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

NCT04406857 | Terminated Phase 1 Results FDA Drug

• 5 other identifiers: NCI-2020-0361010410UM1CA186644UM1CA186712UM1CA186716
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 9

Brief 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.

Conditions

Locally Advanced Rectal Carcinoma; Rectal Adenocarcinoma; Stage II Rectal Cancer AJCC v8; Stage III Rectal Cancer AJCC v8

Outcome Measures

Primary Outcomes (2)

• 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.

  Up to 38 days

• 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.

  Up to 38 days

Secondary Outcomes (5)

• Change in Tissue Biomarker Levels

  Baseline up to 8-12 weeks following completion of chemotherapy

• Percentage of Ropidoxuridine Incorporation in Circulating Granulocytes

  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

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

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

• Pathological Complete Response Rate at the Maximum-tolerated Dose

  At the time of surgery

• Neoadjuvant Rectal Score at the Maximum-tolerated Dose

  At 6-10 weeks following completion of therapy

Other Outcomes (2)

• Relationship Between Extent of Exposure to Radiotherapy and Incidence and Severity of Adverse Events

  Up to 3 years

• Interactions of Capecitabine, IPdR and Their Metabolites

  Up to 3 years

Study Arms (1)

Treatment (ropidoxuridine, capecitabine, radiation therapy)

EXPERIMENTAL

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.

Drug: Capecitabine; Radiation: Radiation Therapy; Drug: Ropidoxuridine

Interventions

Capecitabine DRUG

Given PO

Also known as: Ro 09-1978/000, Xeloda

Treatment (ropidoxuridine, capecitabine, radiation therapy)

Radiation Therapy RADIATION

Undergo radiation therapy

Also known as: Cancer Radiotherapy, ENERGY_TYPE, Irradiate, Irradiated, Irradiation, Radiation, Radiation Therapy, NOS, Radiotherapeutics, Radiotherapy, RT, Therapy, Radiation

Treatment (ropidoxuridine, capecitabine, radiation therapy)

Ropidoxuridine DRUG

Given PO

Also known as: 5-Iodo-2-pyrimidinone 2' deoxyribonucleoside, 5-Iodo-2-pyrimidinone-2'-deoxyribose, IPdR

Treatment (ropidoxuridine, capecitabine, radiation therapy)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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%)

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (9)

Los Angeles County-USC Medical Center

Los Angeles, California, 90033, United States

Location

USC / Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

University of Kentucky/Markey Cancer Center

Lexington, Kentucky, 40536, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

Location

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, 19107, United States

Location

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232, United States

Location

Rhode Island Hospital

Providence, Rhode Island, 02903, United States

Location

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, 84112, United States

Location

Related Publications (1)

• 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.

  PMID: 37369852 DERIVED

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

Capecitabine; Radiotherapy; Radiation; ropidoxuridine

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Therapeutics; Physical Phenomena

Limitations and Caveats

Trial had inadequate accrual rate

Results Point of Contact

• Title: Dr. Charles Kunos
• Organization: University of Kentucky

Charles.Kunos@uky.edu

859-323-6486

Study Officials

• Charles Kunos

  University Health Network Princess Margaret Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 28, 2020
• First Posted: May 29, 2020
• Study Start: March 17, 2021
• Primary Completion: January 18, 2023
• Study Completion: January 18, 2023
• Last Updated: February 26, 2025
• Results First Posted: October 5, 2023

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share

Locations

US (9)