A Phase II Trial Comparing Gemcitabine and Pazopanib Versus Gemcitabine and Docetaxel for Patients With Advanced Soft Tissue Sarcoma

A Randomized, Open-label, Phase II, Multi-center Trial of Gemcitabine (G) With Pazopanib (P) or Gemcitabine (G) With Docetaxel (T) in Previously Treated Subjects With Advanced Soft Tissue Sarcoma

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.

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. Screening tests will be done to ensure subjects are eligible to participate in this study. If the exams, tests and procedures show that subjects can be in the study, and they choose to take part, then they will be "randomized" into one of the two study groups: Group 1 or Group 2. Subjects in Group 1 will receive Gemcitabine 1000 mg/m2 intravenously (directly into a vein) on Day 1 and Day 8 and Pazopanib 800mg by mouth daily. Subjects in Group 2 will receive Gemcitabine 900 mg/m2 intravenously on Day 1 and Day 8 and Docetaxel 100 mg/m2 intravenously on Day 8. Both groups will be in 21 day cycles. Both groups will be asked to complete "quality of life" questionnaires, on their first visit, then at 6 weeks (2nd cycle), 18 weeks (6th cycle) and at the end of study treatment. Subjects will be followed for up to 2 years.

• 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.