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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

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ClinicalTrials.gov Identifier: NCT02180867
Recruitment Status : Recruiting
First Posted : July 3, 2014
Last Update Posted : December 15, 2017
Sponsor:
Information provided by (Responsible Party):

July 1, 2014
July 3, 2014
December 15, 2017
July 11, 2014
June 13, 2018   (Final data collection date for primary outcome 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 ]
    The null (radiation therapy only) 5-year EFS for patients with localized unresectable chemo-resistant tumors is expected to be about 30%.
  • Potential benefit for chemoradiotherapy plus pazopanib hydrochloride defined as protocol week 13 pathologic response (Phase II) [ Time Frame: Week 13 ]
    The expected null (chemotherapy only) pathologic response rate (90%+ necrosis at week 13) is 40%.
  • Potential benefit for radiotherapy plus pazopanib hydrochloride defined as protocol week 10 pathologic response (Phase II/III) [ Time Frame: Week 10 ]
    The expected null (radiation therapy only) pathologic response rate (90%+ necrosis at Week 10) is 10%.
  • Potential benefit for chemoradiotherapy plus pazopanib hydrochloride defined as protocol week 13 pathologic response (Phase II) [ Time Frame: Week 13 ]
    The expected null (chemotherapy only) pathologic response rate (90%+ necrosis at week 13) is 40%.
  • Potential benefit for radiotherapy plus pazopanib hydrochloride defined as protocol week 10 pathologic response (Phase II/III) [ Time Frame: Week 10 ]
    The expected null (radiation therapy only) pathologic response rate (90%+ necrosis at Week 10) is 10%.
  • 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 ]
    The null (radiation therapy only) 5-year EFS for patients with localized unresectable chemo-resistant tumors is expected to be about 30%.
Complete list of historical versions of study NCT02180867 on ClinicalTrials.gov Archive Site
  • Adverse event profile of the treatments delivered (chemo-radiotherapy; radiotherapy) [ Time Frame: Up to 60 months ]
    Will be characterized using the current Common Terminology Criteria for Adverse Events version.
  • 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 ]
    The relative risk of specific failure types will be estimated and compared descriptively using the Cox proportional hazard model.
  • Local failure defined as disease recurrence only at the primary site of disease at diagnosis [ Time Frame: Up to 60 months ]
    The relative risk of specific failure types will be estimated and compared descriptively using the Cox proportional hazard model.
  • 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 ]
    The relative risk of specific failure types will be estimated and compared descriptively using the Cox proportional hazard model.
  • Local failure defined as disease recurrence only at the primary site of disease at diagnosis [ Time Frame: Up to 60 months ]
    The relative risk of specific failure types will be estimated and compared descriptively using the Cox proportional hazard model.
  • 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 ]
    The relative risk of specific failure types will be estimated and compared descriptively using the Cox proportional hazard model.
  • 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 ]
    The relative risk of specific failure types will be estimated and compared descriptively using the Cox proportional hazard model.
  • Adverse event profile of the treatments delivered (chemo-radiotherapy; radiotherapy) characterized using the current Common Terminology Criteria for Adverse Events version [ Time Frame: Up to 60 months ]
  • Change in fludeoxyglucose F 18 (FDG) positron emission tomography (PET) maximum standard uptake value (SUVmax) [ Time Frame: Baseline to week 13 ]
    The FDG-PET images will be assessed as positive or negative at the primary site and PET response will be descriptively compared to the findings at Week 10 or 13 surgery.
  • Circulating Tumor deoxyribonucleic acid (DNA) [ Time Frame: Up to 60 months ]
    Descriptive analyses will be performed.
  • Frequency with which combinations of actionable mutations are observed in individual tumor types [ Time Frame: Up to 60 months ]
    Descriptive statistical analyses will be estimated.
  • Pharmacokinetic parameters of doxorubicin hydrochloride and pazopanib hydrochloride [ Time Frame: Up to 48 hours after the end of infusion ]
    The present trial is designed to allow detection of statistically significant changes in the mean clearance of doxorubicin of at least 25% using a one-sample analysis, which concerns testing an observed experimental mean against the expected (historical) mean of 25.6 L/h/m^2.
  • Rates of actionable mutations on whole genome sequencing [ Time Frame: Up to 60 months ]
    Descriptive and exploratory statistical analyses will be carried out.
  • Relative risk of failure based on both standard imaging and pathologic assessment [ Time Frame: Up to 60 months ]
    Log-rank test will be used to see if one response assessment method produces a larger difference in outcome between the response categories.
  • The relative frequency of actionable mutations across the whole cohort and within more common histological subtypes, like synovial sarcoma and malignant peripheral nerve sheath tumors [ Time Frame: Up to 60 months ]
    Descriptive statistical analyses will be estimated.
  • The relative frequency of actionable mutations across the whole cohort and within more common histological subtypes, like synovial sarcoma and malignant peripheral nerve sheath tumors [ Time Frame: Up to 60 months ]
    Descriptive statistical analyses will be estimated.
  • Frequency with which combinations of actionable mutations are observed in individual tumor types [ Time Frame: Up to 60 months ]
    Descriptive statistical analyses will be estimated.
  • Rates of actionable mutations on whole genome sequencing [ Time Frame: Up to 60 months ]
    Descriptive and exploratory statistical analyses will be carried out.
  • Circulating Tumor DNA [ Time Frame: Up to 60 months ]
    Descriptive analyses will be performed.
  • Pharmacokinetic parameters of doxorubicin hydrochloride and pazopanib hydrochloride [ Time Frame: Up to 48 hours after the end of infusion ]
    The present trial is designed to allow detection of statistically significant changes in the mean clearance of doxorubicin of at least 25% using a one-sample analysis, which concerns testing an observed experimental mean against the expected (historical) mean of 25.6 L/h/m^2.
  • Change in FDG PET SUVmax [ Time Frame: Baseline to week 13 ]
  • Relative risk of failure based on both standard imaging and pathologic assessment [ Time Frame: Up to 60 months ]
    Log-rank test will be used to see if one response assessment method produces a larger difference in outcome between the response categories.
 
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
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)
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.

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.

Interventional
Phase 2
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • 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
  • Drug: Doxorubicin Hydrochloride
    Given IV
    Other Names:
    • 5,12-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
    • Rubex
  • Drug: Ifosfamide
    Given IV
    Other Names:
    • Asta 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-4942
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Pazopanib Hydrochloride
    Given PO
    Other Names:
    • GW786034B
    • Votrient
  • Other: Pharmacological Study
    Correlative studies
  • Radiation: Radiation Therapy
    Undergo radiation therapy
    Other Names:
    • Cancer Radiotherapy
    • Irradiate
    • Irradiated
    • irradiation
    • RADIATION
    • Radiotherapeutics
    • radiotherapy
    • RT
    • Therapy, Radiation
  • Procedure: Therapeutic Conventional Surgery
    Undergo surgery
  • Experimental: Regimen A (pazopanib hydrochloride, chemoradiation)
    See Regimen A Detailed Description.
    Interventions:
    • Drug: Doxorubicin Hydrochloride
    • Drug: Ifosfamide
    • Other: Laboratory Biomarker Analysis
    • Drug: Pazopanib Hydrochloride
    • Other: Pharmacological Study
    • Radiation: Radiation Therapy
    • Procedure: Therapeutic Conventional Surgery
  • Experimental: Regimen B (chemoradiation)
    See Regimen B Detailed Description.
    Interventions:
    • Drug: Doxorubicin Hydrochloride
    • Drug: Ifosfamide
    • Other: Laboratory Biomarker Analysis
    • Other: Pharmacological Study
    • Radiation: Radiation Therapy
    • Procedure: Therapeutic Conventional Surgery
  • Experimental: Regimen C (pazopanib hydrochloride, radiation therapy)

    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.

    Interventions:
    • Other: Laboratory Biomarker Analysis
    • Drug: Pazopanib Hydrochloride
    • Other: Pharmacological Study
    • Radiation: Radiation Therapy
    • Procedure: Therapeutic Conventional Surgery
  • Experimental: Regimen D (radiation therapy)

    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.

    Interventions:
    • Other: Laboratory Biomarker Analysis
    • Other: Pharmacological Study
    • Radiation: Radiation Therapy
    • Procedure: Therapeutic Conventional Surgery
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
340
Not Provided
June 13, 2018   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
2 Years and older   (Child, Adult, Senior)
No
Canada,   Puerto Rico,   United States
 
 
NCT02180867
NCI-2014-01340
NCI-2014-01340 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
s14-02023
ARST1321
ARST1321 ( Other Identifier: Childrens Oncology Group )
ARST1321 ( Other Identifier: CTEP )
U10CA180830 ( U.S. NIH Grant/Contract )
U10CA180886 ( U.S. NIH Grant/Contract )
U10CA098543 ( U.S. NIH Grant/Contract )
No
Not Provided
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Aaron Weiss Children's Oncology Group
National Cancer Institute (NCI)
November 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP