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A Phase I Study of the Combination of Gemcitabine Plus Dasatinib in Patients With Refractory Solid Tumors With an Expanded Cohort in Advanced Pancreatic Cancer


Phase 1
18 Years
N/A
Not Enrolling
Both
Refractory Solid Tumors, Pancreatic Adenocarcinoma

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Trial Information

A Phase I Study of the Combination of Gemcitabine Plus Dasatinib in Patients With Refractory Solid Tumors With an Expanded Cohort in Advanced Pancreatic Cancer


This open-label, multicenter, non-randomized phase I trial of gemcitabine plus once and
twice daily dasatinib is designed to assess the safety, tolerability, maximum tolerated
dose/recommended phase II dose, and preliminary efficacy of this combination in adult
patients with advanced solid tumors and with previously untreated metastatic pancreatic
cancer. Patients will be accrued at Duke University Medical Center, the Duke Oncology
Network, the University of North Carolina at Chapel Hill and Wake Forest Baptist Medical
Center

Patients will be accrued to either of the gemcitabine/dasatinib arms in alternating
sequential order. In the case where there is an open slot on a particular arm but not the
alternative, the enrolled patient will be assigned to that open slot. For example, at the
start of the trial, patient #1 will be treated on the gemcitabine with dasatinib twice daily
dosing arm, patient #2 on the gemcitabine with dasatinib once daily dosing arm, patient #3
on the gemcitabine with dasatinib twice daily dosing arm, and so on. However, if, due to
cohort expansion there is a slot available on one treatment arm but not the other, the
patient will be accrued to the open slot.

Additionally, if one arm is held, delayed, or not pursued, accrual to the alternate arm may
continue. Patients and their treating physicians will not be able to choose on their own
which treatment arm that patient will be assigned to. This enrollment procedure will be the
procedure for the entire trial.

For the dose escalation portion of the trial, patients will only be accrued at Duke
University Medical Center. For the expanded cohort portion of patients with previously
untreated metastatic pancreatic cancer treated at the recommended phase II dose of each arm,
patients may be accrued at Duke University Medical Center,and the sites listed above.

NOTE: The first stage closed as of December 2008. Subjects will only be enrolled into the
second stage of the this study.

- Toxicity will be assessed every visit, and as clinically indicated.

- Dose limiting toxicities will be assessed during cycle 1.

- Efficacy will be assessed every 2 cycles, and as clinically indicated.

- Plasma biomarkers will be assessed at baseline and at every restaging.

- Tissue based biomarkers (tumor and granulation tissue) will be assessed in up to 15
patients treated at Duke only. Tissue biopsy sets (a 4mm "stimulus" biopsy and a 5mm
"granulation" tissue biopsy, both in the same location) will also be done both
pre-treatment and on-treatment. Pre-treatment biopsies will be done on days -7 and 1,
respectively. On-treatment biopsies will be done on days 1 and 8, respectively.


Inclusion Criteria:



Eligibility Criteria Specific for Dose Escalation Phase

- Patients must have histologically confirmed solid tumor malignancy that is metastatic
or unresectable and for which standard therapy would include gemcitabine or for which
standard curative or palliative measures do not exist or are no longer effective.

- Patients must not have had radiation therapy, hormonal therapy, biologic therapy or
chemotherapy for cancer within the 28 days prior to study day 1.

Eligibly Criteria Specific for Expansion Phase at Recommended Phase II Dose

- Histologically or cytologically documented adenocarcinoma of the pancreas.

- Metastatic pancreatic cancer as documented by radiologic study or surgical evidence
of metastatic disease.

- No prior chemotherapy for metastatic pancreatic disease. Patients may have received
a radiosensiting dose of 5-fluorouracil or capecitabine or other agents used as
radiosensitizers with concurrent radiation therapy.

- Last dose of adjuvant chemotherapy must be at least 4 weeks prior to day 1 of the
study drug treatment

- Prior radiation therapy is allowed. prior to day 1 of the study drug treatment. At
least 4 weeks must have elapsed to baseline or grade 1.

- No prior treatment with gemcitabine or dasatinib in the adjuvant or metastatic
setting.

- Prior gemcitabine only allowed if the gemcitabine was administered in the adjuvant
setting and > 6 months has elapsed between diagnosis of metastatic disease and last
gemcitabine treatment.

- No history for other carcinomas within the last five years, except cured non-melanoma
skin cancer, curatively treated in-situ cervical cancer, or localized prostate cancer
with a current PSA of <1.0 mg/dL on 2 successive evaluations, at least 3 months
apart, with the most recent evaluation no more than 4 weeks prior to day 1 of the
study drug treatment. .

Eligibility Criteria for All Subjects

- Age >18 years.

- Karnofsky performance status >70%.

- Life expectancy of at least 3 months.

- Ability to understand and the willingness to sign a written informed consent
document.

- Must meet lab requirements as defined in the protocol

- Patients should be capable of taking oral medications for prolonged compliance.

- Sexually active women of childbearing potential must use an effective method of birth
control.

- All WOCBP MUST have a negative pregnancy test within 7 days prior to first receiving
investigational product.

- Pregnant and/or lactating women will be excluded from this study.

Exclusion Criteria:

- Patients who have had radiation therapy, hormonal therapy, biologic therapy, or
chemotherapy for cancer within 28 days prior to day 1 of the study drug treatment.
Patients receiving hormonal therapy for metastatic prostate or breast cancer may
continue hormonal therapy.

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to day 1 of the study drug treatment

- Core biopsy or other minor surgical procedure excluding study-related procedures or
placement of a vascular access device within 7 days prior to expected start of
treatment.

- Patients who have received any other investigational agents within the 28 days prior
to day 1 of the study drug treatment.

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter drug absorption

- History of myocardial infarction, unstable angina, cardiac or other vascular
stenting, angioplasty, or surgery within 6 months prior to day 1 of the study drug
treatment.

- History of stroke or transient ischemic attack within 6 months prior to day of the
study drug treatment.

- Uncontrolled congestive heart failure defined as New York Heart Association (NYHA)
class II or greater

- Known cardiomyopathy with decreased ejection fraction (less than institutional normal
limits)

- Diagnosed or congenital long QT syndrome

- Any history of clinically significant ventricular arrhythmias (such as ventricular
tachycardia, ventricular fibrillation, or Torsades de pointes)

- Prolonged QTc interval on pre-study electrocardiogram (> 450 msec)

- Patients with a history of significant bleeding episodes (e.g., hemoptysis, upper or
lower GI bleeding) within the previous 6 months of day 1 of the study drug treatment

- Evidence of bleeding diathesis or coagulopathy. Patients on therapeutic
anticoagulation may be enrolled provided that they have been clinically stable on
anti-coagulation for at least 2 weeks prior to day 1 of the study drug treatment

- History of significant bleeding disorder unrelated to cancer

- Medications that inhibit platelet function

- Fluid retention (i.e. pleural effusion, ascites, edema) grade > 2.

- A known history of HIV seropositivity, hepatitis C virus, acute or chronic active
hepatitis B infection, or other serious chronic infection requiring ongoing
treatment.

- Patients currently taking drugs that are generally accepted to have a risk of causing
Torsades de Pointes

- Patients actively taking inhibitors or inducers of CYP3A4

- Patients actively taking proton pump inhibitors or H2 antagonists

- Other concurrent severe and/or poorly controlled medical condition that could
compromise safety of treatment

- Any psychiatric illness/social situations that would limit safety or compliance with
study requirements or may interfere with the interpretation of the results.

- Patients unwilling to or unable to comply with the protocol.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

To determine the MTD/Recommended Phase II Dose (RPTD) of gemcitabine plus dasatinib once daily and twice daily dosing in patients with advanced solid tumors

Outcome Time Frame:

Phase I portion of the study

Safety Issue:

Yes

Principal Investigator

Hope C Uronis, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University

Authority:

United States: Food and Drug Administration

Study ID:

Pro00012976 (9335)

NCT ID:

NCT00598091

Start Date:

April 2007

Completion Date:

May 2012

Related Keywords:

  • Refractory Solid Tumors
  • Pancreatic Adenocarcinoma
  • Solid Tumors
  • Phase I
  • Expanded Cohort
  • Pancreatic Cancer
  • Dasatinib
  • Gemcitabine
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Pancreatic Neoplasms
  • Neoplasms

Name

Location

Duke University Medical CenterDurham, North Carolina  27710
UNC Lineberger, Comprehensive Cancer CenterChapel Hill, North Carolina  27599
Wake Forest Baptist Medical CenterWinston-Salem, North Carolina