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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Cancer

Intervention / Treatment
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* Drug: NOX66
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent Male or female ≥18 years of age Histologic or cytologic confirmed locally advanced or metastatic cancer that has no standard therapeutic alternatives. ECOG Performance status 0-1 A minimum life expectancy of 12 weeks 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 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 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 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 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: Patients who are pregnant or breastfeeding. Uncontrolled infection or systemic disease. 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 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. Any major surgery, radiotherapy, or immunotherapy within the last 21 days (limited palliative radiation is allowed > 2 weeks). 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. No concurrent systemic chemotherapy or biologic therapy is allowed. Known human immunodeficiency virus (HIV) or Hepatitis B or C (active, previously treated or both). History of solid organ transplantation. Psychiatric disorder or social or geographic situation that would preclude study participation. Known unsuitability for treatment with carboplatin including renal disease where there is impaired glomerular filtration rate (GFR).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1a NOX66<br>NOX66 administered daily for 14 day in a 21-day treatment cycle. NOX66 treatment given to two cohorts of patients as 1 of 2 dose regimens: Regimen 1: 400 mg; Regimen 2: 800 mg (idronoxil) | Drug: NOX66<br>* NOX66 administration<br>* Other names: Idronoxil;|
| Experimental: 1b NOX66 and Carboplatin (combined)<br>NOX66 administered on Days 1-7 and carboplatin IV infusion on Day 2 of each 28-day treatment cycle up to 6 cycles. NOX66 at the same dosage received in the Run-In Arm combined with 2 carboplatin doses starting with low dose carboplatin AUC = 4 for treatment cycles 1-3 followed by higher dose carboplatin AUC = 6 for treatment cycles 4-6. | Drug: NOX66<br>* NOX66 administration<br>* Other names: Idronoxil;Drug: Carboplatin<br>* Carboplatin administration<br>* Other names: Paraplatin;|
| Experimental: 2a NOX66 and Carboplatin<br>This arm triggered by observed meaningful clinical responses from the 1b Combination Arm in particular disease indications. Treatment NOX66 + carboplatin administered over 6 cycles each of 28-days at observed clinical response dosage. A maximum of 2 cohorts, each comprising patients with specific tumour type. | Drug: NOX66<br>* NOX66 administration<br>* Other names: Idronoxil;Drug: Carboplatin<br>* Carboplatin administration<br>* Other names: Paraplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experience Dose Limiting Toxicity (DLT) During NOX66 Monotherapy and During NOX66 Combination With Carboplatin | Dose limiting toxicity during monotherapy and combination therapy defined as any Grade 3 or more toxicity (by National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE version 4.03]) (related to therapy) excluding Grade 3 or more neutropenia lasting greater than 5 days or thrombocytopenia associate with bleeding or Grade 4 thrombocytopenia. | Up to 1 month for NOX66 monotherapy from enrollment and up to 7 months from start of NOX66 combination therapy | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Treatment Emergent Adverse Events (SAEs) Related to NOX66. | An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. Treatment-related are events which had causal relationship to study drug as assessed by the Investigator and were suspected to be reasonably related to the study drug. | From enrollment through 30 days after the last cycle of therapy (8 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) at Cycle 3 and at Cycle 6 of Combination Therapy | Objective response rate defined as the percentage of participants achieving a complete response (CR) and or partial response (PR) after treatment with NOX66 and carboplatin therapy as assessed by Response Evaluation Criteria in solid tumors (RECIST) v1.1. CR defined as disappearance of all target and non-target lesions and reduction of any pathological lymph nodes (whether target or non-target) to <10 mm in short axis; PR was defined by a 30% or more decrease in sum of longest diameter (SLD) of target lesions in reference to baseline. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and no new lesions. | Radiological evaluation at baseline and at 3 months and at 6 months | 
| Overall Clinical Response Rate at Cycle 3 and at Cycle 6 of Combination Therapy | Overall Clinical response rate defined as the percentage of participants who achieved complete response (CR) or partial response (PR) or stable disease (SD) as assessed by Response Evaluation Criteria In Solid Tumors (RECIST) criteria v1.1 after combination of NOX66 and carboplatin therapy. CR defined as disappearance of all target and non-target lesions and reduction of any pathological lymph nodes (whether target or non-target) to <10 mm in short axis; PR was defined by a 30% or more decrease in sum of longest diameter (SLD) of target lesions in reference to baseline. Stable disease (SD)=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD was defined as at least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | Radiological evaluation at baseline and at 3 months and at 6 months |