Phase III Trial of Anlotinib, Catequentinib in Advanced Alveolar Soft Part Sarcoma, Leiomyosarcoma, Synovial Sarcoma (APROMISS)

Inclusion Criteria

   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. a. Indication A - ASPS: Histologically proven, unresectable, locally advanced or
   metastatic alveolar soft part sarcoma. b. CLOSED Indication B - LMS: Histologically
   proven, unresectable, recurrent, locally advanced or metastatic leiomyosarcoma (of
   soft tissue, cutaneous origin, vascular origin and of the bone). c. CLOSED Indication
   C - SS: Histologically proven, unresectable, recurrent, locally advanced or metastatic
   synovial sarcoma. d. CLOSED Indication D - LMS: Histologically proven, unresectable,
   recurrent, locally advanced or metastatic leiomyosarcoma (of soft tissue, cutaneous
   origin, and vascular origin).

   4. a. Indication A - ASPS: Subjects with or without prior therapy. b. Indications B -
   LMS: Subjects previously treated with at least one prior line of approved therapy.
   (New Recruitment Suspended) c. Indication C - SS: Subjects previously treated with at
   least one prior line of standard systemic therapy, including first-line anthracycline
   containing regimen (except if medically contraindicated or refused by subject). d.
   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. Patients must have received and progressed on prior therapy and have been
   treated any line with an anthracycline.

   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 (excluding ASPS subjects who have not received prior therapy).

   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 of the chest, abdomen and pelvis (and
   other areas of disease) 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 28 days of enrollment:

      1. Total bilirubin < the upper limit of normal (ULN), unless the patient has
      documented Gilbert's disease for which the total bilirubin should be < 3.

      2. Alanine aminotransferase and aspartate aminotransferase < 2.5 of the ULN (< 5 x
      of ULN for subjects with liver involvement of their cancer)

      3. Amylase and lipase < 1.5 x of ULN

      4. Serum creatinine < 1.5 x of ULN

      5. 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) or by 24 hour urine collection.

      6. International normalize ratio (INR) and the activated partial thromboplastin time
      (aPTT/PTT) < 1.5 x ULN. (Subjects who are therapeutically treated with an agent
      such LMWH or heparin will be allowed to participate provided that no prior
      evidence of an underlying abnormality in coagulation parameters exists)

      7. Platelet count > 100,000 cells/mm3, hemoglobin > 9 g/dL, absolute neutrophil
      count > 1,500 cells/mm3

      8. Alkaline phosphatase limit <2.5 x ULN (<5 x ULN for subjects with liver
      involvement of their cancer)

      9. Urine protein < 30 mg/dL. If urine protein is > 30 mg/dL, a 24-hour urine
      collection will be required and must show total protein excretion <1,000 mg per
      24 hours or spot urine protein (mg/dL) to creatinine (mg/dL) ratio must be <1.0.

12. Left ventricular ejection fraction (LVEF) of > 50% by ECHO or MUGA within 56 days of
   enrollment.

13. 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. Subjects with well managed hypertension who are on oral
   antihypertensives must be on their current medication(s) and stable dose(s) for at
   least 2 weeks prior to enrollment.

Exclusion Criteria

   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. (New Recruitment
   Suspended) c. Indication C - SS: Prior treatment with or have known hypersensitivity
   to dacarbazine.

   d. 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 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 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 (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. History of untreated deep venous thrombosis (DVT) within the past 6 months. Patients
   with recent DVT who are treated with therapeutic anti-coagulating agents (excluding
   therapeutic warfarin which is exclusionary) for at least 14 days prior to start of
   study treatment.

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.

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 (excluding alopecia and neurotoxicity < grade 2)

18. QTcF > 470 msec (per Fridericia's formula) on electrocardiogram within 28 days of
   enrollment.

19. Severe and uncontrolled disease, including:

      1. 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)

      2. Active or failed to control serious infections (CTCAE version 4.03 > grade 2
      infections)

      3. Liver disease such as cirrhosis of the liver, decompensated liver disease,
      chronic active hepatitis needing anti-viral therapy

      4. Renal failure needing hemodialysis or peritoneal dialysis

      5. Poorly controlled diabetes (HgA1C >8)

      6. Untreated and uncontrolled epileptic seizures

      7. History of psychotropic drug abuse and inability to quit

      8. 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; 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, 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.