A Phase III Trial of Anlotinib in Metastatic or Advanced Alveolar Soft Part Sarcoma, Leiomyosarcoma and Synovial Sarcoma
Trial ID or NCT#
This study evaluates the safety and efficacy of AL3818 (anlotinib) hydrochloride in the treatment of metastatic or advanced alveolar soft part sarcoma (ASPS), leiomyosarcoma (LMS), and synovial sarcoma (SS). All participants with ASPS will receive open-label AL3818. In participants with LMS or SS, AL3818 will be compared to IV dacarbazine. Two-thirds of the participants will receive AL3818, one-third of the participants will receive IV dacarbazine.
A Phase III Study of AL3818 (Anlotinib) Hydrochloride Monotherapy in Subjects With Metastatic or Advanced Alveolar Soft Part Sarcoma, Leiomyosarcoma and Synovial Sarcoma
- 1. Written informed consent provided before any study-specific procedures are initiated. Subject must be able to understand and be willing to sign a written informed consent form.
- 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 B - LMS: Histologically proven, unresectable, recurrent, locally advanced or metastatic leiomyosarcoma (of soft tissue, cutaneous origin, vascular origin and of the bone).
- - Indication C - SS: Histologically proven, unresectable, recurrent, locally advanced or metastatic synovial sarcoma.
- 4. Indication A - ASPS: Subjects with no prior therapy or subjects with prior treatment with chemotherapy or an angiogenesis inhibitor (e.g., sunitinib).
- - Indications B - LMS: Subjects previously treated with at least one prior line of approved therapy.
- - Indication C - SS: Subjects previously treated with at least one prior line of approved therapy, including first-line anthracycline containing regimen.
- 5. Show objective disease progression after the last administration of the last standard therapy or have stopped standard therapy due to intolerability (excluding ASPS subjects who have not received prior therapy) within 6 months of enrollment.
- 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- 7. Has measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed by CT or MRI scan within 28 days prior to enrollment.
- 8. Life expectancy of at least 3 months.
- 9. Females of childbearing potential must have a negative pregnancy test (by serum beta-HCG) within 7 days prior to the start of treatment.
- 10. Female of childbearing potential must be surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation), abstinent (at the discretion of the investigator), or agree to use adequate contraception since signing of the informed consent form until at least 3 months after the last study drug administration. Females of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 2 years. - Males must agree to use adequate contraception since signing of the informed consent form until at least 3 months after the last study drug administration. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) at the discretion of the investigator.
- 11. Adequate hematologic, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment:
- - Total bilirubin < the upper limit of normal (ULN)
- - Alanine aminotransferase and aspartate aminotransferase < 2.5 of the ULN (< 5 x of ULN for subjects with liver involvement of their cancer)
- - Amylase and lipase < 1.5 x of ULN
- - Serum creatinine < 1.5 x of ULN
- - Glomerular filtration rate > 30ml/min/1.73 m2 according to the Modified Diet in Renal Disease abbreviated formula or creatinine clearance (CrCL) > 60 ml/min (Cockcroft and Gault)
- - International normalize ratio (INR) and the partial thromboplastin time (PTT) < 1.5 x ULN. (Subjects who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of an underlying abnormality in coagulation parameters exists)
- - Platelet count > 100,000 cells/mm3, hemoglobin > 9 g/dL, absolute neutrophil count > 1,500 cells/mm3
- - Alkaline phosphatase limit <2.5 x ULN (<5 x ULN for subjects with liver involvement of their cancer)
- - Spot urine must not show 1+ or more protein in urine or the subject will require a repeat urinalysis. If repeat urinalysis shows 1+ protein or more, a 24-hour urine collection will be required and must show total protein excretion <1,000 mg per 24 hours.
- 12. Left ventricular ejection fraction (LVEF) of > 50% by Doppler ultrasound assessment
- 1. Prior treatment with or have known hypersensitivity to AL3818.
- 2. a. Indication A - ASPS: Prior treatment with cediranib.
- - b. Indication B- LMS: Prior treatment with or have known hypersensitivity to dacarbazine.
- - c. Indication C - SS: Prior treatment with or have known hypersensitivity to dacarbazine.
- 3. Previous or concurrent cancer that is distinct in primary site or histology from ASPS, LS, or SS within 5 years before enrollment except for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors (Ta, Tis and T1).
- 4. Received last dose of systemic cytotoxic therapy, radiation therapy or therapy with any investigational product within 28 days of enrollment.
- 5. Prior treatment with extended-field radiotherapy within 28 days prior to enrollment or prior treatment with extended-field radiotherapy for evaluating tumor lesions within 14 days prior to enrollment.
- 6. Known active CNS metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided that they are stable with no evidence of progression by imaging, and all neurologic symptoms have returned to baseline, and should not be using corticosteroids for at least 7 days prior to study treatment.
- 7. Cavitary tumors or tumors invading or abutting large blood vessels.
- 8. History of gastrointestinal perforation, abdominal fistula or intra-abdominal abscess within 6 months of enrollment.
- 9. Known history of bleeding disorders (e.g., von Willebrand disease or hemophilia).
- 10. Clinically significant bleeding such as gross hematuria, gastrointestinal bleeding and hemoptysis within 6 months prior to enrollment.
- 11. CTCAE version 4.03 > grade 2 pulmonary hemorrhage or > grade 3 of other forms of bleeding within 28 days prior to enrollment.
- 12. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, arterial thrombosis) within 6 months prior to enrollment.
- 13. Use of aspirin (>325 mg/day) within 10 days prior to the first dose of study treatment. The use of prophylactic therapeutic anti-coagulants are allowed provided that INR or aPTT are within therapeutic limits (according to the medical standard of the enrollment institution) and patient has been on a stable dose of anticoagulants for at least two weeks prior to the first dose of study treatment.
- 14. Serious non-healing wound, active ulcer, or unhealed bone fracture.
- 15. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to 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 (excluding alopecia and neurotoxicity < grade 2)
- 18. QTc > 470 msec on electrocardiogram
- 19. Severe and uncontrolled disease, including:
- - a. Class I and above myocardial ischemia or myocardial infarction, cardiac arrhythmia and Class 2 or above congestive heart failure classified according to New York Heart Association (NYHA)
- - b. Uncontrolled hypertension (systolic blood pressure > 150 mm Hg or diastolic blood pressure > 90 mmHg despite optimal medical management)
- - c. Active or failed to control serious infections (CTCAE version 4.03 > grade 2 infections)
- - d. Liver disease such as cirrhosis of the liver, decompensated liver disease, chronic active hepatitis needing anti-viral therapy
- - e. Renal failure needing hemodialysis or peritoneal dialysis
- - f. Poorly controlled diabetes (fasting blood glucose > 180 mg/dL)
- - g. Untreated and uncontrolled epileptic seizures
- - h. History of psychotropic drug abuse and inability to quit
- - i. Untreated psychiatric disorders
- 20. Known HIV-positive
- 21. Had organ transplantation
- 22. Clinical conditions affecting the intake and use of oral medications (e.g., inability to swallow, chronic diarrhea, and intestinal obstruction)
- 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 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, condition or any other circumstance which in the opinion of the investigator or the sponsor's medical monitor, could compromise adherence to study procedures or study objectives.
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