Testing the Addition of a Radiation Sensitizing Drug, IPdR, to the Usual Chemotherapy Treatment (Capecitabine) During Radiation Therapy for Rectal Cancer
Condition: Locally Advanced Rectal Carcinoma; Rectal Adenocarcinoma; Stage II Rectal Cancer AJCC v8; Stage III Rectal Cancer AJCC v8
MeSH terms: Rectal Neoplasms
Intervention: Capecitabine; Radiation Therapy; Ropidoxuridine
Intervention description: Given PO; Undergo radiation therapy; Given PO
Intervention MeSH terms: Capecitabine; Ropidoxuridine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  At diagnosis, patients must have had histologically proven adenocarcinoma of the
             rectum with no evidence of distant metastases

          -  At diagnosis, the major portion of the tumor must have been intact, and the following
             must be documented:

               -  Distance of the lowest tumor margin from the anal verge; and

               -  Intent for sphincter sparing or non-sphincter sparing surgical resection
                  according to the primary surgeon; and

               -  The majority of the untreated tumor must be < 12 cm from the anal verge or below
                  the peritoneal reflection as determined by the treating surgeon

          -  At diagnosis, the tumor must have been locally advanced stage II (T3-4 N0) or stage
             III (N positive [+]) rectal cancer with at least one of the following:

               -  Distal location (as defined by measurement on magnetic resonance imaging [MRI],
                  endorectal ultrasound [ERUS]/pelvic computed tomography [CT] [with intravenous
                  (IV) contrast] scan or palpable on digital rectal exam [DRE]): cT3-4 =< 5 cm from
                  the anal verge, any N

               -  Bulky: Any cT4 or evidence that the tumor is adjacent to (defined as within 3 mm
                  of) the mesorectal fascia on MRI or ERUS/pelvic CT (with IV contrast) scan

               -  High risk for metastatic disease with 4 or more regional lymph nodes (cN2).
                  Clinical Nodal or "cN" status for eligibility includes the total number of nodes
                  (N2 = 4 or more) in the mesorectal and superior rectal stations measuring >= 1.0
                  cm in any axis on cross sectional or endoscopic imaging. Nodes must measure 1.0
                  cm or greater to be considered positive for this eligibility requirement

               -  Not a candidate for sphincter-sparing surgical resection prior to neoadjuvant
                  therapy (as planned by the primary surgeon)

          -  Patients must have received 8 cycles of neoadjuvant leucovorin, fluorouracil, and
             oxaliplatin (mFOLFOX) and must have completed this therapy at least 3 weeks (and no
             more than 6 weeks) prior to enrollment on this study

          -  Patients must intend to undergo surgical resection of the rectal primary tumor
             following chemoradiotherapy

          -  Age >= 18 years

               -  Because no dosing or adverse event (AE) data are currently available on the use
                  of IPdR in combination with capecitabine and RT in patients < 18 years of age,
                  children are excluded from this study, but will be eligible for future pediatric
                  trials

          -  Eastern Cooperative Oncology Group performance status =< 2 (Karnofsky >= 60%)

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,200/mcL

          -  Platelets >= 100,000/mcL

          -  Hemoglobin > 10 g/dL

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =<
             2.5 x institutional ULN

          -  Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
             institutional ULN

          -  Creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 60
             mL/min/1.73 m^2

          -  Alkaline phosphatase =< 3 x institutional ULN

          -  Sodium, potassium, chloride, bicarbonate, and magnesium within institutional normal
             limits

          -  Patients with acquired immunodeficiency syndrome (acquired immunodeficiency syndrome
             [AIDS]-related illnesses) or known human immunodeficiency virus (HIV) disease must:

               -  Have a CD4 count >= 200 cells/uL within 30 days before enrollment,

               -  Be off all antiretroviral therapy (prophylaxis/treatment) more than 60 days
                  before enrollment, and

               -  Have no evidence of opportunistic infections

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured and be receiving no therapy

          -  Patients with known history or current symptoms of cardiac disease, or history of
             treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
             function using the New York Heart Association functional classification. To be
             eligible for this trial, patients should be class 2B or better

          -  Patients must have the ability to swallow and retain oral medication

          -  The effects of IPdR on the developing human fetus are unknown. For this reason and
             because radiosensitizing agents as well as other therapeutic agents used in this trial
             are known to be teratogenic, women of child-bearing potential (WOCBP)* and men must
             agree to use adequate contraception (hormonal or barrier method of birth control;
             abstinence) prior to study entry and for the duration of study participation. WOCBP
             must have a negative urine or serum pregnancy test within 72 hours prior to
             enrollment. If urine pregnancy results are positive or cannot be confirmed as
             negative, a serum pregnancy test will be required. Should a woman become pregnant or
             suspect she is pregnant while she or her partner is participating in this study, she
             should inform her treating physician immediately. Men treated or enrolled on this
             protocol must also agree to use adequate contraception prior to the study, for the
             duration of study participation, and 4 months after completion of IPdR administration

               -  Women of childbearing potential (WOCBP) is defined as any female who has
                  experienced menarche and who has not undergone surgical sterilization
                  (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause
                  is defined clinically as 12 months of amenorrhea in a woman over 45 in the
                  absence of other biological or physiological causes

          -  Ability to understand and the willingness to sign a written informed consent document.
             Participants with impaired decision-making capacity (IDMC) who have a
             legally-authorized representative (LAR) and/or family member available will also be
             eligible

        Exclusion Criteria:

          -  Patients who have not recovered from adverse events due to prior mFOLFOX6 chemotherapy
             (i.e., have residual toxicities > grade 1) with the exception of alopecia

          -  Patients who are receiving any other investigational agents

          -  Patients with impaired gastrointestinal (GI) function or GI disease that may
             significantly alter the absorption of oral IPdR and capecitabine (e.g. ulcerative
             disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small
             bowel resection). Patients with active inflammatory bowel disease (i.e., patients
             requiring current medical interventions or who are symptomatic) or have a history of
             abdominal surgery or other medical condition that may, in the opinion of the treating
             physician, interfere with GI motility or absorption. Patients with colostomies are
             allowed unless colostomy is for one of the precluded reasons above

          -  Treatment with warfarin is not allowed. However, therapy with heparin, low molecular
             weight heparin (LMWH), and DOACs (direct oral anticoagulating agent) such as
             dabigatran (Pradaxa), rivaroxaban, and apixaban (Eliquis) is allowed

          -  Patients with an active concurrent invasive malignancy

          -  History of prior invasive rectal malignancy, regardless of disease-free interval

          -  Patients who have received pelvic RT for rectal cancer, or prior pelvic RT for any
             other malignancy that would prevent the patient from receiving the required RT for
             this study

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to IPdR or capecitabine

          -  Patients with uncontrolled intercurrent illness

          -  Patients with psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Pregnant women are excluded from this study because IPdR may have the potential for
             teratogenic or abortifacient effects. Because there is an unknown but potential risk
             for adverse events in nursing infants secondary to treatment of the mother with IPdR,
             breastfeeding should be discontinued if the mother is treated with IPdR. These
             potential risks may also apply to other agents used in this study

          -  Patients that received live vaccines within 30 days prior to the first dose of trial
             treatment and while participating in the trial. Examples of live vaccines include, but
             are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow
             fever, rabies, bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal flu
             vaccines that do not contain live virus are permitted

          -  Known homozygous DPD (dihydro pyrimidine dehydrogenase) deficiency

          -  History of, or any evidence of, active non-infectious pneumonitis

          -  Active autoimmune disease that has required systemic treatment within the past 2 years
             (i.e., with use of modifying agents, corticosteroids, or immunosuppressive drugs).
             Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment

          -  History of active TB (Bacillus tuberculosis)

          -  Active or chronic infection requiring systemic therapy

          -  Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form
             of immunosuppressive therapy within 7 days prior to the first dose of study therapy.
             The use of physiologic doses of corticosteroids may be approved after consultation
             with the study principal investigator (PI)

          -  Active seizure disorder uncontrolled by medication

          -  Synchronous colon cancer

          -  Other invasive malignancy within 5 years. Exceptions are colonic polyps, non-melanoma
             skin cancer, or carcinoma-in-situ of the cervix

          -  Antineoplastic therapy (e.g., chemotherapy or targeted therapy) for other invasive
             malignancy within 5 years (for the purposes of this study hormonal therapy is not
             considered chemotherapy)