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Phase II Study for Inoperable Non-Metastatic Pancreatic Cancer (Stage IVA) With Neoadjuvant Gemzar, Taxotere and Xeloda (GTX), and Radiation With Gemzar

Phase 2
18 Years
Open (Enrolling)
Pancreatic Cancer Stage IVA

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Trial Information

Phase II Study for Inoperable Non-Metastatic Pancreatic Cancer (Stage IVA) With Neoadjuvant Gemzar, Taxotere and Xeloda (GTX), and Radiation With Gemzar

The evolution of our regimen, consisting of Gemzar, Taxotere and Xeloda (oral 5FU) (GTX),
was carefully developed over the past three years from laboratory and clinical work.
Initially, in collaboration with Dr. William Sherman of the Division of Medical Oncology we
assessed the clinical effects of two agents, Gemzar and Taxotere in pancreatic cancer
patients. In our in vitro studies we found that as single agents these drugs (Gemzar and
Taxotere) were minimally effective against pancreatic carcinoma lines, which expressed
mutant p53 and activated mutated ras. Activated or mutant ras is found in approximately 95%
of all pancreatic carcinomas. However, when the agents were added together in tissue culture
experiments we found that their activity was additive. The clinical study performed at
Columbia Presbyterian Medical Center demonstrated a 27% objective response rate by CT scan
including one complete response with intent to treat analysis of all 15 patients within the
study. The majority of these patients had metastatic liver disease and a minority had
inoperable pancreatic carcinoma without liver metastases. Though this was a small single
arm, single institution study it did suggest a trend towards improved responses in patients
with this disease when these two agents were combined. In addition, valuable lessons were
learned from the in vitro work with Gemzar and Taxotere. Importantly, we found that this
combination was equally toxic to mutant and wild type p53 pancreatic cancer cells, as well
as to cells with mutant ras. Also, docetaxel pharmacokinetics are more favorable and have
distinct advantages over the use of the other taxane known as paclitaxel. They are the
following: 1) Taxotere enters tumor cells more efficiently than paclitaxel because it is
more lipophilic; 2) Taxotere is not pumped out by the cell by P-glycoprotein as efficiently
as paclitaxel; 3) Taxotere' half life was significantly longer than that of paclitaxel such
that a 60 minute infusion of Taxotere gives you approximate pharmacokinetics as paclitaxel
when administered as a 24 hour continuous infusion. These laboratory studies from the
literature formed the rationale for our use of Taxotere (docetaxel) instead of paclitaxel.

After our initial clinical and laboratory study we went back to the laboratory to
investigate further some of the properties of Gemcitabine, Taxotere added to Xeloda (5-DFUR)
in vitro to maximize biochemical synergy and to minimize toxicity. We found important
characteristics of these drug combinations against pancreatic cancer cells that have been
synthesized into the current protocol. We found that there was sequence specificity for
these drugs in that 5-DFUR should precede Gemzar by 72 to 96 hours and Gemzar should be
added before Taxotere to achieve maximum synergy. Taxotere cytotoxicity was dose dependent
up to 20 nM but then no further cell kill was obtained past that point. This would mean that
one would not need to use high dose Taxotere in a regimen because it would be doubtful
whether increased doses would obtain further cell kill in a linear scale.

We investigated many different combinations of these 3 agents in the laboratory to determine
the best combination to achieve biochemical synergy while decreasing the concentration of
each drug and not lose anti-tumor effect so as to decrease toxicity to patients.

Inclusion Criteria:

- Histologically confirmed adenocarcinoma of pancreas localized to the pancreas, small
bowel, stomach and/or encasing the superior mesenteric artery, vein or portal vein.
(a.k.a. Stage IV A).

- No prior chemotherapy for their pancreatic cancer or radiation to the area of the

- Measurable disease: Any mass reproducibly measurable in two perpendicular diameters
by x-ray, physical examination, CT or MRI scans.

- Ineligible for other high priority national or institutional studies

- Whipple surgery not allowed. Prior surgery is allowed as long as it was not
pancreatic resection (i.e. Whipple surgery) and the time from surgical recovery is
greater than three weeks.

- Non pregnant females who are not breast feeding with a negative serum β-HCG test
within 1 week of starting the study. Men and women of childbearing potential must be
willing to consent to using effective contraception while on treatment and for a
reasonable period thereafter.

- Clinical Parameters

- Life expectancy > 2 months.

- Age 18 to 70 years old

- Performance status 0-2 (ECOG). (See Appendix IV)

- Peripheral Neuropathy must be < grade 1

- Able to tolerate oral medications

- Absolute Neutrophil Count > 1,500 μl

- White Blood Count > 3,000/μl

- Platelet count > 100,000/μl

- BUN < 1.5 x normal

- Creatinine < 1.5 normal

- Hemoglobin > 8.0 g/dl

- Serum Albumin > 2.5 mg/dl

- Total Bilirubin < 5.0 mg/dl

- SGOT, SGPT, Alkaline Phosphatase < 4.0 x ULN

- Hypersensitivity: Patients with a history of severe hypersensitivity reaction to
Taxotere® or other drugs formulated with polysorbate 80 must be excluded.

- Informed Consent: Each patient must be completely aware of the nature of his/her
disease process and must willingly give consent after being informed of the
experimental nature of the therapy, alternatives, potential benefits, side-effects,
risks, and discomforts.

- Prior malignancies in last 5 years other than: curatively treated carcinoma in-situ
of the cervix, non-melanoma skin cancer, prostate or DCIS (ductal carcinoma in-situ)
previously treated successfully (cancer free)

- No serious medical or psychiatric illness preventing informed consent or intensive
treatment (e.g., serious infection).

- Patients known to have HIV will be excluded.

- Patients cannot have received any prior investigational agent/therapy, nor will they
be allowed any investigational agent/therapy while on protocol.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Conversion rate of inoperable to operable

Outcome Time Frame:

10 weeks

Safety Issue:


Principal Investigator

Robert L Fine, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Columbia University


United States: Institutional Review Board

Study ID:




Start Date:

June 2005

Completion Date:

December 2014

Related Keywords:

  • Pancreatic Cancer Stage IVA
  • Pancreatic Neoplasms



Columbia University Medical CenterNew York, New York  10032