| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Alveolar soft part sarcoma, Leiomyosarcoma and Synovial sarcoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| These are types of cancer that affect soft tissues like muscles, joints, uterus, etc. |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10001884 |
| E.1.2 | Term | Alveolar soft part sarcoma metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10024191 |
| E.1.2 | Term | Leiomyosarcoma metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10042864 |
| E.1.2 | Term | Synovial sarcoma metastatic |
| 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 |
Indication A - Alveolar soft part sarcoma (ASPS)
The primary objective is the efficacy of Anlotinib (AL3818) in patients with ASPS and this will be measured by checking if the tumor has reduced in size and how much is has reduced its size.
Indication B - recruitment is closed.
Indication C - Synovial sarcaoma (SS)
The primary objective is to see how long patients will be on treatment without disease progression. In this part Anlotinib (AL3818) is compared with dacarbazine (medication approved for sarcoma).
Indication D - Leiomyosarcoma (LMS)
The primary objective is to see how long patients will be on treatment without disease progression. In this part Anlotinib (AL3818) is compared with placebo. |
|
| E.2.2 | Secondary objectives of the trial |
Indication A - Alveolar soft part sarcoma (ASPS)
The secondary objective is how efficient is Anlotinib (AL3818) and this will be measured by how many patients respond to the treatment in 6 months after starting the drug.
Indication B - recruitment is closed.
Indication C - Synovial sarcoma (SS)
The secondary objective is to see how efficient is Anlotinib (AL3818) is comparison with dacarbazine (medication approved for sarcoma)
Indication D - Leiomyosarcoma (LMS)
The secondary objective is to see how efficient is Anlotinib (AL3818) is comparison with placebo |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients who are able to sign inform consent
2. Male or female at least 18 years of age
3. Indication A – ASPS: Histologically proven, unresectable, locally advanced or metastatic alveolar soft part sarcoma.
Indication C – SS: Histologically proven, unresectable, recurrent, locally advanced or metastatic synovial sarcoma.
Indication D – LMS: Histologically proven, unresectable, recurrent, locally advanced or metastatic leiomyosarcoma (of soft tissue, cutaneous origin, and vascular origin).
4. Indication A – ASPS: Subjects with or without prior therapy.
Indication C – SS: Subjects previously treated with at least one prior line of standard systemic therapy, including first-line anthracycline containing regimen
Indication D – LMS: Treatment of patients with metastatic or advanced leiomyosarcoma (LMS) who have failed at least one prior line of standard therapy and are ineligible for or refuse standard second-line therapy or are suitable for third- and further-line treatment.
5. Show clinical or objective disease progression after the last administration of the last standard therapy or have stopped standard therapy due to intolerability within 6 months of enrollment
6. ECOG 0 or 1
7. Measurable disease as per RECIST 1.1
8. Life expectancy of at least 3 months
9. Female of childbearing potential - negative test at screening and male and female participants willing to use contraception
10. Adequate hematologic, hepatic and renal function as assessed by the following laboratory requirements conducted within 28 days of enrollment
11. Left ventricular ejection fraction (LVEF) of > 50% by ECHO or MUGA within 56 days of enrollment
12. Two readings of systolic blood pressure < 140 mm Hg and diastolic blood pressure < 90 mm Hg at screening taken at least 5 minutes apart in the sitting position after 5 minutes of rest. |
|
| E.4 | Principal exclusion criteria |
1. Prior treatment with or have known hypersensitivity to AL3818
2. Indication A – ASPS: Prior treatment with cediranib
Indication C – SS: Prior treatment with or have known hypersensitivity to dacarbazine.
Indication D – LMS: Prior treatment with anlotinib.
3. Previous or concurrent cancer that is distinct in primary site or histology from ASPS, LMS, or SS within 5 years before enrollment except for successfully treated in situ carcinoma, non-melanoma skin cancer and superficial bladder tumors (Ta, Tis and T1).
4. Received last dose of systemic cytotoxic therapy or investigational therapy within 21 days of enrollment or last dose of hormonal therapy, immunotherapy, targeted therapy or any other type of non-cytotoxic anti-cancer therapy within 14 days of enrollment.
5. Prior treatment with extended-field radiotherapy (EFRT) within 28 days of enrollment or prior treatment with any other form of radiotherapy within 14 days of enrollment.
6. Known active CNS metastases and/or carcinomatous meningitis. Patients with brain mets who are stable can be considered.
7. Cavitary tumors or tumors invading or abutting large blood vessels in the thorax.
8. History of gastrointestinal perforation, abdominal fistula or intra-abdominal abscess within 6 months of enrollment.
9. Known history of bleeding disorders
10. Clinically significant bleeding
11. CTCAE version 4.03 > grade 2 pulmonary hemorrhage or > grade 3 of other forms of bleeding within 28 days prior to enrollment
12. History of untreated deep venous thrombosis (DVT) within the past 6 months
13. Use of aspirin (>325 mg/day) within 10 days prior to the first dose of study treatment
14. Serious non-healing wound, active ulcer
15. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrollment or minor surgical procedure within 7 days of enrollment
16. CTCAE version 4.03 > grade 3 peripheral neuropathy
17. Any unrecovered toxicity reactions of CTCAE version 4.03 > grade 1 caused by any previous therapy
18. QTcF > 470 msec (per Fridericia’s formula) on electrocardiogram within 28 days of enrollment
19. Severe and uncontrolled disease: Class I and above myocardial ischemia or myocardial infarction, cardiac arrhythmia and Class 2 or above congestive heart failure; active serious infections; liver diseases; renal failure; poorly controlled diabetes; untreated or uncontrolled epileptic seizures; drug abuse; untreated psychiatric disorders
20. HIV positive
21. Had organ transplant
22. Not able to take oral medications
23. Females who are pregnant or are breast-feeding
24. Concomitant treatment with strong inhibitors or inducers of CYP1A2, CYP3A4 or CYP3A5; or sensitive substrates with narrow therapeutic index (TI) of CYP3A4, CYP2C9 and CYP2C19; or QT prolongating medications within 14 days prior to enrollment and during the study unless there was an emergent or life-threatening medical condition that required it.
25. Any medical intervention that will exclude patients based on investigator assessment |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Indication A: Alveolar Soft Part Sarcoma (ASPS)
The primary endpoint ORR will be calculated using Fisher’s exact test with 95% CIs using SAS (version 9.14). The lower end of the 95% CIs will be used to evaluate the results of the trial. No inferential procedures will be used to evaluate the trial results.
Indications C: Synovial Sarcoma (SS)
In PFS analysis, the Kaplan-Meier method will be used to estimate PFS median with 95% CI. The Cox model will be used to estimate HR of PFS with 95% CI and to determine the significant difference in PFS medians for the two groups at p = 0.05. Censor cases are defined at the date of the last adequate tumor evaluation before the cut-off date for the patient who have no documented progression or is not known to have died at the date of analysis cut-off. In addition, the following occurrences will also be considered as censor cases: a patient who has two or more missing tumor assessments; a patient who has received an anticancer therapy; and a patient who has no baseline assessment.
Indications D: Leiomyosarcoma (LMS)
In PFS analysis, the Kaplan-Meier method will be used to estimate PFS median with 95% CI. The Cox model will be used to estimate HR of PFS with 95% CI and to determine the significant difference in PFS medians for the two groups at p = 0.05. Censor cases are defined at the date of the last adequate tumor evaluation before the cut-off date for the patient who have no documented progression or is not known to have died at the date of analysis cut-off. In addition, the following occurrences will also be considered as censor cases: a patient who has two or more missing tumor assessments; a patient who has received an anticancer therapy; and a patient who has no baseline assessment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Indication A (Alveolar Soft Part Sarcoma (ASPS)): To evaluate the efficacy of AL3818 for the treatment of ASPS, as measured by objective response rate (ORR) to exclude an ORR of 17% at the lower limit of the 95% confidence interval with an actual ORR of 31.1%.
2. Indication C (Synovial Sarcoma (SS)): To compare the efficacy of AL3818 versus dacarbazine for the treatment of SS, as measured by progression-free survival (PFS).
3. Indication D (Leiomyosarcoma (LMS)): To compare the efficacy of AL3818 versus placebo for the treatment of LMS, as measured by progression-free survival (PFS). |
|
| E.5.2 | Secondary end point(s) |
1. Indication A (Alveolar Soft Part Sarcoma (ASPS)): To evaluate the efficacy of AL3818 for the treatment of ASPS, as measured by duration of response (DOR) of > 6 months.
2. Indication C (Synovial Sarcoma (SS)): To compare the efficacy of AL3818 versus dacarbazine for the treatment of SS, as measured by objective response rate (ORR).
3. Indication D (Leiomyosarcoma (LMS)): To compare the efficacy of AL3818 versus placebo for the treatment of LMS, as measured by objective response rate (ORR).- |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Evaluation of the different indications will be performed after the recruitment is completed for each indication. |
|
| 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) | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| 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 | 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 |
| Italy |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| Patients will be treated until disease progression, consent withdrawal, discontinuation due to AE or SAE or death. The study will finish when all treated patients come off study. |
|
| 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 | 1 |
| 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 | 1 |
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