This pilot phase II study is designed as a test and retest study to investigate [F 18]HX4 as a reliable non-invasive PET imaging marker for detection of tumor hypoxia regions and to establish a threshold for [F 18]HX4 uptake in the tumor. The study will evaluate the relationship between hypoxia biomarkers (HIF1α and CA-IX) by immunohistochemistry (IHC) and tumor uptake of [F 18]HX4 by PET imaging.

A Pilot Phase II Study

The primary objectives for this study are:

• To test the reproducibility of [F-18] HX-4 uptake in tumors by imaging the same patient on sequential days in a test-retest protocol
• To test and confirm the relationship between hypoxia in tumors measured by hypoxia related biomarkers (HIF1α and CA-IX) with immunohistochemistry (IHC) and regional [F-18 HX-4] uptake in tumors with PET/CT.

The secondary objectives for this study are:

• To continue safety evaluation by the collection of safety data from all patients
• To establish the threshold for hypoxia uptake in [F- 18]HX4 PET imaging
• To collect data to test [F-18]HX4 PET imaging as a predictor of response in a subgroup of patients receiving treatment
• To gain experience with [F-18]HX4 PET/CT in order to improve the study design to conduct future studies

Design: An open label, non-randomized, uncontrolled, single group assignment, pilot efficacy study

Procedures: Informed consent, collection of demographic information, medical history, blood labs, physical examination, vital signs, ECGs, two or three sets of [F-18]HX4 dosing and imaging scans including two pretreatment, and one mid-treatment if [F-18]HX4 tumor/background ratio ≥ 1.3 from pre-treatment scans, one pre-treatment [F-18]FDG, one mid-treatment if [F- 18]HX4 tumor/background ratio ≥1.3 from pre-treatment scans, concomitant medication collection, adverse event monitoring, and assessment of tumor response to treatment

Patients: Approximately forty (40) patients who have diagnosis confirmed by histopathological examination of tumor tissue from head/neck, lung, liver, rectal or cervical cancers and will receive chemotherapy, radiation therapy or chemoradiotherapy. This allows for approximately 30 evaluable patients to complete this study at approximately six sites.

Inclusion Criteria:

• Patient is >18 years and male or female of any race / ethnicity

• Patient or patient's legally acceptable representative provides written informed consent and is willing to comply with protocol procedures

• Patient must have histopathologically confirmed head/neck, lung, liver, rectal or cervical cancer with tumor size ≥ 3cm

• Patient has tumor tissue samples available before treatment for future immunohistochemistry biomarker tests (HIF1alpha and CA-IX)

• Patient is scheduled to have or already had a clinical [F 18]FDG PET/CT scan recommended to be within 14 days of the first pre-treatment [F 18]HX4 PET/CT scan and have no treatment intervention in between these two scans

• Patient is scheduled or is intended to be scheduled to receive chemotherapy, radiation or chemoradiotherapy treatment(s) after the pre-treatment [F 18]HX4 PET/CT and [F 18]FDG PET/CT scans for his/her cancer care

• Patient must have hepatic and renal functions as defined by laboratory results within the following ranges:

  • Total bilirubin within 2 times institutional upper limit of normal
  • AST (SGOT) and ALT (SGPT) ≤ 2.5 times institutional upper limits of normal
  • Serum creatinine ≤ 2.5 times institutional limit of normal
  • BUN within 2 times institutional upper limit of normal

Exclusion Criteria:

• Patient is not capable of complying with study procedures

• Female patient is pregnant or nursing

  o Exclude the possibility of pregnancy by one of the following:

  • Confirming in medical history that the patient is post-menopausal for a minimum of one year, or surgically sterile
  • Confirming the patient is using one of the following methods of birth control for a minimum of one month prior to entry into this study: IUD, oral contraceptives, Depo-Provera, or Norplant
  • Confirming a negative urine dipstick test taken the morning of but before receiving [F 18]HX4

• Patient has been involved in an investigative, radioactive research procedure within 7 days and during the study participation period

• Patient has any other condition or personal circumstance that, in the judgment of the investigator, might interfere with the collection of complete data

A total of 50 patients were enrolled. A total of 42 patients received at least one dose of [F-18]HX4. Thirty-nine (39) patients completed two pre-treatment [F-18]HX4 PET/CT scans. Thirty (30) patients had an evaluable tumor response assessment 3 (±1) months after treatment start