A Phase II Trial Comparing Gemcitabine and Pazopanib Versus Gemcitabine and Docetaxel for Patients With Advanced Soft Tissue Sarcoma
Condition: Sarcoma
MeSH terms: Sarcoma
Intervention: Gemcitabine and Pazopanib; Gemcitabine and Docetaxel
Intervention description: Gemcitabine 1000 mg/m2 by IV on day 1 and day 8 of a 21 day cycle. Pazopanib 800 mg by oral tablet daily for a 21 day cycle.; Gemcitabine 900 mg/m2 by IV on day 1 and day 8 of a 21 day cycle. Docetaxel 100 mg/m2 by IV on day 8 of a 21 day cycle.
Intervention MeSH terms: Gemcitabine; Docetaxel
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 90.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Sarcoma; Soft Tissue Sarcoma

Summary:

      This study is for adult subjects with advanced tissue sarcoma. The study involves the drugs
      Pazopanib (Votrient), Gemcitabine (Gemzar), and Docetaxel (Taxotere). The purpose of this
      study is to test the effectiveness and safety of Gemcitabine and Pazopanib compared with
      Gemcitabine and Docetaxel in participants with soft tissue sarcoma.
    

Eligibility criteria:

        -  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.
             Procedures conducted as part of the subject's routine clinical management (e.g., blood
             count, imaging study) 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.

          -  Age ≥ 18 years or legal age of consent if greater than 18 years.

          -  Histologically or cytologically confirmed diagnosis of sarcoma of soft tissue.
             (Patients with liposarcoma, bone sarcoma or GIST will be excluded).

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

          -  Subjects must have metastatic and/or locally advanced or locally recurrent disease
             that is not amenable to curative surgical resection.

          -  A minimum of 1 and a maximum of 3 prior chemotherapy regimens for recurrent/metastatic
             disease. Patients eligible for an anthracycline should have received a prior
             anthracycline containing regimen. Patients who decline or are not eligible for
             anthracycline treatment may be considered for this protocol as a first line treatment.

          -  Patients must have measurable disease by RECIST 1.1. or cutaneous disease amenable to
             serial measurements should be present. Measurable disease (a 'target' lesion) is
             defined as at least one lesion that can be accurately measured in at least one
             dimension (longest diameter to be recorded). Each lesion must be ≥ 10 mm when measured
             by CT (CT scan slice thickness no greater than 5 mm); ≥ 10 mm caliper measurement by
             clinical exam (lesions which cannot be accurately measured with calipers should be
             recorded as non-measurable); and ≥ 20 mm by chest x-ray.

          -  Able to swallow and retain oral medication.

          -  Adequate organ system function

          -  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

        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).

        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. Acceptable contraceptive
        methods, when used consistently and in accordance with both the product label and the
        instructions of the physician, are as follow:

          -  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.

        Exclusion Criteria

          -  Prior therapy with pazopanib, gemcitabine or docetaxel.

          -  Any concern for hypersensitivity to pazopanib, gemcitabine or docetaxel.

          -  Prior malignancy. Note: 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.

          -  History or 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.

          -  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.

        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 and experiencing the "dumping" syndrome.

               -  Presence of uncontrolled infection.

               -  Prior mediastinal radiation

               -  Corrected QT interval (QTc) > 480 msecs using Bazett's formula.

               -  History of any one or more of the following conditions within the past 6 months:

          -  Cardiac angioplasty or stenting

          -  Myocardial infarction

          -  Unstable angina

          -  Coronary artery bypass graft surgery

          -  Symptomatic peripheral vascular disease

          -  Pneumonitis

               -  Class III or IV congestive heart failure, as defined by the New York Heart
                  Association (NYHA) (Appendix D).

               -  Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥ 150
                  mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg].

        Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to
        study entry. BP must be re-assessed on two occasions that are separated by a minimum of 1
        hour; on each of these occasions, the mean (of 3 readings) SBP/DBP values from each BP
        assessment must be < 150/90 mmHg in order for a subject to be eligible for the study.

        -History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary
        embolism or untreated deep venous thrombosis (DVT) within the past 6 months.

        Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating
        agents for at least 6 weeks prior to registration and are fully anti-coagulated are
        eligible.

          -  Prior major surgery or trauma within 28 days prior to first dose of study drug and/or
             presence of any non-healing wound, fracture, or ulcer (procedures such as catheter
             placement not considered to be major).

          -  Evidence of active bleeding or bleeding diathesis.

          -  Known endobronchial lesions and/or lesions infiltrating major pulmonary Hemoptysis in
             excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of study drug.

          -  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.

          -  Unable or unwilling to discontinue use of prohibited medications listed in Section
             5.2.3 for 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.

          -  Treatment with any of the following anti-cancer or non-oncologic investigational
             therapies:

               -  radiation therapy, surgery or tumor embolization within 14 days prior to
                  registration.

               -  chemotherapy, immunotherapy, biologic therapy, investigational therapy or
                  hormonal therapy within 14 days or 2.5 half-lives of a drug (whichever is longer)
                  prior to registration.

               -  non-oncologic investigational products within 30 days or 5 halflives, whichever
                  is longer.

          -  Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is
             progressing in severity, except alopecia.