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)

Summary:

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 tumour cells. Drugs used in chemotherapy, such as ifosfamide and doxorubicin hydrochloride, work in different ways to stop the growth of tumour cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Pazopanib hydrochloride may stop the growth of tumour 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.

Trial Description

Primary Outcome:

  • Event-free survival (EFS) (Phase III)
  • Potential benefit for chemoradiotherapy plus pazopanib hydrochloride defined as protocol week 13 pathologic response (Phase II)
  • Potential benefit for radiation therapy plus pazopanib hydrochloride defined as protocol week 10 pathologic response (Phase II/III)
Secondary Outcome:
  • Adverse event profile of the treatments delivered (chemo-radiotherapy; radiation therapy)
  • 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
  • Local failure defined as disease recurrence only at the primary site of disease at diagnosis
  • Regional failure defined as disease recurrence at lymph nodes regional to the primary disease site, with or without local failure but without distant failure
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 radiation therapy versus preoperative radiation therapy 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 radiation therapy versus preoperative radiation therapy 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 radiation therapy 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 tumour 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 tumours 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 tumour control, distant tumour 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.

View this trial on ClinicalTrials.gov

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