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

NCT03016819 | Recruiting Phase 3 DMC FDA Drug

• 1 other identifier: AL3818-US-004
• Study Type: interventional
• Target: 325
• Locations: 5 countries
• Sites: 24

Brief Summary

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.

Conditions

Alveolar Soft Part Sarcoma; Leiomyosarcoma; Synovial Sarcoma; Soft-Tissue Sarcoma

Outcome Measures

Primary Outcomes (3)

• 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).

  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).

  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.

  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

Secondary Outcomes (2)

• Duration of Response (DOR) (ASPS)

  Up to 48 months

• Objective Response Rate (ORR) (LMS/SS)

  Up to 48 months

Study Arms (7)

Indication A: ASPS AL3818 Arm - CLOSED

EXPERIMENTAL

All subjects with ASPS will be assigned to the open-label AL3818 arm to receive 12 mg AL3818 capsules orally once daily in 21-day cycles (14 days on treatment from Day 1-14, 7 days off treatment from Day 15-21).

Drug: AL3818

Indication B: LMS AL3818 Arm - CLOSED

EXPERIMENTAL

Subjects with LMS will be randomized in a 2:1 ratio to receive either AL3818 or IV dacarbazine. Subjects randomized to AL3818 will receive 12 mg AL3818 capsules orally once daily in 21-day cycles (14 days on treatment from Day 1-14, 7 days off treatment from Day 15-21).

Drug: AL3818

Indication B: LMS Dacarbazine Arm - CLOSED

ACTIVE COMPARATOR

Subjects with LMS will be randomized in a 2:1 ratio to receive either AL3818 or IV dacarbazine. Subjects randomized to IV dacarbazine will receive dacarbazine at a dose of 1000 mg/m\^2 as a 20-120 minute IV infusion on Day 1 of each 21-day treatment cycle.

Drug: Dacarbazine

Indication C: SS AL3818 Arm - CLOSED

EXPERIMENTAL

Subjects with SS will be randomized in a 2:1 ratio to receive either AL3818 or IV dacarbazine. Subjects randomized to AL3818 will receive 12 mg AL3818 capsules orally once daily in 21-day cycles (14 days on treatment from Day 1-14, 7 days off treatment from Day 15-21).

Drug: Dacarbazine

Indication C: SS Dacarbazine Arm - CLOSED

EXPERIMENTAL

Subjects with SS will be randomized in a 2:1 ratio to receive either AL3818 or IV dacarbazine. Subjects randomized to IV dacarbazine will receive dacarbazine at a dose of 1000 mg/m\^2 as a 20-120 minute IV infusion on Day 1 of each 21-day treatment cycle.

Drug: Dacarbazine

Indication D: LMS AL3818 or Placebo Arm - CLOSED

PLACEBO COMPARATOR

Subjects with LMS will be randomized in a 2:1 ratio to receive either AL3818 or placebo in a double-blind manner. AL3818 or placebo will be administrated as one 12 mg capsule orally once daily in 21-day cycles for 14 days on treatment (Days 1-14) and 7 days off treatment (Days 15-21).

Drug: AL3818 or placebo

Indication E: Catequentinib Hydrochloride (AL3818) Study of Concentration-QTc (C-QTc) and Drug-Drug

ACTIVE COMPARATOR

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.

Drug: AL3818; Drug: Midazolam 2 mg for CYP3A4 phenotyping; Drug: Digoxin (0.25mg); Drug: Rosuvastatin 10 mg tablet.

Interventions

Digoxin (0.25mg) DRUG

In indication E, Digoxin will be used to see how catequentinib hydrochloride affects the pharmacokinetics (PK) of P-glycoprotein.

Indication E: Catequentinib Hydrochloride (AL3818) Study of Concentration-QTc (C-QTc) and Drug-Drug

Rosuvastatin 10 mg tablet. DRUG

In indication E, Rosuvastatin will be used to see how catequentinib hydrochloride affects the pharmacokinetics (PK) of breast cancer resistance protein .

Indication E: Catequentinib Hydrochloride (AL3818) Study of Concentration-QTc (C-QTc) and Drug-Drug

Midazolam 2 mg for CYP3A4 phenotyping DRUG

In indication E, midazolam will be used to see how catequentinib hydrochloride affects the pharmacokinetics (PK) of Cytochrome enzyme P450 3A4 (CYP3A4).

Indication E: Catequentinib Hydrochloride (AL3818) Study of Concentration-QTc (C-QTc) and Drug-Drug

AL3818 DRUG

Anlotinib (AL3818) 12 mg orally administered once daily in 21-day cycles (14 days on treatment, 7 days off treatment)

Also known as: Catequentenib, Anlotinib

Indication A: ASPS AL3818 Arm - CLOSED; Indication B: LMS AL3818 Arm - CLOSED; Indication E: Catequentinib Hydrochloride (AL3818) Study of Concentration-QTc (C-QTc) and Drug-Drug

Dacarbazine DRUG

Dacarbazine 1000 mg/m2 as a 20-120 minute IV infusion on Day 1 of each 21-day treatment cycle

Also known as: DTIC

Indication B: LMS Dacarbazine Arm - CLOSED; Indication C: SS AL3818 Arm - CLOSED; Indication C: SS Dacarbazine Arm - CLOSED

AL3818 or placebo DRUG

AL3818 or placebo 12 mg orally administered once daily in 21-day cycles (14 days on treatment, 7 days off treatment)

Indication D: LMS AL3818 or Placebo Arm - CLOSED

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Male or female at least 18 years of age.
• 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).
• \. Open Indication E: Any sarcomas or other solid tumors 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. e. Indication E: Any sarcomas or other solid tumors such as NSCLC, SCLC and Thyroid cancer etc.: Subjects exhausted SOC treatment or refuse for any SOC treatment.
• \. 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).
• \. 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.
• \. Females of childbearing potential must have a negative pregnancy test (by serum beta- HCG) within 7 days prior to the start of treatment.
• \. 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:
• a. Total bilirubin \< the upper limit of normal (ULN), unless the patient has documented Gilbert's disease for which the total bilirubin should be \< 3. b. Alanine aminotransferase and aspartate aminotransferase \< 2.5 of the ULN (\< 5 x of ULN for subjects with liver involvement of their cancer) c. Amylase and lipase \< 1.5 x of ULN d. Serum creatinine \< 1.5 x of ULN e. 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. f. 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) g. Platelet count \> 100,000 cells/mm3, hemoglobin \> 9 g/dL, absolute neutrophil count \> 1,500 cells/mm3 h. Alkaline phosphatase limit \<2.5 x ULN (\<5 x ULN for subjects with liver involvement of their cancer) i. 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.
• \. 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.

You may not qualify if:

• Prior treatment with or have known hypersensitivity to AL3818.
• 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.
• 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).
• 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.
• 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.
• 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.
• Cavitary tumors or tumors invading or abutting large blood vessels in the thorax.
• History of gastrointestinal perforation, abdominal fistula or intra-abdominal abscess within 6 months of enrollment.
• Known history of bleeding disorders (e.g., von Willebrand disease or hemophilia).
• Clinically significant bleeding such as gross hematuria, gastrointestinal bleeding and hemoptysis within 6 months prior to enrollment.
• CTCAE version 4.03 \> grade 2 pulmonary hemorrhage or \> grade 3 of other forms of bleeding within 28 days prior to enrollment.
• 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.
• Serious non-healing wound, active ulcer.

Sponsors & Collaborators

• Advenchen Laboratories, LLC: lead

Study Sites (24)

Mayo Clinic Arizona

Phoenix, Arizona, 85054, United States

COMPLETED

University of California Los Angeles

Los Angeles, California, 90404, United States

COMPLETED

Sarcoma Oncology Center

Santa Monica, California, 90403, United States

RECRUITING

Stanford Medicine Cancer Institute

Stanford, California, 94305, United States

COMPLETED

University of Colorado Denver

Aurora, Colorado, 80045, United States

COMPLETED

Mayo Clinic Jacksonville

Jacksonville, Florida, 32224, United States

COMPLETED

University of Miami Sylvester Comprehensive Cancer Center

Miami, Florida, 33136, United States

COMPLETED

Northwestern University

Chicago, Illinois, 60611, United States

COMPLETED

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109, United States

COMPLETED

Mayo Clinic Rochester

Rochester, Minnesota, 55905, United States

COMPLETED

Washington University St. Louis

St Louis, Missouri, 63130, United States

COMPLETED

Columbia University Medical Center

New York, New York, 10032, United States

WITHDRAWN

Thomas Jefferson Hospital - Sidney Kimmel Cancer Center

Philadelphia, Pennsylvania, 19107, United States

COMPLETED

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15219, United States

COMPLETED

Vanderbilt University

Nashville, Tennessee, 37203, United States

COMPLETED

MD Anderson Cancer Center

Houston, Texas, 77030, United States

COMPLETED

UW Medicine-Seattle Cancer Care Alliance

Seattle, Washington, 98109, United States

COMPLETED

Beijing Cancer Hospital

Beijing, China

COMPLETED

Shanghai Sixth People's Hospital

Shanghai, China

COMPLETED

Istituto Nazionale dei Tumori

Milan, Italy

COMPLETED

University of Palermo

Palermo, Italy

COMPLETED

University Campus Bio-Medico

Rome, Italy

COMPLETED

Hospital de la Santa Creu i Sant Pau

Barcelona, Spain

COMPLETED

Royal Marsden Hospital

London, SW3 6JJ, United Kingdom

NOT YET RECRUITING

MeSH Terms

Conditions

Sarcoma, Alveolar Soft Part; Leiomyosarcoma; Sarcoma, Synovial; Sarcoma

Interventions

anlotinib; Dacarbazine; Midazolam; Digoxin; Rosuvastatin Calcium; Tablets

Condition Hierarchy (Ancestors)

Neoplasms, Muscle Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Connective Tissue

Intervention Hierarchy (Ancestors)

Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Glycosides; Carbohydrates; Sulfonamides; Amides; Fluorobenzenes; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrimidines; Dosage Forms; Pharmaceutical Preparations

Study Officials

• Paul CEO

  Advenchen Laboratories, LLC

  STUDY DIRECTOR

Central Study Contacts

Shiying Clinical Trial Manager

CONTACT

8055301550; Shiyings@advenchen.com

Judy Clinical Trial Manager

CONTACT

8055301550; judyc@advenchen.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Indication D (Leiomyosarcoma, AL3818 vs placebo) of study AL3818-US-004 is double-blinded. Indications A (alveolar soft part sarcoma, single arm with AL3818), B (Leiomyosarcoma, AL3818 vs dacarbazine), C (Synovial sarcoma, AL3818 vs dacarbazine) are open-label.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 6, 2017
• First Posted: January 11, 2017
• Study Start: August 15, 2017
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2028
• Last Updated: February 25, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (17); ES (1); IT (3); GB (1); CN (2)