Bladder Cancer, Epithelial Ovarian Cancer, Fallopian Tube Cancer, Ovarian Cancer
Conditions
Keywords
Ovarian cancer, Ovarian Neoplasms, Primary peritoneal, Epithelial ovarian, Fallopian tube, Bladder cancer, belinostat, PXD101, mixed mullerian cancer of ovarian origin
Brief summary
The study seeks to assess the safety, pharmacodynamics, pharmacokinetics and efficacy of belinostat (PXD101) administered in combination with carboplatin or paclitaxel or both in patients with solid tumours followed by maximum tolerated dose (MTD) expansion (phase II) in ovarian and bladder cancer patients The clinical trial is now in the MTD (phase II) portion of the study enrolling bladder cancer patients. Enrollment of ovarian patients is complete.
Detailed description
MTD Expansion I(Phase II): A total of 18-32 patients with epithelial ovarian, primary peritoneal, fallopian tube or mixed mullerian tumours of ovarian origin, in need of relapse treatment will be enrolled. MTD Expansion II (phase II): A total of 15 patients with urothelial (transitional cell) carcinoma of the bladder will be enrolled.
Interventions
DRUGbelinostat
DRUGPaclitaxel
DRUGCarboplatin
Sponsors
Valerio Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed consent of an IRB (Institutional Review Board) approved consent form. 2. Patients with histologically confirmed solid carcinomas, for which there is no known curative therapy. 3. Performance status (Eastern Cooperative Oncology Group \[ECOG\]) ≤ 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 ULN (upper limit of normal). 2. AST/SGOT (\[Aspartate Amino Transferase/Serum glutamic oxaloacetic transaminase\]), ALT/SGPT (\[Alanine Amino Transferase/Serum glutamic pyruvic transaminase\]) and alkaline phosphatase ≤ 3 times ULN (if liver metastases are present, then ≤ 5 x ULN is allowed). 3. Measured EDTA (\[ethylenediaminetetraacetic acid\]) renal clearance ≥ 45 mL/min (EU sites). At the US sites calculated creatinine clearance ≥ 45 mL/min using the Jeliffe formula. 4. Leukocytes \> 2.5×109/L, neutrophils \> 1.0x109/L, platelets \> 100×109/L. 5. Hemoglobin \> 9.0 g/dL or \> 5.6 mmol/L. 7. Acceptable coagulation status: PT-INR(\[prothrombin-International Normalized Ratio\])/APTT(\[Activated Partial Thromboplastin Time\]) ≤ 1.5 × ULN or in the therapeutic range if on anticoagulation therapy 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 (added in protocol Global version 3.0) Additional Eligibility Criteria at the MTD Expansion only 10. Patients with epithelial ovarian cancer in need of relapse treatment. Changed with protocol Global version 3 to: Patients with epithelial ovarian, primary peritoneal, fallopian tube or mixed mullerian tumors of ovarian origin in need of relapse treatment. Or 11. Patients with urothelial (transitional cell) carcinoma of the bladder who have received up to a maximum of 3 previous chemotherapy regimens in the advanced disease setting (neoadjuvant chemotherapy is not included in the total of chemotherapy regimens), applies only for patients enrolled in Part D. 12. At least one uni-dimensional measurable lesion. Lesions must be measured by CT scan or MRI according to Response Evaluation Criteria in Solid Tumors (RECIST)(Added with protocol Global version 4). Eligibility Criteria for the Site Specific Amendment (Part C) - Advanced solid tumors only 13. Patients with refractory solid tumors other than ovarian cancer.
Exclusion criteria
1. Treatment with investigational agents within the last 4 weeks. 2. Prior anticancer therapy within the last 3 weeks of study dosing including chemotherapy, radiotherapy, endocrine therapy, immunotherapy or use of other investigational agents. Changed with protocol Global version 1; prior anticancer therapy within the last 3 weeks of study dosing including chemotherapy, radiotherapy, endocrine therapy or immunotherapy. 3. Co-existing active infection or any co-existing medical condition likely to interfere with study 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 interval, e.g., repeated demonstration of a QTc interval (\[corrected QT interval \]) \> 500 msec; Long QT Syndrome; the required use of concomitant medication on belinostat infusion days that may cause Torsade de Pointes (see Appendix 1.1, protocol EU version 1.0, Appendix A - Appendix 16.1.1). 4. Altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies. 5. History of a concurrent second malignancy. Changed with Site Specific Amendment (Part D) to: History of a concurrent second malignancy. In patients with urothelial (transitional cell) carcinoma of the bladder an exception is that an incidental finding of localized prostate cancer at the time of radical cystectomy does not preclude inclusion in the study. In such cases a patient will be eligible for inclusion if the Gleason score is ≤6 and the Prostate Specific Antigen (PSA) \<10 ng/mL (if the patient would be on hormonal treatment the PSA must be undetectable).Only applied to patients included in this site specific amendment. 6. History of hypersensitivity to either platinum or paclitaxel that is unable to be desensitized (added with protocol Global version 4). 7. More than 3 prior lines of chemotherapy given for metastatic disease (added with protocol Global version 1). 8. Bowel obstruction or impending bowel obstruction. 9. Known HIV positivity. 10. Any Grade 2 or above drug-related neurotoxicity, following recovery. 11. Changed with protocol Global version 1 to: Any existing Grade 2 or above drug related neurotoxicity due to prior treatment with agents causing neurotoxicity. Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerable Dose (MTD) Belinostat, Part A, | Cycle 1 | To determine the maximum tolerated dose of belinostat (PXD101) in doses up to 1000 mg/m²/day administered in combination with standard doses of carboplatin (AUC of 5) and paclitaxel (175 mg/m2). |
| Dose Limiting Toxicities (DLT), Part A | Cycle 1 | To determine the number of participants experiencing dose limiting toxicities of belinostat (PXD101) in doses up to 1000 mg/m²/day administered in combination with standard doses of carboplatin and paclitaxel or both. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression | Throughout study | Time to progression, defined as the interval between the first dates of treatment until the first notation of disease progression. RECIST criteria |
| Time to Response | Throughout study | Time to response (RECIST) was assessed as the interval between the first dates of treatment until the first notation of response. |
| Duration of Response | Throughout study | Defined as interval from the time criteria for CR or PR are met, until the first date that recurrent or progressive disease is objectively documented. |
| Best Overall Response (CR or PR) | Throughout study until PD (progressive disease) or lost to follow up | Best overall responses were assessed by RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Clinical tumor evaluation will take place after each cycle. Formal radiological evaluation after every 2 cycles. If a response is noted, a follow-up radiographic assessment must be performed 4 weeks (+ 1 week) after the response is noted |
| Belinostat Mean t½ | Cycle 1 Day 1: Cycle 1 day 1: Pre-Infusion, 0 min, 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 3 h 15 min, 3 h 30 min, 4 h, 5 h, 6 h, 6 h 15 min, 6 h 30 min, 7h, 8h, 9h, 24h | — |
| Belinostat AUC (0-infinity) | Cycle 1 Day 1: Cycle 1 day 1: Pre-Infusion, 0 min, 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 3 h 15 min, 3 h 30 min, 4 h, 5 h, 6 h, 6 h 15 min, 6 h 30 min, 7h, 8h, 9h, 24h | — |
| Belinostat Cmax | Cycle 1 day 1: Pre-Infusion, 0 min, 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 3 h 15 min, 3 h 30 min, 4 h, 5 h, 6 h, 6 h 15 min, 6 h 30 min, 7h, 8h, 9h, 24h | — |
| To Determine the Pharmacodynamic Effects of Belinostat (in the Combination) on Histone Acetylation in Peripheral Blood Mononuclear Cells (Selected Sites) | Throughout the study | — |
Countries
Denmark, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A: Dose Escalation 600/5/NA PXD101: 600 mg/m2 30-minute IV infusion every 24 hours for 5 days every 3 weeks (period of 3 weeks is one cycle) Carboplatin: AUC 5 administered 2-3 hours after PXD101 on Cycle Day 3 Paclitaxel: 0 mg/m2 administered 2-3 hours after PXD101 on Cycle Day 3 | 5 |
| Part A: Dose Escalation 600/NA/175 PXD101: 600 mg/m2 30-minute IV infusion every 24 hours for 5 days every 3 weeks (period of 3 weeks is one cycle) Carboplatin: None administered 2-3 hours after PXD101 on Cycle Day 3 Paclitaxel: 175 mg/m2 administered 2-3 hours after PXD101 on Cycle Day 3 | 5 |
| Part A: Dose Escalation 600/5/175 PXD101: 600 mg/m2 30-minute IV infusion every 24 hours for 5 days every 3 weeks (period of 3 weeks is one cycle) Carboplatin: AUC 5 administered 2-3 hours after PXD101 on Cycle Day 3 Paclitaxel: 175 mg/m2 administered 2-3 hours after PXD101 on Cycle Day 3 | 3 |
| Part A: Dose Escalation 800/5/175 PXD101: 800 mg/m2 30-minute IV infusion every 24 hours for 5 days every 3 weeks (period of 3 weeks is one cycle) Carboplatin: AUC 5 administered 2-3 hours after PXD101 on Cycle Day 3 Paclitaxel: 175 mg/m2 administered 2-3 hours after PXD101 on Cycle Day 3 | 4 |
| Part A: Dose Escalation 1000/5/175 PXD101: 1000 mg/m2 30-minute IV infusion every 24 hours for 5 days every 3 weeks (period of 3 weeks is one cycle) Carboplatin: AUC 5 administered 2-3 hours after PXD101 on Cycle Day 3 Paclitaxel: 175 mg/m2 administered 2-3 hours after PXD101 on Cycle Day 3 | 6 |
| Part B: Ovarian Cancer MTD PXD101: 1000 mg/m2 30-minute IV infusion every 24 hours for 5 days every 3 weeks (period of 3 weeks is one cycle) Carboplatin: AUC 5 administered 2-3 hours after PXD101 on Cycle Day 3 Paclitaxel: 175 mg/m2 administered 2-3 hours after PXD101 on Cycle Day 3 | 35 |
| Part C: 3 Hours Infusion, Solid Tumors Except Ovarian Cancer PXD: 1000 mg/m² was administered as a 3 hour IV infusion every 24 hours for 5 days on Day 1-5 every 3 weeks Paclitaxel: 175 mg/m² IV administered 2-3 hours following the infusion of PXD101 on cycle Day 3 Carboplatin: AUC of 5 IV administered 2-3 hours following the infusion of PXD101 on cycle Day 3 (carboplatin after paclitaxel) | 4 |
| Part C: 6 Hours Infusion Solid Tumors, Except Ovarian Cancer PXD: 1000 mg/m² was administered as a 6-hour IV infusion every 24 hours for 5 days on Day 1-5 every 3 weeks Paclitaxel: 175 mg/m² IV administered 2-3 hours following the infusion of PXD101 on cycle Day 3 Carboplatin: AUC of 5 IV administered 2-3 hours following the infusion of PXD101 on cycle Day 3 (carboplatin after paclitaxel) | 3 |
| Part D: Bladder Cancer MTD PXD101: 1000 mg/m² 30-minute IV infusion every 24 hours for 5 days on Day 1-5 every 3 weeks Carboplatin: AUC 5 IV, 2-3 hours following the infusion of PXD101 on Cycle Day 3 Paclitaxel: 175 mg/m² IV, 2-3 hours following the infusion of PXD101 on Cycle Day 3 | 15 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 1 | 1 | 1 | 4 | 1 | 0 | 2 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Patient/Investigator request | 0 | 0 | 0 | 0 | 0 | 9 | 0 | 1 | 3 |
| Overall Study | Progressive disease | 3 | 2 | 2 | 3 | 2 | 21 | 3 | 1 | 5 |
| Overall Study | Withdrawal by Subject | 1 | 3 | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part A: Dose Escalation 600/5/NA | Part A: Dose Escalation 600/NA/175 | Part A: Dose Escalation 600/5/175 | Part A: Dose Escalation 800/5/175 | Part A: Dose Escalation 1000/5/175 | Part B: Ovarian Cancer MTD | Part C: 3 Hours Infusion, Solid Tumors Except Ovarian Cancer | Part C: 6 Hours Infusion Solid Tumors, Except Ovarian Cancer | Part D: Bladder Cancer MTD | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 13 Participants | 0 Participants | 0 Participants | 7 Participants | 21 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 4 Participants | 3 Participants | 4 Participants | 6 Participants | 22 Participants | 4 Participants | 3 Participants | 8 Participants | 59 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants | 0 Participants | 3 Participants | 35 Participants | 3 Participants | 1 Participants | 4 Participants | 52 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 0 Participants | 4 Participants | 3 Participants | 0 Participants | 1 Participants | 2 Participants | 11 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 23 / 23 | 35 / 35 | 7 / 7 | 15 / 15 |
| serious Total, serious adverse events | 17 / 23 | 19 / 35 | 7 / 7 | 7 / 15 |
Outcome results
Primary
Dose Limiting Toxicities (DLT), Part A
To determine the number of participants experiencing dose limiting toxicities of belinostat (PXD101) in doses up to 1000 mg/m²/day administered in combination with standard doses of carboplatin and paclitaxel or both.
Time frame: Cycle 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A | Dose Limiting Toxicities (DLT), Part A | 0 participants |
Primary
Maximum Tolerable Dose (MTD) Belinostat, Part A,
To determine the maximum tolerated dose of belinostat (PXD101) in doses up to 1000 mg/m²/day administered in combination with standard doses of carboplatin (AUC of 5) and paclitaxel (175 mg/m2).
Time frame: Cycle 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A | Maximum Tolerable Dose (MTD) Belinostat, Part A, | 1000 mg/m2 |
Secondary
Belinostat AUC (0-infinity)
Time frame: Cycle 1 Day 1: Cycle 1 day 1: Pre-Infusion, 0 min, 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 3 h 15 min, 3 h 30 min, 4 h, 5 h, 6 h, 6 h 15 min, 6 h 30 min, 7h, 8h, 9h, 24h
Population: The Pharmacokinetic Analysis Subset consisted of 39 patients who enrolled in the study and provided a complete or partial set of pharmacokinetic parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A | Belinostat AUC (0-infinity) | 9116 ng*h/mL | Standard Deviation 1670 |
| Part A: Dose Escalation 600/NA/175 | Belinostat AUC (0-infinity) | 11785 ng*h/mL | Standard Deviation 2445 |
| Part A: Dose Escalation 600/5/175 | Belinostat AUC (0-infinity) | 21057 ng*h/mL | Standard Deviation 11034 |
| Part A: Dose Escalation 800/5/175 | Belinostat AUC (0-infinity) | 31515 ng*h/mL | Standard Deviation 3612 |
| Part A: Dose Escalation 1000/5/175 | Belinostat AUC (0-infinity) | 13107 ng*h/mL | Standard Deviation 1004 |
Secondary
Belinostat Cmax
Time frame: Cycle 1 day 1: Pre-Infusion, 0 min, 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 3 h 15 min, 3 h 30 min, 4 h, 5 h, 6 h, 6 h 15 min, 6 h 30 min, 7h, 8h, 9h, 24h
Population: The Pharmacokinetic Analysis Subset consisted of 41 patients who enrolled in the study and provided a complete or partial set of pharmacokinetic parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A | Belinostat Cmax | 18592 ng/mL | Standard Deviation 4390 |
| Part A: Dose Escalation 600/NA/175 | Belinostat Cmax | 22525 ng/mL | Standard Deviation 6002 |
| Part A: Dose Escalation 600/5/175 | Belinostat Cmax | 31517 ng/mL | Standard Deviation 12684 |
| Part A: Dose Escalation 800/5/175 | Belinostat Cmax | 8340 ng/mL | Standard Deviation 635 |
| Part A: Dose Escalation 1000/5/175 | Belinostat Cmax | 2873 ng/mL | Standard Deviation 210 |
Secondary
Belinostat Mean t½
Time frame: Cycle 1 Day 1: Cycle 1 day 1: Pre-Infusion, 0 min, 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 3 h 15 min, 3 h 30 min, 4 h, 5 h, 6 h, 6 h 15 min, 6 h 30 min, 7h, 8h, 9h, 24h
Population: The Pharmacokinetic Analysis Subset consisted of 39 patients who enrolled in the study and provided a complete or partial set of pharmacokinetic parameters
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A | Belinostat Mean t½ | 1.41 hours | Standard Deviation 0.58 |
| Part A: Dose Escalation 600/NA/175 | Belinostat Mean t½ | 1.16 hours | Standard Deviation 0.133 |
| Part A: Dose Escalation 600/5/175 | Belinostat Mean t½ | 0.898 hours | Standard Deviation 0.161 |
| Part A: Dose Escalation 800/5/175 | Belinostat Mean t½ | 3.76 hours | Standard Deviation 2.9 |
| Part A: Dose Escalation 1000/5/175 | Belinostat Mean t½ | 1.9 hours | Standard Deviation 0.286 |
Secondary
Best Overall Response (CR or PR)
Best overall responses were assessed by RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Clinical tumor evaluation will take place after each cycle. Formal radiological evaluation after every 2 cycles. If a response is noted, a follow-up radiographic assessment must be performed 4 weeks (+ 1 week) after the response is noted
Time frame: Throughout study until PD (progressive disease) or lost to follow up
Population: Primary efficacy analysis population, includes all patients who have been enrolled into the study and received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A | Best Overall Response (CR or PR) | 1 participants |
| Part A: Dose Escalation 600/NA/175 | Best Overall Response (CR or PR) | 0 participants |
| Part A: Dose Escalation 600/5/175 | Best Overall Response (CR or PR) | 0 participants |
| Part A: Dose Escalation 800/5/175 | Best Overall Response (CR or PR) | 0 participants |
| Part A: Dose Escalation 1000/5/175 | Best Overall Response (CR or PR) | 1 participants |
| Part B: Ovarian Cancer MTD | Best Overall Response (CR or PR) | 15 participants |
| Part C: 3 Hours Infusion, Solid Tumors Except Ovarian Cancer | Best Overall Response (CR or PR) | 0 participants |
| Part C: 6 Hours Infusion Solid Tumors, Except Ovarian Cancer | Best Overall Response (CR or PR) | 0 participants |
| Part D: Bladder Cancer MTD | Best Overall Response (CR or PR) | 4 participants |
Secondary
Duration of Response
Defined as interval from the time criteria for CR or PR are met, until the first date that recurrent or progressive disease is objectively documented.
Time frame: Throughout study
Population: Includes patients with response, i.e. 15 patients in Part B, 0 patients in Part C, and 4 patients in Part D. Not done for Part A.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A | Duration of Response | NA days |
| Part A: Dose Escalation 600/5/175 | Duration of Response | NA days |
Secondary
Time to Progression
Time to progression, defined as the interval between the first dates of treatment until the first notation of disease progression. RECIST criteria
Time frame: Throughout study
Population: Per protocol Population, includes all patients who have received at least two cycles (complete treatment days, dose reductions per protocol allowed) of study treatment and who have also had at least one post-baseline tumor assessment. Not done for Part A.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A | Time to Progression | 195 days |
| Part A: Dose Escalation 600/NA/175 | Time to Progression | 150 days |
| Part A: Dose Escalation 600/5/175 | Time to Progression | 136 days |
Secondary
Time to Response
Time to response (RECIST) was assessed as the interval between the first dates of treatment until the first notation of response.
Time frame: Throughout study
Population: Includes patients with response, i.e. 15 patients in Part B, 0 patients in Part C, and 4 patients in Part D. Not done for Part A.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A | Time to Response | NA days |
| Part A: Dose Escalation 600/5/175 | Time to Response | NA days |
Secondary
To Determine the Pharmacodynamic Effects of Belinostat (in the Combination) on Histone Acetylation in Peripheral Blood Mononuclear Cells (Selected Sites)
Time frame: Throughout the study
Population: Histone acetylase analysis was planned, but not successful due to technical issues with the method.