xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT06023641</url>
    </required_header>
    <id_info>
      <org_study_id>RMS2021</org_study_id>
      <nct_id>NCT06023641</nct_id>
    </id_info>
    <brief_title>Treatment of Newly Diagnosed Rhabdomyosarcoma Using Molecular Risk Stratification and Liposomal Irinotecan Based Therapy in Children With Intermediate and High Risk Disease</brief_title>
    <official_title>A Protocol for the Treatment of Newly Diagnosed Rhabdomyosarcoma Using Molecular Risk Stratification and Liposomal Irinotecan Based Therapy in Children With Intermediate and High Risk Disease</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>St. Jude Children's Research Hospital</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>St. Jude Children's Research Hospital</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>Yes</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        This is a phase I-II study to determine safety and efficacy of combining liposomal irinotecan&#xD;
        with vincristine alternating with VAC in intermediate-risk patients, liposomal irinotecan&#xD;
        with temozolomide and vincristine alternating with VAC in high-risk patients and the&#xD;
        chemotherapy combinations when given with concomitant radiation therapy in intermediate and&#xD;
        high risk patients.&#xD;
  &#xD;
        Primary Objective&#xD;
  &#xD;
          -  The primary objective of the Phase I part is to estimate the maximum tolerated doses&#xD;
             (MTDs) and recommended Phase II doses (RP2Ds) of combining liposomal irinotecan with&#xD;
             vincristine alternating with VAC in intermediate-risk patients, liposomal irinotecan&#xD;
             with temozolomide and vincristine alternating with VAC in high-risk patients and the&#xD;
             chemotherapy combinations when given with concomitant radiation therapy in intermediate&#xD;
             and high risk patients.&#xD;
  &#xD;
          -  Estimate event-free survival for intermediate-risk participants treated with VAC and&#xD;
             vincristine and liposomal irinotecan (VLI) with the addition of maintenance therapy with&#xD;
             vinorelbine and cyclophosphamide.&#xD;
  &#xD;
          -  Estimate the event-free survival for high-risk patients treated with VAC and&#xD;
             vincristine, liposomal irinotecan, and temozolomide with the addition of maintenance&#xD;
             therapy with vinorelbine and cyclophosphamide.&#xD;
  &#xD;
          -  Estimate the local recurrence rate for unresected intermediate- and high-risk patients&#xD;
             with initial tumor size with ≥5 cm randomized to between 59.4 GyRBE and 68 GyRBE total&#xD;
             proton radiation dose while receiving VAC/VLI (intermediate-risk) or VAC/VLI plus&#xD;
             temozolomide (high-risk) and maintenance therapy.&#xD;
  &#xD;
        Secondary Objectives&#xD;
  &#xD;
          -  To assess the relation between pharmacogenetic variation in CEP72 genotype and vinca&#xD;
             alkaloid (vincristine; vinorelbine) disposition in children with rhabdomyosarcoma.&#xD;
  &#xD;
          -  To assess the relation between the pharmacogenetic variation in drug metabolizing&#xD;
             enzymes and drug transporters, and the pharmacokinetics of vinca alkaloids, liposomal&#xD;
             irinotecan, and cyclophosphamide in children with rhabdomyosarcoma.&#xD;
  &#xD;
          -  To assess the extent of inter-patient variability in the pharmacokinetics of vinca&#xD;
             alkaloids, liposomal irinotecan, and cyclophosphamide in children with rhabdomyosarcoma,&#xD;
             and explore possible associations between drug disposition and patient specific&#xD;
             covariates (e.g., age, sex, race, weight).&#xD;
  &#xD;
          -  Estimate the cumulative incidence of local recurrence in patients with low-risk disease&#xD;
             treated with either no adjuvant radiation or minimal volume radiation.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        This is a phase I-II study to determine safety and efficacy of combining liposomal irinotecan&#xD;
        with vincristine alternating with VAC in intermediate-risk patients, liposomal irinotecan&#xD;
        with temozolomide and vincristine alternating with VAC in high-risk patients and the&#xD;
        chemotherapy combinations when given with concomitant radiation therapy in intermediate and&#xD;
        high risk patients. The phase I part (dose-finding phase) is a dose-escalation part using the&#xD;
        BOIN design with maximally 18 patients for each of groups (intermediate -risk, high-risk, and&#xD;
        intermediate -and-high-risk-with-early-radiation). Phase I part is to find the maximum&#xD;
        tolerated dose and recommended phase II dose for the subsequent phase II part. Phase II part&#xD;
        has two primary objectives. The first objective will derive the sample size and it is for&#xD;
        efficacy and the endpoint is defined as a 2-year event-free survival (EFS) for each stratum,&#xD;
        with 4 years enrollment and 2 years follow-up for each patient, by 80% power and 5% type I&#xD;
        error rate, a single-arm adaptive phase II design is used to have estimated numbers of&#xD;
        patients for intermediate-risk and high-risk groups are 46 and 33, respectively. The study&#xD;
        will end once the last enrolled patient has been followed by 2 years. The second objective is&#xD;
        to evaluate the local recurrence rate (LRR) of patients with tumor size ≥ 5cm by using a 2:1&#xD;
        randomization design of comparing administration of the two radiation strategies, 59.4 GyRBE&#xD;
        and 68 GyRBE. For this part, 27 additional patients will be required.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 2023</start_date>
    <completion_date type="Anticipated">October 2037</completion_date>
    <primary_completion_date type="Anticipated">October 2034</primary_completion_date>
    <phase>Phase 1/Phase 2</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Non-Randomized</allocation>
      <intervention_model>Single Group Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Maximum tolerated doses (MTDs)</measure>
      <time_frame>4 years</time_frame>
      <description>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. For each of three groups (intermediate-risk, high-risk, and intermediate-and-high-risk-with-early-radiation), we will employ the Bayesian optimal interval (BOIN) design to find the MTD.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Event-free survival (EFS)</measure>
      <time_frame>2 years post, off therapy</time_frame>
      <description>We will estimate the 2-year event-free survival for intermediate-risk and high-risk patients, which is the estimated probability of a patient not having any events within the 2-year follow-up. If an event, including local failure, distant failure, death or loss to follow-up occurs for a patient within 2-year, we call it failure, otherwise call it response.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Local recurrence rate (LRR)</measure>
      <time_frame>2 years</time_frame>
      <description>LRR is defined as a binary endpoint in the study. The local recurrence-free survival (LRFS) is defined as time from randomization to the earlier date of the first of local disease recurrence or death due to any cause. The distant failure will be considered to be the competing risk, patients for whom follow-up ended without clinical improvement will be censored. The goal of the local recurrence rate endpoint is to evaluate the 2-year LRR by comparing the administration of 59.4 GyRBE and 68 GyRBE for patients (pooled intermediate- and high-risk groups) with tumor size greater than or equal to 5cm meeting the eligibility criteria for randomization (no biliary tree or specific extremity cases).&#xD;
  .</description>
    </primary_outcome>
    <number_of_arms>3</number_of_arms>
    <enrollment type="Anticipated">100</enrollment>
    <condition>Rhabdomyosarcoma</condition>
    <arm_group>
      <arm_group_label>Low -risk</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>The participant will receive 12 weeks (4 cycles) of VAC chemotherapy (vincristine, dactinomycin and cyclophosphamide) followed by 12 weeks (4 cycles) of VA chemotherapy (vincristine, dactinomycin).&#xD;
  Each cycle of VAC/VA chemotherapy will last for 3 weeks, for a total of 12 weeks (VAC or VA will be given in Week 1 of each cycle and vincristine will be given Weeks 2 and 3). At week 12, the participant will have scans and tests to reevaluate your tumor's response to the treatment. After surgery and radiation, the participant will receive an additional 12 weeks (4 cycles) of the same chemotherapy without cyclophosphamide. Vincristine and dactinomycin, also called &quot;VA&quot;. After 4 cycles of VA, The investigator will re-evaluate the tumor again at week 24 and the patient will not get any more chemotherapy, but will be closely watched for any signs of tumor recurrence.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Intermediate-risk</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with intermediate and high risk rhabdomyosarcoma. The investigators also want to find the best radiation dose to give for intermediate and high risk patients who have large tumors (&gt; 5 cm).&#xD;
  The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLI chemotherapy (vincristine/liposomal irinotecan). The participant will also have surgery to remove the tumor and radiation therapy during this time. After this therapy is completed you will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>High-risk</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with high risk rhabdomyosarcoma. The investigator also want to find the best radiation dose to give for high risk patients who have large tumors (&gt; 5 cm).&#xD;
  The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLIT chemotherapy (vincristine/liposomal irinotecan/temozolomide). Also having surgery to remove the participants tumor and radiation therapy during this time. After this therapy is completed the patient will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Vincristine</intervention_name>
      <description>Low -risk Administer IV push over 1 minute (or infusion via minibag as per institutional standards) on Day 1 of Weeks 1,8, 15 (3) doses. The maximum dose is 2 mg for all participants.&#xD;
  Intermediate-risk Administer IV, over 1 minute, 3 doses, weekly on day1 High-risk Administer by IV infusion over 1 minute, 3 doses, weekly on day 1,8,15</description>
      <arm_group_label>High-risk</arm_group_label>
      <arm_group_label>Intermediate-risk</arm_group_label>
      <arm_group_label>Low -risk</arm_group_label>
      <other_name>Oncovin</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Dactinomycin</intervention_name>
      <description>Low-risk Administer by slow IV push over 1-5 minutes on Day 1 of Weeks 1, (1) dose. The maximum dose is 2.5 mg for all participants.&#xD;
  Intermediate-risk Administer by slow IV over 1-5 minutes., 1 doses weekly on day 1 High-risk Administer by slow IV over 1-5 minutes, day1</description>
      <arm_group_label>High-risk</arm_group_label>
      <arm_group_label>Intermediate-risk</arm_group_label>
      <arm_group_label>Low -risk</arm_group_label>
      <other_name>(actinomycin-D)</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Cyclophosphamide</intervention_name>
      <description>Low-risk Administer by IV infusion over 30-60 minutes on Day 1, 91) dose, Mesna and hydration will be given with IV cyclophosphamide according to institutional standards.&#xD;
  Intermediate-risk Administer by IV infusion over 30-60 minutes, 1 dose, day 1 High-risk Administer by IV infusion over 30-60 minutes, 1 dose, day1</description>
      <arm_group_label>High-risk</arm_group_label>
      <arm_group_label>Intermediate-risk</arm_group_label>
      <arm_group_label>Low -risk</arm_group_label>
      <other_name>Cytoxan®.</other_name>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Surgical Resection</intervention_name>
      <description>Low, Intermediate and High-risk</description>
      <arm_group_label>High-risk</arm_group_label>
      <arm_group_label>Intermediate-risk</arm_group_label>
      <arm_group_label>Low -risk</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>Proton beam radiation or external beam radiation or brachytherapy</intervention_name>
      <description>Low, Intermediate and High-risk</description>
      <arm_group_label>High-risk</arm_group_label>
      <arm_group_label>Intermediate-risk</arm_group_label>
      <arm_group_label>Low -risk</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Liposomal irinotecan</intervention_name>
      <description>Intermediate and High-risk Administer by IV infusion over 90 minutes, 1 dose on day 1 Liposomal irinotecan should be premedicated with dexamethasone (or an equivalent corticosteroid) if not contraindicated. Premedication with diphenhydramine and an H2 receptor antagonist (i.e., famotidine) are also encouraged.</description>
      <arm_group_label>High-risk</arm_group_label>
      <arm_group_label>Intermediate-risk</arm_group_label>
      <other_name>(Onivyde®)</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Vinorelbine</intervention_name>
      <description>Intermediate and High-risk Administer via slow IV push over 6-10 minutes (or infusion via minibag as per institutional standards) on Day 1 of Weeks 43-45, 47-49, 51-53, 55-57, 59-61, 63-65.</description>
      <arm_group_label>High-risk</arm_group_label>
      <arm_group_label>Intermediate-risk</arm_group_label>
      <other_name>Navelbine</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Temozolomide</intervention_name>
      <description>High-risk Administer PO (or by NG or G tube) 5 doses, on Days 1-5 When administering with liposomal irinotecan, administer temozolomide prior to liposomal irinotecan. Preferably, administer on an empty stomach (at least 1 hour before and 2 hours after food) to improve absorption. When using temozolomide capsules, round dose to the nearest 5 mg capsule. The capsule may be opened, and contents mixed with applesauce or apple juice. A compounded oral suspension is also available. If emesis occurs within 20 minutes of taking a dose of temozolomide, then the dose may be repeated once.</description>
      <arm_group_label>High-risk</arm_group_label>
      <other_name>Temodar</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Filgrastim, peg-filgrastim</intervention_name>
      <description>Low, Intermediate and High-risk:&#xD;
  Prophylactic myeloid growth factor support (Filgrastim or Pegfilgrastim) should be used after all VAC cycles for patients on the high-risk arm. Start myeloid growth factor support (for example, filgrastim 5 mcg/kg/dose SubQ daily until the ANC is ≥ 2000/μL after the expected nadir OR pegfilgrastim 0.1 mg/kg/dose [for patients &lt; 45 kg] or 6 mg/dose [for patients ≥ 45 kg] SubQ x 1 dose) 24-48 hours after VAC cycles. Filgrastim may be continued without regard to VCR. Discontinue filgrastim at least 24 hours before the start of the next cycle. Prophylactic myeloid growth factor support should NOT be used after VLIT cycles or during maintenance chemotherapy.</description>
      <arm_group_label>High-risk</arm_group_label>
      <arm_group_label>Intermediate-risk</arm_group_label>
      <other_name>Neupogen</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
          • Newly diagnosed participants with the diagnosis of rhabdomyosarcoma (RMS) of any subtype.&#xD;
          This includes embryonal rhabdomyosarcoma (fusion negative), alveolar rhabdomyosarcoma&#xD;
          (fusion positive), as well as spindle cell and sclerosing&#xD;
  &#xD;
          • Must have either low-, intermediate-risk or high-risk disease, defined as:&#xD;
  &#xD;
            1. Low-risk: TP53 and MYOD1 negative AND&#xD;
  &#xD;
               • Embryonal, congenital/infantile spindle cell, or spindle cell/sclerosing FOXO1&#xD;
               fusion negative histology&#xD;
  &#xD;
                 -  Stage 1 Group I, Group II&#xD;
  &#xD;
                 -  Stage 1 Group III orbital only&#xD;
  &#xD;
                 -  Stage 2 Group I, Group II&#xD;
  &#xD;
            2. Intermediate-risk: MYOD1 and TP53 negative AND&#xD;
  &#xD;
               • Embryonal, congenital/infantile spindle cell, or spindle cell/sclerosing FOXO1&#xD;
               fusion negative histology o Stage 1 Group III non orbit o Stage 3 Group I/II&#xD;
  &#xD;
               o Stage 2/3 Group III&#xD;
  &#xD;
                 -  Stage 4 Group IV and Oberlin 0-1&#xD;
  &#xD;
                    • Alveolar, spindle cell/sclerosing FOXO1 fusion positive histology&#xD;
  &#xD;
                 -  Stage 1-3, Group I-III N0&#xD;
  &#xD;
            3. High-risk: All MYOD1 and TP53 mutant tumors regardless of stage and Group AND/OR&#xD;
  &#xD;
                 -  Embryonal, congenital/infantile spindle cell or spindle cell/sclerosing FOXO1&#xD;
                    fusion negative o Group IV ≥ 10 year of age and Oberlin ≥ 2&#xD;
  &#xD;
                 -  Alveolar, spindle cell/sclerosing FOXO1 fusion positive&#xD;
  &#xD;
                      -  N1&#xD;
  &#xD;
                      -  Stage 4 Group IV&#xD;
  &#xD;
               See Appendices I and II for Staging and Clinical Grouping.&#xD;
  &#xD;
               Age &lt; 22 years (eligible for enrollment until 22nd birthday)&#xD;
  &#xD;
               • Performance level corresponding to ECOG score of 0, 1, or 2. The Lansky performance&#xD;
               score should be used for participants &lt; 16 years (see Appendix VII).&#xD;
  &#xD;
                 -  Participant has received no prior radiotherapy or chemotherapy for&#xD;
                    rhabdomyosarcoma (excluding steroids) unless an emergency situation requires&#xD;
                    local tumor treatment (discuss with PI).&#xD;
  &#xD;
                 -  Initiation of chemotherapy is planned within 6 weeks (42 days) of the definitive&#xD;
                    biopsy or surgical resection.&#xD;
  &#xD;
                 -  Adequate bone marrow function defined as:&#xD;
  &#xD;
                 -  Peripheral absolute neutrophil count (ANC) ≥ 750/μL&#xD;
  &#xD;
                 -  Platelet count ≥ 75,000/μL (transfusion independent)&#xD;
  &#xD;
                 -  Adequate liver function defined as total bilirubin &lt; 1.5 x upper limit of normal&#xD;
                    (ULN) for age. Participants with biliary or hepatic primaries with bilirubin&#xD;
                    values greater than 1.5 x ULN may be enrolled on study if all other eligibility&#xD;
                    criteria are met.&#xD;
  &#xD;
               Adequate renal function defined as:&#xD;
  &#xD;
               Creatinine clearance or radioisotope GFR &gt; 70 mL/min/1.732 or serum creatinine based&#xD;
               on age as follows:&#xD;
  &#xD;
               Age Maximum serum creatinine (mg/dL) Male Female&#xD;
  &#xD;
               1 month to &lt; 6 months 0.4 0.4 6 months to &lt; 1 year 0.5 0.5 Age Maximum serum&#xD;
               creatinine (mg/dL)&#xD;
  &#xD;
                 1. to &lt; 2 years 0.6 0.6&#xD;
  &#xD;
                 2. to &lt; 6 years 0.8 0.8&#xD;
  &#xD;
               6 to &lt; 10 years 1 1 10 to &lt; 13 years 1.2 1.2 13 to &lt; 16 years 1.5 1.4 &gt; 16 years 1.7&#xD;
               1.4&#xD;
  &#xD;
               The threshold creatinine values in this table were derived from the Schwartz formula&#xD;
               for estimating GFR25 utilizing child length and stature. Data published by the CDC.&#xD;
  &#xD;
               Participants with urinary tract obstruction by tumor must meet the renal function&#xD;
               criteria listed above AND must have unimpeded urinary flow established via&#xD;
               decompression of the obstructed portion of the urinary tract.&#xD;
  &#xD;
               • Adequate pulmonary function defined as: no evidence of dyspnea at rest and a pulse&#xD;
               oximetry &gt; 94% if there is a clinical indication for determination. Pulmonary function&#xD;
               tests are not required.&#xD;
  &#xD;
               • Patients requiring emergency radiation therapy are eligible for enrollment on this&#xD;
               trial. See Section 4.11 for radiation therapy guidelines.&#xD;
  &#xD;
               • No evidence of active, uncontrolled infection.&#xD;
  &#xD;
               All participants and/or their parents or legal guardians must sign a written informed&#xD;
               consent.&#xD;
  &#xD;
               Exclusion Criteria:&#xD;
  &#xD;
               • Patients who have received any chemotherapy (excluding steroids).&#xD;
  &#xD;
               • Patients who have received prior full course RT at the primary site of disease. This&#xD;
               does not exclude patients that received emergent radiation.&#xD;
  &#xD;
                 -  Ongoing or history of non-infectious interstitial lung disease requiring&#xD;
                    significant medical intervention.&#xD;
  &#xD;
                 -  Sexually active patients of reproductive potential who have not agreed to use an&#xD;
                    effective contraceptive method for the duration of their study participation and&#xD;
                    for at least 3 months after treatment is completed.&#xD;
  &#xD;
                 -  Female patients who are pregnant are not eligible since fetal toxicities or&#xD;
                    teratogenic effects have been noted for several of the study drugs. Female&#xD;
                    participants &gt; 10 years of age or post-menarchal must have a negative serum or&#xD;
                    urine pregnancy test within 24 hours prior to beginning treatment.&#xD;
  &#xD;
                 -  Lactating females who are or plan to breastfeed their infants are not eligible.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>N/A</minimum_age>
      <maximum_age>22 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Alberto Pappo, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>St. Jude Children's Research Hospital</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Alberto Pappo, MD</last_name>
      <phone>(901) 595-2322</phone>
      <email>alberto.pappo@stjude.org</email>
    </overall_contact>
    <location>
      <facility>
        <name>Sanford University</name>
        <address>
          <city>Palo Alto</city>
          <state>California</state>
          <zip>94304</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Raya Saab, MD</last_name>
        <phone>650-497-8953</phone>
        <email>rsaab@stanford.edu</email>
      </contact>
      <investigator>
        <last_name>Raya Saab, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>St. Jude Children's Research Hospital</name>
        <address>
          <city>Memphis</city>
          <state>Tennessee</state>
          <zip>38105</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Alberto Pappo, MD</last_name>
        <phone>901-595-2322</phone>
        <email>referralinfo@stjude.org</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Cook Children's Medical Center</name>
        <address>
          <city>Fort Worth</city>
          <state>Texas</state>
          <zip>76104-2796</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Karen Albritton, MD</last_name>
        <phone>682-885-4007</phone>
        <email>karen.albritton@cookchildrens.org</email>
      </contact>
      <investigator>
        <last_name>Karen Albritton</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <link>
      <url>http://www.stjude.org</url>
      <description>St. Jude Children's Research Hospital</description>
    </link>
    <link>
      <url>http://www.stjude.org/protocols</url>
      <description>Clinical Trials Open at St. Jude</description>
    </link>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 27, 2023</study_first_submitted>
    <study_first_submitted_qc>August 27, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 5, 2023</study_first_posted>
    <last_update_submitted>August 27, 2023</last_update_submitted>
    <last_update_submitted_qc>August 27, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 5, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Rhabdomyosarcoma</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Dactinomycin</mesh_term>
      <mesh_term>Cyclophosphamide</mesh_term>
      <mesh_term>Temozolomide</mesh_term>
      <mesh_term>Irinotecan</mesh_term>
      <mesh_term>Vincristine</mesh_term>
      <mesh_term>Vinorelbine</mesh_term>
      <mesh_term>Lenograstim</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request</ipd_description>
      <ipd_info_type>Study Protocol</ipd_info_type>
      <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
      <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
      <ipd_time_frame>Data will be made available at the time of article publication.</ipd_time_frame>
      <ipd_access_criteria>Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.</ipd_access_criteria>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT06023641
  org study id: RMS2021
  nct id: NCT06023641
  lead sponsor: 
  has dmc: No
  is fda regulated drug: Yes
  is fda regulated device: No
  is us export: Yes
  This is a phase I-II study to determine safety and efficacy of combining liposomal irinotecan
        with vincristine alternating with VAC in intermediate-risk patients, liposomal irinotecan
        with temozolomide and vincristine alternating with VAC in high-risk patients and the
        chemotherapy combinations when given with concomitant radiation therapy in intermediate and
        high risk patients.
  
        Primary Objective
  
          -  The primary objective of the Phase I part is to estimate the maximum tolerated doses
             (MTDs) and recommended Phase II doses (RP2Ds) of combining liposomal irinotecan with
             vincristine alternating with VAC in intermediate-risk patients, liposomal irinotecan
             with temozolomide and vincristine alternating with VAC in high-risk patients and the
             chemotherapy combinations when given with concomitant radiation therapy in intermediate
             and high risk patients.
  
          -  Estimate event-free survival for intermediate-risk participants treated with VAC and
             vincristine and liposomal irinotecan (VLI) with the addition of maintenance therapy with
             vinorelbine and cyclophosphamide.
  
          -  Estimate the event-free survival for high-risk patients treated with VAC and
             vincristine, liposomal irinotecan, and temozolomide with the addition of maintenance
             therapy with vinorelbine and cyclophosphamide.
  
          -  Estimate the local recurrence rate for unresected intermediate- and high-risk patients
             with initial tumor size with ≥5 cm randomized to between 59.4 GyRBE and 68 GyRBE total
             proton radiation dose while receiving VAC/VLI (intermediate-risk) or VAC/VLI plus
             temozolomide (high-risk) and maintenance therapy.
  
        Secondary Objectives
  
          -  To assess the relation between pharmacogenetic variation in CEP72 genotype and vinca
             alkaloid (vincristine; vinorelbine) disposition in children with rhabdomyosarcoma.
  
          -  To assess the relation between the pharmacogenetic variation in drug metabolizing
             enzymes and drug transporters, and the pharmacokinetics of vinca alkaloids, liposomal
             irinotecan, and cyclophosphamide in children with rhabdomyosarcoma.
  
          -  To assess the extent of inter-patient variability in the pharmacokinetics of vinca
             alkaloids, liposomal irinotecan, and cyclophosphamide in children with rhabdomyosarcoma,
             and explore possible associations between drug disposition and patient specific
             covariates (e.g., age, sex, race, weight).
  
          -  Estimate the cumulative incidence of local recurrence in patients with low-risk disease
             treated with either no adjuvant radiation or minimal volume radiation.
  This is a phase I-II study to determine safety and efficacy of combining liposomal irinotecan
        with vincristine alternating with VAC in intermediate-risk patients, liposomal irinotecan
        with temozolomide and vincristine alternating with VAC in high-risk patients and the
        chemotherapy combinations when given with concomitant radiation therapy in intermediate and
        high risk patients. The phase I part (dose-finding phase) is a dose-escalation part using the
        BOIN design with maximally 18 patients for each of groups (intermediate -risk, high-risk, and
        intermediate -and-high-risk-with-early-radiation). Phase I part is to find the maximum
        tolerated dose and recommended phase II dose for the subsequent phase II part. Phase II part
        has two primary objectives. The first objective will derive the sample size and it is for
        efficacy and the endpoint is defined as a 2-year event-free survival (EFS) for each stratum,
        with 4 years enrollment and 2 years follow-up for each patient, by 80% power and 5% type I
        error rate, a single-arm adaptive phase II design is used to have estimated numbers of
        patients for intermediate-risk and high-risk groups are 46 and 33, respectively. The study
        will end once the last enrolled patient has been followed by 2 years. The second objective is
        to evaluate the local recurrence rate (LRR) of patients with tumor size ≥ 5cm by using a 2:1
        randomization design of comparing administration of the two radiation strategies, 59.4 GyRBE
        and 68 GyRBE. For this part, 27 additional patients will be required.
  allocation: Non-Randomized
  intervention model: Single Group Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Maximum tolerated doses (MTDs)
  time frame: 4 years
  description: 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. For each of three groups (intermediate-risk, high-risk, and intermediate-and-high-risk-with-early-radiation), we will employ the Bayesian optimal interval (BOIN) design to find the MTD.
  measure: Event-free survival (EFS)
  time frame: 2 years post, off therapy
  description: We will estimate the 2-year event-free survival for intermediate-risk and high-risk patients, which is the estimated probability of a patient not having any events within the 2-year follow-up. If an event, including local failure, distant failure, death or loss to follow-up occurs for a patient within 2-year, we call it failure, otherwise call it response.
  measure: Local recurrence rate (LRR)
  time frame: 2 years
  description: LRR is defined as a binary endpoint in the study. The local recurrence-free survival (LRFS) is defined as time from randomization to the earlier date of the first of local disease recurrence or death due to any cause. The distant failure will be considered to be the competing risk, patients for whom follow-up ended without clinical improvement will be censored. The goal of the local recurrence rate endpoint is to evaluate the 2-year LRR by comparing the administration of 59.4 GyRBE and 68 GyRBE for patients (pooled intermediate- and high-risk groups) with tumor size greater than or equal to 5cm meeting the eligibility criteria for randomization (no biliary tree or specific extremity cases).
  .
  arm group label: Low -risk
  arm group type: Experimental
  description: The participant will receive 12 weeks (4 cycles) of VAC chemotherapy (vincristine, dactinomycin and cyclophosphamide) followed by 12 weeks (4 cycles) of VA chemotherapy (vincristine, dactinomycin).
  Each cycle of VAC/VA chemotherapy will last for 3 weeks, for a total of 12 weeks (VAC or VA will be given in Week 1 of each cycle and vincristine will be given Weeks 2 and 3). At week 12, the participant will have scans and tests to reevaluate your tumor's response to the treatment. After surgery and radiation, the participant will receive an additional 12 weeks (4 cycles) of the same chemotherapy without cyclophosphamide. Vincristine and dactinomycin, also called "VA". After 4 cycles of VA, The investigator will re-evaluate the tumor again at week 24 and the patient will not get any more chemotherapy, but will be closely watched for any signs of tumor recurrence.
  arm group label: Intermediate-risk
  arm group type: Experimental
  description: The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with intermediate and high risk rhabdomyosarcoma. The investigators also want to find the best radiation dose to give for intermediate and high risk patients who have large tumors (> 5 cm).
  The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLI chemotherapy (vincristine/liposomal irinotecan). The participant will also have surgery to remove the tumor and radiation therapy during this time. After this therapy is completed you will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
  arm group label: High-risk
  arm group type: Experimental
  description: The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with high risk rhabdomyosarcoma. The investigator also want to find the best radiation dose to give for high risk patients who have large tumors (> 5 cm).
  The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLIT chemotherapy (vincristine/liposomal irinotecan/temozolomide). Also having surgery to remove the participants tumor and radiation therapy during this time. After this therapy is completed the patient will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
  intervention type: Drug
  intervention name: Vincristine
  description: Low -risk Administer IV push over 1 minute (or infusion via minibag as per institutional standards) on Day 1 of Weeks 1,8, 15 (3) doses. The maximum dose is 2 mg for all participants.
  Intermediate-risk Administer IV, over 1 minute, 3 doses, weekly on day1 High-risk Administer by IV infusion over 1 minute, 3 doses, weekly on day 1,8,15
  arm group label: High-risk
  arm group label: Intermediate-risk
  arm group label: Low -risk
  other name: Oncovin
  intervention type: Drug
  intervention name: Dactinomycin
  description: Low-risk Administer by slow IV push over 1-5 minutes on Day 1 of Weeks 1, (1) dose. The maximum dose is 2.5 mg for all participants.
  Intermediate-risk Administer by slow IV over 1-5 minutes., 1 doses weekly on day 1 High-risk Administer by slow IV over 1-5 minutes, day1
  arm group label: High-risk
  arm group label: Intermediate-risk
  arm group label: Low -risk
  other name: (actinomycin-D)
  intervention type: Drug
  intervention name: Cyclophosphamide
  description: Low-risk Administer by IV infusion over 30-60 minutes on Day 1, 91) dose, Mesna and hydration will be given with IV cyclophosphamide according to institutional standards.
  Intermediate-risk Administer by IV infusion over 30-60 minutes, 1 dose, day 1 High-risk Administer by IV infusion over 30-60 minutes, 1 dose, day1
  arm group label: High-risk
  arm group label: Intermediate-risk
  arm group label: Low -risk
  other name: Cytoxan®.
  intervention type: Procedure
  intervention name: Surgical Resection
  description: Low, Intermediate and High-risk
  arm group label: High-risk
  arm group label: Intermediate-risk
  arm group label: Low -risk
  intervention type: Procedure
  intervention name: Proton beam radiation or external beam radiation or brachytherapy
  description: Low, Intermediate and High-risk
  arm group label: High-risk
  arm group label: Intermediate-risk
  arm group label: Low -risk
  intervention type: Drug
  intervention name: Liposomal irinotecan
  description: Intermediate and High-risk Administer by IV infusion over 90 minutes, 1 dose on day 1 Liposomal irinotecan should be premedicated with dexamethasone (or an equivalent corticosteroid) if not contraindicated. Premedication with diphenhydramine and an H2 receptor antagonist (i.e., famotidine) are also encouraged.
  arm group label: High-risk
  arm group label: Intermediate-risk
  other name: (Onivyde®)
  intervention type: Drug
  intervention name: Vinorelbine
  description: Intermediate and High-risk Administer via slow IV push over 6-10 minutes (or infusion via minibag as per institutional standards) on Day 1 of Weeks 43-45, 47-49, 51-53, 55-57, 59-61, 63-65.
  arm group label: High-risk
  arm group label: Intermediate-risk
  other name: Navelbine
  intervention type: Drug
  intervention name: Temozolomide
  description: High-risk Administer PO (or by NG or G tube) 5 doses, on Days 1-5 When administering with liposomal irinotecan, administer temozolomide prior to liposomal irinotecan. Preferably, administer on an empty stomach (at least 1 hour before and 2 hours after food) to improve absorption. When using temozolomide capsules, round dose to the nearest 5 mg capsule. The capsule may be opened, and contents mixed with applesauce or apple juice. A compounded oral suspension is also available. If emesis occurs within 20 minutes of taking a dose of temozolomide, then the dose may be repeated once.
  arm group label: High-risk
  other name: Temodar
  intervention type: Drug
  intervention name: Filgrastim, peg-filgrastim
  description: Low, Intermediate and High-risk:
  Prophylactic myeloid growth factor support (Filgrastim or Pegfilgrastim) should be used after all VAC cycles for patients on the high-risk arm. Start myeloid growth factor support (for example, filgrastim 5 mcg/kg/dose SubQ daily until the ANC is ≥ 2000/μL after the expected nadir OR pegfilgrastim 0.1 mg/kg/dose [for patients < 45 kg] or 6 mg/dose [for patients ≥ 45 kg] SubQ x 1 dose) 24-48 hours after VAC cycles. Filgrastim may be continued without regard to VCR. Discontinue filgrastim at least 24 hours before the start of the next cycle. Prophylactic myeloid growth factor support should NOT be used after VLIT cycles or during maintenance chemotherapy.
  arm group label: High-risk
  arm group label: Intermediate-risk
  other name: Neupogen
  criteria: 
  gender: All
  minimum age: N/A
  maximum age: 22 Years
  healthy volunteers: No
  last name: Alberto Pappo, MD
  role: Principal Investigator
  affiliation: St. Jude Children's Research Hospital
  last name: Alberto Pappo, MD
  phone: (901) 595-2322
  email: alberto.pappo@stjude.org
  facility: 
  contact: 
  investigator: 
  facility: 
  contact: 
  facility: 
  contact: 
  investigator: 
  country: United States
  url: http://www.stjude.org
  description: St. Jude Children's Research Hospital
  url: http://www.stjude.org/protocols
  description: Clinical Trials Open at St. Jude
  responsible party type: Sponsor
  mesh term: Rhabdomyosarcoma
  mesh term: Dactinomycin
  mesh term: Cyclophosphamide
  mesh term: Temozolomide
  mesh term: Irinotecan
  mesh term: Vincristine
  mesh term: Vinorelbine
  mesh term: Lenograstim
  sharing ipd: Yes
  ipd description: Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request
  ipd info type: Study Protocol
  ipd info type: Statistical Analysis Plan (SAP)
  ipd info type: Informed Consent Form (ICF)
  ipd time frame: Data will be made available at the time of article publication.
  ipd access criteria: Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.