Clinical Trials /

Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Non-rhabdomyosarcoma Soft Tissue Sarcomas That Can Be Removed by Surgery

NCT02180867

Description:

This randomized phase II/III trial studies how well pazopanib hydrochloride, combination chemotherapy, and radiation therapy work and compares it to radiation therapy alone or in combination with pazopanib hydrochloride or combination chemotherapy in treating patients with newly diagnosed non-rhabdomyosarcoma soft tissue sarcomas that can be removed by surgery. Radiation therapy uses high energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as ifosfamide and doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether radiation therapy works better when given with or without combination chemotherapy and/or pazopanib hydrochloride in treating patients with non-rhabdomyosarcoma soft tissue sarcomas.

Related Conditions:
  • Soft Tissue Sarcoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Non-rhabdomyosarcoma Soft Tissue Sarcomas That Can Be Removed by Surgery
  • Official Title: Pazopanib Neoadjuvant Trial in Non-Rhabdomyosarcoma Soft Tissue Sarcomas (PAZNTIS): A Phase II/III Randomized Trial of Preoperative Chemoradiation or Preoperative Radiation Plus or Minus Pazopanib (NSC# 737754)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2014-01340
  • SECONDARY ID: NCI-2014-01340
  • SECONDARY ID: ARST1321
  • SECONDARY ID: ARST1321
  • SECONDARY ID: ARST1321
  • SECONDARY ID: U10CA180830
  • SECONDARY ID: U10CA180886
  • SECONDARY ID: U10CA098543
  • NCT ID: NCT02180867

Conditions

  • Adult Fibrosarcoma
  • Alveolar Soft Part Sarcoma
  • Angiomatoid Fibrous Histiocytoma
  • Atypical Fibroxanthoma
  • Clear Cell Sarcoma of Soft Tissue
  • Epithelioid Malignant Peripheral Nerve Sheath Tumor
  • Epithelioid Sarcoma
  • Extraskeletal Myxoid Chondrosarcoma
  • Extraskeletal Osteosarcoma
  • Fibrohistiocytic Neoplasm
  • Glomus Tumor of the Skin
  • Inflammatory Myofibroblastic Tumor
  • Intimal Sarcoma
  • Leiomyosarcoma
  • Liposarcoma
  • Low Grade Fibromyxoid Sarcoma
  • Low Grade Myofibroblastic Sarcoma
  • Malignant Cutaneous Granular Cell Tumor
  • Malignant Peripheral Nerve Sheath Tumor
  • Malignant Triton Tumor
  • Mesenchymal Chondrosarcoma
  • Myxofibrosarcoma
  • Myxoid Chondrosarcoma
  • Myxoinflammatory Fibroblastic Sarcoma
  • Nerve Sheath Neoplasm
  • PEComa
  • Pericytic Neoplasm
  • Plexiform Fibrohistiocytic Tumor
  • Sclerosing Epithelioid Fibrosarcoma
  • Stage IB Soft Tissue Sarcoma AJCC v7
  • Stage IIB Soft Tissue Sarcoma AJCC v7
  • Stage III Soft Tissue Sarcoma AJCC v7
  • Stage IV Soft Tissue Sarcoma AJCC v7
  • Synovial Sarcoma
  • Undifferentiated (Embryonal) Sarcoma
  • Undifferentiated High Grade Pleomorphic Sarcoma of Bone

Interventions

DrugSynonymsArms
Doxorubicin Hydrochloride5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, RubexRegimen A (pazopanib hydrochloride, chemoradiation)
IfosfamideAsta Z 4942, Asta Z-4942, Cyfos, Holoxan, Holoxane, Ifex, IFO, IFO-Cell, Ifolem, Ifomida, Ifomide, Ifosfamidum, Ifoxan, IFX, Iphosphamid, Iphosphamide, Iso-Endoxan, Isoendoxan, Isophosphamide, Mitoxana, MJF 9325, MJF-9325, Naxamide, Seromida, Tronoxal, Z 4942, Z-4942Regimen A (pazopanib hydrochloride, chemoradiation)
Pazopanib HydrochlorideGW786034B, VotrientRegimen A (pazopanib hydrochloride, chemoradiation)

Purpose

This randomized phase II/III trial studies how well pazopanib hydrochloride, combination chemotherapy, and radiation therapy work and compares it to radiation therapy alone or in combination with pazopanib hydrochloride or combination chemotherapy in treating patients with newly diagnosed non-rhabdomyosarcoma soft tissue sarcomas that can be removed by surgery. Radiation therapy uses high energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as ifosfamide and doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether radiation therapy works better when given with or without combination chemotherapy and/or pazopanib hydrochloride in treating patients with non-rhabdomyosarcoma soft tissue sarcomas.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To identify the dose of pazopanib hydrochloride (pazopanib) that is feasible when given in
      combination with radiation or chemoradiation in pediatric and adult patients newly diagnosed
      with unresected intermediate- and high-risk non-rhabdomyosarcoma soft tissue sarcomas
      (NRSTS).

      II. To compare the rates of near complete pathologic response (> 90% necrosis) with the
      addition of pazopanib to preoperative chemoradiation versus preoperative chemoradiation alone
      for potentially resectable > 5 cm, grade 3 intermediate to high risk chemotherapy-sensitive
      NRSTS in the phase II portion of the study for this cohort.

      III. To compare the rates of near complete pathologic response (> 90% necrosis) with the
      addition of pazopanib to preoperative radiotherapy versus preoperative radiotherapy alone for
      potentially resectable intermediate to high risk adult and pediatric NRSTS in the phase II
      portion of the study for this cohort (using a phase II decision rule to go onto the phase III
      portion of the study).

      IV. To compare the rates of event-free survival (EFS) with the addition of pazopanib to
      preoperative radiotherapy versus preoperative radiotherapy alone for localized intermediate
      to high risk adult and pediatric NRSTS in the phase III portion of the study for this cohort
      if the phase II decision rule is passed.

      SECONDARY OBJECTIVES:

      I. To estimate the rates of local failure, regional failure, distant metastasis free
      survival, disease-free survival, and overall survival with the addition of pazopanib to
      preoperative chemoradiation or preoperative radiation in intermediate to high risk adult and
      pediatric NRSTS.

      II. To compare the pattern of recurrence (local, regional and distant) between preoperative
      chemoradiation or radiation with the addition of pazopanib for adult and pediatric NRSTS.

      III. To define the toxicities of ifosfamide and doxorubicin hydrochloride (doxorubicin)
      chemotherapy and radiation when used in combination with pazopanib in intermediate to high
      risk adult and pediatric NRSTS.

      IV. To define the toxicities of preoperative radiotherapy when used in combination with
      pazopanib in intermediate to high risk adult and pediatric NRSTS.

      TERTIARY OBJECTIVES:

      I. To gain insight into the disease biology of childhood and adult NRSTS through analysis of
      actionable mutations and whole genome sequencing.

      II. To determine if microvessel density and circulating tumor deoxyribonucleic acid (DNA)
      predict response to pazopanib and outcome.

      III. To determine the effect of pazopanib on doxorubicin exposure in children and adults with
      NRSTS.

      IV. To evaluate change in fludeoxyglucose F 18 (FDG) positron emission tomography (PET)
      maximum standard uptake value (SUVmax) from baseline to week 10 or 13 in patients with
      unresected tumors and to correlate this change with pathologic response and EFS.

      V. To compare the rate of response by standard imaging and pathologic assessment to determine
      which correlates better with local tumor control, distant tumor control, EFS, and overall
      survival.

      OUTLINE: This is a dose-escalation study of pazopanib hydrochloride.

      CHEMOTHERAPY COHORT: Patients eligible for chemotherapy cohort are randomized to 1 of 2
      treatment regimens.

      REGIMEN A:

      INDUCTION PHASE: Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on
      weeks 1-12, ifosfamide intravenously (IV) over 2-4 hours on days 1-3 on weeks 1, 4, 7, 10,
      and doxorubicin hydrochloride IV over 1-15 minutes on days 1-2 on weeks 1 and 4. At least 24
      hours after the completion of week 4 doxorubicin hydrochloride, patients undergo radiation
      therapy on weeks 4-10.

      SURGERY: Patients undergo surgery on week 13.

      CONTINUATION PHASE: Patients receive pazopanib hydrochloride PO QD on weeks 16-25, ifosfamide
      IV over 2-4 hours on days 1-3 on weeks 16 and 19, and doxorubicin hydrochloride IV over 1-15
      minutes on days 1-2 on weeks 16, 19, and 22. At least 24 hours after the completion of
      doxorubicin hydrochloride, if required, patients undergo radiation therapy on weeks 16-25 for
      a total of 45 Gy. Patients with impaired wound healing within 6 weeks of the date of surgery,
      have week 16 chemotherapy postponed until radiation therapy (if needed) begins. Patients with
      impaired wound healing within 8 weeks of the date of surgery, are removed from protocol
      therapy effective the date 8 weeks after week 13 surgery.

      REGIMEN B:

      INDUCTION PHASE: Patients receive ifosfamide IV over 2-4 hours on days 1-3 on weeks 1, 4, 7,
      10 and doxorubicin hydrochloride IV over 1-15 minutes on days 1-2 on weeks 1 and 4. At least
      24 hours after the completion of week 4 doxorubicin hydrochloride, patients undergo radiation
      therapy on weeks 4-10.

      SURGERY: Patients undergo surgery on week 13.

      CONTINUATION PHASE: Patients receive ifosfamide IV over 2-4 hours on days 1-3 on weeks 16 and
      19 and doxorubicin hydrochloride IV over 1-15 minutes on days 1-2 on weeks 16, 19, and 22. At
      least 24 hours after the completion of doxorubicin hydrochloride, if required, patients
      undergo radiation therapy on weeks 16-25 for a total of 45 Gy. Patients with impaired wound
      healing within 6 weeks of the date of surgery, have week 16 chemotherapy postponed until
      radiation therapy (if needed) begins. Patients with impaired wound healing within 8 weeks of
      the date of surgery, are removed from protocol therapy effective the date 8 weeks after week
      13 surgery.

      NON-CHEMOTHERAPY COHORT: Patients eligible for non-chemotherapy cohort are randomized to 1 of
      2 treatment regimens.

      REGIMEN C:

      INDUCTION PHASE: Patients receive pazopanib hydrochloride PO QD on weeks 1-9. Patients
      undergo radiation therapy on weeks 1-7.

      SURGERY: Patients undergo surgery on week 10.

      CONTINUATION PHASE: Patients receive pazopanib hydrochloride PO QD on weeks 13-25. Patients
      undergo radiation therapy on weeks 13-16 for a total of 50 Gy. Patients with impaired wound
      healing within 8 weeks of the date of surgery, are removed from protocol therapy effective
      the date 8 weeks after week 10 surgery.

      REGIMEN D:

      INDUCTION PHASE: Patients undergo radiation therapy on weeks 1-7.

      SURGERY: Patients undergo surgery on week 10.

      CONTINUATION PHASE: Patients undergo radiation therapy on weeks 13-16 for a total of 50 Gy.
      Patients with impaired wound healing within 8 weeks of the date of surgery, are removed from
      protocol therapy effective the date 8 weeks after week 10 surgery.

      After completion of study treatment, patients are followed up at 6, 12, 18, 24, 30, 36, 48,
      and 60 months.
    

Trial Arms

NameTypeDescriptionInterventions
Regimen A (pazopanib hydrochloride, chemoradiation)ExperimentalSee Regimen A Detailed Description.
  • Doxorubicin Hydrochloride
  • Ifosfamide
  • Pazopanib Hydrochloride
Regimen B (chemoradiation)ExperimentalSee Regimen B Detailed Description.
  • Doxorubicin Hydrochloride
  • Ifosfamide
Regimen C (pazopanib hydrochloride, radiation therapy)ExperimentalINDUCTION PHASE: Patients receive pazopanib hydrochloride PO QD on weeks 1-9. Patients undergo radiation therapy on weeks 1-7. SURGERY: Patients undergo surgery on week 10. CONTINUATION PHASE: Patients receive pazopanib hydrochloride PO QD on weeks 13-25. Patients undergo radiation therapy on weeks 13-16 for a total of 50 Gy. Patients with impaired wound healing within 8 weeks of the date of surgery, are removed from protocol therapy effective the date 8 weeks after week 10 surgery.
  • Pazopanib Hydrochloride
Regimen D (radiation therapy)ExperimentalINDUCTION PHASE: Patients undergo radiation therapy on weeks 1-7. SURGERY: Patients undergo surgery on week 10. CONTINUATION PHASE: Patients undergo radiation therapy on weeks 13-16 for a total of 50 Gy. Patients with impaired wound healing within 8 weeks of the date of surgery, are removed from protocol therapy effective the date 8 weeks after week 10 surgery.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Newly diagnosed and histopathologically confirmed, potentially resectable NRSTS of the
                 extremity and trunk will be eligible for the chemotherapy or non-chemotherapy 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:
    
                   -  Extremities: upper (including shoulder) and lower (including hip)
    
                   -  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 2 or 3 AND
    
              -  One of the following chemosensitive histologies as defined in the World Health
                 Organization (WHO) classification of soft tissue tumors (with some evidence of good
                 response to chemoradiation and of sufficient high risk of metastases, or clear
                 evidence of metastases):
    
                   -  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 not otherwise
                      specified [NOS]")
    
                   -  Synovial sarcoma
    
                   -  Angiosarcoma of soft tissue
    
                   -  Adult fibrosarcoma
    
                   -  Mesenchymal (extraskeletal) chondrosarcoma
    
                   -  Leiomyosarcoma
    
                   -  Liposarcoma (excluding myxoid liposarcoma)
    
                   -  Undifferentiated pleomorphic sarcoma
    
                   -  Embryonal sarcoma of the liver
    
              -  Patients meeting the above criteria (histology, size, and grade) with the EXCEPTION of
                 histologies noted above 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 above 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 non-chemotherapy cohort:
    
                   -  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
    
                   -  Synovial sarcoma
    
                   -  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 tumors for which we have consensus data of chemotherapy-resistance are eligible
                 only for the non-chemotherapy cohort:
    
                   -  So-called fibrohistiocytic tumors - plexiform fibrohistiocytic tumor, giant cell
                      tumor of soft tissues
    
                   -  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
    
                   -  Tumors of uncertain differentiation - epithelioid sarcoma, alveolar soft part
                      sarcoma, clear cell sarcoma of soft tissue, angiomatoid fibrous histiocytoma,
                      ossifying fibromyxoid tumor, 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
    
                   -  Chondro-osseous tumors - extraskeletal osteosarcoma
    
                   -  Pericytic (perivascular) tumors - malignant glomus tumor
    
                   -  Nerve sheath tumors - malignant peripheral nerve sheath tumor, malignant granular
                      cell tumor, epithelioid malignant peripheral nerve sheath tumor, malignant Triton
                      tumor
    
                   -  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) with the EXCEPTION of
                 histologies noted above may enroll on the non-chemotherapy cohort at the discretion of
                 the enrolling investigator; patients meeting these criteria with the EXCEPTION of
                 histologies noted above but medically deemed unable to receive chemotherapy or who
                 elect not to receive chemotherapy are eligible for the non-chemotherapy cohort; note
                 that tumors arising in bone are NOT eligible for this study
    
              -  Extent of disease:
    
                   -  Patients with non-metastatic and metastatic disease are eligible
    
                   -  Initially unresectable patients, with or without metastatic disease, are eligible
                      as long as there is a commitment at enrollment to resect the primary tumor
    
              -  Sufficient tissue and blood must be available to submit for required biology studies
    
              -  Lansky performance status score >= 70 for patients =< 16 years of age
    
              -  Karnofsky performance status score >= 70 for patients > 16 years of age
    
              -  Absolute neutrophil count >= 1500/uL; Note: no transfusions are permitted 7 days prior
                 to laboratory studies to determine eligibility
    
              -  Platelet count >= 100,000/uL; Note: no transfusions are permitted 7 days prior to
                 laboratory studies to determine eligibility
    
              -  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
    
              -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
                 mL/min/1.73 m^2 or normal serum creatinine based on age/gender as follows:
    
                   -  2 to < 6 years; 0.8 mg/dL male; 0.8 mg/dL female
    
                   -  6 to < 10 years; 1 mg/dL male; 1 mg/dL female
    
                   -  10 to < 13 years; 1.2 mg/dL male; 1.2 mg/dL female
    
                   -  13 to < 16 years; 1.5 mg/dL male; 1.4 mg/dL female
    
                   -  >= 16 years; 1.5 mg/dL male; 1.4 mg/dL female
    
              -  Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
    
              -  Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
                 serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x
                 upper limit of normal (ULN) for age
    
              -  Shortening fraction of >= 27% by echocardiogram OR ejection fraction of >= 50% by
                 radionuclide angiogram
    
              -  Corrected QT interval (QTc) < 480 msec
    
              -  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
    
              -  Patients on low molecular weight heparin or Coumadin (with a stable international
                 normalized ratio [INR]) are eligible
    
              -  Patient must have a life expectancy of at least 3 months with appropriate therapy
    
              -  All patients and/or their parents or legal guardians must sign a written informed
                 consent
    
              -  All institutional, Food and Drug Administration (FDA), and National Cancer Institute
                 (NCI) requirements for human studies must be met
    
            Exclusion Criteria:
    
              -  Patients with grade 1 NRSTS tumors of any size are not eligible
    
              -  Patients with known central nervous system (CNS) metastases are not eligible; Note:
                 brain imaging is not an eligibility requirement
    
              -  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)
    
              -  Patients with gross total resection of the primary tumor prior to enrollment on
                 ARST1321 are NOT eligible; patients who have experienced tumor recurrence after a
                 gross total tumor resection are NOT eligible
    
              -  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 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 (e.g., doxorubicin, daunorubicin)
                      or ifosfamide chemotherapy
    
                   -  Patients must have had no prior use of pazopanib or similar multi-targeted
                      tyrosine kinase inhibitors (TKI)
    
                   -  Patients must have had no prior radiotherapy to tumor-involved sites
    
                   -  Note: patients previously treated for a non-NRSTS cancer are eligible provided
                      they meet the prior therapy requirements; 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-in-situ or prostate cancer
                 with low risk factors
    
              -  CYTOCHROME P450 3A4 (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 non-nucleoside reverse-transcriptase
                 inhibitors (NNRTIs), diltiazem, verapamil, and grapefruit juice are not eligible
    
              -  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)
    
              -  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
    
              -  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
    
                   -  Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or other
                      gastrointestinal conditions which increase the risk of perforation
    
                   -  History of abdominal fistula, gastrointestinal perforation or intra-abdominal
                      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 New York Heart Association (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 eligible
    
              -  Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral
                 therapy are ineligible
    
              -  Patients who are receiving any other investigational agent(s)
    
              -  Pregnancy and breast feeding:
    
                   -  Female patients who are pregnant are ineligible
    
                   -  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
    
                   -  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
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:2 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Event-free survival (EFS) (Phase III)
    Time Frame:Time to the first occurrence of progression, relapse after response, secondary cancer or death from any cause, assessed up to 60 months
    Safety Issue:
    Description:The null (radiation therapy only) 5-year EFS for patients with localized unresectable chemo-resistant tumors is expected to be about 30%.

    Secondary Outcome Measures

    Measure:Adverse event profile of the treatments delivered (chemo-radiotherapy; radiotherapy)
    Time Frame:Up to 60 months
    Safety Issue:
    Description:Will be characterized using the current Common Terminology Criteria for Adverse Events version.
    Measure:Distant failure defined as disease recurrence at sites other than the primary site and diagnosis and nodes regional to that site (metastatic disease, whether or not present at diagnosis), with or without loco-regional failure
    Time Frame:Up to 60 months
    Safety Issue:
    Description:The relative risk of specific failure types will be estimated and compared descriptively using the Cox proportional hazard model.
    Measure:Local failure defined as disease recurrence only at the primary site of disease at diagnosis
    Time Frame:Up to 60 months
    Safety Issue:
    Description:The relative risk of specific failure types will be estimated and compared descriptively using the Cox proportional hazard model.
    Measure:Regional failure defined as disease recurrence at lymph nodes regional to the primary disease site, with or without local failure but without distant failure
    Time Frame:Up to 60 months
    Safety Issue:
    Description:The relative risk of specific failure types will be estimated and compared descriptively using the Cox proportional hazard model.

    Details

    Phase:Phase 2/Phase 3
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:National Cancer Institute (NCI)

    Last Updated

    September 13, 2017