Activity and Tolerability of Pazopanib in Advanced and/or Metastatic Liposarcoma. A Phase II Clinical Trial
Condition: Advanced and / or Metastatic Liposarcoma
MeSH terms: Liposarcoma
Intervention: Pazopanib
Intervention description: Patients will receive oral pazopanib, 800mg once daily and treatment will continue until disease progression, development of unacceptable toxicity, noncompliance, withdrawal of consent by the patient or investigator decision.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 52.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Advanced; Metastatic; Liposarcoma; Pazopanib

Summary:

      Soft tissue and bone sarcomas are rare malignant tumors, which encompasses a large family of
      more than 50 histologically distinct tumor subtypes, all of which share a putative
      mesenchymal origin. In the case of soft tissue sarcomas (STS) surgical excision is the
      mainstay of treatment, but despite curative surgery, around half of patients develop distant
      metastases and die from disease. Few therapeutic approaches are currently available to
      patients with unresectable, locally advanced, or metastatic STS and only anthracyclines,
      ifosfamide and trabectedin have shown activity, with response rates of 20-40% in previously
      untreated patients. Recent and ongoing trials have investigated a variety of combination
      chemotherapeutic regimens (variously employing ifosfamide, doxorubicin, gemcitabine,
      temozolomide, vincristine, cisplatin, and dacarbazine, among others) as well as targeted
      therapies, which in some cases have yielded improvements in response rate but which have had
      little impact on survival. No other medical option is currently available, and the median
      survival of patients with soft-tissue sarcoma with non-resectable metastases is around 12-15
      months, and approximately 8 months after second line chemotherapy.

      Liposarcomas are STS which account for at least 20% of all STS in adults. They can be further
      classified into 3 histologically and biologically different subtypes: well-differentiated
      liposarcoma/dedifferentiated liposarcoma (ALT-WD), myxoid or round cell liposarcoma and
      pleomorphic liposarcoma.

      ALT-WD liposarcomas are locally aggressive rarely metastasizing tumors characterized by ring
      or giant marker chromosomes on the cytogenetic analysis and by amplification of the 12q13-21
      region on Fluorescence In Situ Hybridization (FISH) (MDM2, CDK4 and HMGIC). They account for
      about 40% iv of liposarcomas with a 5 year Overall survival (OS) around 80%. In a series of
      WD/DD treated with several regimens response rate was 12.5% OS 15 months and median PFS 3.6
      months(95 confidence interval (CI): 3.3-5.9) Mixoid /round cell liposarcoma accounts for
      45-50% of all liposarcomas. They tend to metastasize to unusual soft tissue and bone
      locations. High histologic grade with more than 5% of round cell component is associated with
      a 5-year OS of 50% approximately. They are characterized by t(23;16)(q13-14;p11) which leads
      to the fusion of CHOP and TLS genes Pleomorphic liposarcoma accounts for approximately 5-10%
      of all liposarcomas, characterized by high grade features with frequent and early lung
      metastasis and cytogenetically by high chromosome counts and complex structural
      rearrangements.

      VEGF is expressed in many STS in which increased expression is associated with higher grade
      and worse prognosis.

      Pazopanib is an oral angiogenesis inhibitor that targets mainly VEGFR, PDGFR and c-kit.
      Recently the results of a phase II trial of pazopanib in STS have been published. It was a
      four-cohort 2-stages study. The liposarcoma stratum was closed after the first stage because
      of a PFS at 12 weeks of 17% (3 out of 17 patients did not progressed after 12 weeks). After
      central pathologic review, 2 other patients initially classified as other STS were found to
      have liposarcoma with stable disease at 12 weeks (5/19: 26% PFS12w), thus fulfilling criteria
      for cohort expansion. Phase II study had been completed and in phase III study patients with
      liposarcomas were excluded so therefore data on the liposarcoma cohort are inconclusive.

      Furthermore the positive results of the phase III study PALETTE have been recently
      communicated, encouraging this treatment in other sarcomas: progression-free survival (PFS)
      per independent review was significantly prolonged with pazopanib (median: 4.6 vs 1.5 months;
      HR=0.31, 95% CI 0.24-0.40; P<0.0001). The interim analysis for overall survival shows a
      statistically non-significant improvement of pazopanib vs placebo (median: 11.9 vs 10.4
      months, HR=0.83, 95% CI 0.62-1.09).

      Soluble factors associated with efficacy and toxicity of pazopanib in these patients had been
      also reported. Decreases in VEGFR2 and increase in PlGF were both associated with toxicity
      (HTA and TSH elevation) and poorer prognosis.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Subjects must provide written informed consent prior to performance of study-specific
             procedures or assessments and must be willing to comply with treatment and follow-up.

             Informed consent must be obtained prior to start of the specified screening window.

             Procedures conducted as part of the subject's routine clinical management (e.g., blood
             count, imaging study such as bone scan) and obtained prior to signing of informed
             consent may be utilized for screening or baseline purposes provided these procedures
             are conducted as specified in the protocol.

          2. Age ≥ 18 years or legal age of consent if greater than 18 years

          3. Histological confirmed diagnosis of high or intermediate grade malignant liposarcoma
             with metastatic or locally advanced disease. Formalin fixed paraffin embedded tumour
             block and/or representative H/E (haematoxylin/eosin) slides must be available for
             central pathologic review to classify tumors in the 2 eligible subtypes:

             Well-differentiated liposarcoma/de-differentiated liposarcoma (ALT-WD) Myxoid/round
             cell liposarcoma

          4. Patient must have documentation of disease progression within 6 months prior to study
             entry.

          5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

          6. Measurable disease by RECIST v1.1 criteria. At least one measurable lesion located
             outside of a previously irradiated area. If the only measurable lesion is in a
             previously irradiated area, RECIST progression should be documented after
             radiotherapy, in the previous 6 months before study entry.

          7. The patient should not be considered eligible for surgery or radical radiotherapy.
             e.g. Patients to whom surgery/radiotherapy can not be performed with a curative intent
             due to the extension of the disease. In the case of radiotherapy, it may also be
             limited due to a previous treatment with radiotherapy in the same area.

          8. The patient must have either been considered ineligible for systemic chemotherapy or
             received at least one previous regimen for relapsed, refractory or metastatic disease.
             A maximum of three previous lines for advanced/metastatic disease are allowed.

             Patients not eligible for systemic chemotherapy:

             Because of age, a biological condition or patient-refusal Generally, patients that
             received anthracyclines in the adjuvant setting are not eligible for first line
             therapy with this agent for advanced disease.

             Patients with a solitary kidney or >60 years old are usually not the best candidates
             for treatment with regular doses of ifosfamide.

          9. Tumor tissue must be provided for all subjects for biomarker analysis before/during
             treatment with investigational product.

         10. The patient should be able to swallow and retain study drug

         11. Adequate organ system function as defined:

             Absolute neutrophil count (ANC)≥ 1.5 X 109/L Hemoglobin ≥ 9 g/dL (5.6 mmol/L)
             Platelets ≥ 100 X 109/L Prothrombin time (PT) or international normalized ratio (INR)≤
             1.2 X ULN Activated partial thromboplastin time (aPTT)≤ 1.2 X ULN Total bilirubin≤ 1.5
             X ULN Alanine amino transferase (ALT) and Aspartate aminotransferase (AST) ≤ 2.5 X ULN
             Serum creatinine ≤ 1.5 mg/dL (133 µmol/L)Or, if >1.5 mg/dL: Calculated creatinine
             clearance (ClCR)≥ 30 mL/min to ≥ 50 mL/min Urine Protein to Creatinine Ratio (UPC) <1
             Or, 24-hour urine protein <1g

               1. Subjects may not have had a transfusion within 7 days of screening assessment.

               2. Subjects receiving anticoagulant therapy are eligible if their INR is stable and
                  within the recommended range for the desired level of anticoagulation.

               3. Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of
                  normal) are not permitted.

               4. If UPC ≥ 1, then a 24-hour urine protein must be assessed. Subjects must have a
                  24-hour urine protein value <1 g to be eligible. Use of urine dipstick for
                  baseline renal function assessment is not acceptable.

         12. A female is eligible to enter and participate in this study if she is of:

             Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
             including any female who has had:

             A hysterectomy A bilateral oophorectomy (ovariectomy) A bilateral tubal ligation Is
             post-menopausal Female subjects not using hormone replacement therapy (HRT) must have
             experienced total cessation of menses for ≥ 1 year and be greater than 45 years in
             age, OR, in questionable cases, have a follicle stimulating hormone (FSH) value >40
             mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L).

             Female subjects using HRT must have experienced total cessation of menses for ≥ 1 year
             and be greater than 45 years of age OR have had documented evidence of menopause based
             on FSH and estradiol concentrations prior to initiation of HRT

             Childbearing potential, including any female who has had a negative serum pregnancy
             test within 2 weeks prior to the first dose of study treatment, preferably as close to
             the first dose as possible, and agrees to use adequate contraception. The acceptable
             contraceptive methods, when used consistently and in accordance with both the product
             label and the instructions of the physician, are as follows:

             Complete abstinence from sexual intercourse for 14 days before exposure to
             investigational product, through the dosing period, and for at least 21 days after the
             last dose of investigational product Oral contraceptive, either combined or
             progestogen alone Injectable progestogen Implants of levonorgestrel Estrogenic vaginal
             ring Percutaneous contraceptive patches Intrauterine device (IUD) or intrauterine
             system (IUS) with a documented failure rate of less than 1% per year Male partner
             sterilization (vasectomy with documentation of azoospermia) prior to the female
             subject's entry into the study, and this male is the sole partner for that subject
             Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps)
             with a vaginal spermicidal agent (foam/gel/film/cream/suppository) Female subjects who
             are lactating should discontinue nursing prior to the first dose of study drug and
             should refrain from nursing throughout the treatment period and for 14 days following
             the last dose of study drug

         13. LVEF above the lower limit of normal for the institution, based on ECHO or MUGA.

        Exclusion Criteria:

          1. Prior history of malignancies other than liposarcoma. Subjects who have had another
             malignancy and have been disease-free for 3 years, or subjects with a history of
             completely resected non-melanomatous skin carcinoma or successfully treated in situ
             carcinoma are eligible.

          2. Clinical evidence of central nervous system (CNS) metastases or leptomeningeal
             carcinomatosis, except for individuals who have previously-treated CNS metastases, are
             asymptomatic, and have had no requirement for steroids or anti-seizure medication for
             6 months prior to first dose of study drug. Screening with CNS imaging studies
             (computed tomography [CT] or magnetic resonance imaging [MRI]) is required only if
             clinically indicated or if the subject has a history of CNS metastases.

          3. Clinically significant gastrointestinal abnormalities that may increase the risk for
             gastrointestinal bleeding including, but not limited to:

             Active peptic ulcer disease Known intraluminal metastatic lesion/s with risk of
             bleeding Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or
             other gastrointestinal conditions with increased risk of perforation History of
             abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28
             days prior to beginning study treatment.

          4. Clinically significant gastrointestinal abnormalities that may affect absorption of
             investigational product including, but not limited to:

             Malabsorption syndrome Major resection of the stomach or small bowel.

          5. Corrected QT interval (QTc) > 480 msecs

          6. History of any one or more of the following cardiovascular conditions within the past
             6 months:

             Cardiac angioplasty or stenting Myocardial infarction Unstable angina Coronary artery
             bypass graft surgery Symptomatic peripheral vascular disease Class III or IV
             congestive heart failure, as defined by the New York Heart Association (NYHA)

          7. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 mmHg
             or diastolic blood pressure (DBP) of ≥ 90mmHg].

             Initiation or adjustment of antihypertensive medication(s) is permitted prior to study
             entry. Following antihypertensive medication initiation or adjustment, blood pressure
             (BP) must be re-assessed three times at approximately 2-minute intervals. At least 24
             hours must have elapsed between anti-hypertensive medication initiation or adjustment
             and BP measurement. These three values should be averaged to obtain the mean diastolic
             blood pressure and the mean systolic blood pressure. The mean SBP / DBP ratio must be
             <140/90 mmHg (OR 150/90 mm Hg, if this criterion is approved by Safety Review Team) in
             order for a subject to be eligible for the study.

          8. History of cerebrovascular accident including transient ischemic attack (TIA),
             pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.

             Subjects with recent DVT who have been treated with therapeutic anti-coagulating
             agents for at least 6 weeks are eligible

          9. Major surgery or trauma within 28 days prior to first dose of investigational product
             and/or presence of any non-healing wound, fracture, or ulcer (procedures such as
             catheter placement not considered to be major surgery).

         10. Evidence of active bleeding or bleeding diathesis.

         11. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that
             increase the risk of pulmonary hemorrhage.

             Lesions infiltrating major pulmonary vessels (contiguous tumour and vessels) are
             excluded; however, the presence of a tumor that is touching, but not infiltrating
             (abutting) the vessels is acceptable (CT with contrast is strongly recommended to
             evaluate such lesions).

         12. Recent hemoptysis (≥ ½ teaspoon of red blood within 8 weeks before first dose of study
             drug).

         13. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that
             could interfere with subject's safety, provision of informed consent, or compliance to
             study procedures.

         14. Unable or unwilling to discontinue use of prohibited medications listed in section 7.4
             of this protocol or at least 14 days or five half-lives of a drug (whichever is
             longer) prior to the first dose of study drug and for the duration of the study.

         15. Treatment with any of the following anti-cancer therapies:

             radiation therapy, surgery or tumor embolization within 14 days prior to the first
             dose of Pazopanib chemotherapy, immunotherapy, biologic therapy, investigational
             therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is
             longer) prior to the first dose of Pazopanib

         16. Administration of any non-oncologic investigational drug within 30 days or 5 half
             lives whichever is longer prior to receiving the first dose of study treatment

         17. Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is
             progressing in severity, except alopecia.