Health TrialsbyHealthPanel

NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)

ConditionsAdipocytic NeoplasmLiposarcomaAtypical FibroxanthomaAngiomatoid Fibrous HistiocytomaFibrosarcoma NOSMyxofibrosarcomaAngiosarcomaOsteosarcoma, ExtraskeletalDedifferentiated LiposarcomaMyxoid LiposarcomaPleomorphic LiposarcomaMyxoid Pleomorphic LiposarcomaLow Grade Fibromyxoid SarcomaSclerosing Epithelioid FibrosarcomaMalignant Tenosynovial Giant Cell Tumor of Soft TissueEpithelioid HemangioendotheliomaGlomus TumorInflammatory LeiomyosarcomaLeiomyosarcomaOssifying Fibromyxoid Tumor, MalignantMyoepitheliomaSynovial SarcomaEpithelioid SarcomaPerineurioma, MalignantClear Cell SarcomaExtraskeletal Myxoid ChondrosarcomaGranular Cell Tumor, MalignantMelanotic Malignant Nerve Sheath TumorMalignant Peripheral Nerve Sheath TumorPerivascular Epithelioid Tumor, MalignantIntimal SarcomaMyoepithelial CarcinomaUndifferentiated SarcomaPleomorphic Sarcoma, UndifferentiatedRound Cell Sarcoma, UndifferentiatedNTRK-Rearranged Spindle Cell NeoplasmPhosphaturic Mesenchymal Tumor, MalignantRound Cell SarcomaWell Differentiated LiposarcomaGiant Cell Tumor of Soft Parts NOSLow Grade Myofibroblastic SarcomaDermatofibrosarcoma Protuberans, Fibrosarcomatous
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
AgeUp to 30
SponsorSt. Jude Children's Research Hospital

About this trial

The study participant has been diagnosed with non-rhabdomyosarcoma (NRSTS).

Primary Objectives

Intermediate-Risk

* To estimate the 3-year event-free survival for intermediate-risk patients treated with ifosfamide, doxorubicin, pazopanib, surgery, and maintenance pazopanib, with or without RT. * To characterize the pharmacokinetics of pazopanib and doxorubicin in combination with ifosfamide in intermediate-risk participants, to assess potential covariates to explain the inter- and intra-individual pharmacokinetic variability, and to explore associations between clinical effects and pazopanib and doxorubicin pharmacokinetics.

High-Risk

* To estimate the maximum tolerated dose (MTD) and/or the recommended phase 2 dosage (RP2D) of selinexor in combination with ifosfamide, doxorubicin, pazopanib, and maintenance pazopanib in high-risk participants. * To characterize the pharmacokinetics of selinexor, pazopanib and doxorubicin in combination with ifosfamide in high-risk participants, to assess potential covariates to explain the inter- and intra-individual pharmacokinetic variability, and to explore associations between clinical effects and selinexor, pazopanib and doxorubicin pharmacokinetics.

Secondary Objectives

* To estimate the cumulative incidence of primary site local failure and distant metastasis-free, disease-free, event-free, and overall survival in participants treated on the risk-based treatment strategy defined in this protocol. * To define and describe the CTCAE Grade 3 or higher toxicities, and specific grade 1-2 toxicities, in low- and intermediate-risk participants. * To study the association between radiation dosimetry in participants receiving radiation therapy and the incidence and type of dosimetric local failure, normal adjacent tissue exposure, and musculoskeletal toxicity. * To evaluate the objective response rate (complete and partial response) after 3 cycles for high-risk patients receiving the combination of selinexor with ifosfamide, doxorubicin, pazopanib, and maintenance pazopanib. * To assess the relationship between the pharmacogenetic variation in drug-metabolizing enzymes or drug transporters and the pharmacokinetics of selinexor, pazopanib, and doxorubicin in intermediate- or high-risk patients.

Exploratory Objectives

* To explore the correlation between radiographic response, pathologic response, survival, and toxicity, and tumor molecular characteristics, as assessed through next-generation sequencing (NGS), including whole genome sequencing (WGS), whole exome sequencing (WES), and RNA sequencing (RNAseq). * To explore the feasibility of determining DNA mutational signatures and homologous repair deficiency status in primary tumor samples and to explore the correlation between these molecular findings and the radiographic response, survival, and toxicity of patients treated on this protocol. * To explore the feasibility of obtaining DNA methylation profiling on pretreatment, post-induction chemotherapy, and recurrent (if possible) tumor material, and to assess the correlation with this and pathologic diagnosis, tumor control, and survival outcomes where feasible. * To explore the feasibility of obtaining high resolution single-cell RNA sequencing of pretreatment, post-induction chemotherapy, and recurrent (if possible) tumor material, and to characterize the longitudinal changes in tumor heterogeneity and tumor microenvironment. * To explore the feasibility of identifying characteristic alterations in non-rhabdomyosarcoma soft tissue sarcoma in cell-free DNA (cfDNA) in blood as a non-invasive method of detecting and tracking changes during therapy, and to assess the correlation of cfDNA and mutations in tumor samples. * To describe cardiovascular and musculoskeletal health, cardiopulmonary fitness among children and young adults with NRSTS treated on this protocol. * To investigate the potential prognostic value of serum cardiac biomarkers (high-sensitivity cardiac troponin I (hs-cTnI), N-terminal pro B-type natriuretic peptide (NT-Pro-BNP), serial electrocardiograms (EKGs), and serial echocardiograms in patients receiving ifosfamide, doxorubicin, and pazopanib, with or without selinexor. * To define the rates of near-complete pathologic response (\>90% necrosis) and change in FDG PET maximum standard uptake value (SUVmax) from baseline to week 13 in intermediate risk patients with initially unresectable tumors treated with induction pazopanib, ifosfamide, and doxorubicin, and to correlate this change with tumor control and survival outcomes. * To determine the number of high-risk patients initially judged unresectable at diagnosis that are able to undergo primary tumor resection after treatment with ifosfamide, doxorubicin, selinexor, and pazopanib. * To identify the frequency with which assessment of volumes of interest (VOIs) of target lesions would alter RECIST response assessment compared with standard linear measurements.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Patients must be 1-30 years at the time of the biopsy that established the diagnosis of NRSTS.

Surgical Resection: Patients who had an upfront resection prior to enrollment will be eligible if they are able to begin therapy within 28 days of resection assuming other eligibility criteria are met. Delayed resection is preferred for all patients with intermediate and high-risk disease.

Lansky performance status score ≥ 60 for patients ≤ 16 years of age. Karnofsky performance status score ≥ 60 for patients >16 years of age. Note patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

Low-grade tumor of any size where R0 or R1 surgical margins are anticipated or achieved.

Disqualifiers

Patients with known primary CNS sarcoma or CNS metastases are not eligible. Note: Brain imaging is not an eligibility requirement. Tumors with intracranial extension will be allowed.

Patients with the following histologic diagnosis are not eligible: intermediate locally aggressive tumors as defined by WHO, malignant rhabdoid tumor, alveolar soft part sarcoma, infantile fibrosarcoma, unresectable/metastatic dermatofibrosarcoma protuberans, inflammatory myofibroblastic tumor, desmoid fibromatosis, rhabdomyosarcoma, desmoplastic small round cell tumor, BCOR-CCNB3 fusion positive sarcoma.

Bleeding diathesis: Patients with evidence of active bleeding or bleeding diathesis will be excluded (Note: Patients aged > 17 years with excess of 2.5 mL of hemoptysis are not eligible).

Uncontrolled hypertension: Patients with uncontrolled hypertension (CTCAE v5 Grade ≥ 2) are ineligible. Hypertension must be well controlled on stable doses of medication for at least two weeks.

Trial design

Design model

Factorial

Treatments tested in this trial

  • Surgical resection

    Procedure/Surgery

    Low, Intermediate and High-risk Surgery to remove tumor (standard of care)

  • Proton beam radiation therapy

    Radiation

    Low, Intermediate and High-risk Radiation therapy is considered standard of care for patients with NRSTS who have positive tumor margins. However, the dose that will be given in this study is higher than what is usually given, therefore, the dose of radiation in this study is research. Radiation will start about 3 to 6 weeks after your surgery, depending on how quickly you recover from surgery. Radiation will be given daily (Monday through Friday) for about 5 to 6 weeks.

  • Pazopanib

    Drug

    Intermediate and High-risk By mouth, either by tablet or a liquid suspension, 7 doses, days 1 to 7

  • Ifosfamide

    Drug

    Intermediate and High-risk Ifosfamide is a structural analogue of cyclophosphamide. Into the vein (IV) over about 3 hours, 3 doses, days 1, 2, and 3

  • Doxorubicin

    Drug

    Intermediate and High-risk An anthracycline antibiotic isolated from cultures of Streptomyces peucetius. Intermediate, High-risk Into the vein (IV) over about 1 hour, 2 doses, days 1 and 2

  • Selinexor

    Drug

    High-risk Dosage and route of administration: Selinexor tablets for oral administration should be taken at approximately the same time each day without regards to meals. Selinexor is a selective inhibitor of nuclear export (SINE). Selinexor specifically blocks XPO1-mediated nuclear export by forming a slowly reversible covalent bond with the nuclear export protein XPO1 By mouth, either by tablet or a liquid suspension, 1 dose and day 3

Treatment groups

139 Participants
are divided into 6 treatment groups

6

Treatment groups

See each treatment group below.

Group A: Low-Risk Subset AExperimental treatment 2 interventions
Group B: Low-Risk Subset BExperimental treatment 2 interventions
Group C: Intermediate-Risk Subset A (participants with low grade tumors):Experimental treatment 5 interventions
Group D: Intermediate-Risk Subset B (participants with high-grade tumors between 5 and 10 cm in sizeExperimental treatment 5 interventions
Group E: Intermediate-Risk Subset C (participants with high-grade tumors > 10 cm):Experimental treatment 5 interventions
Group F: High-Risk - 2 groupsExperimental treatment 6 interventions

Trial outcomes

Primary outcomes

1

Event-free survival (EFS)

We will estimate the 3-year event-free survival for intermediate-risk patients, which is the estimated probability of a patient not having any events within the 3-year follow-up. The events are defined as including local failure, regional failure, distant failure, a subsequent malignant neoplasm, or death, whichever occurred first.

Time frame
9 years (6 years of accrual and 3 year follow-up after enrollment of last patient
2

Maximum tolerated dose (MTD) and/or the recommended phase 2 dosage (RP2D)

MTD is defined in the study as the highest treatment dose that would deliver desirable treatment effects without resulting in a target toxicity rate greater than 0.3. We will employ the Bayesian optimal interval (BOIN) design to find the MTD in high-risk participants.

Time frame
4 years]

Secondary outcomes

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

St. Jude Children's Research Hospital

Lead sponsor

Source ClinicalTrials.gov
Apply now