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Locally Advanced Rectal CarcinomaPhase 1NCT04406857

Testing the Addition of a Radiation Sensitizing Drug, IPdR, to the Usual Chemotherapy Treatment (Capecitabine) During Radiation Therapy for Rectal Cancer

A Phase 1 study testing Capecitabine, Radiation Therapy and Ropidoxuridine in people with Locally Advanced Rectal Carcinoma and Rectal Adenocarcinoma, run by National Cancer Institute (NCI) at 9 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Capecitabine, Radiation Therapy and Ropidoxuridine
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1 participants
Where
9 sitesUnited States
Study dates
17 Mar 2021to 18 Jan 2023
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
Show all 35Show fewer
  • 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

Who cannot join

  • 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
Show all 22Show fewer
  • 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)

Trial locations and contacts

9 sites in 1 country.

9 sites in 1 country

United States9 sites

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

  • University of Kentucky/Markey Cancer Center

    Lexington, Kentucky, 40536

  • Los Angeles County-USC Medical Center

    Los Angeles, California, 90033

  • USC / Norris Comprehensive Cancer Center

    Los Angeles, California, 90033

  • University of Oklahoma Health Sciences Center

    Oklahoma City, Oklahoma, 73104

  • Thomas Jefferson University Hospital

    Philadelphia, Pennsylvania, 19107

  • University of Pittsburgh Cancer Institute (UPCI)

    Pittsburgh, Pennsylvania, 15232

  • Rhode Island Hospital

    Providence, Rhode Island, 02903

  • Huntsman Cancer Institute/University of Utah

    Salt Lake City, Utah, 84112

Other trials in United States

About this study

Official title: A Phase 1 Study of IPdR in Combination With Capecitabine and Radiotherapy in Rectal Cancer

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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.

  1. 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:

  1. 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.

Being tested
Capecitabine, Radiation Therapy, Ropidoxuridine
Medical subject headings
Rectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CapecitabineDrug

    Also called Ro 09-1978/000, Xeloda

    Given PO

  • Radiation TherapyRadiation

    Also called Cancer Radiotherapy, ENERGY_TYPE, Irradiate, Irradiated

    Undergo radiation therapy

  • RopidoxuridineDrug

    Also called 5-Iodo-2-pyrimidinone 2' deoxyribonucleoside, 5-Iodo-2-pyrimidinone-2'-deoxyribose, IPdR

    Given PO

Study groups in NCT04406857
Study groupRoleWhat they receive
Treatment (ropidoxuridine, capecitabine, radiation therapy)ExperimentalPatients 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.
Receives: Drug: Capecitabine; Radiation: Radiation Therapy; Drug: Ropidoxuridine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum-tolerated Dose

    The maximum-tolerated dose is defined as the dose below which 2 or more of 6 patients experience dose-limiting toxicities attributable to ropidoxuridine.

    Measured: Up to 38 days

  2. Incidence of Dose-limiting Toxicities (Part IB)

    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.

    Measured: Up to 38 days

Secondary outcomes (5)

  1. Change in Tissue Biomarker Levels

    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.

    Measured: Baseline up to 8-12 weeks following completion of chemotherapy

  2. Percentage of Ropidoxuridine Incorporation in Circulating Granulocytes

    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.

    Measured: 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

  3. Percentage of Ropidoxuridine Incorporation in Circulating Granulocytes, Peripheral Blood Counts, and Toxicities

    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.

    Measured: Prior to the ropidoxuridine on day 8, and at 1-2 hours following the ropidoxuridine dose on days 21 and 35

  4. Pathological Complete Response Rate at the Maximum-tolerated Dose

    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.

    Measured: At the time of surgery

  5. Neoadjuvant Rectal Score at the Maximum-tolerated Dose

    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.

    Measured: At 6-10 weeks following completion of therapy

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 May 2020
  2. Study start17 Mar 2021
  3. Primary completion18 Jan 2023
  4. Study completion18 Jan 2023

Why it stopped: Inadequate accrual rate

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
1 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04406857
Sponsor's protocol ID
NCI-2020-03610
Other IDs
NCI-2020-03610, 10410, 10410, UM1CA186644, UM1CA186712, UM1CA186716
Status last verified
Feb 2025
First submitted
28 May 2020
Last updated
26 Feb 2025
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: 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.

Publications

  • Kunos CA, Piekarz R, Collins JM, Kinsella TJ. A case report of typhlitis during novel use of ropidoxuridine-capecitabine-radiotherapy for treatment-naive rectal cancer. Cancer Chemother Pharmacol. 2023 Aug;92(2):151-155. doi: 10.1007/s00280-023-04561-4. Epub 2023 Jun 27.

    PubMed 37369852

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Capecitabine, Radiation Therapy and Ropidoxuridine in people with Locally Advanced Rectal Carcinoma and Rectal Adenocarcinoma, run by National Cancer Institute (NCI) at 9 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 35 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 26 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 9 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 5 Oct 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum-tolerated Dose (time frame: Up to 38 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04406857, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Feb 2025.

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