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Radiation dose: 64 Gy over 32 fractions, prophylactic nodes treated to 50 Gy over 25 fractions, boost to tumor and radiologically positive nodes to total dose of 64 Gy over 32 total fractions.

Radiation dose: 68 Gy over approximately 34 fractions, prophylactic nodes treated to 50 Gy over 25 fractions, boost to tumor and radiologically positive nodes to 68 Gy over 34 total fractions.

Radiation dose: 72 Gy over 36 total fractions, prophylactic nodes treated to 50 Gy over 25 fractions, boost to tumor and radiologically positive nodes to 72 Gy over 36 total fractions

825 mg/m\^2 twice daily during radiation therapy. (Fluorouracil (5-FU) may be used at the discretion of the treating medical oncologists.) This chemotherapy will be given during the initial radiation dose (50 Gy over 25 frac) and continue for Cohorts A, B, and C.

Initial Dose of Radiation before Dose Escalation

Cohort A will receive 14 Gy boost for a total of 64 Gy over 32 total fractions.

Cohort A: Dose Escalation Radiation

Cohort B will receive 18 Gy boost for a total of 68 Gy over 34 total fractions.

Cohort B: Dose Escalation Radiation

Cohort C will receive 22 Gy boost for a total of 72 Gy over 36 total fractions.

Cohort C: Dose Escalation Radiation

After the completion of radiation, subjects will receive up to eight cycles of systemic chemotherapy. (FOLFIRINOX may be used at the discretion of the treating medical oncologists.)

FOLFOX

Medical College of Wisconsin Cancer Center Clinical Trials Office

William Hall, MD

Carrie Peterson, MD

This study is a prospective, open-label, phase I design.

Study Rationale: There are limited studies evaluating real-time adaptive radiation therapy for locally advanced (Stage I-III) rectal adenocarcinoma with the goal of accomplishing organ preservation. We are testing higher doses of radiation therapy, using a novel method of real-time adaptive MRI-based radiation therapy treatment.

Hypothesis: We hypothesize that adaptive magnetic resonance (MR) -guided radiation therapy will result in acceptable toxicity and that a maximum-tolerated dose can be determined in a phase I setting.

Intervention Description: The intervention in this circumstance is higher doses of radiation therapy focused within the tumor given using adaptive MR guidance. Radiation Doses being applied in this study:

Cohort A- 64 Gy over 32 fractions, prophylactic nodes treated to 50 Gy over 25 fractions, boost to tumor and radiologically positive nodes to total dose of 64 Gy over 32 total fractions.

Cohort B- 68 Gy over approximately 34 fractions, prophylactic nodes treated to 50 Gy over 25 fractions, boost to tumor and radiologically positive nodes to 68 Gy over 34 total fractions.

Cohort C- 72 Gy over 36 total fractions, prophylactic nodes treated to 50 Gy over 25 fractions, boost to tumor and radiologically positive nodes to 72 Gy over 36 total fractions.

Dose-Limiting Toxicity from Radiation Therapy: A dose-limiting toxicity (DLT) as per NCI CTCAE version 5. Specifically, this encompasses the need for additional treatments including the following: transfusion, invasive intervention, or hospitalization indicated. The presence of such a DLT would result in the halting of radiation therapy and impact on the dose levels of radiation therapy applied in the trial.

MRI-Guided Adaptive Radiation Therapy for Organ Preservation in Rectal Cancer

This will be measured by NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grades 3, 4 and 5 will be serious.

Four weeks following completion of chemotherapy, radiation therapy (RT), and neoadjuvant systemic chemotherapy, the patient will be evaluated by the study surgeon to assess local response.

CCR is defined as meeting the following criteria:

1. No palpable tumor on digital exam.
2. Endoscopic evaluation consistent with the following.

   1. Flat scar with no ulceration and intact mucosa.
   2. Disappearance of neoplastic pit pattern without use of magnification.
   3. Disappearance of neoplastic nodule or stenosis.

Four weeks following completion of chemotherapy, RT, and neoadjuvant systemic chemotherapy, the patient will be evaluated by the study surgeon to assess local response.

CCR is defined as meeting the following criteria:

1. No palpable tumor on digital exam.
2. Endoscopic evaluation consistent with the following.

   1. Flat scar with no ulceration and intact mucosa.
   2. Disappearance of neoplastic pit pattern without use of magnification.
   3. Disappearance of neoplastic nodule or stenosis.

Four weeks following completion of chemotherapy, RT, and neoadjuvant systemic chemotherapy, the patient will be evaluated by the study surgeon to assess local response.

A noncomplete clinical response is defined as any state not meeting the following criteria:

1. No palpable tumor on digital exam.
2. Endoscopic evaluation consistent with the following.

   1. Flat scar with no ulceration and intact mucosa.
   2. Disappearance of neoplastic pit pattern without use of magnification.
   3. Disappearance of neoplastic nodule or stenosis. If the tumor site does not meet the above criteria, the patient will be classified as noncomplete response (NCR).

Blood samples (10 mL each time) will be collected. ctDNA is measured in percentage: variant allele fraction percentage. For simplicity this will be reported at baseline, the end of radiation, the end of neoadjuvant treatment and annually for two years.

Number of subjects experiencing a dose-limiting toxicity (DLT) as per NCI CTCAE version 5, encompasses the need for additional treatments including the following: transfusion, invasive intervention, or hospitalization indicated. The presence of such a DLT would result in the halting of radiation therapy and impact on the dose levels of radiation therapy applied in the trial.

The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems (coded as 1), slight problems (coded as 2), moderate problems (coded as 3), severe problems (coded as 4) and extreme problems (coded as 5). The score is expressed as a five-digit number. The second part of the instrument (EQ VAS) records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' (score of 100) and 'The worst health you can imagine' (score of 0).

The MSKCC BFI comprises 18 items covering the frequency of various symptoms and is divided into three sub-scales and four single items. It is scored on a 5-point Likert scale ranging from "always" to "never". The sub-scales scores are summarised as: A 6-item frequency sub-scale (6-30), a four-item dietary sub-scale (4-20), and a four-item urgency sub-scale (4-20). A global score can be calculated as the sum of the sub-scale scores. A total score (possible score range 18-90) can be calculated by adding all the item scores (sub-scale scores plus single item scores). A higher score indicates better bowel function.

This scoring system cross-tabulates frequencies and different anal incontinence presentations (Gas/Liquid/Solid/Pad use/Need for lifestyle alterations) and sums the returned score to a total of 0-20 (where 0 = perfect continence and 20 = complete incontinence). Each of the incontinence presentations is graded equally.

Spots Global Cancer Trial Database for cohort a: dose escalation radiation