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

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

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.

Study Overview

• Status: Terminated
• Conditions: Metastatic Soft-tissue Sarcoma
• Intervention / Treatment: Drug: NOX66; Drug: NOX66; Drug: NOX66; Drug: NOX66; Drug: Doxorubicin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida - Oncology
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Site name Washington University School of Medicine in Saint Louis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose-Escalation Cohort 1: NOX66 800 mg + Doxorubicin	Drug: NOX66; 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.; Drug: NOX66; 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.; Drug: NOX66; 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.; Drug: NOX66; 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.; Drug: Doxorubicin; 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.
Experimental: Dose-Escalation Cohort 2: NOX66 1200 mg + Doxorubicin	Drug: NOX66; 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.; Drug: NOX66; 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.; Drug: NOX66; 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.; Drug: NOX66; 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.; Drug: Doxorubicin; 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.
Experimental: Dose-Escalation Cohort 3: NOX66 1800 mg + Doxorubicin	Drug: NOX66; 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.; Drug: NOX66; 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.; Drug: NOX66; 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.; Drug: NOX66; 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.; Drug: Doxorubicin; 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.
Experimental: Dose-Expansion Cohort: NOX66 + Doxorubicin	Drug: NOX66; 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.; Drug: NOX66; 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.; Drug: NOX66; 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.; Drug: NOX66; 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.; Drug: Doxorubicin; 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.

What is the study measuring?

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.	From first study treatment with DOX66 monotherapy through study completion, approximately of 14 months and 20 days. From February 11, 2022, to May 1, 2023

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)

Collaborators and Investigators

• Sponsor: Noxopharm Limited

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2022
• Primary Completion (Actual): May 1, 2023
• Study Completion (Actual): May 26, 2023

Study Registration Dates

• First Submitted: October 20, 2021
• First Submitted That Met QC Criteria: October 20, 2021
• First Posted (Actual): October 29, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: November 24, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Doxorubicin; Maximum tolerated dose; Dose-escalation study; Dose-expansion study
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Connective and Soft Tissue; Sarcoma; Antibiotics, Antineoplastic; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Topoisomerase Inhibitors; Topoisomerase II Inhibitors; Doxorubicin
• Other Study ID Numbers: NOX66-004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No