THIS STUDY IS CURRENTLY RECRUITING PATIENTS WITH ALVEOLAR SOFT PART SARCOMA ONLY AND IS NO LONGER RECRUITING PATIENTS WITH SYNOVIAL SARCOMA OR LEIOMYOSARCOMA. 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.
THIS STUDY IS CURRENTLY RECRUITING PATIENTS WITH ALVEOLAR SOFT PART SARCOMA ONLY AND IS NO LONGER RECRUITING PATIENTS WITH SYNOVIAL SARCOMA OR LEIOMYOSARCOMA. 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). - CLOSED 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 In indication E-- A total sample size of 25 subjects will be enrolled to collect baseline PK and ECG data. A total of 18 patients are projected to complete collecting fourth cycle (C4) PK and ECG data. This C-QTc study will assess the potential for cardiac repolarization delays following administration of catequentinib hydrochloride. This assessment involves examination of the QT interval at the drug concentrations of baseline and fourth cycle of steady state which was concluded by population PK results. Catequentinib hydrochloride is a strong Cytochrome enzyme P450 3A4 (CYP3A4) inhibitor and mild inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) based on the in vitro assay. This designed DDI study will assess how catequentinib hydrochloride affects the pharmacokinetics (PK) of midazolam (a known probe substrate of CYP3A4), Digoxin (a known probe substrate of P-gp) and rosuvastatin (a known probe substrate of BCRP) after the treatments of fourth cycles.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
325
Anlotinib (AL3818) 12 mg orally administered once daily in 21-day cycles (14 days on treatment, 7 days off treatment)
Dacarbazine 1000 mg/m2 as a 20-120 minute IV infusion on Day 1 of each 21-day treatment cycle
AL3818 or placebo 12 mg orally administered once daily in 21-day cycles (14 days on treatment, 7 days off treatment)
In indication E, midazolam will be used to see how catequentinib hydrochloride affects the pharmacokinetics (PK) of Cytochrome enzyme P450 3A4 (CYP3A4).
In indication E, Digoxin will be used to see how catequentinib hydrochloride affects the pharmacokinetics (PK) of P-glycoprotein.
In indication E, Rosuvastatin will be used to see how catequentinib hydrochloride affects the pharmacokinetics (PK) of breast cancer resistance protein .
Mayo Clinic Arizona
Phoenix, Arizona, United States
COMPLETEDUniversity of California Los Angeles
Los Angeles, California, United States
COMPLETEDSarcoma Oncology Center
Santa Monica, California, United States
RECRUITINGStanford Medicine Cancer Institute
Stanford, California, United States
COMPLETEDUniversity of Colorado Denver
Aurora, Colorado, United States
COMPLETEDMayo Clinic Jacksonville
Jacksonville, Florida, United States
COMPLETEDUniversity of Miami Sylvester Comprehensive Cancer Center
Miami, Florida, United States
COMPLETEDNorthwestern University
Chicago, Illinois, United States
COMPLETEDUniversity of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States
COMPLETEDMayo Clinic Rochester
Rochester, Minnesota, United States
COMPLETED...and 14 more locations
Objective Response Rate (ORR) (ASPS)
To determine ORR in subjects with ASPS, defined as percentage of subjects who achieve a Complete Response (CR) or Partial Response (PR) as best responses according to RECIST 1.1 as evaluated by a blinded independent radiological review (BICR).
Time frame: Up to 48 months
Progression Free Survival (PFS) (LMS/SS)
To compare PFS in subjects with LMS or SS randomized to AL3818 versus dacarbazine, defined a median number of months from the date of randomization until the first documented sign of disease progression or death due to any causes, whichever occurs earlier as evaluated by a blinded independent radiologic review (BICR).
Time frame: From time of randomization to the date of disease progression or death from any cause, up to 48 months
Assess the ECG and the PK parameters of catequentinib hydrocoloride in probe substance (Indication E)
To assess the ECGs and the PK parameters of catequentinib hydrocoloride in the administration of single-dose midazolam and single-dose of combined administration of P-gp and BCRP substrates digoxin and rosuvastatin in cancer patients.
Time frame: Each patient study duration is designed to end between C4D18-D21 when the first RECIST and final visit are planned. Whole study duration is approximately 12 months and no any follow up is planned
Duration of Response (DOR) (ASPS)
To determine DOR in subjects with ASPS, defined as median number of months from date of first documented objective response until first documented sign of disease progression or death due to any causes
Time frame: Up to 48 months
Objective Response Rate (ORR) (LMS/SS)
To compare ORR in subjects with LMS or SS randomized to AL3818 versus dacarbazine, defined as percentage of subjects who achieve a Complete Response (CR) or Partial Response (PR) as best responses according to RECIST 1.1 as evaluated by a blinded independent radiological review (BICR).
Time frame: Up to 48 months
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