A Phase I/II Clinical Trial of PXD101 in Combination With Doxorubicin in Patients With Soft Tissue Sarcomas

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I/II Clinical Trial of PXD101 in Combination With Doxorubicin in Patients With Soft Tissue Sarcomas

Conditions
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Dose Escalation: Solid Tumors, MTD: Soft Tissue Sarcomas

Intervention / Treatment
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* Drug: PXD101
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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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 Haemoglobin > 9.0 g/dL or > 5.6 mmol/l Acceptable coagulation status: PT and APTT ([activated partial thromboplastin time ]) within ≤ 1.5 times upper limit of normal or in the therapeutic range if on anticoagulation. A negative pregnancy test for women of childbearing potential. For men and women of child producing potential, the use of effective contraceptive methods during the study is required Serum potassium within normal range 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) Presence of metastatic disease that, in the opinion of the investigator, would require palliative treatment within 4 weeks of enrolment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: PXD101 and doxorubicin (BelDox)<br>5-day PXD101 IV schedule with dose escalation combined with 1 day doxorubicin dose escalation IV | Drug: PXD101<br>* Administered in combination with doxorubicin (BelDox)<br>* Other names: PXD101 (Belinostat);Drug: Doxorubicin<br>* Administered in combination with PXD101 (BelDox)<br>* Other names: Doxorubicin (Adriamycin);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) PXD101 | Maximum Tolerated Dose (MTD) of PXD101treatment | During Cohort 1 to 4, Cycle 1 only, up to 3 weeks | 
| Maximum Tolerated Dose (MTD) of Doxorubicin | Maximum Tolerated Dose (MTD) of doxorubicin | During Cohort 1 to 4, Cycle 1 only, up to 3 weeks | 
| Dose Limiting Toxicity (DLT) | Dose Limiting Toxicity (DLT) of PXD101 and doxorubicin combination treatment | Throughout study | 
| Objective Response (CR and PR) | 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. | Throughout study, after every 2 cycles | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | The disease control rate, defined as best overall response of either objective response or stable disease (CR or PR or SD) following up to 6 cycles of treatment with confirmation according to the RECIST criteria | Throughout study, after every 2 cycles | 
| Belinostat AUC (Time 0 to Last Measurement) | Measure the AUC of belinostat alone (Day 4 values) and in the presence of doxorubicin (Day 5 values) at the Maximum Tolerated Dose level: belinostat 1000 mg/m2 and doxorubicin 75 mg/m2 | 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 | Measure the Cmax of belinostat alone (Day 4 values) and in the presence of doxorubicin (Day 5 values) at the Maximum Tolerated Dose level: belinostat 1000 mg/m2 and doxorubicin 75 mg/m2 | 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 | Measure the t½ of belinostat alone (Day 4 values) and in the presence of doxorubicin (Day 5 values) at the Maximum Tolerated Dose level: belinostat 1000 mg/m2 and doxorubicin 75 mg/m2 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I/II trial, Solid tumors, Soft tissue sarcoma, PXD101, Doxorubicin