<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/NCT04406857</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2020-03610</org_study_id>
    <secondary_id>NCI-2020-03610</secondary_id>
    <secondary_id>10410</secondary_id>
    <secondary_id>10410</secondary_id>
    <secondary_id>UM1CA186644</secondary_id>
    <secondary_id>UM1CA186712</secondary_id>
    <secondary_id>UM1CA186716</secondary_id>
    <nct_id>NCT04406857</nct_id>
  </id_info>
  <brief_title>Testing the Addition of a Radiation Sensitizing Drug, IPdR, to the Usual Chemotherapy Treatment (Capecitabine) During Radiation Therapy for Rectal Cancer</brief_title>
  <official_title>A Phase 1 Study of IPdR in Combination With Capecitabine and Radiotherapy in Rectal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies the side effects and best dose of ropidoxuridine and how well it&#xD;
      works when added to the usual chemotherapy treatment (capecitabine) during radiation therapy&#xD;
      for the treatment of patients with stage II-III rectal cancer. Ropidoxuridine may help&#xD;
      radiation therapy work better by making cancer cells more sensitive to the radiation therapy.&#xD;
      Chemotherapy drugs, such as capecitabine, work in different ways to stop the growth of tumor&#xD;
      cells, either by killing the cells, by stopping them from dividing, or by stopping them from&#xD;
      spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors.&#xD;
      This study is being done to find out whether ropidoxuridine in addition to capecitabine and&#xD;
      radiation therapy works better in treating patients with rectal cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the maximum tolerated dose (MTD) of oral (PO) ropidoxuridine (IPdR) when&#xD;
      administered with capecitabine (825 mg/m^2 twice daily [BID]) and radiation therapy (RT)&#xD;
      (50.4 Gy in 28 fractions).&#xD;
&#xD;
      II. To determine the toxicities Common Terminology Criteria for Adverse Events (CTCAE)&#xD;
      version (v) 5 of the combined modality therapy, IPdR + capecitabine + RT.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To establish the pharmacokinetics (PK) of once daily (QD) IPdR when combined with&#xD;
      capecitabine.&#xD;
&#xD;
      II. To evaluate iododeoxyuridine (IUdR) incorporation in circulating granulocytes and&#xD;
      correlate these levels with IPdR plasma PK and clinical/laboratory toxicities.&#xD;
&#xD;
      III. To assess IUdR incorporation in tumor cells obtained from the surgical resection&#xD;
      specimen and correlate IUdR incorporation in tumor cells with IPdR PK.&#xD;
&#xD;
      IV. To assess IUdR incorporation in tumor cells obtained from the surgical resection specimen&#xD;
      and correlate IUdR incorporation in tumor cells with tumor response as measured by&#xD;
      pathological complete response (pCR) rate and neoadjuvant rectal (NAR) score.&#xD;
&#xD;
      V. To determine the pCR rate of IPdR + capecitabine + RT at the IPdR MTD as a measure of&#xD;
      anti-tumor activity.&#xD;
&#xD;
      VI. To determine the NAR score of IPdR + capecitabine + RT at the IPdR MTD.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To explore the relationship between extent of exposure to RT and the development and&#xD;
      severity of adverse events.&#xD;
&#xD;
      II. To explore the drug/drug/metabolite interactions between capecitabine, IPdR, and their&#xD;
      metabolites.&#xD;
&#xD;
      OUTLINE: This is a phase IA, dose-escalation study of ropidoxuridine followed by a phase IB&#xD;
      study.&#xD;
&#xD;
      Patients receive ropidoxuridine PO QD over 7 days per week and capecitabine PO BID over 6&#xD;
      days per week for 6 weeks. Patients also undergo radiation therapy over 1 fraction per day&#xD;
      for 5 days per week (Monday-Friday) during weeks 1-5 and for 3 days during week 6 in the&#xD;
      absence of disease progression or unacceptable toxicity. Approximately 8-12 weeks after&#xD;
      completion of treatment with ropidoxuridine, capecitabine, and radiation therapy, patients&#xD;
      undergo standard of care surgery.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 4 and 8-12 weeks following&#xD;
      chemoradiation therapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Inadequate accrual rate&#xD;
  </why_stopped>
  <start_date type="Actual">October 7, 2020</start_date>
  <completion_date type="Actual">January 18, 2023</completion_date>
  <primary_completion_date type="Actual">January 18, 2023</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</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 dose</measure>
    <time_frame>Up to 38 days</time_frame>
    <description>The maximum-tolerated dose is defined as the dose below which 2 or more of 6 patients experience dose-limiting toxicities attributable to ropidoxuridine.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of dose-limiting toxicities (Part IB)</measure>
    <time_frame>Up to 38 days</time_frame>
    <description>Assessed by Common Terminology Criteria for Adverse Events version 5 and reached when any two grade 3 treatment-related non-hematologic toxicities or one grade 4 treatment-related hematologic and/or gastrointestinal toxicity are observed in two of the 6 patients enrolled at that dose level.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in tissue biomarker levels</measure>
    <time_frame>Baseline up to 8-12 weeks following completion of chemotherapy</time_frame>
    <description>Will be measured on continuous and binary scales will be assessed using Wilcoxon signed rank or McNemar's tests, respectively (two-sided; alpha = 0.05). Associations between therapeutic response and baseline biomarker values or temporal changes in biomarkers will be explored using Fisher's exact tests or Wilcoxon rank sum tests.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of ropidoxuridine incorporation in circulating granulocytes</measure>
    <time_frame>Prior to ropidoxuridine dose and at 30, 60, 120, and 240 minutes after ropidoxuridine dose on day 8, then at 1-2 hours after ropidoxuridine dose on days 21 and 35</time_frame>
    <description>Will correlate these levels with ropidoxuridine plasma pharmacokinetics. Two-sided Fisher's z-test with significance level of 0.05 and power of 80% will be used and the study will reject the null hypothesis (lack of correlation or r0 = 0) if we observe a correlation with r ranging from 0.79 for N = 10 subjects to 0.49 for N = 30 subjects.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of ropidoxuridine incorporation in circulating granulocytes, peripheral blood counts, and toxicities</measure>
    <time_frame>Prior to the ropidoxuridine on day 8, and at 1-2 hours following the ropidoxuridine dose on days 21 and 35</time_frame>
    <description>For the correlation of percentage of ropidoxuridine deoxyribonucleic acid incorporation in circulating granulocytes and peripheral blood counts and toxicities, assuming the target prevalence of grade 3/4 toxicity of 30%, the study will have a power of 80% with significance level of 0.05 on a two-sample means test to rule out the null hypothesis (equal means in groups with/ without grade 3/4 toxicity, m0 = m1) if the observed mean percentage of ropidoxuridine-deoxyribonucleic acid incorporation for patients with grade 3/4 toxicity is m1 = 3.3 times the mean m0 in the other group for N = 10 enrolled subjects, and m1 = 2.1 times the mean m0 for N = 30.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pathological complete response rate at the maximum-tolerated dose</measure>
    <time_frame>At the time of surgery</time_frame>
    <description>In rectal cancer, the absence of viable tumor cells in the resection specimen (primary tumor mass, surrounding tissue and lymph nodes, T0 N0 M0) at the time of surgery, termed pathologic complete response. Pathologic complete response determination will be made by the pathologist at the treating institution.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neoadjuvant rectal score at the maximum-tolerated dose</measure>
    <time_frame>At 6-10 weeks following completion of therapy</time_frame>
    <description>Neoadjuvant rectal score is calculated based on the clinical T stage (cT), pathological T (pT) and pN stages as neoadjuvant rectal score = [5pN- 3 (cT- pT) + 12]2 / 9.61.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Relationship between extent of exposure to radiotherapy and incidence and severity of adverse events</measure>
    <time_frame>Up to 3 years</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Interactions of capecitabine, IPdR and their metabolites</measure>
    <time_frame>Up to 3 years</time_frame>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">1</enrollment>
  <condition>Locally Advanced Rectal Carcinoma</condition>
  <condition>Rectal Adenocarcinoma</condition>
  <condition>Stage II Rectal Cancer AJCC v8</condition>
  <condition>Stage III Rectal Cancer AJCC v8</condition>
  <arm_group>
    <arm_group_label>Treatment (ropidoxuridine, capecitabine, radiation therapy)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive ropidoxuridine PO QD over 7 days per week and capecitabine PO BID over 6 days per week for 6 weeks. Patients also undergo radiation therapy over 1 fraction per day for 5 days per week (Monday-Friday) during weeks 1-5 and for 3 days during week 6 in the absence of disease progression or unacceptable toxicity. Approximately 8-12 weeks after completion of treatment with ropidoxuridine, capecitabine, and radiation therapy, patients undergo standard of care surgery.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Capecitabine</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (ropidoxuridine, capecitabine, radiation therapy)</arm_group_label>
    <other_name>Ro 09-1978/000</other_name>
    <other_name>Xeloda</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Radiation Therapy</intervention_name>
    <description>Undergo radiation therapy</description>
    <arm_group_label>Treatment (ropidoxuridine, capecitabine, radiation therapy)</arm_group_label>
    <other_name>Cancer Radiotherapy</other_name>
    <other_name>ENERGY_TYPE</other_name>
    <other_name>Irradiate</other_name>
    <other_name>Irradiated</other_name>
    <other_name>Irradiation</other_name>
    <other_name>Radiation</other_name>
    <other_name>Radiation Therapy, NOS</other_name>
    <other_name>Radiotherapeutics</other_name>
    <other_name>Radiotherapy</other_name>
    <other_name>RT</other_name>
    <other_name>Therapy, Radiation</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ropidoxuridine</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (ropidoxuridine, capecitabine, radiation therapy)</arm_group_label>
    <other_name>5-Iodo-2-pyrimidinone 2' deoxyribonucleoside</other_name>
    <other_name>5-Iodo-2-pyrimidinone-2'-deoxyribose</other_name>
    <other_name>IPdR</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  At diagnosis, patients must have had histologically proven adenocarcinoma of the&#xD;
             rectum with no evidence of distant metastases&#xD;
&#xD;
          -  At diagnosis, the major portion of the tumor must have been intact, and the following&#xD;
             must be documented:&#xD;
&#xD;
               -  Distance of the lowest tumor margin from the anal verge; and&#xD;
&#xD;
               -  Intent for sphincter sparing or non-sphincter sparing surgical resection&#xD;
                  according to the primary surgeon; and&#xD;
&#xD;
               -  The majority of the untreated tumor must be &lt; 12 cm from the anal verge or below&#xD;
                  the peritoneal reflection as determined by the treating surgeon&#xD;
&#xD;
          -  At diagnosis, the tumor must have been locally advanced stage II (T3-4 N0) or stage&#xD;
             III (N positive [+]) rectal cancer with at least one of the following:&#xD;
&#xD;
               -  Distal location (as defined by measurement on magnetic resonance imaging [MRI],&#xD;
                  endorectal ultrasound [ERUS]/pelvic computed tomography [CT] [with intravenous&#xD;
                  (IV) contrast] scan or palpable on digital rectal exam [DRE]): cT3-4 =&lt; 5 cm from&#xD;
                  the anal verge, any N&#xD;
&#xD;
               -  Bulky: Any cT4 or evidence that the tumor is adjacent to (defined as within 3 mm&#xD;
                  of) the mesorectal fascia on MRI or ERUS/pelvic CT (with IV contrast) scan&#xD;
&#xD;
               -  High risk for metastatic disease with 4 or more regional lymph nodes (cN2).&#xD;
                  Clinical Nodal or &quot;cN&quot; status for eligibility includes the total number of nodes&#xD;
                  (N2 = 4 or more) in the mesorectal and superior rectal stations measuring &gt;= 1.0&#xD;
                  cm in any axis on cross sectional or endoscopic imaging. Nodes must measure 1.0&#xD;
                  cm or greater to be considered positive for this eligibility requirement&#xD;
&#xD;
               -  Not a candidate for sphincter-sparing surgical resection prior to neoadjuvant&#xD;
                  therapy (as planned by the primary surgeon)&#xD;
&#xD;
          -  Patients must have received 8 cycles of neoadjuvant leucovorin, fluorouracil, and&#xD;
             oxaliplatin (mFOLFOX) and must have completed this therapy at least 3 weeks (and no&#xD;
             more than 6 weeks) prior to enrollment on this study&#xD;
&#xD;
          -  Patients must intend to undergo surgical resection of the rectal primary tumor&#xD;
             following chemoradiotherapy&#xD;
&#xD;
          -  Age &gt;= 18 years&#xD;
&#xD;
               -  Because no dosing or adverse event (AE) data are currently available on the use&#xD;
                  of IPdR in combination with capecitabine and RT in patients &lt; 18 years of age,&#xD;
                  children are excluded from this study, but will be eligible for future pediatric&#xD;
                  trials&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group performance status =&lt; 2 (Karnofsky &gt;= 60%)&#xD;
&#xD;
          -  Leukocytes &gt;= 3,000/mcL&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1,200/mcL&#xD;
&#xD;
          -  Platelets &gt;= 100,000/mcL&#xD;
&#xD;
          -  Hemoglobin &gt; 10 g/dL&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x institutional upper limit of normal (ULN)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =&lt;&#xD;
             2.5 x institutional ULN&#xD;
&#xD;
          -  Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =&lt; 2.5 x&#xD;
             institutional ULN&#xD;
&#xD;
          -  Creatinine =&lt; 1.5 x institutional ULN OR glomerular filtration rate (GFR) &gt;= 60&#xD;
             mL/min/1.73 m^2&#xD;
&#xD;
          -  Alkaline phosphatase =&lt; 3 x institutional ULN&#xD;
&#xD;
          -  Sodium, potassium, chloride, bicarbonate, and magnesium within institutional normal&#xD;
             limits&#xD;
&#xD;
          -  Patients with acquired immunodeficiency syndrome (acquired immunodeficiency syndrome&#xD;
             [AIDS]-related illnesses) or known human immunodeficiency virus (HIV) disease must:&#xD;
&#xD;
               -  Have a CD4 count &gt;= 200 cells/uL within 30 days before enrollment,&#xD;
&#xD;
               -  Be off all antiretroviral therapy (prophylaxis/treatment) more than 60 days&#xD;
                  before enrollment, and&#xD;
&#xD;
               -  Have no evidence of opportunistic infections&#xD;
&#xD;
          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated&#xD;
             and cured and be receiving no therapy&#xD;
&#xD;
          -  Patients with known history or current symptoms of cardiac disease, or history of&#xD;
             treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac&#xD;
             function using the New York Heart Association functional classification. To be&#xD;
             eligible for this trial, patients should be class 2B or better&#xD;
&#xD;
          -  Patients must have the ability to swallow and retain oral medication&#xD;
&#xD;
          -  The effects of IPdR on the developing human fetus are unknown. For this reason and&#xD;
             because radiosensitizing agents as well as other therapeutic agents used in this trial&#xD;
             are known to be teratogenic, women of child-bearing potential (WOCBP)* and men must&#xD;
             agree to use adequate contraception (hormonal or barrier method of birth control;&#xD;
             abstinence) prior to study entry and for the duration of study participation. WOCBP&#xD;
             must have a negative urine or serum pregnancy test within 72 hours prior to&#xD;
             enrollment. If urine pregnancy results are positive or cannot be confirmed as&#xD;
             negative, a serum pregnancy test will be required. Should a woman become pregnant or&#xD;
             suspect she is pregnant while she or her partner is participating in this study, she&#xD;
             should inform her treating physician immediately. Men treated or enrolled on this&#xD;
             protocol must also agree to use adequate contraception prior to the study, for the&#xD;
             duration of study participation, and 4 months after completion of IPdR administration&#xD;
&#xD;
               -  Women of childbearing potential (WOCBP) is defined as any female who has&#xD;
                  experienced menarche and who has not undergone surgical sterilization&#xD;
                  (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause&#xD;
                  is defined clinically as 12 months of amenorrhea in a woman over 45 in the&#xD;
                  absence of other biological or physiological causes&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document.&#xD;
             Participants with impaired decision-making capacity (IDMC) who have a&#xD;
             legally-authorized representative (LAR) and/or family member available will also be&#xD;
             eligible&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who have not recovered from adverse events due to prior mFOLFOX6 chemotherapy&#xD;
             (i.e., have residual toxicities &gt; grade 1) with the exception of alopecia&#xD;
&#xD;
          -  Patients who are receiving any other investigational agents&#xD;
&#xD;
          -  Patients with impaired gastrointestinal (GI) function or GI disease that may&#xD;
             significantly alter the absorption of oral IPdR and capecitabine (e.g. ulcerative&#xD;
             disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small&#xD;
             bowel resection). Patients with active inflammatory bowel disease (i.e., patients&#xD;
             requiring current medical interventions or who are symptomatic) or have a history of&#xD;
             abdominal surgery or other medical condition that may, in the opinion of the treating&#xD;
             physician, interfere with GI motility or absorption. Patients with colostomies are&#xD;
             allowed unless colostomy is for one of the precluded reasons above&#xD;
&#xD;
          -  Treatment with warfarin is not allowed. However, therapy with heparin, low molecular&#xD;
             weight heparin (LMWH), and DOACs (direct oral anticoagulating agent) such as&#xD;
             dabigatran (Pradaxa), rivaroxaban, and apixaban (Eliquis) is allowed&#xD;
&#xD;
          -  Patients with an active concurrent invasive malignancy&#xD;
&#xD;
          -  History of prior invasive rectal malignancy, regardless of disease-free interval&#xD;
&#xD;
          -  Patients who have received pelvic RT for rectal cancer, or prior pelvic RT for any&#xD;
             other malignancy that would prevent the patient from receiving the required RT for&#xD;
             this study&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to IPdR or capecitabine&#xD;
&#xD;
          -  Patients with uncontrolled intercurrent illness&#xD;
&#xD;
          -  Patients with psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
          -  Pregnant women are excluded from this study because IPdR may have the potential for&#xD;
             teratogenic or abortifacient effects. Because there is an unknown but potential risk&#xD;
             for adverse events in nursing infants secondary to treatment of the mother with IPdR,&#xD;
             breastfeeding should be discontinued if the mother is treated with IPdR. These&#xD;
             potential risks may also apply to other agents used in this study&#xD;
&#xD;
          -  Patients that received live vaccines within 30 days prior to the first dose of trial&#xD;
             treatment and while participating in the trial. Examples of live vaccines include, but&#xD;
             are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow&#xD;
             fever, rabies, bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal flu&#xD;
             vaccines that do not contain live virus are permitted&#xD;
&#xD;
          -  Known homozygous DPD (dihydro pyrimidine dehydrogenase) deficiency&#xD;
&#xD;
          -  History of, or any evidence of, active non-infectious pneumonitis&#xD;
&#xD;
          -  Active autoimmune disease that has required systemic treatment within the past 2 years&#xD;
             (i.e., with use of modifying agents, corticosteroids, or immunosuppressive drugs).&#xD;
             Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid&#xD;
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a&#xD;
             form of systemic treatment&#xD;
&#xD;
          -  History of active TB (Bacillus tuberculosis)&#xD;
&#xD;
          -  Active or chronic infection requiring systemic therapy&#xD;
&#xD;
          -  Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form&#xD;
             of immunosuppressive therapy within 7 days prior to the first dose of study therapy.&#xD;
             The use of physiologic doses of corticosteroids may be approved after consultation&#xD;
             with the study principal investigator (PI)&#xD;
&#xD;
          -  Active seizure disorder uncontrolled by medication&#xD;
&#xD;
          -  Synchronous colon cancer&#xD;
&#xD;
          -  Other invasive malignancy within 5 years. Exceptions are colonic polyps, non-melanoma&#xD;
             skin cancer, or carcinoma-in-situ of the cervix&#xD;
&#xD;
          -  Antineoplastic therapy (e.g., chemotherapy or targeted therapy) for other invasive&#xD;
             malignancy within 5 years (for the purposes of this study hormonal therapy is not&#xD;
             considered chemotherapy)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Charles Kunos</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Health Network Princess Margaret Cancer Center LAO</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Los Angeles County-USC Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>USC / Norris Comprehensive Cancer Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kentucky/Markey Cancer Center</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40536</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ohio State University Comprehensive Cancer Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Oklahoma Health Sciences Center</name>
      <address>
        <city>Oklahoma City</city>
        <state>Oklahoma</state>
        <zip>73104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Thomas Jefferson University Hospital</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh Cancer Institute (UPCI)</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rhode Island Hospital</name>
      <address>
        <city>Providence</city>
        <state>Rhode Island</state>
        <zip>02903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Huntsman Cancer Institute/University of Utah</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>May 28, 2020</study_first_submitted>
  <study_first_submitted_qc>May 28, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 29, 2020</study_first_posted>
  <last_update_submitted>February 2, 2023</last_update_submitted>
  <last_update_submitted_qc>February 2, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 3, 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>Rectal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Capecitabine</mesh_term>
    <mesh_term>Ropidoxuridine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.</ipd_description>
    <ipd_url>https://grants.nih.gov/policy/sharing.htm</ipd_url>
  </patient_data>
  <pending_results>
    <submitted>June 1, 2023</submitted>
    <returned>June 26, 2023</returned>
    <submitted>June 29, 2023</submitted>
    <returned>June 30, 2023</returned>
    <submitted>August 16, 2023</submitted>
    <returned>August 17, 2023</returned>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


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/NCT04406857
org study id: NCI-2020-03610
secondary id: NCI-2020-03610
secondary id: 10410
secondary id: 10410
secondary id: UM1CA186644
secondary id: UM1CA186712
secondary id: UM1CA186716
nct id: NCT04406857
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This phase I trial studies the side effects and best dose of ropidoxuridine and how well it
      works when added to the usual chemotherapy treatment (capecitabine) during radiation therapy
      for the treatment of patients with stage II-III rectal cancer. Ropidoxuridine may help
      radiation therapy work better by making cancer cells more sensitive to the radiation therapy.
      Chemotherapy drugs, such as capecitabine, 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. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors.
      This study is being done to find out whether ropidoxuridine in addition to capecitabine and
      radiation therapy works better in treating patients with rectal cancer.
PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) of oral (PO) ropidoxuridine (IPdR) when
      administered with capecitabine (825 mg/m^2 twice daily [BID]) and radiation therapy (RT)
      (50.4 Gy in 28 fractions).

      II. To determine the toxicities Common Terminology Criteria for Adverse Events (CTCAE)
      version (v) 5 of the combined modality therapy, IPdR + capecitabine + RT.

      SECONDARY OBJECTIVES:

      I. To establish the pharmacokinetics (PK) of once daily (QD) IPdR when combined with
      capecitabine.

      II. To evaluate iododeoxyuridine (IUdR) incorporation in circulating granulocytes and
      correlate these levels with IPdR plasma PK and clinical/laboratory toxicities.

      III. To assess IUdR incorporation in tumor cells obtained from the surgical resection
      specimen and correlate IUdR incorporation in tumor cells with IPdR PK.

      IV. To assess IUdR incorporation in tumor cells obtained from the surgical resection specimen
      and correlate IUdR incorporation in tumor cells with tumor response as measured by
      pathological complete response (pCR) rate and neoadjuvant rectal (NAR) score.

      V. To determine the pCR rate of IPdR + capecitabine + RT at the IPdR MTD as a measure of
      anti-tumor activity.

      VI. To determine the NAR score of IPdR + capecitabine + RT at the IPdR MTD.

      EXPLORATORY OBJECTIVES:

      I. To explore the relationship between extent of exposure to RT and the development and
      severity of adverse events.

      II. To explore the drug/drug/metabolite interactions between capecitabine, IPdR, and their
      metabolites.

      OUTLINE: This is a phase IA, dose-escalation study of ropidoxuridine followed by a phase IB
      study.

      Patients receive ropidoxuridine PO QD over 7 days per week and capecitabine PO BID over 6
      days per week for 6 weeks. Patients also undergo radiation therapy over 1 fraction per day
      for 5 days per week (Monday-Friday) during weeks 1-5 and for 3 days during week 6 in the
      absence of disease progression or unacceptable toxicity. Approximately 8-12 weeks after
      completion of treatment with ropidoxuridine, capecitabine, and radiation therapy, patients
      undergo standard of care surgery.

      After completion of study treatment, patients are followed up at 4 and 8-12 weeks following
      chemoradiation therapy.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum-tolerated dose
time frame: Up to 38 days
description: The maximum-tolerated dose is defined as the dose below which 2 or more of 6 patients experience dose-limiting toxicities attributable to ropidoxuridine.
measure: Incidence of dose-limiting toxicities (Part IB)
time frame: Up to 38 days
description: Assessed by Common Terminology Criteria for Adverse Events version 5 and reached when any two grade 3 treatment-related non-hematologic toxicities or one grade 4 treatment-related hematologic and/or gastrointestinal toxicity are observed in two of the 6 patients enrolled at that dose level.
measure: Change in tissue biomarker levels
time frame: Baseline up to 8-12 weeks following completion of chemotherapy
description: Will be measured on continuous and binary scales will be assessed using Wilcoxon signed rank or McNemar's tests, respectively (two-sided; alpha = 0.05). Associations between therapeutic response and baseline biomarker values or temporal changes in biomarkers will be explored using Fisher's exact tests or Wilcoxon rank sum tests.
measure: Percentage of ropidoxuridine incorporation in circulating granulocytes
time frame: Prior to ropidoxuridine dose and at 30, 60, 120, and 240 minutes after ropidoxuridine dose on day 8, then at 1-2 hours after ropidoxuridine dose on days 21 and 35
description: Will correlate these levels with ropidoxuridine plasma pharmacokinetics. Two-sided Fisher's z-test with significance level of 0.05 and power of 80% will be used and the study will reject the null hypothesis (lack of correlation or r0 = 0) if we observe a correlation with r ranging from 0.79 for N = 10 subjects to 0.49 for N = 30 subjects.
measure: Percentage of ropidoxuridine incorporation in circulating granulocytes, peripheral blood counts, and toxicities
time frame: Prior to the ropidoxuridine on day 8, and at 1-2 hours following the ropidoxuridine dose on days 21 and 35
description: For the correlation of percentage of ropidoxuridine deoxyribonucleic acid incorporation in circulating granulocytes and peripheral blood counts and toxicities, assuming the target prevalence of grade 3/4 toxicity of 30%, the study will have a power of 80% with significance level of 0.05 on a two-sample means test to rule out the null hypothesis (equal means in groups with/ without grade 3/4 toxicity, m0 = m1) if the observed mean percentage of ropidoxuridine-deoxyribonucleic acid incorporation for patients with grade 3/4 toxicity is m1 = 3.3 times the mean m0 in the other group for N = 10 enrolled subjects, and m1 = 2.1 times the mean m0 for N = 30.
measure: Pathological complete response rate at the maximum-tolerated dose
time frame: At the time of surgery
description: In rectal cancer, the absence of viable tumor cells in the resection specimen (primary tumor mass, surrounding tissue and lymph nodes, T0 N0 M0) at the time of surgery, termed pathologic complete response. Pathologic complete response determination will be made by the pathologist at the treating institution.
measure: Neoadjuvant rectal score at the maximum-tolerated dose
time frame: At 6-10 weeks following completion of therapy
description: Neoadjuvant rectal score is calculated based on the clinical T stage (cT), pathological T (pT) and pN stages as neoadjuvant rectal score = [5pN- 3 (cT- pT) + 12]2 / 9.61.
measure: Relationship between extent of exposure to radiotherapy and incidence and severity of adverse events
time frame: Up to 3 years
measure: Interactions of capecitabine, IPdR and their metabolites
time frame: Up to 3 years
arm group label: Treatment (ropidoxuridine, capecitabine, radiation therapy)
arm group type: Experimental
description: Patients receive ropidoxuridine PO QD over 7 days per week and capecitabine PO BID over 6 days per week for 6 weeks. Patients also undergo radiation therapy over 1 fraction per day for 5 days per week (Monday-Friday) during weeks 1-5 and for 3 days during week 6 in the absence of disease progression or unacceptable toxicity. Approximately 8-12 weeks after completion of treatment with ropidoxuridine, capecitabine, and radiation therapy, patients undergo standard of care surgery.
intervention type: Drug
intervention name: Capecitabine
description: Given PO
arm group label: Treatment (ropidoxuridine, capecitabine, radiation therapy)
other name: Ro 09-1978/000
other name: Xeloda
intervention type: Radiation
intervention name: Radiation Therapy
description: Undergo radiation therapy
arm group label: Treatment (ropidoxuridine, capecitabine, radiation therapy)
other name: Cancer Radiotherapy
other name: ENERGY_TYPE
other name: Irradiate
other name: Irradiated
other name: Irradiation
other name: Radiation
other name: Radiation Therapy, NOS
other name: Radiotherapeutics
other name: Radiotherapy
other name: RT
other name: Therapy, Radiation
intervention type: Drug
intervention name: Ropidoxuridine
description: Given PO
arm group label: Treatment (ropidoxuridine, capecitabine, radiation therapy)
other name: 5-Iodo-2-pyrimidinone 2' deoxyribonucleoside
other name: 5-Iodo-2-pyrimidinone-2'-deoxyribose
other name: IPdR
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Charles Kunos
role: Principal Investigator
affiliation: University Health Network Princess Margaret Cancer Center LAO
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Rectal Neoplasms
mesh term: Capecitabine
mesh term: Ropidoxuridine
sharing ipd: Yes
ipd description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
ipd url: https://grants.nih.gov/policy/sharing.htm
submitted: June 1, 2023
returned: June 26, 2023
submitted: June 29, 2023
returned: June 30, 2023
submitted: August 16, 2023
returned: August 17, 2023