Non-Operative Management and Early Response Assessment in Rectal Cancer

Study Overview
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Brief Summary
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The investigators' data from a phase I study of short course radiation therapy followed by chemotherapy showed 74% complete clinical response (cCR). Given the promising response rate, the investigators are evaluating short course radiation therapy (SCRT) followed by chemotherapy in a multi-institution phase II trial to validate the cCR rate of this treatment paradigm. SCRT has not been prospectively evaluated in non-operative management for patients with non-metastatic rectal adenocarcinoma.

Official Title
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Non-Operative Management and Early Response Assessment in Rectal Cancer

Conditions
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Adenocarcinoma of the Lower Rectum

Intervention / Treatment
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* Radiation: Radiation therapy
* Drug: FOLFOX regimen
* Other: Functional Assessment of Cancer Therapy-Colorectal cancer (FACT-C) questionnaire
* Procedure: Rectal biopsy samples
* Procedure: Blood for ctDNA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of biopsy proven stage I-IIIB (cT1-3, N0-2a, M0) adenocarcinoma of the rectum; staging must also be based on multidisciplinary evaluation including MRI Tumor ≤ 12 cm from anal verge as determined by MRI or endoscopy Clinically detectable (MR, endoscopy, or DRE) tumor present Eastern Cooperative Oncology Group (ECOG) performance status 0-2 At least 18 years of age Adequate bone marrow function defined as: Absolute neutrophil count (ANC) > 1,500 cells/mm3 Hemoglobin> 8 g/dl Platelets >100,000 cells/mm3 Women of childbearing potential 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. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Able to understand and willing to sign an Institutional Review Board (IRB)-approved written informed consent document. Exclusion Criteria Prior radiation therapy, chemotherapy or extirpative surgery for rectal cancer. Prior oxaliplatin or capecitabine use for any malignancy No prior radiation therapy to the pelvis. A history of other malignancy (except non-melanomatous skin cancers) with the exception of malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease. Currently receiving any investigational agents. A history of allergic reaction attributed to compounds of similar chemical or biologic composition to capecitabine, 5FU, oxaliplatin, or leucovorin. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia. Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test within 14 days of study entry. Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective antiretroviral therapy (ART) according to Department of Health and Human Services (DHHS) treatment guidelines is recommended. HIV testing for patients without a history of HIV is not a protocol requirement.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiation + FOLFOX<br>Pelvic radiotherapy 5GY x 5 fractions once daily Radiation to extra-mesorectal node 7 Gy x 5 fractions once daily FOLFOX should begin 2-4 weeks after completion of radiotherapy and will consist of FOLFOX x 8 cycles (16 weeks). Oxaliplatin day 1 every 14 days Leucovorin day 1 every 14 days. Levoleucovorin may be substituted if leucovorin is not available. 5-FU bolus day 1 every 14 days 5-FU infusion day 1 every 14 days over 46 hours Alternatively CAPOX (capecitabine and oxaliplatin) may be given for 5 cycles over 15 weeks. An optional simultaneous integrated boost of 30 Gy in 5 fractions to the primary tumor is permitted | Radiation: Radiation therapy<br>* -Monday-Friday treatment is strongly recommended<br>Drug: FOLFOX regimen<br>* -CAPOX can be given as alternative<br>Other: Functional Assessment of Cancer Therapy-Colorectal cancer (FACT-C) questionnaire<br>* -Baseline, completion of chemotherapy (3-8 weeks after the end of chemotherapy), and 10 to 14 months after radiotherapy<br>Procedure: Rectal biopsy samples<br>* -Multiple biopsy samples of the rectal tumor will be taken from the patient tumor prior to treatment initiation for genomic extraction. For patients at affiliate sites who do not have enough tissue from the diagnostic biopsy, a repeat pre-treatment biopsy is optional.<br>Procedure: Blood for ctDNA<br>* -Prior to the start of treatment, Post radiation therapy labs (with standard of care (SOC) CBC/CMP prior to start of cycle 1 of chemotherapy), Day 1 of cycle 2 of chemotherapy (with SOC CBC/CMP), Completion of chemotherapy (3-8 weeks after the end of chemotherapy), 10-14 months after RT (if this visit aligns with a follow-up time point, one draw can be used to satisfy both time points), months 3, 6, 9, 12, 16, 20, 24 until salvage surgery or 2 years from completion of chemotherapy (whichever is first)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical complete response rate | -Criteria for clinical complete response: No residual gross tumor at procto/sigmoidoscopy;, or only erythematous scar or ulcer No palpable tumor on DRE No radiographic evidence of tumor on MRI No suspicious mesorectal lymph nodes on MRI Negative biopsy from scar, ulcer, or former tumor site (if necessary according to surgeon's judgment) | Completion of treatment (estimated to be 22 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Criteria for progressive disease: Increase in the size of primary tumor by RECIST criteria (increase of at least 20% from nadir in the sum of the target lesion, with an absolute increase of at least 5 mm) New metastatic disease PFS is defined as the time from date of treatment to death or progression, which occurs first. The alive patients without progression are censored as the last date follow-up. | 2 years | 
| Incidence of grade 3 or higher toxicity during treatment | -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting. | Completion of treatment (estimated to be 22 weeks) | 
| Incidence of post chemoradiotherapy grade 3 or higher toxicity | -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting. | 1 year | 
| Quality of anorectal function as measured by the FACT-C questionnaire | Questionnaire with 5 sections (physical well-being, social/family well being, emotional well-being, functional well-being, and additional concerns) Answers to the questions range from 0=not at all to 4=very much. The higher the total score the lower quality of life | 1 year (between 10-14 months post treatment start date) | 
| Organ preservation rate |  | 1 year | 
| Organ preservation rate |  | 2 years |