a study of nox66 plus doxorubicin in anthracycline-naïve, adult patients with soft tissue sarcoma

Conditions: Metastatic Soft-tissue Sarcoma

Summary: 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)

Keywords: doxorubicin dose-escalation study dose-expansion study maximum tolerated dose