| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| A cancer of the endothelial cells. |
|
| 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 | 10002476 |
| E.1.2 | Term | Angiosarcoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| To compare PFS of TRC105 and pazopanib vs single agent pazopanib in patients with unresectable angiosarcoma. |
|
| E.2.2 | Secondary objectives of the trial |
• To compare the objective response rate (ORR) of TRC105 and pazopanib vs single agent pazopanib in patients with unresectable angiosarcoma
• To compare overall survival (OS) of TRC105 and pazopanib vs single agent pazopanib in patients with unresectable angiosarcoma
• To assess the overall safety and tolerability of TRC105 and pazopanib vs single agent pazopanib in patients with unresectable angiosarcoma
• To characterize patient reported outcomes between the two arms of the study
• To characterize the pharmacokinetic (PK) profile of TRC105 and pazopanib between the two arms of the study
• To assess PFS and ORR by Investigator assessment between the two arms of the study
• To characterize the immunogenicity of TRC105 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically-confirmed angiosarcoma that is not amenable to curative intent surgery (e.g., metastatic or bulky disease and disease for which surgical resection would carry an unacceptable risk to the patient). Pathology report will be reviewed by sponsor prior to randomization.
2. Documented progression on or following most recent systemic chemotherapy regimen (not required for chemotherapy-naïve patients), within 4 months prior to screening
3. Measurable disease by RECIST v1.1
4. Age of 18 years or older; in addition, patients age 12 to 17 years may enroll beginning in Cohort 2 if weight ≥ 40 kg
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
6. 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 patient’s pre-study baseline (except alopecia or neuropathy)
7. Adequate organ function as defined by the following criteria:
• Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT])
and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x upper limit of normal (ULN) or ≤ 5 x ULN in cases of liver metastases
• Total serum bilirubin ≤ 1.5 x ULN
• Absolute neutrophil count (ANC) ≥ 1500/μL
• Platelets ≥ 100,000/μL (without transfusion support within 28 days prior to randomization)
• Hemoglobin ≥ 9.0 g/dL (without transfusion support within 14 days prior to randomization; erythropoietin or darbepoetin permitted)
• Serum creatinine ≤ 1.5 times the upper limit of normal or creatinine clearance > 30 mL/min by Cockcroft-Gault formula
• International normalized ratio (INR) ≤ 1.2 unless the patient is receiving a direct Factor Xa inhibitor
8. Willingness and ability to consent (and assent if under age 18) for self to participate in study
9. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
10. Angiosarcoma tumor specimen, if available
11. Men who are sterile (including vasectomy confirmed by post vasectomy semen analysis) OR agree to use a condom with spermicide and to not donate sperm during the study and for at least 180 days following last dose of TRC105 or pazopanib
12. Woman 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 (i.e., no menstrual bleeding for more than 12 months in a 1 or to that patient’s pre-study baseline (except alopecia or neuropathy) women aged 45 years or more), OR woman of child bearing potential who test negative for pregnancy at time of enrollment based on serum pregnancy test and agree to use at least 2 acceptable methods of birth control, one of which must be highly effective, during the study and for at least 180 days after stopping TRC105 or pazopanib |
|
| E.4 | Principal exclusion criteria |
1. Prior treatment with TRC105
2. Prior treatment with any VEGF inhibitor
3. More than two prior lines (may be combination regimens) of chemotherapy for angiosarcoma (neoadjuvant/adjuvant treatment does not count as a line of treatment)
4. Current treatment or participation on another therapeutic clinical trial
5. Women who are pregnant or breastfeeding
6. Receipt of systemic anticancer therapy, including investigational agents, within 5 times the agent’s elimination half-life or 14 days of starting study treatment, whichever is shorter
7. Major surgical procedure or significant traumatic injury within 4 weeks prior to randomization and must have fully recovered from any such procedure or injury; planned surgery (if applicable) or the anticipated need for a major surgical procedure within the next six months. Note: the following are not considered to be major procedures and are permitted up to 7 days before randomization: Thoracentesis, paracentesis, laparoscopy, thoracoscopy, tube thoracostomy, bronchoscopy, endoscopic ultrasonographic procedures, mediastinoscopy, skin biopsies, and imaging-guided biopsy for diagnostic purposes
8. Patients who have received wide field radiotherapy ≤ 28 days (defined as > 50% of volume of pelvic bones or equivalent) or limited field radiation for palliation < 14 days prior to randomization
9. Uncontrolled hypertension defined as systolic > 150 or diastolic > 100 mm Hg on the average of the 3 most recent BP readings. Anti-hypertensives may be started prior to randomization.
10. Ascites or pleural effusion requiring intervention or that required intervention or recurred within three months prior to randomization
11. Pericardial effusion (except trace effusion identified by echocardiogram) within three months prior to randomization
12. History of brain involvement with cancer, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease. Patients with radiated or resected lesions are permitted, provided the lesions are fully treated and inactive, patients are asymptomatic, and no steroids have been administered for at least 28 days prior to randomization
13. 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 6 months prior to randomization. Deep venous thrombosis within 3 months prior to randomization unrelated to a central venous catheter, unless the patient is anti-coagulated without the use of warfarin for at least 2 weeks prior to randomization. In this situation, low molecular weight heparin or a direct Factor Xa inhibitor is preferred
14. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g., hereditary hemorrhagic telangiectasia). Patients with bleeding cutaneous lesions not actively requiring transfusions are eligible. Patients who have been uneventfully anti-coagulated with a direct Factor Xa inhibitor or low molecular weight heparin are eligible
15. Hemoptysis (> ½ teaspoon [2.5 mL] of bright red blood) within 6 months prior to randomization
16. Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to randomization
17. Known active viral or nonviral hepatitis or cirrhosis
18. Peptic ulcer within the past 3 months prior to randomization, unless treated for the condition and complete resolution has been documented by esophagogastroduodenoscopy (EGD)
19. Presence of tumor(s) invading into the heart or great vessels (including carotid artery) or another location where bleeding is associated with high morbidity including patients with primary cardiac or great vessel angiosarcoma
20. Gastrointestinal perforation or fistula in the 6 months prior to randomization unless underlying risk has been resolved (e.g., through surgical resection or repair)
21. Presence of a malabsorption syndrome, gastrointestinal disorder, or gastrointestinal surgery that could affect the absorption of pazopanib
22. History of prior malignancy except adequately treated basal cell or squamous cell skin cancer or adequately treated, with curative intent, cancer from which the patient is currently in complete remission per Investigator’s judgment; patients with history of breast cancer and no evidence of disease on hormonal therapy to prevent recurrence and patients with prostate cancer on adjuvant hormonal therapy with undetectable PSA are eligible
23. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness
24. Active infection that requires systemic treatment
25. Concurrent use or receipt of a strong CYP3A4 inducer within 12 days prior to randomization or a strong CYP3A4 inhibitor within 7 days prior to randomization |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PFS is defined as time from randomization to either first disease progression (per independent radiology review of images by RECIST 1.1) or death from any cause. For the purpose of analysis for patients who are alive at the time of analysis and have not had disease progression, the following rules will apply: (1) The patient will be censored on the date of the last tumor assessment documenting absence of progressive disease; (2) if the patient was
given antitumor treatment other than study drug treatment, the patient will be censored as of the date of the last tumor assessment prior to initiating that antitumor therapy; (3) if the patient was removed from study for toxicity or other reason, the patient will be censored as of the date of the last tumor assessment on study. With regard to missed tumor assessments, in the event of one missed tumor assessment followed by a subsequent assessment of progressive disease (PD), the subsequent PD assessment qualifies as objective tumor progression. In the event of more than one consecutive missing tumor assessment followed by a subsequent assessment of PD, the patient will be censored at the last adequate tumor assessment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Tumor assessments are conducted every 42 days from randomization. |
|
| E.5.2 | Secondary end point(s) |
• Objective response rate (ORR) is defined as the number of patients with a best response of complete response (CR) or partial response (PR) divided by the number of randomized patients. ORR is defined as the best response designation recorded between the date of randomization and the date of documented progression, as determined by Central Radiographic Review according to RECIST 1.1, or date of subsequent therapy, whichever occurs first. For patients without documented progression or subsequent therapy, all available response designations will contribute to the ORR determination. A designation of CR or PR in this study requires confirmation at a subsequent consecutive assessment at least 4 weeks following the initial designation of CR or PR, respectively. Duration of response (DR) will be reported in patients who achieve ORR, but without a formal statistical comparison between arms.
• Overall Survival (OS) is defined as the time between the date of randomization and the date of death from any cause. Overall survival will be calculated in days as: Date of Death – Date of Randomization +1. Subjects alive or lost to follow-up at the time of analysis will be censored at the date when they were last known to be alive.
• Type, incidence, severity (graded by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] Version 4.03), timing, seriousness, and relatedness of AEs and laboratory abnormalities.
• Patient reported outcomes as measured by the EuroQol five dimensions questionnaire (EQ-5D-5L) and the EORTC QLQ-C30 questionnaire.
• TRC105 and pazopanib pharmacokinetic (PK) concentrations will be measured using validated methods from peak and trough samples.
• Anti-TRC105 antibodies will be measured using validated methods and anti-drug antibody (ADA) titers will be correlated with PK parameters and AEs. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As described in schedule of assessments in protocol. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| Austria |
| France |
| Germany |
| Italy |
| Poland |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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