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

• ClinicalTrials.gov Identifier: NCT00878800
• Recruitment Status: Completed
• First Posted: April 9, 2009
• Results First Posted: December 29, 2014
• Last Update Posted: July 28, 2015
• Sponsor: Onxeo
• Collaborator: Spectrum Pharmaceuticals, Inc
• Information provided by (Responsible Party): Onxeo

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Dose Escalation: Solid Tumors; MTD: Soft Tissue Sarcomas	Drug: PXD101; Drug: Doxorubicin	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 41 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Clinical Trial of PXD101 in Combination With Doxorubicin in Patients With Soft Tissue Sarcomas
• Study Start Date: December 2006
• Actual Primary Completion Date: October 2012
• Actual Study Completion Date: October 2012

Arms and Interventions

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 Name: PXD101 (Belinostat); Drug: Doxorubicin; Administered in combination with PXD101 (BelDox); Other Name: Doxorubicin (Adriamycin)

Outcome Measures

Primary Outcome Measures :

1. 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
2. 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
3. Dose Limiting Toxicity (DLT) [ Time Frame: Throughout study ]
   Dose Limiting Toxicity (DLT) of PXD101 and doxorubicin combination treatment
4. 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 Outcome Measures :

1. Time to Response [ Time Frame: Throughout study, after every 2 cycles ]
2. Duration of Response [ Time Frame: Throughout study, after every 2 cycles ]
3. Time to Progression [ Time Frame: Throughout study, after every 2 cycles ]
4. Disease Control Rate (CR or PR or SD) [ Time Frame: Throughout study, after every 2 cycles ]
   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
5. Belinostat AUC (Time 0 to Last Measurement) [ Time Frame: 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 ]
   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
6. Belinostat Cmax [ Time Frame: 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 ]
   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
7. Belinostat t½ [ Time Frame: 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 ]
   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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Denmark

Herlev Hospital, Department of Oncology

Herlev, Denmark, DK-2730

Århus Hospital, Department of Oncology

Århus, Denmark, DK-8000 C

United Kingdom

The Royal Marsden NHS Trust, Cancer Research

Surrey, United Kingdom, SM2 5PT Surrey

Sponsors and Collaborators

Onxeo

Spectrum Pharmaceuticals, Inc

Investigators

• Study Director: e-mail contact via enquires@topotarget.com; Onxeo

More Information

• Responsible Party: Onxeo
• ClinicalTrials.gov Identifier: NCT00878800
• Other Study ID Numbers: PXD101-CLN-14
• First Posted: April 9, 2009
• Results First Posted: December 29, 2014
• Last Update Posted: July 28, 2015
• Last Verified: July 2015

Keywords provided by Onxeo:

Phase I/II trial; Solid tumors; Soft tissue sarcoma; PXD101; Doxorubicin

Additional relevant MeSH terms:

Sarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Doxorubicin; Liposomal doxorubicin; Belinostat; Antibiotics, Antineoplastic; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Histone Deacetylase Inhibitors