A Study of Neoadjuvant Photodynamic Immunomodulation for Colon Cancer

A Phase I/II Study of Neoadjuvant Photodynamic Immunomodulation for Colon Cancer

The central hypothesis for this study is that it is safe and feasible to administer intraluminal photodynamic therapy (PDT) to colon cancers by colonoscopy to induce localized inflammatory/immune response. The objective is to demonstrate the feasibility and safety of PDT to colon cancer patients administered before surgery and to characterize the inflammatory/immune response at the tumor site and systemically. The long-term objective of these studies is to modify he natural biology of colorectal cancers and improve patient survival.

The central hypothesis for this study is that it is safe and feasible to administer intraluminal photodynamic therapy (PDT) to colon cancers, via colonoscopy, in the neoadjuvant setting to induce localized tumor cell death and an inflammatory/immune response with an increased Th1 component, utilizing 5-ALA as a photosensitizer. The objective is to conduct an initial phase I/II clinical study to demonstrate the feasibility and safety of colonoscopic, neoadjuvant intraluminal PDT to colon cancer patients administered 96 hours pre-resection, to characterize the inflammatory/immune response at the PDT treated tumor site, and to evaluate the systemic anti-tumor immune response. The long-term objective of these studies is to provide an easily administered, adjunctive, therapeutic maneuver that lacks systemic toxicity, with the potential to modulate the natural biology of colorectal cancers that have not elicited a favorable anti-tumor immune response and to improve patient survival.

Inclusion Criteria:

1. Patients must have a histologically proven diagnosis of colorectal cancer.
2. Have clinical stage I, II, or III disease.
3. Expected survival must be greater than twelve (12) months.
4. A Karnofsky Performance Status (KPS) must be 70 or greater (Appendix I).
5. Patients must be >21 years of age.
6. No prior therapy.
7. Female patients must not be lactating and must be surgically sterile (via hysterectomy or bilateral tubal ligation), postmenopausal, or using acceptable methods of contraception if they are of child bearing potential. Female patients of childbearing potential must also have a negative serum pregnancy test.
8. Patients must be able to understand and sign an informed consent form, which must comply with U.S. regulations (U.S. 21 CFR 50) and ICH guidelines.
9. Eligible patients must have adequate initial hematologic and coagulation parameters, hemoglobin ≥ 11g/dl, platelet count >50,000, Protime and Prothrombin Time ≤ 1.5 x normal.
10. Eligible patients must have adequate bone marrow, liver and renal function: ANC > 1500/μL, Platelets >100,000 x μL, total bilirubin < the upper limit of normal (ULN), and creatinine clearance (CrCl) > 45 mL/min

Exclusion Criteria:

1. Any co-morbidity that precludes primary surgical resection of the colorectal tumor.

2. Any significant general organ system compromise including:

   • Liver function, transaminases ≥ 2 x,
   • Renal function, Cr ≥ 1.5 x upper limit of normal
   • Pulmonary function, room air O2 saturation <90%
   • Cardiovascular function, Patients with significant (Class III or IV) cardiovascular disease according to the New York Heart Association's functional criteria (Appendix II)
   • Gastrointestinal function, i.e. active inflammatory bowel disease or active peptic ulcer disease.

3. Any contraindication to repeat colonoscopy, such as idiosyncratic reactivity to conscious sedation medications.

4. Prior treatment for the diagnosis of colorectal cancer, including surgical resection.

5. Stage IV colorectal cancer, i.e. the clinical presence of metastases

6. Prior malignant diagnosis except for the basal cell epithelioma of the skin.

7. Persistent fever greater than 38 C.

8. Mineral overload syndromes for Lead, Zinc, Copper or Iron.

9. Use of any agent that modulates 5-ALA metabolism and porphyrin synthesis, e.g. St. John's Wort.

10. Required use of corticosteroids or immune suppression for any reason including an organ allograft or HIV infection

11. Patients with any acute or chronic illness including cardiovascular disease (e.g. history of atrial fibrillation or ventricular arrhythmias) or history of myocardial infarction, autoimmune state, or any psychiatric illness that in the opinion of the Investigators would compromise treatment.

12. Use of investigational drugs within 30 days of execution of the informed consent form.