1
Infections and infestations - Other	2/39 (5.1%)	2
Joint infection	1/39 (2.6%)	1
Mucosal infection	1/39 (2.6%)	1
Papulopustular rash	1/39 (2.6%)	1
Tooth infection	2/39 (5.1%)	3
Upper respiratory infection	4/39 (10.3%)	5
Urinary tract infection	1/39 (2.6%)	1
Injury, poisoning and procedural complications
Hip fracture	1/39 (2.6%)	1
Spinal fracture	1/39 (2.6%)	1
Investigations
Alanine aminotransferase increased	7/39 (17.9%)	12
Alkaline phosphatase increased	10/39 (25.6%)	12
Aspartate aminotransferase increased	8/39 (20.5%)	11
Blood bilirubin increased	6/39 (15.4%)	10
Creatinine increased	5/39 (12.8%)	6
Lipase increased	1/39 (2.6%)	1
Lymphocyte count decreased	29/39 (74.4%)	44
Neutrophil count decreased	27/39 (69.2%)	50
Platelet count decreased	29/39 (74.4%)	53
Serum amylase increased	1/39 (2.6%)	1
Weight gain	2/39 (5.1%)	3
Weight loss	11/39 (28.2%)	14
White blood cell decreased	31/39 (79.5%)	65
Metabolism and nutrition disorders
Anorexia	13/39 (33.3%)	14
Hypercalcemia	1/39 (2.6%)	1
Hyperglycemia	21/39 (53.8%)	29
Hyperkalemia	4/39 (10.3%)	5
Hypoalbuminemia	11/39 (28.2%)	13
Hypocalcemia	13/39 (33.3%)	18
Hypoglycemia	1/39 (2.6%)	1
Hypokalemia	7/39 (17.9%)	8
Hypomagnesemia	4/39 (10.3%)	4
Hyponatremia	15/39 (38.5%)	19
Hypophosphatemia	2/39 (5.1%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	1/39 (2.6%)	1
Back pain	5/39 (12.8%)	5
Bone pain	1/39 (2.6%)	1
Flank pain	2/39 (5.1%)	2
Generalized muscle weakness	2/39 (5.1%)	2
Musculoskeletal and connective tissue disorder - Other	2/39 (5.1%)	2
Neck pain	3/39 (7.7%)	3
Pain in extremity	5/39 (12.8%)	6
Trismus	1/39 (2.6%)	1
Nervous system disorders
Dizziness	7/39 (17.9%)	7
Dysgeusia	2/39 (5.1%)	2
Headache	6/39 (15.4%)	6
Intracranial hemorrhage	1/39 (2.6%)	1
Memory impairment	1/39 (2.6%)	1
Peripheral sensory neuropathy	9/39 (23.1%)	9
Syncope	3/39 (7.7%)	3
Tremor	1/39 (2.6%)	1
Psychiatric disorders
Agitation	1/39 (2.6%)	1
Anxiety	7/39 (17.9%)	9
Depression	4/39 (10.3%)	4
Renal and urinary disorders
Urinary retention	2/39 (5.1%)	2
Urine discoloration	1/39 (2.6%)	1
Reproductive system and breast disorders
Irregular menstruation	1/39 (2.6%)	2
Pelvic pain	1/39 (2.6%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/39 (2.6%)	1
Atelectasis	1/39 (2.6%)	1
Cough	8/39 (20.5%)	8
Dyspnea	7/39 (17.9%)	9
Epistaxis	1/39 (2.6%)	1
Hoarseness	2/39 (5.1%)	2
Nasal congestion	3/39 (7.7%)	3
Pleural effusion	1/39 (2.6%)	1
Pneumonitis	1/39 (2.6%)	1
Pulmonary edema	1/39 (2.6%)	1
Sore throat	3/39 (7.7%)	3
Wheezing	3/39 (7.7%)	3
Skin and subcutaneous tissue disorders
Alopecia	3/39 (7.7%)	5
Scalp pain	1/39 (2.6%)	1
Vascular disorders
Hot flashes	2/39 (5.1%)	2
Hypertension	1/39 (2.6%)	1
Thromboembolic event	9/39 (23.1%)	9

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.