Safety, PK and Efficacy of NOX66 as a Monotherapy and Combined With Carboplatin in Refractory Solid Tumours

Phase Ia/Ib and Potential Phase IIa Study of the Safety and Pharmacokinetics of NOX66 Both as a Monotherapy and in Combination With Carboplatin in Patients With Refractory Solid Tumours

The study evaluates the safety and activity of NOX66 in patients with refractory solid tumors that are non responsive to standard therapies.

This is a two part with a potential third part, open-label, multicenter, dose escalation study of NOX66 as monotherapy and in combination with carboplatin.

Idronoxil is a synthetic small molecule that pre-clinical studies have identified as a strong candidate for development as a chemo-sensitising drug.

Human studies using idronoxil administered in oral and intravenous dosage forms have shown that the drug is highly susceptible to Phase 2 metabolism, resulting in loss of bio-activity.

NOX66 is idronoxil in a new dosage formulation developed specifically to protect the drug from Phase 2 metabolism and thereby ensure retention of the majority of administered drug in a bio-active form.

The main purpose of the current study is to confirm the safety of the new dosage formula both as a monotherapy and in combination with carboplatin, given that it is anticipated that the drug will be present in the body in a bio-active form at considerably higher levels than previously achieved.

A secondary objective is to observe if NOX66 is able to restore response to carboplatin in tumours considered unresponsive to this chemotherapy, and moreover to provide a meaningful clinical benefit in combination with a lower-than-normal dosage of carboplatin.

Patients will be drawn from 5 cancer types: prostate cancer, lung cancer, breast cancer, ovarian cancer, head and neck cancer.

The study will commence with a Phase 1a (Run-in) arm comparing the relative tolerability and safety of two different dosages of idronoxil/NOX66 as a 14-day monotherapy course.

Providing there is no dose limiting toxicity (DLT), patients then progress onto the Phase 1b (Combination) arm of the study, remaining on the same dosage. In this arm, patients receive 6 treatment cycles, each of 28 days comprising NOX66 (idronoxil) treatment on Days 1-7 and carboplatin on Day 2 of each treatment cycle.

Any meaningful clinical responses occurring in the Phase 1b (Combination) Arm will trigger a Phase IIa (Combination) Arm where an additional 10 patients will be recruited into a maximum of 2 cohorts of the same tumour type (prostate, lung, breast, ovarian, or head and neck). These patients will receive the same combination dosage providing the observed clinical responses and treated with that dosage for a maximum of 6 treatment cycles.

Inclusion Criteria:

1. Provision of informed consent

2. Male or female ≥18 years of age

3. Histologic or cytologic confirmed locally advanced or metastatic cancer that has no standard therapeutic alternatives.

4. ECOG Performance status 0-1

5. A minimum life expectancy of 12 weeks

6. 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

7. Female patients who are known to be capable of conception should have a negative serum pregnancy test (beta-human chorionic gonadotropin (β-hCG)) within 1 week of starting the study

8. All potentially fertile patients will agree to use an effective form of contraception during the study and for 90 days following the last dose of NOX66 (an effective form of contraception is defined as an oral contraceptive or a double barrier method

9. 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 Grade 1

10. At least 21 days must have elapsed prior to Day 1 Cycle 1 since radiotherapy (limited palliative radiation is allowed > 2 weeks), immunotherapy or following major surgery and any surgical incision should be completely healed

Exclusion Criteria:

1. Patients who are pregnant or breastfeeding.
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.
4. Patients with QTc of > 470 msec on screening ECG. (If a patient has QTc interval >470 msec on screening ECG, the screening ECG may be repeated twice (at least 24 hours apart). The average QTc from the 3 screening ECGs must be <470 msec in order for the patient to be eligible for the study.
5. Any major surgery, radiotherapy, or immunotherapy within the last 21 days (limited palliative radiation is allowed > 2 weeks).
6. Chemotherapy regimens with delayed toxicity within the last 4 weeks. Chemotherapy regimens given continuously or on a weekly basis with limited potential or delayed toxicity within the last 2 weeks.
7. No concurrent systemic chemotherapy or biologic therapy is allowed.
8. Known human immunodeficiency virus (HIV) or Hepatitis B or C (active, previously treated or both).
9. History of solid organ transplantation.
10. Psychiatric disorder or social or geographic situation that would preclude study participation.
11. Known unsuitability for treatment with carboplatin including renal disease where there is impaired glomerular filtration rate (GFR).