Clinical Trials /

A Phase III Trial of Anlotinib in Metastatic or Advanced Alveolar Soft Part Sarcoma, Leiomyosarcoma and Synovial Sarcoma

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: A Phase III Trial of Anlotinib in Metastatic or Advanced Alveolar Soft Part Sarcoma, Leiomyosarcoma and Synovial Sarcoma
  • Official Title: A Phase III Study of AL3818 (Anlotinib) 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
AL 3818AnlotinibIndication A: ASPS AL3818 Arm
DacarbazineDTICIndication B: LMS Dacarbazine Arm

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).

      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).
    

Trial Arms

NameTypeDescriptionInterventions
Indication A: ASPS AL3818 ArmExperimentalAll 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).
  • AL 3818
Indication B: LMS AL3818 ArmExperimentalSubjects 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).
  • AL 3818
Indication B: LMS Dacarbazine ArmActive 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 ArmExperimentalSubjects 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).
  • AL 3818
Indication C: SS Dacarbazine ArmActive 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

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. 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
                  approved therapy.

               -  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
             investigator.

         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

        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.

               -  c. Indication C - SS: Prior treatment with or have known hypersensitivity to
                  dacarbazine.

          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
             T1).

          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
             treatment.

          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
                  infections)

               -  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.
      
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

November 27, 2017