Altered Chemotherapy Sequencing During Neoadjuvant Therapy for Patients With Stage II or III Rectal Adenocarcinoma

A Pilot and Phase II Study of Altered Chemotherapy Sequencing During Neoadjuvant Therapy for Patients With Stage II or III Rectal Adenocarcinoma

The primary objective of the pilot portion of this study is to establish the safety and tolerability of an extended treatment break period in patients who have undergone neoadjuvant chemoradiotherapy as well as use of systemic therapy during this break.

Study Overview

• Status: Withdrawn
• Conditions: Stage II Rectal Cancer; Stage III Rectal Cancer
• Intervention / Treatment: Drug: Capecitabine; Drug: 5-FU; Drug: Leucovorin; Drug: Oxaliplatin; Radiation: radiation; Procedure: total mesorectal excision

Detailed Description

The proposed protocol aims to continue tumor-directed therapy during the typical "break period" in an effort to improve on both local tumor response as well as distant disease control. First, the duration from completion of chemoradiotherapy would increase from 6-8 weeks to 9-11 weeks. As noted above, this may allow for further cell death with resultant pathologic downstaging. Secondly, the protocol calls for continued systemic therapy during the 9-11 week period, thus allowing continuation of therapies directed towards both the primary as well as distant sites of disease. The primary aim of this pilot study would be to establish the feasibility of this intensified neoadjuvant approach, especially with respect to tolerability of the subsequent pelvic surgery. A subsequent phase II portion will evaluate the efficacy of this treatment approach.

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed study-specific informed consent form
2. Age > 18 years old
3. Zubrod performance status 0-1
4. Biopsy proven primary malignancy
5. AJCC Stage II or III disease (T3-4 and/or N1-2 disease) as determined by endoscopic ultrasound and/or MRI staging
6. Pretreatment rectal endoscopic ultrasound and pelvic MRI, colonoscopy, CT of chest, abdomen, and pelvis, and laboratory values as discussed below

Exclusion Criteria:

1. History of inflammatory bowel disease
2. Previous pelvic radiotherapy
3. A major psychiatric illness which would limit understanding of the proposed protocol treatment and consent process.
4. Men and women of reproductive potential must agree to use an effective contraception method
5. Pregnant or lactating women

6. Severe, active co-morbidity, defined as

   • Unstable angina and/or CHF requiring hospitalization within the last six months
   • Transmural myocardial infarction within the last 6 months
   • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
7. Presence of metastatic disease, including liver metastases
8. Laboratory values out of range

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: arm one; RT + Chemo + surgery

Drug: Capecitabine; Capecitabine will be delivered concurrently with the radiation therapy, at a dose of 1650 mg/m2 divided in even BID doses. It will only be taken on the days of radiation treatment (Monday-Friday, except for holidays). The A.M. dose of the capecitabine must be taken at least one hour prior to the radiation treatment.; Drug: 5-FU; 5-FU 400 mg/m2, iv bolus on day 1 followed by 2400 mg/m2 iv over 46 hours of each cycle. A cycle is delivered every two weeks. Three cycles will be given prior to the surgery. Five additional cycles will be given after surgery.; Drug: Leucovorin; Leucovorin 400 mg/m2, IV, over 2 hours before 5-FU on day 1 of each cycle. A cycle is delivered every two weeks. Three cycles will be given prior to the surgery. Five additional cycles will be given after surgery.; Drug: Oxaliplatin; Oxaliplatin 85mg/m2 IV on day 1 of each cycle. A cycle is delivered every two weeks. Three cycles will be given prior to the surgery. Five additional cycles will be given after surgery.; Radiation: radiation; 28-30 fractions of radiation, given once a day, five days per week (Monday-Friday, except for holidays). The prescribed fraction dose is 180 cGy; the total radiation dose is thus 5040-5400 cGy. The primary treatment fields will be treated with 25 fractions of 180 cGy/fraction with a "boost" of 3-5 fractions of 180 cGy subsequently delivered.; Procedure: total mesorectal excision; Optimal surgical technique involving use of total mesorectal excision (TME) is mandated. The type of surgery, either low anterior resection with sparing of the sphincter mechanism or sphincter-eliminating abdominoperineal resection (APR), will be at the discretion of the attending surgeon.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary study endpoint for the phase I portion of this study is to assess surgical complications through the Clavien grading system.	The adverse events will be followed prospectively from the date of surgery for 90 days. Dose-limiting toxicity (DLT) will be defined as > grade 3 anastomotic stricture or leak, infection (including pelvic abscess or wound infection), small bowel obstruction, or fistualization. Any other post-operative complication thought related directly to the surgical intervention that is a grade 3 or higher Clavien complication will also be considered dose-limiting toxicity.	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary endpoint of the phase II portion of the study is complete pathologic response.	9 to 11 weeks after the completion of the initial chemoradiotherapy.	9 to 11 weeks

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): November 1, 2012

Study Registration Dates

• First Submitted: February 21, 2011
• First Submitted That Met QC Criteria: February 23, 2011
• First Posted (Estimate): February 24, 2011

Study Record Updates

• Last Update Posted (Actual): August 20, 2020
• Last Update Submitted That Met QC Criteria: August 19, 2020
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Adenocarcinoma; Rectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Protective Agents; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Capecitabine; Oxaliplatin; Leucovorin
• Other Study ID Numbers: STU 082010-335