Study of Anlotinib Hydrochloride and Toripalimab in Subjects With Unresectable or Metastatic Undifferentiated Pleomorphic Sarcoma

Brief Title

Study of Anlotinib Hydrochloride and Toripalimab in Subjects With Unresectable or Metastatic Undifferentiated Pleomorphic Sarcoma

Official Title

A Single-arm, Single-center Prospective Study of Anlotinib Hydrochloride and Toripalimab in Subjects With Unresectable or Metastatic Undifferentiated Pleomorphic Sarcoma Patients

Brief Summary

      The investigators hypothesize that combination anlotinib with toripalimab will improve
      progression-free survival relative to historical controls in patients with Unresectable or
      Metastatic Undifferentiated Pleomorphic Sarcoma.

Detailed Description

      This is a single-institution, open-label, single-arm Phase II study to determine the efficacy
      and safety of anlotinib in combination with Toripalimab compared with historical controls as
      first-line treatment in patients with Unresectable or Metastatic Undifferentiated Pleomorphic

      Since the primary endpoint is survival outcome, progression-free survival (PFS) sample size
      calculation is based on a single-arm survival design. The investigators will employ early
      stopping rules for lack of efficacy, based on previously reported historical controls
      progression-free rate at 3 months was 57% in MFH and This study predicts that as the
      First-Line treatment of Undifferentiated Pleomorphic Sarcoma, progression-free rate at 3
      months is expected to reach more than 80%.

      Patients will be treated with once a day dosing of anlotinib alone for the first 7 days,
      followed by concurrent anlotinib administered once a day at 12mg orally (PO), plus
      intravenous administration of toripalimab every 21 days. Patients will be assessed every six
      weeks for toxicity. After the first five patients are enrolled, the investigators will assess
      safety of the combination. If 2 or fewer patients exhibit dose-limiting toxicity (DLT), the
      investigators will then proceed with intrapatient titration of anlotinib dosing at each cycle
      based on the presence or absence of predefined toxicities.

      Correlative studies characterizing T-cells in tumor tissue and in peripheral blood will be
      performed at three timepoints: 1. pre-treatment, 2. on-treatment on cycle 3 day 1, and 3.
      off-study. Additional exploratory imaging investigations, and assessment of circulating tumor
      cells are included for all patients.

      Trial therapy will last until withdrawal of consent, disease progression and/or unacceptable
      toxicity, whichever occurs first.

Study Phase

Phase 2

Study Type


Primary Outcome

Rate of Participants Achieving 3-Month Progression-Free Survival (PFS)

Secondary Outcome

 Rate of Participants Achieving 6-Month and 12-Month Progression-Free Survival (PFS)


Soft Tissue Sarcomas



Study Arms / Comparison Groups

 anlotinib + Toripalimab
Description:  Concurrent anlotinib and Toripalimab therapy, with Blood Draw and Tumor Specimen Collection for correlative studies


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

July 19, 2019

Completion Date

July 19, 2023

Primary Completion Date

July 19, 2022

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must have histologically confirmed Undifferentiated Pleomorphic Sarcoma with
             pathology review required for any outside samples.

             Only patients with untreated and rejected first-line standard chemotherapy with
             high-grade Undifferentiated Pleomorphic Sarcoma can be enrolled

          2. Any other histology or standard of care therapy not specifically addressed will be
             reviewed by the principal investigator and pathologist for final determination of

          3. Measurable disease as defined by RECIST v1.1

          4. Radiographic progression as defined by RECIST v1.1, based on comparison between two
             radiographic studies no greater than 3 months apart. or Inability to undergo complete
             resection of the disease by surgery.

          5. Adequate organ function as defined:


               1. Absolute neutrophil count (ANC) ≥1,000 / microliter (mcL)

               2. Platelets ≥75,000 / mcL

               3. Hemoglobin ≥8 g/dL without transfusion or erythropoietin (EPO) dependency (within
                  7 days of assessment)


             Serum creatinine ≤1.5 X upper limit of normal (ULN) OR Measured or calculated
             creatinine clearance ≥ 60 mL/min for subject with creatinine levels > 1.5 X
             institutional ULN. (GFR can also be used in place of creatinine or CrCl). Creatinine
             clearance should be calculated per institutional standard.


               1. Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with
                  total bilirubin levels > 1.5 ULN.

               2. Aspartate Aminotransferase (AST/SGOT) and Alanine Transaminase (ALT/SGPT) ≤ 2.5 X
                  ULN OR ≤ 5 X ULN for subjects with liver metastases.

               3. Albumin >2.5 mg/dL


               1. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless
                  subject is receiving anticoagulant therapy as long as PT or PTT is within
                  therapeutic range of intended use of anticoagulants.

               2. Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is
                  receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
                  of intended use of anticoagulants.

          6. Age ≥ 16 years.

          7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          8. Expected Survival Time: Over 3 months;

          9. Patients must consent and be willing to undergo three core needle biopsies at
             baseline, prior to starting Cycle 3, and at off-study. At least one tumor site must be
             amenable to biopsy in the judgment of the interventional radiologist.

         10. Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to receiving the first dose of study medication. If
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
             will be required.

         11. Females of child bearing potential that are sexually active must agree to either
             practice 2 medically accepted highly effective methods of contraception at the same
             time or abstain from heterosexual intercourse from the time of signing the informed
             consent through 120 days after the last dose of study drug. See Appendix G for
             protocol-approved highly effective methods of contraceptive combinations. Subjects of
             childbearing potential are those who have not been surgically sterilized or have not
             been free from menses for > 1 year.

               1. Negative test for pregnancy is required of females of child-bearing potential; A
                  female of child bearing potential is any woman, regardless of sexual orientation
                  or whether they have undergone tubal ligation, who meets the following criteria:
                  1. has not undergone a hysterectomy or bilateral oophorectomy; or 2. has not been
                  naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
                  at any time in the preceding 24 consecutive months or 730 days).

               2. Conception while on treatment must be avoided

         12. Male subjects should agree to use an adequate method of contraception starting with
             the first dose of study therapy through 120 days after the last dose of study therapy.
             Prior history of vasectomy does NOT replace requirement for contraceptive use.

         13. Suitable venous access to allow for all study related blood sampling

         14. Ability to understand and willingness to sign a written informed consent document.

         15. For minors that are 16 to 18 years of age, assent and parental (or legally acceptable
             representative) written informed consent must be obtained.

        Exclusion Criteria:

          1. Prior therapy with anlotinib. Patients who have received prior tyrosine kinase
             inhibitor (TKI) therapy including imatinib, sunitinib, pazopanib, or similar. Patients
             who have received immunotherapy including Programmed death 1 (PD-1)/Programmed
             death-ligand 1 (PD-L1) and CTLA-4.

          2. Hypersensitivity to anlotinib, pembrolizumab or any of its excipients.

          3. Patients may not be receiving any other investigational agents (within 4 weeks prior
             to Cycle 1, day 1).

          4. If subject received palliative surgery, they must have recovered adequately from the
             toxicity and/or complications from the intervention prior to starting therapy.

          5. Additional known malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin, or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy, or in situ cervical cancer.

          6. Patients with end-organ dysfunction as defined in inclusion criterion (i.e. #6 above).

          7. Patients with bone-only lesions.

          8. Patients with underlying immune deficiency, chronic infections including HIV,
             hepatitis, or tuberculosis (TB) or autoimmune disease.

          9. Any major unhealed wound, ulcer, or fracture occurred in a patient who had undergone
             major surgery or trauma within 4 weeks and/or had any bleeding or bleeding episodes
             which the degree is bigger than CTCAE 3 grade within 4 weeks prior to enrollment.

         10. Arteriovenous thrombosis events occurred within 6 months. Such as cerebrovascular
             accidents (including transient ischemic attacks), deep vein thrombosis and pulmonary

         11. History of steroid-related (non-infectious) pneumonia or current pneumonia.

         12. Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis or leptomeningeal disease. Subjects with previously treated brain
             metastases may participate provided they are stable (without evidence of progression
             by imaging for at least four weeks prior to the first dose of trial treatment and any
             neurologic symptoms have returned to baseline), have no evidence of new or enlarging
             brain metastases, and are not using steroids for at least 7 days prior to trial
             treatment. This exception does not include carcinomatous meningitis which is excluded
             regardless of clinical stability.

         13. Concomitant (or receipt of) treatment with medications that may affect the metabolism
             of pembrolizumab and/or axitinib within 7 days prior to Cycle 1, day 1 of anlotinib.

         14. Has received a live vaccine within 30 days of planned start of study therapy. Note:
             Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
             are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
             attenuated vaccines, and are not allowed.

         15. Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 120 days after the last dose of trial treatment.

         16. Any uncontrolled, intercurrent illness including but not limited to ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac

         17. rolonged corrected QT (QTc) interval on Screening EKG >475 ms. Ejection Fraction <40%
             by 2D echocardiogram (ECHO) at Screening.

         18. Any serious medical or psychiatric illness/condition including substance use disorders
             likely in the judgment of the Investigator(s) to interfere or limit compliance with
             study requirements/treatment.

         19. Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.




16 Years - N/A

Accepts Healthy Volunteers



, 139 4488 8991, [email protected]

Location Countries


Location Countries


Administrative Informations



Organization ID


Responsible Party


Study Sponsor

Di Wu

Study Sponsor

, , 

Verification Date

July 2019