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

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.

Study Overview

• Status: Completed
• Conditions: Dose Escalation: Solid Tumors; MTD: Soft Tissue Sarcomas
• Intervention / Treatment: Drug: PXD101; Drug: Doxorubicin

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Herlev, Denmark, DK-2730
    • Herlev Hospital, Department of Oncology
  • Århus, Denmark, DK-8000 C
    • Århus Hospital, Department of Oncology
• United Kingdom
  • Surrey, United Kingdom, SM2 5PT Surrey
    • The Royal Marsden NHS Trust, Cancer Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed consent of an IEC (Independent Ethics Committee)-approved Information consent form
2. 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
3. Performance status (ECOG) ≤ 2
4. Life expectancy of at least 3 months
5. Age ≥ 18 years

6. Acceptable liver, renal and bone marrow function including the following:

   1. Bilirubin ≤ 1.5 times upper limit of normal (ULN)
   2. 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)
   3. Serum creatinine ≤ 1.5 times upper limit of normal (ULN)
   4. Leucocytes > 2.5 x 109/ L, neutrophils > 1.0 x 109/L, platelets > 100 x 109/L
   5. Haemoglobin > 9.0 g/dL or > 5.6 mmol/l
7. 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.
8. 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
9. Serum potassium within normal range

Exclusion Criteria:

1. Treatment with investigational agents within the last 4 weeks
2. Prior anticancer therapy, within the last 3 weeks of trial dosing including chemotherapy, radiotherapy, endocrine therapy or immunotherapy
3. 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.
4. Altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies
5. Concurrent second malignancy
6. History of hypersensitivity to doxorubicin
7. 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
8. Bowel obstruction or impending bowel obstruction
9. Known HIV positivity
10. LVEF ([left ventricular ejection fraction]) below normal range (45% by MUGA)
11. Presence of metastatic disease that, in the opinion of the investigator, would require palliative treatment within 4 weeks of enrolment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Onxeo
• Collaborators: Spectrum Pharmaceuticals, Inc

Study record dates

Study Major Dates

• Study Start: December 1, 2006
• Primary Completion (ACTUAL): October 1, 2012
• Study Completion (ACTUAL): October 1, 2012

Study Registration Dates

• First Submitted: April 7, 2009
• First Submitted That Met QC Criteria: April 8, 2009
• First Posted (ESTIMATE): April 9, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): July 28, 2015
• Last Update Submitted That Met QC Criteria: July 7, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Keywords: Solid tumors; Doxorubicin; Soft tissue sarcoma; PXD101; Phase I/II trial
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Histone Deacetylase Inhibitors; Doxorubicin; Liposomal doxorubicin; Belinostat
• Other Study ID Numbers: PXD101-CLN-14