A Study of NOX66 Plus Doxorubicin in Anthracycline-naïve, Adult Patients With Soft Tissue Sarcoma

Study Overview
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Brief Summary
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This is a Phase I, open-label, dose-escalation and dose-expansion study of NOX66 given rectally, in cohorts of patients with metastatic soft tissue sarcoma (STS) who have not been exposed to anthracycline therapy, using a fixed dose-escalation schema every 21 days to establish the maximum tolerated dose (MTD) of the combination of NOX66 and doxorubicin.

Detailed Description
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The study will contain dose-escalation cohorts and dose-expansion cohorts. The study design allows an exploration of different doses of NOX66 with safety monitoring to ensure the safety of the patients. Dose-escalation cohorts: It will include three planned Treatment Groups (800, 1200, 1800 mg daily) and patients enrolled in these groups will receive 7 days of monotherapy treatment with NOX66 followed by a 5-day washout period. Thereafter, patients will enter a combination therapy (only if no significant toxicity is observed during monotherapy). This will commence with Cycle 1, which will consist of 7 days of NOX66, and on Day 2 of the 21-day cycle, doxorubicin will be administered. Patients will continue to be treated for up to 6 x 21-day cycles of NOX66 and doxorubicin. New patients will be entered at the next dose level of NOX66, if no dose-limiting toxicities have occurred among the first 3 patients at the end of cycle 1. During the dose-escalation, MTD of the combination of NOX66 and doxorubicin will be determined. Dose-expansion cohort: On completion of the dose-escalation cohort, patients will be enrolled into a dose-expansion at the MTD of the combination of NOX66 and doxorubicin. All patients will enter directly into 21-day combination cycles and will be given NOX66 therapy for 7 days and doxorubicin will be administered on Day 2 of each cycle. Treatment will be terminated upon disease progression, unacceptable toxicity, or a maximum of 6 cycles.

Official Title
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A Dose Escalation and Dose Expansion Study of NOX66 Plus Doxorubicin in Anthracycline-naïve, Adult Patients With Soft Tissue Sarcoma - CEP-2

Conditions
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Metastatic Soft-tissue Sarcoma

Intervention / Treatment
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* Drug: NOX66
* Drug: NOX66
* Drug: NOX66
* Drug: NOX66
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients with a histologically confirmed diagnosis of metastatic or recurrent soft tissue sarcoma Patients for whom treatment with doxorubicin is considered to be appropriate Left ventricular ejection fraction ≥ 50% Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Disease that is considered measurable according to RECIST v1.1. Exclusion Criteria: Histologically or cytologically confirmed Kaposi's sarcoma, gastrointestinal stromal tumor (GIST), extra-skeletal myxoid chondrosarcoma, epithelioid hemangioendothelioma, and desmoid tumor Untreated metastases to the central nervous system Received previous treatment with anthracyclines and anthracenediones Previous radiation therapy to the mediastinal or pericardial area A known allergy to any of the treatment components Patient not willing to use suppositories Patients with a colostomy 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 (e.g., inflamed hemorrhoids, fissures, or lesions of the anus or rectum) Patients with fecal impaction, chronic idiopathic constipation, or chronic diarrhea or alternating irritable bowel disease Patients with inflammatory bowel disease Previous treatment with an investigational agent or the non-approved use of a drug or device within 4 weeks before study entry Uncontrolled diabetes mellitus Patients who require concomitant use of strong inhibitors or inducers of CYP3A4, CYP2D6 or P- glycoprotein (P- gp)

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: Dose-Escalation Cohort 1: NOX66 800 mg + Doxorubicin<br> | Drug: NOX66<br>* NOX66 800 mg (400 mg suppository twice daily [BID]). Monotherapy: 7 days of NOX66 followed by 5 days washout. Combination therapy: 7 days of NOX66 followed by 14 days washout in a 21-day cycle, for up to 6 cycles.<br>Drug: Doxorubicin<br>* Doxorubicin will be given at 75 mg/m^2 as an intravenous infusion on Day 2 of the 21-day cycle for up to 6 cycles.<br>|
| Experimental: Dose-Escalation Cohort 2: NOX66 1200 mg + Doxorubicin<br> | Drug: NOX66<br>* NOX66 1200 mg daily (600 mg suppository BID). Monotherapy: 7 days of NOX66 followed by 5 days washout. Combination therapy: 7 days of NOX66 followed by 14 days washout in a 21-day cycle, for up to 6 cycles.<br>Drug: Doxorubicin<br>* Doxorubicin will be given at 75 mg/m^2 as an intravenous infusion on Day 2 of the 21-day cycle for up to 6 cycles.<br>|
| Experimental: Dose-Escalation Cohort 3: NOX66 1800 mg + Doxorubicin<br> | Drug: NOX66<br>* NOX66 1800 mg daily (600 mg suppository thrice daily). Monotherapy: 7 days of NOX66 followed by 5 days washout. Combination therapy: 7 days of NOX66 followed by 14 days washout in a 21-day cycle, for up to 6 cycles.<br>Drug: Doxorubicin<br>* Doxorubicin will be given at 75 mg/m^2 as an intravenous infusion on Day 2 of the 21-day cycle for up to 6 cycles.<br>|
| Experimental: Dose-Expansion Cohort: NOX66 + Doxorubicin<br> | Drug: NOX66<br>* MTD of the combination of NOX66 and doxorubicin will be determined in the dose-escalation cohort of the study. The selected dose will be administered in combination with Doxorubicin.<br>Drug: Doxorubicin<br>* Doxorubicin will be given at 75 mg/m^2 as an intravenous infusion on Day 2 of the 21-day cycle for up to 6 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation: Number of patients with dose-limiting toxicities (DLTs) | Determination of the MTD of NOX66 in combination with doxorubicin. 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. | Cycle 1 of each dose (Cycle length is 21 days) | 
| Number of patients with adverse events (AEs) for NOX66 | Characterization of the safety and tolerability of NOX66. | Assessed up to 18 months from first combination treatment (Cycle1 Day 1) | 
| Number of patients with change in brain natriuretic peptide (BNP) levels from baseline | The number of patients with BNP levels greater than 500 pg/mL and with BNP levels between 100 and 500 pg/mL from baseline will be presented. | Baseline (Day 1) and Cycles 1, 3, 5 and the end of Cycle 6 (Cycle length is 21 days) or Early termination (assessed up to 6 months) | 
| Number of patients with change in troponin levels from baseline | Number of patients with change in troponin levels from baseline will be evaluated to characterize safety and tolerability of NOX66. | Baseline (Day 1) and Cycles 1, 3, 5 and the end of Cycle 6 (Cycle length is 21 days) or Early termination (assessed up to 6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-Escalation (Monotherapy): Maximum observed blood drug concentration (Cmax) for idronoxil and idronoxil metabolites | Determination of single-and multiple-dose pharmacokinetics (PK) of idronoxil | Dose-Escalation (Monotherapy): Days 1 and 7 | 
| Dose-Escalation (Monotherapy): Time to reach Cmax (Tmax) for idronoxil and idronoxil metabolites | Determination of single-and multiple-dose PK of idronoxil | Dose-Escalation (Monotherapy): Days 1 and 7 | 
| Dose-Escalation (Monotherapy): Area under the blood concentration time curve (AUC) from time 0 to the last measurable concentration (AUC-last) for idronoxil and idronoxil metabolites | Determination of single-and multiple-dose PK of idronoxil | Dose-Escalation (Monotherapy): Days 1 and 7 | 
| Dose-Escalation (Monotherapy): AUC from time 0 to end or dosing interval (τ) [AUCτ] for idronoxil and idronoxil metabolites | Determination of single-and multiple-dose PK of idronoxil | Dose-Escalation (Monotherapy): Days 1 and 7 | 
| Dose-Escalation (Monotherapy): AUC from time 0 to infinity (AUCinf) for idronoxil and idronoxil metabolites | Determination of single-and multiple-dose PK of idronoxil | Dose-Escalation (Monotherapy): Days 1 and 7 | 
| Dose-Escalation (Monotherapy): Terminal elimination rate constant (kel) for idronoxil and idronoxil metabolites | Determination of single-and multiple-dose PK of idronoxil. Terminal elimination rate constant will be calculated from a semi-log plot of the blood concentration versus time (kel^a) | Dose-Escalation (Monotherapy): Days 1 and 7 | 
| Dose-Escalation (Monotherapy): Terminal elimination phase half-life (T1/2) | Determination of single-and multiple-dose PK of idronoxil | Dose-Escalation (Monotherapy): Days 1 and 7 | 
| Dose-Escalation (Combination) and Dose-Expansion: Plasma concentrations of idronoxil and idronoxil metabolites or doxorubicin and doxorubicinol | Determination of single-and multiple-dose PK of idronoxil and doxorubicin | Dose-Escalation (Combination): Days 2, 7, and 8; Dose-Expansion: Days 2 and 7 | 
| Dose-Escalation and Dose-Expansion: Disease control rate (DCR) | Evaluation of preliminary efficacy of NOX66 in combination with doxorubicin. DCR is defined as the percentage of patients with a best overall response of complete response (CR), partial response (PR) or stable disease, and will be assessed based on change from baseline imaging by (Response Evaluation Criteria in Solid Tumors [RECIST] v1.1. | At the end of Cycles 2, 4 and 6 (Cycle length is 21 days) and at Months 6, 9 and 12 and at the End of Study (assessed up to 18 months from first combination treatment) | 
| Dose-Escalation and Dose-Expansion: Objective response rate (ORR) | Evaluation of preliminary efficacy of NOX66 in combination with doxorubicin. The ORR, defined as the percentage of patients with CR and PR, and will be assessed based on change from baseline imaging by (RECIST) v1.1. | At the end of Cycles 2, 4 and 6 (Cycle length is 21 days) and at Months 6, 9 and 12 and at the End of Study (assessed up to 18 months from first combination treatment) | 
| Dose-Escalation and Dose-Expansion: Complete response (CR) | Evaluation of preliminary efficacy of NOX66 in combination with doxorubicin. CR will be assessed based on change from baseline imaging (RECIST) v1.1. | At the end of Cycles 2, 4 and 6 (Cycle length is 21 days) and at Months 6, 9 and 12 and at the End of Study (assessed up to 18 months from first combination treatment) | 
| Dose-Escalation and Dose-Expansion: Partial response (PR) | Evaluation of preliminary efficacy of NOX66 in combination with doxorubicin. PR will be assessed based on change from baseline imaging (RECIST) v1.1. | At the end of Cycles 2, 4 and 6 (Cycle length is 21 days) and at Months 6, 9 and 12 and at the End of Study (assessed up to 18 months from first combination treatment) | 
| Dose-Escalation and Dose-Expansion: Stable disease (SD) | Evaluation of preliminary efficacy of NOX66 in combination with doxorubicin. SD will be assessed based on change from baseline imaging (RECIST) v1.1. | At the end of Cycles 2, 4 and 6 (Cycle length is 21 days) and at Months 6, 9 and 12 and at the End of Study (assessed up to 18 months from first combination treatment) | 
| Dose-Escalation and Dose-Expansion: Progression free survival (PFS) | Evaluation of preliminary efficacy of NOX66 in combination with doxorubicin. PFS is defined as the time in months from initial treatment until death, disease progression, or censoring. | Initial treatment until death, disease progression, or censoring (assessed up to 18 months from first combination treatment) | 
| Dose-Escalation and Dose-Expansion: Progressive disease (PD) | Evaluation of preliminary efficacy of NOX66 in combination with doxorubicin. PD will be assessed based on change from baseline imaging (RECIST) v1.1. | At the end of Cycles 2, 4 and 6 (Cycle length is 21 days) and at Months 6, 9 and 12 and at the End of Study (assessed up to 18 months from first combination treatment) | 
| Dose-Escalation and Dose-Expansion: Overall survival (OS) | Evaluation of preliminary efficacy of NOX66 in combination with doxorubicin. OS is defined as the time in months from initial treatment until death or censoring. | Initial treatment until death, or censoring and at the End of Study (assessed up to 18 months from first combination treatment) | 
| Dose-Escalation and Dose-Expansion: Change from baseline in European Organization for Research and Treatment Core Quality of Life Questionnaire v3.0) (EORTC QLQ-C30) | Determination of quality of life (QOL) of NOX66 in combination with doxorubicin. 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 the overall quality of life which are rated on a 7-point scale (range 1-7) where higher scores represent a better quality of life. | Cycle 1 Day 1 (Cycle length is 21 days) until Months 6, 9 and 12 of the follow-up period and at the End of Study (assessed up to 18 months from first combination treatment) | 
| Fatigue change from baseline measured using the EORTC QLQ-FA12 questionnaire | Determination of quality of life (QOL) of NOX66 in combination with doxorubicin. Fatigue will be measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - EORTC QLQ-FA12. The QLQ-FA12 incorporates three multi-item scales to assess physical fatigue, emotional fatigue, and cognitive fatigue. In addition, two single items assess interference with daily life and social sequelae. All of the scales and single-item measures range in score from 0 to 100. For all the scales and single items, a high score represents a high level of symptomatology or problems. | Cycle 1 Day 1 (Cycle length is 21 days) until Months 6, 9 and 12 of the follow-up period and at the End of Study (assessed up to 18 months from first combination treatment) | 
| Change from baseline in brief pain inventory- Short Form (BPI-SF) questionnaire | Determination of quality of life (QOL) of NOX66 in combination with doxorubicin. 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. | Cycle 1 Day 1 (Cycle length is 21 days) until Months 6, 9 and 12 of the follow-up period and at the End of Study (assessed up to 18 months from first combination treatment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Doxorubicin, Dose-escalation study, Dose-expansion study, Maximum tolerated dose