Clinical Trials /

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

NCT03016819

Description:

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.

Related Conditions:
  • Alveolar Soft Part Sarcoma
  • Leiomyosarcoma
  • Synovial Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Phase III Trial of Anlotinib, Catequentinib in Advanced Alveolar Soft Part Sarcoma, Leiomyosarcoma, Synovial Sarcoma (APROMISS)
  • Official Title: A Phase III Study of AL3818 (Anlotinib, Catequentinib) Hydrochloride Monotherapy in Subjects With Metastatic or Advanced Alveolar Soft Part Sarcoma, Leiomyosarcoma and Synovial Sarcoma

Clinical Trial IDs

  • ORG STUDY ID: AL3818-US-004
  • NCT ID: NCT03016819

Conditions

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

Interventions

DrugSynonymsArms
AL3818Catequentenib, AnlotinibIndication A: ASPS AL3818 Arm - OPEN
DacarbazineDTICIndication B: LMS Dacarbazine Arm - CLOSED
AL3818 or placeboIndication D: LMS AL3818 or Placebo Arm - OPEN

Purpose

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.

Detailed Description

      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). - OPEN
    

Trial Arms

NameTypeDescriptionInterventions
Indication A: ASPS AL3818 Arm - OPENExperimentalAll 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).
  • AL3818
Indication B: LMS AL3818 Arm - CLOSEDExperimentalSubjects 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).
  • AL3818
Indication B: LMS Dacarbazine Arm - CLOSEDActive ComparatorSubjects 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.
  • Dacarbazine
Indication C: SS AL3818 Arm - CLOSEDExperimentalSubjects 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).
  • Dacarbazine
Indication C: SS Dacarbazine Arm - CLOSEDActive ComparatorSubjects 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.
  • Dacarbazine
Indication D: LMS AL3818 or Placebo Arm - OPENPlacebo ComparatorSubjects 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).
  • AL3818 or placebo

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR) (ASPS)
Time Frame:Up to 48 months
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure:Duration of Response (DOR) (ASPS)
Time Frame:Up to 48 months
Safety Issue:
Description: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
Measure:Objective Response Rate (ORR) (LMS/SS)
Time Frame:Up to 48 months
Safety Issue:
Description: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).

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Advenchen Laboratories, LLC

Last Updated

December 9, 2020