Metastatic Soft-tissue Sarcoma
Conditions
Keywords
Doxorubicin, Dose-escalation study, Dose-expansion study, Maximum tolerated dose
Brief 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.
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.
Interventions
DRUGNOX66
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.
DRUGDoxorubicin
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.
Sponsors
Noxopharm Limited
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation: Number of Patients With Dose-limiting Toxicities (DLTs) | Cycle 1 of each dose (Cycle length is 21 days) | 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. |
| Number of Patients With Adverse Events (AEs) for 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 | Characterization of the safety and tolerability of NOX66. |
Countries
United States
Participant flow
Recruitment details
Thirty patients were screened
Participants by arm
| Arm | Count |
|---|---|
| Dose-Escalation Cohort 1: NOX66 800 mg + Doxorubicin 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.
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. | 3 |
| Dose-Escalation Cohort 2: NOX66 1200 mg + Doxorubicin 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.
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. | 3 |
| Dose-Escalation Cohort 3: NOX66 1800 mg + Doxorubicin 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.
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. | 3 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Progressive Disease | 1 | 0 | 0 | 0 |
| Overall Study | Study Terminated by Sponsor | 0 | 0 | 3 | 0 |
| Overall Study | unkown | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Dose-Escalation Cohort 1: NOX66 800 mg + Doxorubicin | Total | Dose-Escalation Cohort 3: NOX66 1800 mg + Doxorubicin | Dose-Escalation Cohort 2: NOX66 1200 mg + Doxorubicin |
|---|---|---|---|---|
| Age, Continuous | 54.3 years STANDARD_DEVIATION 10.07 | 51.3 years STANDARD_DEVIATION 10.11 | 47.7 years STANDARD_DEVIATION 17.57 | 52.0 years STANDARD_DEVIATION 7.81 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 6 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 6 Participants | 3 Participants | 1 Participants |
| Region of Enrollment United States | 3 participants | 9 participants | 3 participants | 3 participants |
| Sex: Female, Male Female | 3 Participants | 6 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 0 Participants | 3 Participants | 2 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 1 / 3 | 1 / 3 | 0 / 3 |
Outcome results
Primary
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.
Time frame: Cycle 1 of each dose (Cycle length is 21 days)
Population: Patients that received at least one dose of NOX66
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose-Escalation Cohort 1: NOX66 800 mg + Doxorubicin | Dose Escalation: Number of Patients With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Dose-Escalation Cohort 2: NOX66 1200 mg + Doxorubicin | Dose Escalation: Number of Patients With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Dose-Escalation Cohort 3: NOX66 1800 mg + Doxorubicin | Dose Escalation: Number of Patients With Dose-limiting Toxicities (DLTs) | 0 Participants |
Primary
Number of Patients With Adverse Events (AEs) for NOX66
Characterization of the safety and tolerability of NOX66.
Time frame: 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
Population: Patients treated with at least one dose of NOX66
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose-Escalation Cohort 1: NOX66 800 mg + Doxorubicin | Number of Patients With Adverse Events (AEs) for NOX66 | At least one TEAE possibly related to NOX66 | 3 Participants |
| Dose-Escalation Cohort 1: NOX66 800 mg + Doxorubicin | Number of Patients With Adverse Events (AEs) for NOX66 | With at least one SAE | 1 Participants |
| Dose-Escalation Cohort 1: NOX66 800 mg + Doxorubicin | Number of Patients With Adverse Events (AEs) for NOX66 | With at least one Adverse Event | 3 Participants |
| Dose-Escalation Cohort 1: NOX66 800 mg + Doxorubicin | Number of Patients With Adverse Events (AEs) for NOX66 | With at least one TEAE (Treatment Emergent Adverse Event) | 3 Participants |
| Dose-Escalation Cohort 1: NOX66 800 mg + Doxorubicin | Number of Patients With Adverse Events (AEs) for NOX66 | At least one TEAE related to NOX66 | 0 Participants |
| Dose-Escalation Cohort 2: NOX66 1200 mg + Doxorubicin | Number of Patients With Adverse Events (AEs) for NOX66 | With at least one SAE | 1 Participants |
| Dose-Escalation Cohort 2: NOX66 1200 mg + Doxorubicin | Number of Patients With Adverse Events (AEs) for NOX66 | With at least one Adverse Event | 3 Participants |
| Dose-Escalation Cohort 2: NOX66 1200 mg + Doxorubicin | Number of Patients With Adverse Events (AEs) for NOX66 | With at least one TEAE (Treatment Emergent Adverse Event) | 3 Participants |
| Dose-Escalation Cohort 2: NOX66 1200 mg + Doxorubicin | Number of Patients With Adverse Events (AEs) for NOX66 | At least one TEAE possibly related to NOX66 | 2 Participants |
| Dose-Escalation Cohort 2: NOX66 1200 mg + Doxorubicin | Number of Patients With Adverse Events (AEs) for NOX66 | At least one TEAE related to NOX66 | 0 Participants |
| Dose-Escalation Cohort 3: NOX66 1800 mg + Doxorubicin | Number of Patients With Adverse Events (AEs) for NOX66 | At least one TEAE related to NOX66 | 1 Participants |
| Dose-Escalation Cohort 3: NOX66 1800 mg + Doxorubicin | Number of Patients With Adverse Events (AEs) for NOX66 | At least one TEAE possibly related to NOX66 | 1 Participants |
| Dose-Escalation Cohort 3: NOX66 1800 mg + Doxorubicin | Number of Patients With Adverse Events (AEs) for NOX66 | With at least one Adverse Event | 3 Participants |
| Dose-Escalation Cohort 3: NOX66 1800 mg + Doxorubicin | Number of Patients With Adverse Events (AEs) for NOX66 | With at least one SAE | 0 Participants |
| Dose-Escalation Cohort 3: NOX66 1800 mg + Doxorubicin | Number of Patients With Adverse Events (AEs) for NOX66 | With at least one TEAE (Treatment Emergent Adverse Event) | 3 Participants |