Hyperpolarized Pyruvate Injection in Subjects With Prostate Cancer

A Phase 1 Ascending-dose Study to Assess the Safety and Tolerability and Imaging Potential of Hyperpolarized Pyruvate (13C) Injection in Subjects With Prostate Cancer

Current imaging options do not assess prostate cancer well. This study will combine two magnetic resonance imaging modalities, MRI and MRSI, in order to determine the utility to physicians and patients with prostate cancer in making treatment decisions and seeing how well various types of treatment work. Hyperpolarized pyruvate (13C) is an investigational product that may enhance the imaging capability of MRI and MRSI. Hyperpolarized pyruvate will be injected into the body to determine how it is metabolized and how it's metabolism can be assessed using MR imaging.

The purpose of this study is to determine the safety and metabolism of hyperpolarized pyruvate in humans, and how this can be used to increase the effectiveness of MR imaging with regards to patient care.

This is a phase 1 clinical study of an investigational medicinal product (IMP), hyperpolarized Pyruvate (13C) Injection. The study includes the acquisition of magnetic resonance (MR) data and will be performed in men with prostate cancer and intact prostates.

A standard dose-escalation design will be used; initially, 6 subjects will receive IMP at each dose level. As data on both the dynamics of arrival of the IMP and potential imaging efficacy are needed at each dose level, requiring the use of separate MR acquisition sequences, a modified 3+3 design will be applied in each dose cohort. The first 3 subjects will undergo dynamic 13C imaging to define the kinetics of delivery and metabolism of IMP, and the second 3 subjects will undergo 13C MR spectroscopic imaging (MRSI) to obtain 3-dimensional (3-D) spatial information about metabolism of IMP in regions of the prostate with and without cancer involvement.

After the apparent maximum tolerated dose (MTD) has been established, there will be an expansion of the 3-D imaging cohort to 6 subjects (9 subjects in total at this dose level) to obtain additional information regarding safety at the MTD. If >2 subjects from this cohort of 9 subjects experience a dose-limiting toxicity (DLT), the next lower dose will be defined as the MTD. At the dose level with the highest contrast to noise ratio (dose level less than or equal to the MTD) there will be an expansion of the imaging cohort to include another 15 subjects for a total of 18 subjects who undergo 13C 3-D scanning at this dose, to obtain exploratory information concerning the time course and SNR (signal to noise ratio) of the presence of hyperpolarized [1 13C] pyruvate and its metabolites in regions of cancer and benign prostate tissues. The information provided by these data will be used to develop the MR imaging protocol for future clinical trials that will seek to address the sensitivity and specificity of the technology.

INCLUSION CRITERIA:

1. The subject has biopsy-proven prostate cancer and is either undergoing active surveillance ("watchful waiting") or pre primary local treatment for prostate cancer (i.e., prior to either radiation therapy or radical prostatectomy).

2. The subject is able and willing to comply with study procedures and provide signed and dated informed consent.

3. The subject has concordant MRI/1H MRSI findings from a prior MR staging exam performed within 8 weeks of the 13C MRSI exam performed in this study with IMP, or is willing to undergo MRI/1H MRSI in connection with the study exam.

4. Negative test for hepatitis B and hepatitis C.

5. Eastern Cooperative Oncology Group Performance Status of 0 or 1.

6. Laboratory criteria for protocol entry:

   • Absolute neutrophil count (ANC) >/= 1500 cells/microLiters
   • Hemoglobin >/= 9.0 gm/dL
   • Platelets >/= 100,000 cells/microLiters
   • Estimated creatinine clearance >/= 60 mL/min (by the Cockcroft Gault equation)
   • Bilirubin within normal range
   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) within normal range

7. Willing to use contraception during and for 1 month after completion of the study.

EXCLUSION CRITERIA:

1. The subject has received, or is scheduled to receive, another IMP from 1 month before to 1 month after inclusion in this study.
2. Current or prior androgen deprivation therapy; previous use of a 5-alpha reductase inhibitor is allowed, provided it was discontinued at least 1 month prior to study entry.
3. Poorly controlled hypertension, with blood pressure at study entry >150/90.
4. Contraindication for or inability to tolerate MRI examination.
5. Prostate biopsy within 12 weeks prior to study entry.
6. BMI of less than 18.5 or greater than 32. At the 0.43 ml/kg dose, subject body weight should be less than or equal to 100 kg owing to limitations in the amount of IMP available.
7. Congestive heart failure or New York Heart Association (NYHA) status >2.
8. A past or present medical history of clinically significant electrocardiogram (EKG) abnormalities, including QT prolongation, a family history of prolonged QT interval syndrome, or myocardial infarction (MI) less than 1 year ago with ensuing unstable EKG.
9. Ongoing acute or chronic pulmonary bronchospastic disease, including a history of chronic obstructive pulmonary disease or asthma, with an exacerbation within the past year.