Axitinib and Pembrolizumab in Subjects With Advanced Alveolar Soft Part Sarcoma and Other Soft Tissue Sarcomas
Condition: Alveolar Soft Part Sarcoma; Soft Tissue Sarcomas
MeSH terms: Sarcoma; Sarcoma, Alveolar Soft Part
Intervention: Axitinib; Pembrolizumab
Intervention description: 5 mg tablets twice daily oral dose administered for 7 consecutive weeks on Cycle 1. A safety lead-in consisting of the initial five patients, intrapatient dose escalation of Axitinib will be permitted based on the absence of predefined toxicities. Twice daily oral dose between 2 mg to 10 mg Axitinib tablets will be administered on subsequent 6 week cycles until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first.; 200 mg intravenous infusion administered every 21 weeks beginning week 2 of Cycle 1 for a maximum of up to 2 years or until withdrawal of consent, disease progression and/or unacceptable toxicity as assessed by treating physician, whichever occurs first.
Intervention MeSH terms: Pembrolizumab; Axitinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 33.0
Sex: All
Minimum age: 16 Years
Healthy volunteers: No
Keywords: Advanced Alveolar Soft Part Sarcoma; ASPS; STS

Summary:

      The purpose of this research study is to test if Axitinib together with Pembrolizumab can
      slow tumor growth and know the side effects of the combination treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients must have histologically confirmed sarcoma with pathology review required for
             any outside samples.

          2. The following histologies may be enrolled without prior treatment:

               -  alveolar soft part sarcoma,

               -  clear cell sarcoma,

               -  epithelioid hemangioendothelioma, and

               -  chordoma.

          3. The following histologies may be enrolled ONLY if refractory to anthracycline-based
             chemotherapy or if the patient refuses to undergo standard of care treatment:

               -  synovial sarcoma,

               -  rhabdomyosarcoma,

               -  malignant peripheral nerve sheath tumors,

               -  dedifferentiated, pleomorphic or myxoid/round cell liposarcoma,

               -  leiomyosarcoma,

               -  malignant phylloides tumor,

               -  high grade undifferentiated pleomorphic sarcomas (HGUPS/MFH),

               -  angiosarcoma,

               -  spindle cell sarcoma, not otherwise specified (NOS)

               -  malignant myoepithelioma.

          4. The following histologies may be enrolled ONLY if refractory to at least one line of
             chemotherapy or if the patient refuses to undergo standard of care treatment:

               -  solitary fibrous tumor/hemangiopericytoma.

          5. The following histologies may be enrolled ONLY if refractory to at least first-line
             targeted therapy or if the patient refuses to undergo standard of care treatment:

               -  gastrointestinal stromal tumors,

               -  extraskeletal myxoid chondrosarcoma,

               -  PEComa.

          6. Primary tumors of bone including Ewing's sarcoma, osteosarcoma, and dedifferentiated
             chondrosarcoma may only be enrolled if there are measurable target lesions occurring
             in soft tissue and they are refractory to standard of care anthracycline-based
             chemotherapy.

          7. Any other histology or standard of care therapy not specifically addressed will be
             reviewed by the principal investigator and pathologist for final determination of
             eligibility.

          8. Measurable disease as defined by RECIST v1.1 (provided in Section 14.0).

          9. Radiographic progression as defined by RECIST v1.1, based on comparison between two
             radiographic studies no greater than 6 months apart.

         10. Inability to undergo complete resection of the disease by surgery.

         11. Adequate organ function as defined:

               -  Hematological

                    -  Absolute neutrophil count (ANC) ≥1,000 / microliter (mcL)

                    -  Platelets ≥75,000 / mcL

                    -  Hemoglobin ≥8 g/dL without transfusion or erythropoietin (EPO) dependency
                       (within 7 days of assessment)

               -  Renal

                    -  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.

               -  Hepatic

                    -  Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects
                       with total bilirubin levels > 1.5 ULN.

                    -  Aspartate Aminotransferase (AST/SGOT) and Alanine Transaminase (ALT/SGPT) ≤
                       2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases.

                    -  Albumin >2.5 mg/dL

               -  Coagulation

                    -  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.

                    -  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.

         12. Age ≥ 16 years.

         13. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

         14. 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.

         15. 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.

         16. 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.

               -  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).

               -  Conception while on treatment must be avoided

         17. 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.

         18. Suitable venous access to allow for all study related blood sampling

         19. Ability to understand and willingness to sign a written informed consent document.

         20. 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 axitinib. Patients are permitted to have received prior tyrosine
             kinase inhibitor (TKI) therapy including imatinib, sunitinib, pazopanib, or similar.
             Patients may have received prior Programmed death 1 (PD-1)/Programmed death-ligand 1
             (PD-L1) directed therapy.

          2. Hypersensitivity to axitinib, 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. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Cycle 1, day 1 or
             has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents
             administered more than 4 weeks earlier.

          5. Patient has had prior chemotherapy, targeted small molecule therapy, or radiation
             therapy within 2 weeks prior to Cycle 1, Day 1 or has not recovered (i.e., ≤ Grade 1
             or at baseline) from adverse events due to agents administered more than 4 weeks
             earlier. Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may
             qualify for the study. Note: If subject received major surgery, they must have
             recovered adequately from the toxicity and/or complications from the intervention
             prior to starting therapy.

          6. 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.

          7. Patients with end-organ dysfunction as defined in inclusion criterion (i.e. #11
             above).

          8. Patients with bone-only lesions.

          9. Patients with underlying immune deficiency, chronic infections including HIV,
             hepatitis, or tuberculosis (TB) or autoimmune disease.

         10. Patients with underlying hematologic issues including bleeding diathesis, known
             previous GI bleeding requiring intervention within the past 6 months, active pulmonary
             emboli or deep vein thromboses (DVT) that are not stable on anticoagulation regimen.

         11. Has known history of, or any evidence of active, non-infectious pneumonitis.

         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 axitinib.

         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
             arrhythmia

         17. Prolonged corrected QT (QTc) interval on Screening EKG >475 ms.

         18. Ejection Fraction <40% by 2D echocardiogram (ECHO) at Screening.

         19. 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.

         20. 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.