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.
APROMISS is a phase 3 study evaluating 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). Population pharmacokinetics and exploratory
exposure-response analyses will also be conducted in subjects receiving AL3818.
Indication A: 56 subjects with metastatic or advanced ASPS not amenable to surgical resection
will receive open-label AL3818 at a dose of 12 mg once daily in 21-day cycles (14 days on
treatment, 7 days off treatment) until disease progression (defined by RECIST version 1.1) ot
unacceptable toxicity. The primary endpoint is objective response rate (ORR), secondary
endpoint is duration of response (DOR).
Indication B: 68 subjects with metastatic or advanced LMS who have failed at least one prior
line of approved therapy will be enrolled and randomized in a 2:1 ratio to receive either
AL3818 (12 mg once daily in 21-day cycles) or IV dacarbazine until disease progression
(defined by RECIST version 1.1) or unacceptable toxicity. Subjects randomized to dacarbazine
will have the option to crossover and receive AL3818 at the time of documented disease
progression. The primary endpoint is progression free survival (PFS), the secondary endpoint
is objective response rate (ORR).
Indication C: 95 subjects with with metastatic or advanced SS who have failed at least one
prior line of approved therapy, including first-line anthracycline-containing chemotherapy,
will be enrolled and randomized in a 2:1 ratio to receive either AL3818 (12 mg once daily in
21-day cycles) or IV dacarbazine until disease progression (defined by RECIST version 1.1) or
unacceptable toxicity. Subjects randomized to dacarbazine will have the option to crossover
and receive AL3818 at the time of documented disease progression. The primary endpoint is
progression free survival (PFS), the secondary endpoint is objective response rate (ORR).
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
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
- 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
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
- c. Indication C - SS: Prior treatment with or have known hypersensitivity to
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
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
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
- 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.