Safety and Tolerability of NOX66 in Combination With Palliative Radiotherapy in Patients With Late-Stage Prostate Cancer

The study is intended as a Proof of Concept and dose confirmation study. The primary objective of this study is to observe safety and tolerability of idronoxil (NOX66) in combination with radiotherapy (at palliative doses) in patients with metastatic castrate-resistant prostate cancer (CRPC) and to confirm dose in order to progress to Phase 2/3.

This study will investigate three escalating doses of NOX66 in combination with palliative dose of radiation therapy to establish safety profile and / or obtain efficacy signals and to determine the optimal dose for future radiation therapy combination studies.

The key hypotheses to be tested in this study are:

1. That NOX66 can be safely added to palliative dose radiation therapy.
2. That NOX66 may sensitise tumours to palliative doses of radiation therapy
3. That NOX66 in combination with radiation therapy may trigger or augment an abscopal effect

Participants will have a minimum of 1 symptomatic lesion amenable to radiation therapy.

Radiation therapy will be delivered at a 20Gy dosage over 5 fractions. NOX66 will be taken on 13 consecutive days starting 1 day prior to radiotherapy.

The response of irradiated and non-irradiated target tumour lesions will be measured by CT/MRI scan and RECIST1.1 criteria at three time points post treatment. Pain response will be evaluated using the Brief Pain Inventory-Short Form (BPI-SF) instrument at five time points post treatment.

Patients will be suitable for the study as they become indicated for palliative radiation therapy for management of their cancer.

This study will enrol up to 24 patients in 3 NOX66 dose level cohorts of 4 patients (n=12) and an expansion cohort of 12 patients. Dose escalation decisions will be based on patients who experience adverse events directly related to NOX66 treatment.

Following the review of accumulated safety data, disease status and treatment efficacy signals at WEEK 6 for the first 12 patients, the Study Steering Committee will determine the dose at which to continue treatment for the expansion patient Cohort 4 in the study. A further 12 patients will be recruited at this dose level.

Eligibility Criteria:
Inclusion Criteria:

1. Provision of informed consent
2. ≥ 18 years of age
3. Histologically confirmed prostate cancer and/or PSA of \>100 ng/mL at original diagnosis
4. Metastatic disease evidenced by either CT/MRI imaging or bone scan
5. Objective evidence of disease progression as defined by either:

   i. Radiographic progression of in nodal or visceral metastases and bone disease progression with 2 or more new lesions ii. Rising PSA value ≥2ng/ml in at least 3 measurements, at least 1 week apart, with castrate levels of serum testosterone.
6. Eligible to receive palliative radiation therapy for management of disease
7. At least one symptomatic lesion which is suitable for radiation therapy
8. ECOG Performance status 0-2
9. A minimum life expectancy of 24 weeks
10. Adequate bone marrow, hepatic and renal function as evidenced by:

    * Absolute neutrophil count (ANC) \> 1.5 x 109/L
    * Platelet count \> 100 x 109/L
    * Hemoglobin \> 9.0 g/dL
    * Serum bilirubin \< 1.5 x ULN
    * AST/ALT (SGOT/SGPT) \< 2.5 x ULN for the reference laboratory or \< 5 x ULN in the presence of liver metastases
    * Serum creatinine \< 1.5 x ULN
11. Ongoing androgen deprivation therapy with luteinizing hormone-releasing hormone (LHRH) agonist or antagonist
12. At least 4 weeks must have elapsed prior to commencement of NOX66 treatment since prior chemotherapy, investigational drug or biologic therapy and any toxicity associated with these treatments has recovered to ≤ NCI-CTCAE (version 4.03) Grade 1.
13. At least 21 days must have elapsed following major surgery and any surgical incision should be completely healed.

Exclusion Criteria:

1. Tumour involvement of the central nervous system
2. Uncontrolled infection or systemic disease
3. Clinically significant cardiac disease not well controlled with medication (e.g. congestive heart failure, symptomatic coronary artery disease, angina, and cardiac arrhythmias) or myocardial infarction within the last 12 months

   • Patients with a QTc \> 470 msec on screening ECG
4. Concurrent systemic chemotherapy or biological therapy
5. Any situation where the use of suppository therapy is contra-indicated or impractical (eg. chronic diarrhoea, colostomy, ulcerative colitis).
6. Known human immunodeficiency virus (HIV) or Hepatitis B or C (active, previously treated or both)
7. Any subject whose testosterone is not suppressed i.e. is \> 0.5nmols/L
8. Any other reason which, in the opinion of the investigator, will preclude suitable participation in the study.