Dose Escalation: Solid Tumors, MTD: Soft Tissue Sarcomas
Conditions
Keywords
Phase I/II trial, Solid tumors, Soft tissue sarcoma, PXD101, Doxorubicin
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.
Interventions
DRUGPXD101
Administered in combination with doxorubicin (BelDox)
DRUGDoxorubicin
Administered in combination with PXD101 (BelDox)
Sponsors
Spectrum Pharmaceuticals, Inc
Valerio Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) PXD101 | During Cohort 1 to 4, Cycle 1 only, up to 3 weeks | Maximum Tolerated Dose (MTD) of PXD101treatment |
| Maximum Tolerated Dose (MTD) of Doxorubicin | During Cohort 1 to 4, Cycle 1 only, up to 3 weeks | Maximum Tolerated Dose (MTD) of doxorubicin |
| Dose Limiting Toxicity (DLT) | Throughout study | Dose Limiting Toxicity (DLT) of PXD101 and doxorubicin combination treatment |
| Objective Response (CR and PR) | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 |
| Time to Response | Throughout study, after every 2 cycles | — |
| 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 | 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 |
| 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 | 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 |
| 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 | 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 |
Countries
Denmark, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: BelDox IV (600/50) PXD101 + doxorubicin: 5-day PXD101 600 mg/m² combined with doxorubicin 50 mg/m² | 3 |
| Cohort 2: BelDox IV (600/75) PXD101 + doxorubicin: 5-day PXD101 600 mg/m² combined with doxorubicin 75 mg/m² | 7 |
| Cohort 3: BelDox IV (800/75) PXD101 + doxorubicin: 5-day PXD101 800 mg/m² combined with doxorubicin 75 mg/m² | 9 |
| Cohort 4: BelDox IV (1000/75) PXD101 + doxorubicin: 5-day PXD101 1000 mg/m² combined with doxorubicin 75 mg/m² | 6 |
| MTD Expansion: BelDox IV (1000/75) PXD101 + doxorubicin: 5-day PXD101 1000 mg/m² combined with doxorubicin 75 mg/m² | 16 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 | 0 | 1 |
| Overall Study | Death | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Other | 1 | 1 | 0 | 0 | 1 |
| Overall Study | Progressive disease | 1 | 5 | 6 | 5 | 13 |
| Overall Study | Withdrew consent | 1 | 1 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Cohort 1: BelDox IV (600/50) | Cohort 2: BelDox IV (600/75) | Cohort 3: BelDox IV (800/75) | Cohort 4: BelDox IV (1000/75) | MTD Expansion: BelDox IV (1000/75) | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 1 Participants | 2 Participants | 5 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 5 Participants | 8 Participants | 4 Participants | 11 Participants | 31 Participants |
| Sex: Female, Male Female | 0 Participants | 4 Participants | 4 Participants | 0 Participants | 7 Participants | 15 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 5 Participants | 6 Participants | 9 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 7 / 7 | 9 / 9 | 6 / 6 | 16 / 16 |
| serious Total, serious adverse events | 2 / 3 | 4 / 7 | 5 / 9 | 2 / 6 | 10 / 16 |
Outcome results
Primary
Dose Limiting Toxicity (DLT)
Dose Limiting Toxicity (DLT) of PXD101 and doxorubicin combination treatment
Time frame: Throughout study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation | Dose Limiting Toxicity (DLT) | 0 Dose limiting toxicity |
| MTD Expansion | Dose Limiting Toxicity (DLT) | 0 Dose limiting toxicity |
Primary
Maximum Tolerated Dose (MTD) of Doxorubicin
Maximum Tolerated Dose (MTD) of doxorubicin
Time frame: During Cohort 1 to 4, Cycle 1 only, up to 3 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation | Maximum Tolerated Dose (MTD) of Doxorubicin | 75 mg/m2 |
Primary
Maximum Tolerated Dose (MTD) PXD101
Maximum Tolerated Dose (MTD) of PXD101treatment
Time frame: During Cohort 1 to 4, Cycle 1 only, up to 3 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation | Maximum Tolerated Dose (MTD) PXD101 | 1000 mg/m² |
Primary
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.
Time frame: Throughout study, after every 2 cycles
Population: The full-analysis set (FAS) comprises all patients enrolled in the study and receiving at least one dose of study drug, and for whom at least one tumor assessment was performed post baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation | Objective Response (CR and PR) | 8 percentage of participants |
| MTD Expansion | Objective Response (CR and PR) | 12.5 percentage of participants |
Secondary
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
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
Population: The pharmacokinetic population consisted of all patients who were dosed and had evaluable pharmacokinetic data. Dose level belinostat 1000 mg/m² and belinostat 1000 mg/m² plus doxorubicin 75 mg/m² is presented.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation | Belinostat AUC (Time 0 to Last Measurement) | 23100 ng*h/mL | Geometric Coefficient of Variation 35.4 |
| MTD Expansion | Belinostat AUC (Time 0 to Last Measurement) | 22100 ng*h/mL | Geometric Coefficient of Variation 43.2 |
Secondary
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
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
Population: The pharmacokinetic population consisted of all patients who were dosed and had evaluable pharmacokinetic data. Dose level belinostat 1000 mg/m² and belinostat 1000 mg/m² plus doxorubicin 75 mg/m² is presented.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation | Belinostat Cmax | 41100 ng/mL | Geometric Coefficient of Variation 35 |
| MTD Expansion | Belinostat Cmax | 37000 ng/mL | Geometric Coefficient of Variation 59.1 |
Secondary
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
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
Population: The pharmacokinetic population consisted of all patients who were dosed and had evaluable pharmacokinetic data. Dose level belinostat 1000 mg/m² and belinostat 1000 mg/m² plus doxorubicin 75 mg/m² is presented.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation | Belinostat t½ | 1.48 hours | Geometric Coefficient of Variation 71.3 |
| MTD Expansion | Belinostat t½ | 2.13 hours | Geometric Coefficient of Variation 119.4 |
Secondary
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
Time frame: Throughout study, after every 2 cycles
Population: The full-analysis set (FAS) comprises all patients enrolled in the study and receiving at least one dose of study drug, and for whom at least one tumor assessment was performed post baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation | Disease Control Rate (CR or PR or SD) | 72.0 percentage of participants |
| MTD Expansion | Disease Control Rate (CR or PR or SD) | 68.8 percentage of participants |
Secondary
Duration of Response
Time frame: Throughout study, after every 2 cycles
Population: Includes only patients with response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation | Duration of Response | 3.9 Months |
| MTD Expansion | Duration of Response | 7.9 Months |
Secondary
Time to Progression
Time frame: Throughout study, after every 2 cycles
Population: Includes only patients with disease progression.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation | Time to Progression | 3.7 months |
| MTD Expansion | Time to Progression | 6.0 months |
Secondary
Time to Response
Time frame: Throughout study, after every 2 cycles
Population: Includes all 41 patients in the FAS population. 37 patients were censored due to no response, 23 in the Dose Escalation group and 14 in the MTD Expansion group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation | Time to Response | NA months |
| MTD Expansion | Time to Response | NA months |