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

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.

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.

Eligibility Criteria:
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)