During the dose-finding phase, patients will be non-randomly assigned to treatment with pazopanib. (Regimen A) (Regimen C)

Transcription

1 EXPERIMENTAL DESIGN SCHEMAS DOSE FINDING PHASE During the dose-finding phase, patients will be non-randomly assigned to treatment with pazopanib. Chemotherapy Cohort Non-Chemotherapy Cohort (Regimen A) (Regimen C) The Chemotherapy Cohort dose-finding phase is closed and dose level 1 has been found as the MTD, effective May Study Entry First 10 patients begin at Dose Level 1 Study Entry First 10 patients begin at Dose Level 1 Pazopanib # 2 cycles of ID XRT begins Week 4 Pazopanib # XRT begins Week 1 Week 6: Comparison and Measures of Feasibility Week 6: Comparison and Measures of Feasibility Dose level adjustments Dose level adjustments Therapy to continue as outlined in the efficacy phase schema Therapy to continue as outlined in the efficacy phase schema # Pazopanib (Tablet formulation, PO once daily) Dose Level Pediatric Dose Adult Dose mg/m mg mg/m mg mg/m mg I: Ifosfamide, 2.5 grams/m 2 /dose IV on Days 1, 2, 3 (7.5 grams/m 2 /cycle) D: Doxorubicin, 37.5 mg/m 2 /dose IV on Days 1, 2 (75 mg/ m 2 /cycle) One cycle of ID is 21 days. 11

2 EFFICACY PHASE- CHEMOTHERAPY COHORT Study Entry and Randomization Regimen A Regimen B INDUCTION Pazopanib* dose level 1 daily Weeks 1-12 along with 2 cycles of ID and XRT begins Week 4 INDUCTION 2 cycles of ID and 2 cycles of I Evaluation (Week 13) Progressive Disease Evaluation (Week 13) Primary Site Surgery Off Protocol Therapy Primary Site Surgery CONTINUATION Pazopanib* dose level 1 daily Weeks along with 2 cycles of ID and 1 cycle of D Postoperative Boost Radiotherapy at Week 16 for gross or microscopic residual tumor** after surgery CONTINUATION 2 cycles of ID and 1 cycle of D Surgery/Radiotherapy to metastatic sites at completion of and recovery from assigned therapy End of Protocol Therapy *Pazopanib is to be held pre- and post-surgery. I = Ifosfamide; D = Doxorubicin. Each cycle lasts 21 days. ** Postoperative boost radiotherapy is required for gross residual disease and is optional for positive margins. 12

3 EFFICACY PHASE- NON-CHEMOTHERAPY COHORT Study Entry and Randomization Regimen C Regimen D INDUCTION Pazopanib * daily Weeks Radiation Therapy XRT begins Week 1 INDUCTION Radiation Therapy Alone Evaluation (Week 10) Progressive Disease Evaluation (Week 10) Primary Site Surgery Off Protocol Therapy Primary Site Surgery CONTINUATION Pazopanib daily Weeks Postoperative Boost Radiotherapy** CONTINUATION Postoperative Boost Radiotherapy** Surgery/Radiotherapy to metastatic sites at completion of and recovery from assigned therapy End of Protocol Therapy * Dose determined in the dose finding phase. Pazopanib is to be held pre- and post-surgery. ** Postoperative boost radiotherapy is required for gross residual disease and optional for positive margins. 13

4 3.1.7 Randomization Randomization will take place at the time a patient is enrolled via OPEN. The treatment will be randomly assigned based on the statistical design of the trial. 3.2 Patient Eligibility Criteria Important note: The eligibility criteria listed below are interpreted literally and cannot be waived. All clinical and laboratory data required for determining eligibility of a patient enrolled on this trial must be available in the patient's medical/research record which will serve as the source document for verification at the time of audit. The investigator is responsible for ensuring that all eligibility criteria are met. All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older than seven (7) days at the start of therapy. Laboratory tests need not be repeated if therapy starts within seven (7) days of obtaining labs to assess eligibility. If a post-enrollment lab value is outside the limits of eligibility, or laboratory values are > 7 days old, then the following laboratory evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with differential, bilirubin, ALT (SGPT) and serum creatinine. If the recheck is outside the limits of eligibility, the patient may not receive protocol therapy and will be considered off protocol therapy. Imaging, cardiac and pulmonary function studies, including those used to determine eligibility, must be obtained within 3 weeks prior to enrollment (repeat imaging if necessary). See Section 7.1 for required studies to be obtained prior to starting protocol therapy Age Patients must be 2 years at the time of the biopsy that established the diagnosis of NRSTS will be eligible. Note: Eligible patients must have a Body Surface Area 0.5 m 2 AND be able to swallow whole tablets (see Section and Section ) Diagnosis Newly diagnosed and histopathologically confirmed, potentially resectable NRSTS of the extremity and trunk will be eligible for the chemotherapy or nonchemotherapy cohort based on: Evidence of chemotherapy sensitivity of the histologic sarcoma subtype based on existing evidence from prior clinical trials Sufficient risk of metastatic disease to warrant chemotherapy based on size and grade and Medically deemed able or unable to undergo chemotherapy. Notes: An incisional biopsy or core biopsy is preferred. Fine needle aspiration biopsy is not acceptable to establish the diagnosis. ELIGIBLE SITES: Please refer to Appendix II. o Extremities: upper (including shoulder) and lower (including hip) 32

5 o Trunk: body wall INELIGIBLE SITES: Head and neck, visceral organs (with the exception of embryonal sarcoma of the liver), retroperitoneum, peritoneum, pelvis within the confines of the bony pelvis Eligibility for chemotherapy cohort: Stage T2a/b (> 5 cm) and Grade 3 (see Appendix III) AND One of the following chemosensitive histologies as defined in the WHO Classification of Soft Tissue Tumours (with some evidence of good response to chemoradiation and of sufficient high risk of metastases, or clear evidence of metastases) (Appendix IV): o Unclassified soft tissue sarcomas that are too undifferentiated to be placed in a specific pathologic category in the WHO classification (often called undifferentiated soft tissue sarcoma or soft tissue sarcoma NOS ) o Synovial sarcoma o Angiosarcoma of soft tissue o Adult fibrosarcoma o Mesenchymal (extraskeletal) chondrosarcoma o Leiomyosarcoma o Liposarcoma (excluding myxoid liposarcoma) o Undifferentiated pleomorphic sarcoma o Embryonal sarcoma of the liver Patients meeting the above criteria (histology, size, and grade) with the EXCEPTION of histologies noted in may enroll on the chemotherapy cohort or the non-chemotherapy cohort at the discretion of the enrolling investigator. Patients meeting these criteria with the EXCEPTION of histologies noted in but medically deemed unable to receive chemotherapy or who elect not to receive chemotherapy are eligible for the non-chemotherapy cohort Patients with the following histologies are only eligible for the chemotherapy cohort and cannot enroll on the nonchemotherapy cohort: o Unclassified soft tissue sarcomas that are too undifferentiated to be placed in a specific pathologic category in the WHO classification (often called undifferentiated soft tissue sarcoma or soft tissue sarcoma NOS ) in patients < 30 years of age o Synovial sarcoma o Embryonal sarcoma of the liver Eligibility for non-chemotherapy cohort: Patients with any size of Grade 2 or 3 of the following Intermediate (rarely metastasizing) or malignant tumors, as defined in the WHO Classification of Soft Tissue Tumours (see Appendices II and III) for which we have consensus data of 33

6 chemotherapy-resistance are eligible only for the nonchemotherapy cohort: o So-called fibrohistiocytic tumors plexiform fibrohistiocytic tumor, giant cell tumor of soft tissues o Fibroblastic/myofibroblastic tumors solitary fibrous tumor, malignant solitary fibrous tumor, inflammatory myofibroblastic tumor, low grade myofibroblastic sarcoma, myxoinflammatory fibroblastic sarcoma, atypical myxoinflammatory fibroblastic tumor, myxofibrosarcoma, low grade fibromyxoid sarcoma, sclerosing epithelioid fibrosarcoma o Tumors of uncertain differentiation epithelioid sarcoma, alveolar soft part sarcoma, clear cell sarcoma of soft tissue, angiomatoid fibrous histiocytoma, ossifying fibromyxoid tumour, myoepithelioma, myoepithelial carcinoma, extraskeletal myxoid chondrosarcoma, neoplasms with perivascular epithelioid cell differentiation (PEComa), intimal sarcoma, atypical fibroxanthoma, mixed tumor NOS, phosphaturic mesenchymal tumor, malignant ossifying fibromyxoid tumor, malignant mixed tumor, malignant phosphaturic mesenchymal tumor o Chondro-osseous tumors extraskeletal osteosarcoma o Pericytic (perivascular) tumors malignant glomus tumor o Nerve sheath tumors - malignant peripheral nerve sheath tumor, malignant granular cell tumor, epithelioid malignant peripheral nerve sheath tumor, malignant Triton tumor o Undifferentiated sarcomas (with a specific pathologic category in the WHO classification) - undifferentiated round cell sarcoma, undifferentiated epithelioid sarcoma, undifferentiated spindle cell sarcoma Patients meeting the criteria (histology, size, and grade) in Section with the EXCEPTION of histologies noted in may enroll on the non-chemotherapy cohort at the discretion of the enrolling investigator. Patients meeting these criteria with the EXCEPTION of histologies noted in but medically deemed unable to receive chemotherapy or who elect not to receive chemotherapy are eligible for the nonchemotherapy cohort. Note that tumors arising in bone are NOT eligible for this study Extent of Disease a) Patients with non-metastatic and metastatic disease are eligible. b) Initially unresectable patients, with or without metastatic disease, are eligible as long as there is a commitment at enrollment to resect the primary tumor. 34

7 3.2.4 Specimen Submission Sufficient tissue and blood must be available to submit for required biology studies (see Section ) Performance Level Lansky performance status score 70 for patients 16 years of age. Karnofsky performance status score 70 for patients >16 years of age Organ Function Requirements Adequate bone marrow function defined as: - Absolute neutrophil count 1500/µL - Platelet count 100,000/µL - Hemoglobin: 8 g/dl for patients 16 years of age 9 g/dl for patients > 16 years of age Note: No transfusions are permitted 7 days prior to laboratory studies to determine eligibility Adequate renal function defined as: - Creatinine clearance or radioisotope GFR 70 ml/min/1.73 m 2 or - A normal serum creatinine based on age/gender as follows: Age Maximum Serum Creatinine (mg/dl) Male Female 2 to < 6 years to < 10 years to < 13 years to < 16 years years The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR 150 utilizing child length and stature data published by the CDC Adequate liver function defined as: - Total bilirubin 1.5 x upper limit of normal (ULN) for age - SGOT (AST) or SGPT (ALT) < 2.5 x upper limit of normal (ULN) for age Adequate cardiac function defined as: - Shortening fraction of 27% by echocardiogram OR Ejection fraction of 50% by radionuclide angiogram. - QTc < 480 msec 35

8 Adequate pulmonary function defined as: - No evidence of dyspnea at rest, no exercise intolerance, and a resting pulse oximetry reading > 94% on room air if there is clinical indication for determination Anticoagulation Patients on low molecular weight heparin or coumadin (with a stable INR) are eligible Life Expectancy Patient must have a life expectancy of at least 3 months with appropriate therapy Exclusion Criteria Patients with Grade 1 NRSTS tumors of any size are not eligible Patients with known CNS metastases are not eligible. Note: Brain imaging is not an eligibility requirement Bleeding Diathesis Patients with evidence of active bleeding or bleeding diathesis will be excluded (Note: Patients aged > 17 years with excess of 2.5 ml of hemoptysis are not eligible) Tumor Resection Patients with gross total resection of the primary tumor prior to enrollment on are NOT eligible. Patients who have experienced tumor recurrence after a gross total tumor resection are NOT eligible Uncontrolled hypertension Patients with uncontrolled hypertension are ineligible. Uncontrolled hypertension is defined as follows: Patients aged 17 years: greater than 95th percentile systolic and diastolic blood pressure based on age and height (see Appendix V) which is not controlled by one anti-hypertensive medication. Patients aged > 17 years: systolic blood pressure 140 mmhg and/or diastolic blood pressure 90 mmhg that is not controlled by one anti-hypertensive medication Prior Therapy Patients must have had no prior anthracycline (eg, doxorubicin, daunorubicin) or ifosfamide chemotherapy Patients must have had no prior use of pazopanib or similar multitargeted TKI Patients must have had no prior radiotherapy to tumor-involved sites. 36

9 Note: Patients previously treated for a non-nrsts cancer are eligible provided they meet the prior therapy requirements and the criterion in Section is not applicable. Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier are excluded Other types of invasive malignancy that are not disease free within 3 years except for non-melanoma skin cancer, lentigo maligna, any carcinoma-insitu or prostate cancer with low risk factors CYP3A4 Substrates WITH Narrow Therapeutic Indices: Patients chronically receiving medications known to be metabolized by CYP3A4 and with narrow therapeutic indices within 7 days prior to study enrollment, including but not limited to pimozide, aripiprazole, triazolam, ergotamine and halofantrine are not eligible. Note: the use of fentanyl is permitted CYP3A4 Inhibitors: Patients chronically receiving drugs that are known potent CYP3A4 inhibitors within 7 days prior to study enrollment, including but not limited to itraconazole, clarithromycin, erythromycin, many NNRTIs, diltiazem, verapamil, and grapefruit juice are not eligible. See Appendix VI CYP3A4 Inducers: Patients chronically receiving drugs that are known potent CYP3A4 inducers within 14 days prior to study enrollment, including but not limited to carbamazepine, phenobarbital, phenytoin, rifampin, and St. John s wort are not eligible (with the exception of Glucocorticoids). See Appendix VI Certain medications that are associated with a risk for QTc prolongation and/or Torsades de Pointes, although not prohibited, should be avoided or replaced with medications that do not carry these risks, if possible. Comprehensive lists of agents that that are associated with a risk for QTc prolongation and/or Torsades de Pointes can be found in Appendix VII Subjects with any condition that may impair the ability to swallow or absorb oral medications/investigational product including: any lesion, whether induced by tumor, radiation or other conditions, which makes it difficult to swallow capsules or pills prior surgical procedures affecting absorption including, but not limited to major resection of stomach or small bowel active peptic ulcer disease malabsorption syndrome Subjects with any condition that may increase the risk of gastrointestinal bleeding or gastrointestinal perforation, including active peptic ulcer disease known intraluminal metastatic lesions 37

10 inflammatory bowel disease (eg, ulcerative colitis, Crohn s disease) or other gastrointestinal conditions which increase the risk of perforation history of abdominal fistula, gastrointestinal perforation or intraabdominal abscess within 28 days prior to beginning study treatment Subjects with any of the following cardiovascular conditions within the past 6 months cerebrovascular accident (CVA) or transient ischemic attack (TIA) cardiac arrhythmia admission for unstable angina cardiac angioplasty or stenting coronary artery bypass graft surgery pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT which has been treated with therapeutic anticoagulation for less than 6 weeks arterial thrombosis symptomatic peripheral vascular disease. Class III or IV heart failure as defined by the NYHA functional classification system. A subject who has a history of Class II heart failure and is asymptomatic on treatment may be considered eligible History of serious or non-healing wound, ulcer, or bone fracture Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Patients who are unable to swallow whole tablets are not eligible Patients with a Body Surface Area < 0.5 m 2 are not be eligible HIV-positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with pazopanib. In addition, these subjects are at increased risk of lethal infections when treated with marrow-suppressive therapy Patients who are receiving any other investigational agent(s) Pregnancy and Breast Feeding Female patients who are pregnant are ineligible due to risks of fetal and teratogenic adverse events as seen in animal/human studies Lactating females are not eligible unless they have agreed not to breastfeed their infants during treatment and for a period of 1 month following completion of treatment. 38

11 Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained Unwillingness to use an effective contraceptive method for the duration of their study participation and for at least 1 month after treatment is completed if sexually active with reproductive potential Regulatory All patients and/or their parents or legal guardians must sign a written informed consent All institutional, FDA, and NCI requirements for human studies must be met. 39