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INDUCTION PHASE: Patients receive pazopanib 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 PO QD on weeks 13-25. If applicable, patients undergo additional radiation therapy at week 13.

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

SURGERY: Patients undergo surgery on week 10.

CONTINUATION PHASE: If applicable, patients undergo additional radiation therapy at week 13.

Doxorubicin Hydrochloride

Pazopanib

Pazopanib Hydrochloride

Radiation Therapy

Therapeutic Conventional Surgery

Aaron R Weiss

This randomized phase II/III trial studies how well pazopanib, when combined with chemotherapy and radiation therapy or radiation therapy alone, work in the treatment of patients with newly diagnosed non-rhabdomyosarcoma soft tissue sarcomas that can eventually be removed by surgery. Radiation therapy uses high energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as ifosfamide and doxorubicin, 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 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether these therapies can be safely combined and if they work better when given together in treating patients with non-rhabdomyosarcoma soft tissue sarcomas.

PRIMARY OBJECTIVES:

I. To identify the dose of 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 2 or 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 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.

EXPLORATORY 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 study starts as a dose-escalation study of pazopanib.

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

REGIMEN A:

INDUCTION PHASE: Patients receive pazopanib 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 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, patients undergo radiation therapy on weeks 4-10.

SURGERY: Patients undergo surgery on week 13.

CONTINUATION PHASE: Patients receive pazopanib PO QD on weeks 16-25, ifosfamide IV over 2-4 hours on days 1-3 on weeks 16 and 19, and doxorubicin IV over 1-15 minutes on days 1-2 on weeks 16, 19, and 22. If applicable, patients undergo additional radiation therapy at week 16

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, 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 IV over 1-15 minutes on days 1-2 on weeks 16, 19, and 22. If applicable, patients undergo additional radiation therapy at week 16.

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

REGIMEN C:

INDUCTION PHASE: Patients receive pazopanib 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 PO QD on weeks 13-25. If applicable, patients undergo additional radiation therapy at week 13.

REGIMEN D:

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

SURGERY: Patients undergo surgery on week 10.

CONTINUATION PHASE: If applicable, patients undergo additional radiation therapy at week 13.

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

Radiation Therapy With or Without Combination Chemotherapy or Pazopanib 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)

Descriptive statistical analyses will be provided to estimate 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.

Descriptive analyses will be performed to summarize the prevalence of ctDNA.

Pharmacokinetic parameters such as the clearance of doxorubicin and pazopanib will be estimated.

To evaluate change in FDG 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.

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

The dose of pazopanib that is feasible when given in combination with radiation or chemoradiation in pediatric unresected intermediate- and high-risk NRSTS patients. Initially, up to 10 patients (minimum of 3 patients ≥ 2 and \< 18 years of age and 3 patients ≥ 18 years of age) eligible for each of the two study cohorts were non-randomly assigned (to generate 8 patients evaluable for toxicity) to receive treatment with pazopanib at dose level 1. A protocol-defined list of pazopanib-associated adverse events were defined as dose-limiting toxicities. The pazopanib dose determined to be feasible was based on the number of patient-reported dose-limiting toxicities encountered.

The dose of pazopanib that is feasible when given in combination with radiation or chemoradiation in adult unresected intermediate- and high-risk NRSTS patients. Initially, up to 10 patients (minimum of 3 patients ≥ 2 and \< 18 years of age and 3 patients ≥ 18 years of age) eligible for each of the two study cohorts were non-randomly assigned (to generate 8 patients evaluable for toxicity) to receive treatment with pazopanib at dose level 1. A protocol-defined list of pazopanib-associated adverse events were defined as dose-limiting toxicities. The pazopanib dose determined to be feasible was based on the number of patient-reported dose-limiting toxicities encountered.

A responder is defined by more than (90% tumor necrosis at week 13). A non-responder has less than 90% necrosis or progressive disease before week 13.

A responder is defined by more than 90% tumor necrosis at week 10. A non-responder has less than 90% necrosis or progressive disease before week 10.

Time to the first occurrence of relapse, progression, secondary cancer or death from any cause.

Defined as disease recurrence only at the primary site of disease at diagnosis. The relative risk of specific failure types will be estimated and compared descriptively using the Cox proportional hazard model.

Defined as disease recurrence at lymph nodes regional to the primary disease site, with or without local failure but without distant failure. The relative risk of specific failure types will be estimated and compared descriptively using the Cox proportional hazard model.

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. The relative risk of specific failure types will be estimated and compared descriptively using the Cox proportional hazard model.

Participants who experienced Grade 3 or higher toxicity was assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).

National Cancer Institute (NCI)

Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.

Dose-Finding Level 1 CR:

Adult: Pazopanib 600 mg; Pediatric: Pazopanib 350 mg/m2

Dose-Finding Level 1 CR

Dose-Finding Level 1 RT:

Adult: Pazopanib 600 mg; Pediatric: Pazopanib 350 mg/m2

Dose-Finding Level 1 RT

Dose-Finding Level 2 RT:

Adult: Pazopanib 800 mg; Pediatric: Pazopanib 450 mg/m2

Dose-Finding Level 2 RT

Regimen A

Regimen B

Regimen C: Radiation therapy plus pazopanib

Regimen C

Regimen D

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

It was pre-specified to combine adult and pediatric participants for analysis as they received an equivalent dose of Pazopanib. There were no patients enrolled onto Dose-Finding Level 0 CR and Dose-Finding Level 2 CR or Dose-Finding Level 0 RT.

Results Reporting Coordinator

Dose-Finding CR: Chemoradiation plus pazopanib

All Pediatric Dose Finding CR Cohorts

Dose-Finding RT: Radiation therapy plus pazopanib

All Pediatric Dose Finding RT Cohorts

Pediatric patients, excluding 1 ineligible patient in Dose-Finding CR group and 1 ineligible patient in Dose-Finding RT group

Feasible Dose: Pediatric

All Adult Dose Finding CR Cohorts

All Adult Dose Finding RT Cohorts

Adult patients, excluding 1 ineligible patient in Dose-Finding RT group

Feasible Dose: Adult

It was pre-specified to combine adult and pediatric participants for analysis as they received an equivalent dose of Pazopanib. There were no patients enrolled onto Dose-Finding Level 0 CR or Dose-Finding Level 2 CR. 19 Regimen A patients and 23 Regimen B patients were excluded.

Percentage of Chemoradiotherapy Patients With Positive Pathologic Response at Week 13

It was pre-specified to combine adult and pediatric participants for analysis as they received an equivalent dose of Pazopanib. There were no patients enrolled onto Dose Level 0 RT. 3 Regimen C patients excluded: 1 patient did not receive treatment and 2 missing review; 4 Regimen D patients excluded due to missing review.

Percentage of Radiotherapy Patients With Positive Pathologic Response at Week 10

Data for the phase III portion of the study were never collected because the RT arm was closed earlier due to slow accrual.

Percentage of Radiotherapy Patients Failure Free at 5 Years Following Study Entry

Percentage of Patients Local Failure Free at 5 Years Following Study Entry

Percentage of Patients Regional Failure Free at 5 Years Following Study Entry

Percentage of Patients Distant Failure Free at 5 Years Following Study Entry

Pediatric Patients

Adult Patients

Dose-Finding Level 2 RT:

Adult: Pazopanib 800 mg; Pediatric:

Pazopanib 450 mg/m2

Percentage of Patients Who Experienced Grade 3 or Higher Toxicity Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Before Surgery in Treating Patients With Newly Diagnosed Non-rhabdomyosarcoma Soft Tissue Sarcomas That Can Be Removed by Surgery	NCT02180867	Alveolar Soft P... Angiomatoid Fib... Atypical Fibrox... Clear Cell Sarc... Epithelioid Mal... Epithelioid Sar... Extraskeletal M... Extraskeletal O... Fibrohistiocyti... Fibrosarcoma Inflammatory My... Intimal Sarcoma Leiomyosarcoma Liposarcoma Liver Embryonal... Low Grade Fibro... Low Grade Myofi... Malignant Cutan... Malignant Perip... Malignant Trito... Mesenchymal Cho... Myxofibrosarcom... Myxoid Chondros... Myxoinflammator... Nerve Sheath Ne... PEComa Pericytic Neopl... Plexiform Fibro... Sclerosing Epit... Skin Glomus Tum... Stage IB Soft T... Stage IIB Soft ... Stage III Soft ... Stage IV Soft T... Synovial Sarcom... Undifferentiate...	Doxorubicin Doxorubicin Hyd... Ifosfamide Pazopanib Pazopanib Hydro... Radiation Thera... Therapeutic Con...	2 Years -	National Cancer Institute (NCI)
Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Before Surgery in Treating Patients With Newly Diagnosed Non-rhabdomyosarcoma Soft Tissue Sarcomas That Can Be Removed by Surgery	NCT02180867	Alveolar Soft P... Angiomatoid Fib... Atypical Fibrox... Clear Cell Sarc... Epithelioid Mal... Epithelioid Sar... Extraskeletal M... Extraskeletal O... Fibrohistiocyti... Fibrosarcoma Inflammatory My... Intimal Sarcoma Leiomyosarcoma Liposarcoma Liver Embryonal... Low Grade Fibro... Low Grade Myofi... Malignant Cutan... Malignant Perip... Malignant Trito... Mesenchymal Cho... Myxofibrosarcom... Myxoid Chondros... Myxoinflammator... Nerve Sheath Ne... PEComa Pericytic Neopl... Plexiform Fibro... Sclerosing Epit... Skin Glomus Tum... Stage IB Soft T... Stage IIB Soft ... Stage III Soft ... Stage IV Soft T... Synovial Sarcom... Undifferentiate...	Doxorubicin Doxorubicin Hyd... Ifosfamide Pazopanib Pazopanib Hydro... Radiation Thera... Therapeutic Con...	2 Years -	National Cancer Institute (NCI)

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