A Phase I/II Clinical Trial of PXD101 in Combination With Doxorubicin in Patients With Soft Tissue Sarcomas
Overview
- Phase
- Phase 1
- Intervention
- PXD101
- Conditions
- Dose Escalation: Solid Tumors
- Sponsor
- Valerio Therapeutics
- Enrollment
- 41
- Locations
- 3
- Primary Endpoint
- Maximum Tolerated Dose (MTD) PXD101
- Status
- Completed
- Last Updated
- 10 years ago
Overview
Brief Summary
Open-label, multicentre, dose-escalation Phase I/II study to evaluate safety, efficacy, pharmacodynamics, and pharmacokinetics of the combination of PXD101 with doxorubicin administered q 3 weeks in patients with advanced solid tumours. Once the Maximum Tolerable Dose has been established, up to a total of 20-40 patients with Soft Tissue Sarcoma may be enrolled at the MTD dose level to examine efficacy and safety in this specific patient population. The trial is stopped if no more than 2 responses are seen among the first 20 of these patients.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Signed consent of an IEC (Independent Ethics Committee)-approved Information consent form
- •A. For the dose escalation phase: Patients with histological or cytological confirmed solid tumours (including sarcomas), for which there is no known curative therapy B. For the MTD expansion phase: Patients with an established diagnosis of soft tissue sarcoma in need of first line chemotherapy and with measurable disease
- •Performance status (ECOG) ≤ 2
- •Life expectancy of at least 3 months
- •Age ≥ 18 years
- •Acceptable liver, renal and bone marrow function including the following:
- •Bilirubin ≤ 1.5 times upper limit of normal (ULN)
- •AST (\[Aspartate Amino Transferase\]\](SGOT), ALT (SGPT) and Alkaline Phosphatase ≤ 3 times upper limit of normal (if liver metastases are present, then ≤ 5 x ULN is allowed)
- •Serum creatinine ≤ 1.5 times upper limit of normal (ULN)
- •Leucocytes \> 2.5 x 109/ L, neutrophils \> 1.0 x 109/L, platelets \> 100 x 109/L
Exclusion Criteria
- •Treatment with investigational agents within the last 4 weeks
- •Prior anticancer therapy, within the last 3 weeks of trial dosing including chemotherapy, radiotherapy, endocrine therapy or immunotherapy
- •Co-existing active infection or any co-existing medical condition likely to interfere with trial procedures, including significant cardiovascular disease (New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months, unstable angina, congestive heart failure requiring therapy, unstable arrhythmia or a need for anti-arrhythmic therapy, or evidence of ischemia on ECG, marked baseline prolongation of QT/QTc (\[corrected QT interval \]) interval, e.g., repeated demonstration of a QTc interval \> 500 msec; Long QT Syndrome; the required use of concomitant medication on PXD101 infusion days that may cause Torsade de Pointes.
- •Altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies
- •Concurrent second malignancy
- •History of hypersensitivity to doxorubicin
- •A. For dose escalation phase: More than two prior doses of anthracycline, more than three prior lines of chemotherapy given for metastatic disease B. For MTD expansion phase: Prior chemotherapy
- •Bowel obstruction or impending bowel obstruction
- •Known HIV positivity
- •LVEF (\[left ventricular ejection fraction\]) below normal range (45% by MUGA)
Arms & Interventions
Experimental: PXD101 and doxorubicin (BelDox)
5-day PXD101 IV schedule with dose escalation combined with 1 day doxorubicin dose escalation IV
Intervention: PXD101
Experimental: PXD101 and doxorubicin (BelDox)
5-day PXD101 IV schedule with dose escalation combined with 1 day doxorubicin dose escalation IV
Intervention: Doxorubicin
Outcomes
Primary Outcomes
Maximum Tolerated Dose (MTD) PXD101
Time Frame: During Cohort 1 to 4, Cycle 1 only, up to 3 weeks
Maximum Tolerated Dose (MTD) of PXD101treatment
Maximum Tolerated Dose (MTD) of Doxorubicin
Time Frame: During Cohort 1 to 4, Cycle 1 only, up to 3 weeks
Maximum Tolerated Dose (MTD) of doxorubicin
Dose Limiting Toxicity (DLT)
Time Frame: Throughout study
Dose Limiting Toxicity (DLT) of PXD101 and doxorubicin combination treatment
Objective Response (CR and PR)
Time Frame: Throughout study, after every 2 cycles
Measured by response rate using the RECIST (Response Evaluation Criteria in Solid Tumors) response criteria (response rate: Complete Response (CR) and Partial Response (PR)) following up to 6 cycles of treatment.
Secondary Outcomes
- Time to Response(Throughout study, after every 2 cycles)
- Duration of Response(Throughout study, after every 2 cycles)
- Time to Progression(Throughout study, after every 2 cycles)
- Disease Control Rate (CR or PR or SD)(Throughout study, after every 2 cycles)
- Belinostat AUC (Time 0 to Last Measurement)(Cycle 1, Day 4 and Day 5, pre-infusion, at end of infusion and at 5 min, 15 min, 30 min, 1 h, 2 h, 2 h and 15 min, 2 h and 30 min, 3 h, 4 h, 6 h, 8 h and 24 h post infusion)
- Belinostat Cmax(Cycle 1, Day 4 and Day 5, pre-infusion, at end of infusion and at 5 min, 15 min, 30 min, 1 h, 2 h, 2 h and 15 min, 2 h and 30 min, 3 h, 4 h, 6 h, 8 h and 24 h post infusion)
- Belinostat t½(Cycle 1, Day 4 and Day 5, pre-infusion, at end of infusion and at 5 min, 15 min, 30 min, 1 h, 2 h, 2 h and 15 min, 2 h and 30 min, 3 h, 4 h, 6 h, 8 h and 24 h post infusion)