A Study of NOX66 and External Beam Radiotherapy in Patients With Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors

Study Overview
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Brief Summary
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This is a Phase 1b/Phase 2a, open-label, multicenter study to determine the safety, tolerability, recommended Phase 2 dose (RP2D), efficacy, pharmacokinetics (PK) and pharmacodynamic (PD) properties of idronoxil when rectally administered as a suppository (NOX66) to patients with any solid tumor (Part 1) and patients with metastatic castration-resistant prostate cancer (mCRPC), breast cancer (BC) and non-small-cell lung cancer (NSCLC) (Part 2) who are eligible for low-dose external beam radiotherapy (EBRT) for at least one symptomatic or minimally symptomatic lesion (for the prevention of symptoms).

Detailed Description
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The study is divided into 2 parts: Part 1 (dose escalation) and Part 2 (dose expansion). The study design allows an exploration of different doses of NOX66 (800 mg, 1200 mg, 1600 mg and 2400 mg) with safety monitoring to ensure the safety of the patients. In Cycle 1, NOX66 will be administered for 14 days followed by a 7-day rest period on a 21-day cycle. From Cycle 2 onwards, NOX66 will be administered for 7 days followed by a 7-day rest period on a 14-day cycle. Patients will continue to receive NOX66 on a cyclical basis until disease progression, unacceptable toxicity, withdrawal of consent, start of a new anticancer therapy, withdrawal of the patient by the Investigator or the end of study is reached.

Official Title
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A Phase 1b/2a Multicenter Study of NOX66 and External Beam Radiotherapy in Patients With Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors

Conditions
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Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors

Intervention / Treatment
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* Drug: NOX66
* Drug: NOX66
* Drug: NOX66
* Drug: NOX66
* Drug: NOX66
* Radiation: EBRT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has a minimum life expectancy of 6 months Histological or cytological confirmation of prostate cancer, BC, NSCLC and any other solid tumors Confirmed metastatic disease by imaging Documented disease progression following first or later lines of anticancer systemic treatment Patient is eligible for low-dose EBRT for at least one lesion Patients with prior RT are eligible, only if there is no potential for field overlap between the prior RT and the planned RT For patients with BC or NSCLC: Patient must have at least one measurable lesion as per RECIST v1.1 (in Part 2 only) Patient has ECOG performance status of 0 to 2 Adequate bone marrow, renal, and liver function Metastatic Castration-resistant Prostate Cancer: Baseline testosterone levels ≤ 14.4 ng/dL and ongoing medical castration must be maintained throughout the duration of the study; patient has evidence of symptomatic and/or progressive disease Breast Cancer Patients: Known hormone receptor status (estrogen receptors/progesterone receptors or estrogen receptors alone). Breast cancer patients are allowed to be on background hormonal treatment. Exclusion Criteria: Patient has tumor involvement of the central nervous system Impaired cardiac functioning or clinically significant cardiac disease Uncontrolled hypertension despite two concomitant antihypertensive therapies Patients who have had a colectomy (total or left hemicolectomy) with re-anastomosis Patients for whom administration of the suppositories are likely to cause pain or difficulties in absorption Patients with fecal impaction or uncontrolled irritable bowel disease Patients with inflammatory bowel disease Any other disease, metabolic dysfunction, physical examination finding or clinical laboratory finding that, in the Investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent Patients with oligometastatic disease (fewer than 5 metastatic lesions) amenable to standard therapy will be excluded Patients who have had RT to the region of the rectum or will require RT to the region of the rectum during the trial Uncontrolled active infection requiring intravenous antibiotic, antiviral or anti-fungal medications within 14 days before the first dose administration Receiving or having received anticancer treatment Patient has received corticosteroids at a dose of > 10 mg prednisone/day or equivalent for any reason within 4 weeks prior to receiving the first dose administration Patient is not willing to use suppositories Patient has a positive reverse transcription polymerase chain reaction (RT-PCR) test for severe acute respiratory coronavirus 2 (SARS-CoV-2) prior to Screening or enrollment, or has clinical signs and symptoms consistent with SARS-CoV-2 infection; e.g., fever, dry cough, dyspnea, sore throat, fatigue or positive SARS-CoV-2 test result within 2 weeks prior to Screening.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Dose Cohort 1: NOX66 800 mg<br> | Drug: NOX66<br>* NOX66 800 mg daily (400 mg suppository twice daily [BID]).<br>Radiation: EBRT<br>* The dose levels of EBRT will be either 8 Gy as a single fraction, or 20/25 Gy as 5 fractions given over 5 to 10 days.<br>|
| Experimental: Part 1: Dose Cohort 2: NOX66 1200 mg<br> | Drug: NOX66<br>* NOX66 1200 mg daily (600 mg suppository BID).<br>Radiation: EBRT<br>* The dose levels of EBRT will be either 8 Gy as a single fraction, or 20/25 Gy as 5 fractions given over 5 to 10 days.<br>|
| Experimental: Part 1: Dose Cohort 3: NOX66 1600 mg<br> | Drug: NOX66<br>* NOX66 1600 mg daily (800 mg suppository BID).<br>Radiation: EBRT<br>* The dose levels of EBRT will be either 8 Gy as a single fraction, or 20/25 Gy as 5 fractions given over 5 to 10 days.<br>|
| Experimental: Part 1: Dose Cohort 4: NOX66 2400 mg<br> | Drug: NOX66<br>* NOX66 2400 mg daily (1200 mg suppository BID).<br>Radiation: EBRT<br>* The dose levels of EBRT will be either 8 Gy as a single fraction, or 20/25 Gy as 5 fractions given over 5 to 10 days.<br>|
| Experimental: Part 2: Arm 1: Patients with mCRPC (RP2D NOX66)<br> | Drug: NOX66<br>* NOX66 RP2D<br>Radiation: EBRT<br>* The dose levels of EBRT will be either 8 Gy as a single fraction, or 20/25 Gy as 5 fractions given over 5 to 10 days.<br>|
| Experimental: Part 2: Arm 2: Patients with BC or NSCLC (RP2D NOX66)<br> | Drug: NOX66<br>* NOX66 RP2D<br>Radiation: EBRT<br>* The dose levels of EBRT will be either 8 Gy as a single fraction, or 20/25 Gy as 5 fractions given over 5 to 10 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 (Dose Escalation): Number of dose-limiting toxicities (DLTs) | Determination of the maximum tolerated dose (MTD) and RP2D of NOX66 in combination with low-dose EBRT in patients with any solid tumor. MTD is defined as the dose level at which no more than 1 patient out of 6 experiences a DLT at the end of Cycle 1. RP2D is the highest dose administered at which no more than 1 patient out of 6 experiences a DLT at the end of Cycle 1 and the dosage form, including the dosing frequency, is acceptable to patients. | Cycle 1 (Day 1 to Day 21) | 
| Part 2 (Dose Expansion): Arm 1 (mCRPC only): Number of patients with change from Baseline in prostate-specific antigen (PSA) at the end of Cycles 3 and 6 | Evaluation of the effect of NOX66 on PSA response in patients with mCRPC. PSA response is defined as the proportion of patients with a reduction in PSA in plasma (ng/mL) of ≥ 30% from baseline at the end of Cycles 3 and 6. | At the end of Cycle 3 (Week 7) & Cycle 6 (Week 13) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and Part 2: Incidence of adverse events (AEs) for NOX66 | Characterization of the safety and tolerability of NOX66. | From Screening (Days -28 to -2) until the Follow-up visit/End of Study (EOS) (up to 30 months) | 
| Part 1 and Part 2: Incidence of AEs related to 2 dose levels of EBRT | Evaluation of the safety and tolerability of both doses of EBRT (8 Gy or 20/25 Gy). | From Screening (Days -28 to -2) until the Follow-up visit/EOS (up to 30 months) | 
| Maximum observed concentration (Cmax) for idronoxil and selected metabolites | Evaluation of the exposure of idronoxil. | Days 1, 2, 6, 14 and 15 of Cycle 1 (21-day Cycle), and Days 1 and 8 of Cycles 2 and 3 (14-day Cycles) | 
| Time to first occurrence of Cmax (Tmax) for idronoxil and selected metabolites | Evaluation of the exposure of idronoxil. | Days 1, 2, 6, 14 and 15 of Cycle 1 (21-day Cycle), and Days 1 and 8 of Cycles 2 and 3 (14-day Cycles) | 
| Area under the concentration-time curve (AUC) from time zero (predose) to time of last quantifiable concentration (AUC(0-t)) for idronoxil and selected metabolites | Evaluation of the exposure of idronoxil. | Days 1, 2, 6, 14 and 15 of Cycle 1 (21-day Cycle), and Days 1 and 8 of Cycles 2 and 3 (14-day Cycles) | 
| AUC from time zero (predose) to 6 hours postdose (AUC(0-6)) for idronoxil and selected metabolites | Evaluation of the exposure of idronoxil. | Days 1, 2, 6, 14 and 15 of Cycle 1 (21-day Cycle), and Days 1 and 8 of Cycles 2 and 3 (14-day Cycles) | 
| AUC from time zero (predose) to 12 hours postdose (AUC(0-12)) for idronoxil and selected metabolites | Evaluation of the exposure of idronoxil. | Days 1, 2, 6, 14 and 15 of Cycle 1 (21-day Cycle), and Days 1 and 8 of Cycles 2 and 3 (14-day Cycles) | 
| AUC from time zero (predose) extrapolated to infinity (AUC(0-inf)) for idronoxil and selected metabolites | Evaluation of the exposure of idronoxil. | Days 1, 2, 6, 14 and 15 of Cycle 1 (21-day Cycle), and Days 1 and 8 of Cycles 2 and 3 (14-day Cycles) | 
| Minimum observed concentration (Cmin) for idronoxil and selected metabolites | Evaluation of the exposure of idronoxil. | Days 1, 2, 6, 14 and 15 of Cycle 1 (21-day Cycle), and Days 1 and 8 of Cycles 2 and 3 (14-day Cycles) | 
| Terminal phase half-life (t½) for idronoxil and selected metabolites | Evaluation of the exposure of idronoxil. | Days 1, 2, 6, 14 and 15 of Cycle 1 (21-day Cycle), and Days 1 and 8 of Cycles 2 and 3 (14-day Cycles) | 
| Part 1 and Part 2: Number of patients (mCRPC only) with change from Baseline in PSA at any time point | Evaluation of the preliminary clinical efficacy of NOX66 plus low-dose EBRT in patients with mCRPC. | Screening, Day 1 of Cycles 1 to 5, every second cycle thereafter, and at End of Treatment (EOT)/ Early Discontinuation (ED) Visit, and each 12-weekly (±2 weeks) follow-up visits (Cycle 1:21-day Cycle, Cycle 2 onwards:14-day Cycles) (up to 30 months) | 
| Part 1 and Part 2: Overall response rate (ORR) | Evaluation of the preliminary clinical efficacy of NOX66 plus low-dose EBRT in patients with mCRPC and other solid tumors. The ORR, defined as the percentage of patients with CR and PR, will be assessed based on change from baseline imaging (Response Evaluation Criteria in Solid Tumors [RECIST] v1.1 [all tumor types] and Prostate Cancer Working Group 3 [PCWG3] criteria [mCRPC] for measurable or evaluable lesions). | Every 8 weeks (± 7 days) from the first dose administration up to Week 26, and every 12 weeks (± 2 weeks) thereafter until disease progression (up to 30 months) | 
| Part 1 and Part 2: Duration of response | Evaluation of the preliminary clinical efficacy of NOX66 plus low-dose EBRT in patients with mCRPC and other solid tumors. Duration of response is defined as the time from the first documented overall response of CR, PR or SD to the first documented overall response of progressive disease. | Up to 30 months | 
| Part 1 and Part 2: Change from Baseline in Eastern Cooperative Oncology Group (ECOG) scores | Evaluation of the preliminary clinical efficacy of NOX66 plus low-dose EBRT in patients with mCRPC and other solid tumors. ECOG is a 6-point scale where 0= Fully active, 1= Restricted in physically strenuous activity, 2=Up and about more than 50% of waking hours, 3= Capable of only limited selfcare, confined to a bed or chair more than 50% of waking hours, 4= Completely disabled, and 5=Dead. Higher scores mean a worse outcome. | Screening, Day 1 of Cycles 1 to 3, every second cycle thereafter (i.e., Cycles 5, 7, 9, 11 etc.) and the EOT/ED Visit (Cycle 1:21-day Cycle, Cycle 2 onwards:14-day Cycles) (Up to 30 months) | 
| Part 1 and Part 2: Change from Baseline in tumor size | Evaluation of the preliminary clinical efficacy of NOX66 plus low-dose EBRT in patients with mCRPC and other solid tumors. | Screening, every 8 weeks (± 7 days) from the first study dose administration up to Week 26, and every 12 weeks (± 2 weeks) thereafter until disease progression, withdrawal of consent, initiation of new anticancer therapy or death (up to 30 months) | 
| Part 1 and Part 2: Change from Baseline in tumor number | Evaluation of the preliminary clinical efficacy of NOX66 plus low-dose EBRT in patients with mCRPC and other solid tumors. | Screening, every 8 weeks (± 7 days) from the first study dose administration up to Week 26, and every 12 weeks (± 2 weeks) thereafter until disease progression, withdrawal of consent, initiation of new anticancer therapy or death (up to 30 months) | 
| Part 2: Arm 1: Progression-free survival (PFS) | Evaluation of the preliminary clinical efficacy of NOX66 plus low-dose EBRT in patients with mCRPC. Progression-free survival is defined as the duration of time from first dose administration to date of disease progression is objectively documented, including tumor progression, early discontinuation or death prior to data cut off. | Every 8 weeks (± 7 days) from the first dose administration up to Week 26, and every 12 weeks (± 2 weeks) thereafter until disease progression according to RECIST v1.1 criteria (up to 30 months) | 
| Part 2: Arm 1: Overall survival (OS) | Evaluation of the preliminary clinical efficacy of NOX66 plus low-dose EBRT in patients with mCRPC. Overall survival is defined as time from the date of first dose administration to date of death due to any cause. | Up to 30 months | 
| Part 1 and Part 2: Change from baseline in pain scores based on the Brief Pain Inventory - Short Form (BPI-SF) questionnaire | The effects of NOX66 on pain and other cancer-related signs and symptoms will be explored. Worst pain, general pain and pain's interference with daily life will be assessed during the study drug using the BPI-SF. The BPI-SF comprises a total of 15 items measuring 2 domains: pain severity and pain interference. Items measuring pain severity (including 'worst pain') are rated on an 11 point numeric rating scale ranging from 0=No pain to 10=Pain as bad as you can imagine. Higher scores mean a worse outcome. | Screening, on Day 1 of Cycles 3 and 5, followed by every 4 cycles thereafter (e.g., Cycle 9, Cycle 13 etc.), and at the EOT/ED Visit (each cycle is 14 days) (Up to 30 months) | 
| Part 1 and Part 2: Number of patients with skeletal-related events (SREs) and symptomatic skeletal events (SSEs) | The effects of NOX66 on pain and other cancer-related signs and symptoms will be explored. Skeletal-related events and SSEs will be evaluated based on the patient's clinical history and examinations, including but not limited to incidence of fractures and pain. | Up to 30 months | 
| Part 1 and Part 2: Change of dose of morphine administration and analgesic use | The effects of NOX66 on pain and other cancer-related signs and symptoms will be explored. The dose of morphine administration and analgesic use will be assessed based on the patient's concomitant medication use assessment. | Up to 30 months | 
| Part 1 and Part 2: Change of frequency of morphine administration and analgesic use | The effects of NOX66 on pain and other cancer-related signs and symptoms will be explored. The frequency of morphine administration and analgesic use will be assessed based on the patient's concomitant medication use assessment. | Up to 30 months | 
| Part 1 and Part 2: Quality of life (QoL) as assessed by change from Baseline in Patient Experience Questionnaire (PEQ) | The Sponsor has developed a questionnaire to evaluate the patient's experience with the suppository dosage form. This will consist of a set of 10 questions, with some questions requiring simple yes or no answers, and other questions are to be rated on a scale of 10 (range 1 to 10) where higher scores mean a worse outcome. | Day 2 of Cycle 1 (21-day Cycle), Day 1 of Cycle 3 (14-day Cycle) and at the EOT/ED Visit (up to 30 months) | 
| Part 1 and Part 2: QoL as assessed by change from Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients (EORTC-QLQ-C30) | The questionnaire assesses important functioning domains (e.g., physical, emotional, social) and common cancer symptoms (e.g., fatigue, pain, nausea, vomiting, appetite loss). The instrument is composed of 30 items. All symptom scales range from 1-4 with higher values representing higher levels of symptoms, except for the items that evaluate overall quality of life which are rated on a 7-point scale (range 1-7) where higher score represent a better quality of life. | Screening, on Day 1 of Cycles 3 and 5, followed by every 4 cycles thereafter (e.g., Cycle 9, Cycle 13 etc.), and at the EOT/ED Visit (each cycle is 14 days) (up to 30 months) | 
| Part 1 and Part 2: QoL as assessed by change from Baseline in Functional Assessment of Cancer Therapy - Prostate (FACT-P) (mCRPC only) | The FACT-P questionnaire is a relevant, worldwide tool used for assessing the health-related QoL in men with prostate cancer. The FACT-P is a 39-item questionnaire composed of the FACT-General (FACT-G) original subscales (Physical Well-being, Social/Family Well-being, Emotional Well-being and Functional Well-being) and a Prostate Cancer Subscale. Each item is rated on a 5-point scale ranging from 0 (not at all) to 4 (very much). A higher score indicates a better QoL. | Screening, on Day 1 of Cycles 3 and 5, followed by every 4 cycles thereafter (e.g., Cycle 9, Cycle 13 etc.), and at the EOT/ED Visit (each cycle is 14 days) (up to 30 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dose Escalation, Dose Expansion, Prostate-specific antigen, Maximum tolerated dose, Recommended Phase 2 dose