| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Study of Oraxol in Subjects with Cutaneous Angiosarcoma |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10002477 |
| E.1.2 | Term | Angiosarcoma metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of the study is:
• To determine the response rate within 6 months after initiation of treatment with Oraxol in subjects with cutaneous angiosarcoma |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
• To assess the overall safety and tolerability of Oraxol in subjects with cutaneous angiosarcoma
• To determine the progression-free survival (PFS) after initiation of treatment with Oraxol in subjects with cutaneous angiosarcoma
• To determine the overall survival (OS) after initiation of treatment with Oraxol in subjects with cutaneous angiosarcoma
• To determine the duration of response in subjects with cutaneous angiosarcoma
• To determine the time to best response in subjects with cutaneous angiosarcoma |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Eligible subjects must have/be:
1. Willingness and ability to give informed consent, prior to any study-specific procedures and willingness to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
2. Age of 18 years or older
3. Histologically-confirmed cutaneous angiosarcoma that is not amenable to curative intent surgery (eg, locally advanced disease and disease for which surgical resection would carry an unacceptable risk of recurrence or morbidity to the subject)
4. Subjects who have not received taxanes for the treatment of angiosarcoma
5. Measurable disease per RECIST v.1.1
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤1
7. Resolution of all acute AEs resulting from prior cancer therapies to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03) Grade ≤1 or to that subject’s baseline
8. Adequate organ function as defined by the following criteria:
• Adequate renal function as evidenced by serum creatinine ≤1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥50 mL/min per the Cockcroft and Gault formula
• Adequate bone marrow function as evidenced by
o absolute neutrophil count (ANC) ≥1.5 × 109/L
o hemoglobin ≥9.0 g/dL (<9.0 g/dL is acceptable if it is corrected by transfusion), and
o platelet count ≥100 × 109/L
• Adequate liver function as evidenced by
o total bilirubin within normal limits
o alanine aminotransferase (ALT) ≤3×ULN, and aspartate aminotransferase (AST) ≤3×ULN
o gamma-glutamyl transferase (GGT) ≤10×ULN, and
o alkaline phosphatase ≤3×ULN
9. Able to swallow pills whole and retain oral medications
10. Sexually active male subjects including men who are sterile (including vasectomy confirmed by post vasectomy semen analysis) must agree to use a condom with spermicide and to not donate sperm from the time of screening until 6 months following the last dose of Oraxol
11. Women of non-child bearing potential due to surgical sterilization (at least 6 weeks following surgical bilateral oophorectomy with or without hysterectomy or tubal ligation) confirmed by medical history or menopause (ie, no menstrual bleeding for more than 12 months in a woman aged ≥45 years), OR women of childbearing potential who test negative for pregnancy at time of enrollment based on serum pregnancy test must be using a highly effective method of contraception from the time of screening until 6 months following the last dose of Oraxol.
12. Life expectancy of at least 3 months, in the opinion of the Investigator |
|
| E.4 | Principal exclusion criteria |
Eligible subjects must not have/be:
1. Subjects with metastases outside of local lymph node involvement
2. Concurrent treatment or participation on other therapeutic clinical trial for angiosarcoma. Participation in companion studies sponsored by local institutions, including biological correlates, is permitted.
3. Women who are pregnant or breastfeeding
4. Receipt of systemic cytotoxic therapy, including investigational agents, within 14 days or 5 halflives of the first study dosing day, whichever is longer
5. Major surgery or trauma within 28 days prior to first dose of investigational product.
Note: The following are not considered to be major procedures and are permitted before treatment administration: thoracentesis, paracentesis, catheter placement, port placement, laparoscopy, thoracoscopy, tube thoracostomy, bronchoscopy, endoscopic ultrasonographic procedures, mediastinoscopy, skin biopsies, and imaging-guided biopsy for diagnostic purposes.
6. Subjects who have received wide-field radiotherapy to the pelvis ≤3 months (defined as >50% of volume of pelvic bones or equivalent) or limited-field radiation for palliation ≤3 months prior to treatment administration. Angiosarcoma lesions in the radiation field are not evaluable unless they have developed progressive disease following radiation.
7. History of brain involvement with cancer, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease.
8. Angina, myocardial infarction, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG) within 3 months prior to treatment administration
9. Active bleeding or bleeding diathesis actively requiring transfusions; Note: subjects with cutaneous ulcers from angiosarcoma or who have skin lesions with bleeding are allowed to participate.
10. Thrombolytic use (except to maintain IV catheters) within 10 days prior to treatment administration
11. Presence of a malabsorption syndrome or major resection of the stomach or small bowel that could affect the absorption of Oraxol
12. Known active viral or non-viral hepatitis or cirrhosis
13. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness
14. Active infection that requires systemic treatment
15. Concurrent use of a strong cytochrome P450 (CYP) 3A4 inducer (eg, rifampin or St. John's Wort) or a strong CYP3A4 inhibitor (eg, ketoconazole) within 14 days prior to treatment administration
16. Concurrent use of a strong CYP2C8 inhibitor (eg, gemfibrozil) or inducer (eg, rifampin) within
14 days prior to treatment administration
17. Concurrent use of an oral medication with a narrow therapeutic index known to be a P-glycoprotein (P-gp) substrate within 24 hours prior to treatment administration
18. Concurrent use of a medication known to be a strong P-gp inhibitor or inducer within 14 days prior to treatment administration
19. History of hypersensitivity to paclitaxel, not attributed to a hypersensitivity-type reaction to Cremophor® or history of hypersensitivity-type reaction to polysorbate 80 or other components of the formulation of Oraxol
20. Other severe acute or chronic medical (including bone marrow suppressive diseases) or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation, impede the ability of the subject to complete all protocol-specified activities, or may interfere with the interpretation of study results and, in the judgement of the Investigator, would make the subject inappropriate for this study |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary activity endpoint will be response rate (RR) within 6 months (RR6 months), defined as confirmed complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria10 at 2 consecutive assessments within 6 months after initiation of therapy. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Response rate (RR) within 6 months |
|
| E.5.2 | Secondary end point(s) |
• Safety: Evaluation of AEs, clinical laboratory safety data, and other safety assessments
• Activity: Progression-free survival, defined as the time from treatment initiation to the time of disease progression (radiologically or clinically) or death, whichever occurs first
• Activity: Overall survival, defined as the time from treatment initiation to death from any cause
• Activity: Duration of response, defined as the duration from the first documentation of CR or PR to disease progression (radiologically or clinically)
• Activity: Time to best response, defined as the time from the treatment initiation to best response |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Ongoing until end of study. Main treatment phase, plus the 2 year follow up post treatment phase. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Pilot study to evaluate the activity, safety and tolerability of Oraxol in up to 43 subjects |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Hong Kong |
| Taiwan |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| LVLS plus two year follow up |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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