Efficacy of Doxycycline on Metakaryote Cell Death in Patients With Resectable Pancreatic Cancer

BACKGROUND AND RATIONALE:

Pancreatic tumors have two distinct cell populations -- eukaryotic tumor cells and
metakaryotic cells. The first cell type divides quickly but must stop at a certain point.
Metakaryotic cells, also called cancer stem cells, divide less frequently but have an
unlimited number of cell divisions. Chemotherapy works well on eukaryotic cells. Metakaryotic
cells are resistant to chemotherapy and radiation, so they are more difficult to eliminate.

Massachusetts Institute of Technology basic science researchers working with the Medical
College of Wisconsin pancreatic cancer group demonstrated in the laboratory that doxycycline
can kill both eukaryotic and metakaryotic cells.

This study's goal is to discover if the metakaryocidal drug doxycycline kills any significant
fraction of the metakaryotic cells found in treated pancreatic tumors. Targeting metakaryotic
cells may decrease cancer relapse and metastases. The development of antimetakaryotics is
vital for pancreatic cancer patients, who are at risk for disease recurrence and
cancer-related death.

STUDY OBJECTIVES:

Primary Objectives:

To assess the efficacy of doxycycline on inducing metakaryotic cell death in primary
pancreatic tumors from patients with resectable pancreatic cancer.

Secondary Objectives:

- To determine the plasma drug concentrations of the study drug at baseline and at days 1,
3, 5, 8, 15, 22, 29, and at restaging and at the time surgery.

- To assess the histopathologic treatment response of the primary tumors which have
undergone neoadjuvant gemcitabine based chemoradiation and concurrent doxycycline
therapy.

- To enumerate the number of observed dead/dying metakaryotes per 1 gram of resected
pancreatic tissue.

STUDY PROCEDURES:

Patients will take 100 mg doxycycline twice daily for a period of eight weeks (56 days).
Following standard-of-care (not study trial-related) chemotherapy, patients will receive
radiation therapy. Patients will receive doxycycline beginning on the first day of radiation
therapy. Following this, patients will undergo surgery four to five weeks after completion of
chemoradiation. Doxycycline will be discontinued five to seven days prior to surgery.

This study involves pharmacokinetic studies, which means that patients will have blood draws
several times so that serum levels may be evaluated.

Inclusion Criteria:

- Histologically or cytologically confirmed pancreatic adenocarcinoma which may be
acquired using a fine needle aspiration.

- Not received any prior therapy.

- Established resectable pancreatic cancer based on radiographic imaging.

- Patients who will receive neoadjuvant therapy (chemoradiation) are eligible.

- Age ≥18 years.

- ECOG performance status ≤2 (Karnofsky ≥60%).

- Have no active or chronic infection with HIV, Hepatitis B or Hepatitis C

- Life expectancy of greater than six months.

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

- Normal organ and marrow function as defined below:

1. leukocytes ≥3,000/mcL

2. absolute neutrophil count ≥1,500/mcL

3. platelets ≥100,000/mcL

4. total bilirubin < 2 mg/dL or has demonstrated progressive decline within two
weeks of biliary decompression to allow for appropriate gemcitabine dose
modification.

5. AST(SGOT)/ALT(SGPT) ≤3 × institutional upper limit of normal

6. Creatinine clearance ≥60 mL/min/1.73 m2

Exclusion Criteria:

- Patients with more clinically advanced pancreatic cancer (borderline resectable,
locally advanced, or metastatic).

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant women are excluded from this study because the effects of metakaryocidal
agents have the potential for teratogenic or abortifacient effects.

- Previous history of other malignancy (other than cured basal or squamous cell
carcinoma of the skin or cured in-situ carcinoma of the cervix) within two years of
study enrollment.

- Active or chronic HIV, hepatitis B or hepatitis C.

- Patients who are receiving other investigational drugs or enrolled in other clinical
trials.

- Inability to undergo scheduled blood acquisition per protocol.

- Drug specific exclusion including history of allergic reactions to tetracyclines.

- Prior treatment with doxycycline within a seven day washout period prior to initiating
treatment with alternate antimetakaryocidal medication.