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). - OPEN
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). - CLOSED
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). -
CLOSED
Indication D - LMS: 106 subjects with histologically proven, unresectable, recurrent, locally
advanced or metastatic leiomyosarcoma (of soft tissue, cutaneous origin, and vascular origin
who have failed at least one prior line of standard therapy (including anthracycline-based
therapy) and are ineligible for or refuse standard second-line therapy or are suitable for
third- and further-line treatment will be enrolled. Subjects will be randomized with a 2:1
ratio to receive either blinded AL3818 or placebo with approximately 71 subjects in the
AL3818 group and 35 subjects in the placebo group until disease progression (defined by
RECIST version 1.1) or unacceptable toxicity. Subjects randomized to placebo will have the
option to crossover and receive AL3818 at the time of documented disease progression (and
after crossover unblinding). The primary endpoint is progression free survival (PFS), the
secondary endpoint is objective response rate (ORR). - CLOSED
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. Indication B - LMS: Histologically proven,
unresectable, recurrent, locally advanced or metastatic leiomyosarcoma (of soft
tissue, cutaneous origin, vascular origin and of the bone). (New Recruitment
Suspended) c. Indication C - SS: Histologically proven, unresectable, recurrent,
locally advanced or metastatic synovial sarcoma. d. 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.
