Hypofractionated Pencil-Beam Scanning Intensity-modulated Proton Therapy (IMPT) in Recurrent Rectal Cancer

Study Overview
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Brief Summary
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The purpose of this trial is to determine the maximum tolerated dose (MTD) of hypofractionated IMPT for the reirradiation of locoregionally recurrent rectal cancer.

Official Title
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Hypofractionated Pencil-Beam Scanning Intensity-modulated Proton Therapy (IMPT) in the Reirradiation of Locoregionally Recurrent Rectal Cancer - IMPARC

Conditions
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Recurrent Rectal Cancer

Intervention / Treatment
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* Radiation: Hypofractionated Pencil-Beam Scanning Intensity-modulated Proton Therapy
* Device: MEVION S250i Hyperscan and Adaptive Aperture Proton Therapy Machine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of biopsy-proven adenocarcinoma of the rectum, anus or rectosigmoid junction of any stage now with recurrent disease in the pelvis One prior course of radiation therapy to the pelvis for rectal cancer ECOG performance status 0-2 At least 18 years of age 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 IRB-approved written informed consent document. Exclusion Criteria: Patients with pre-existing radiosensitizing conditions, such as connective tissue disorders (i.e. lupus, scleroderma) and genetic mutations (i.e. ataxia-telangiectasia) A history of other malignancy 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, basal cell or squamous cell carcinoma of the skin that were treated with local resection only, or carcinoma in situ of the cervix. Patients with history of prostate cancer treated without radiotherapy and no evidence of disease are eligible More than one prior course of radiation to the pelvis for rectal cancer Prior radiation to the pelvis for disease other than rectal cancer Tumor in the rectum/colon requiring radiation therapy to the full circumference of the rectum/colon. Current treatment with any investigational agents. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or unstable angina pectoris Pregnant and/or breastfeeding. Women of childbearing potential must have a negative urine or serum pregnancy test within 14 days of study entry.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1: Hypofractionated Pencil-Beam Scanning Intensity-modulated Proton Therapy (IMPT)<br>Radiotherapy will consist of five fractions, delivered once daily, with pencil beam scanning proton beam therapy using the defined dose in dose level 1. The use of Intensity Modulated Radiation Therapy (IMRT) with photon beam therapy is permitted at the discretion of the treating investigator in order to avoid extended treatment delays due to logistical reasons (e.g. machine downtime). | Radiation: Hypofractionated Pencil-Beam Scanning Intensity-modulated Proton Therapy<br>* When feasible it is strongly recommended that radiotherapy begin on a Monday<br>* Other names: IMPT;Device: MEVION S250i Hyperscan and Adaptive Aperture Proton Therapy Machine<br>* -The device that will administer the IMPT<br>|
| Experimental: Dose Level 2: Hypofractionated Pencil-Beam Scanning Intensity-modulated Proton Therapy (IMPT)<br>Radiotherapy will consist of five fractions, delivered once daily, with pencil beam scanning proton beam therapy using the defined dose in dose level 2. The use of Intensity Modulated Radiation Therapy (IMRT) with photon beam therapy is permitted at the discretion of the treating investigator in order to avoid extended treatment delays due to logistical reasons (e.g. machine downtime). | Radiation: Hypofractionated Pencil-Beam Scanning Intensity-modulated Proton Therapy<br>* When feasible it is strongly recommended that radiotherapy begin on a Monday<br>* Other names: IMPT;Device: MEVION S250i Hyperscan and Adaptive Aperture Proton Therapy Machine<br>* -The device that will administer the IMPT<br>|
| Experimental: Dose Level 3: Hypofractionated Pencil-Beam Scanning Intensity-modulated Proton Therapy (IMPT)<br>Radiotherapy will consist of five fractions, delivered once daily, with pencil beam scanning proton beam therapy using the defined dose in dose level 3. The use of Intensity Modulated Radiation Therapy (IMRT) with photon beam therapy is permitted at the discretion of the treating investigator in order to avoid extended treatment delays due to logistical reasons (e.g. machine downtime). | Radiation: Hypofractionated Pencil-Beam Scanning Intensity-modulated Proton Therapy<br>* When feasible it is strongly recommended that radiotherapy begin on a Monday<br>* Other names: IMPT;Device: MEVION S250i Hyperscan and Adaptive Aperture Proton Therapy Machine<br>* -The device that will administer the IMPT<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of reirradiation using hypofractionated IMPT | MTD is defined as the dose associated with a 35% probability of dose-limiting toxicity (DLT). DLT is defined as any toxicity listed below that occurs within 6 months from start of treatment and is considered possibly, probably, or definitely related to proton reirradiation: Any grade 5 toxicities Any grade 4-5 GI toxicities Bowel obstruction Grade 3-5: diarrhea; anal, colonic, or bowel ulcers; bladder perforation; any fistula formations; peripheral motor/sensory neuropathy of the pelvis above baseline; osteonecrosis/soft tissue necrosis; radiation dermatitis; hematuria; hematochezia; bowel/pelvic hemorrhage; reproductive tract toxicity Toxicity will be graded using CTCAE v5 | Through 6 months from start of treatment for all participants enrolled (estimated to be 42 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical complete response rate | -DRE, endoscopy, and cross sectional imaging will be used to measure clinical complete response rate | Within 6 weeks to 3 months post-completion of radiation therapy (estimated to be 7 weeks to 3 months and 1 week)) | 
| Median freedom from locoregional progression (FFLP) | -Defined as time from end of radiation therapy to date of first instance of local or regional tumor progression | At 12 months post-radiation therapy (estimated to be 12 months and 1 week) | 
| Median overall survival (OS) |  | At 12 months post-radiation therapy (estimated to be 12 months and 1 week) | 
| Median progression-free survival (PFS) | -Defined as time from end of radiation therapy to the earliest date of locoregional progression, distant progression, or death from any cause | At 12 months post-radiation therapy (estimated to be 12 months and 1 week) | 
| Change in quality of life as measured by the EORTC QLQ-C30 | -The EORTC QLQ-C30 consists of a 30-question questionnaire, which assesses patient well-being with five functional scales (the physical, role, emotional, cognitive, social, and global). It also includes three symptom scales (fatigue, pain, nausea/vomiting) and six single items (dyspnea, sleep disturbance, appetite loss, diarrhea, constipation, and financial impact). Single-item QL scores for overall physical condition (question 29), overall quality of life (question 30), and the global and social functioning scales have been shown to be prognostic for overall survival in adult patients with advanced malignancies | Prior to start of radiation therapy, 1-2 weeks post radiation therapy, 3 months post radiation therapy, 6 months post radiation therapy, 9 months post radiation therapy and 12 months post radiation therapy | 
| Change in quality of life as measured by the EORTC QLQ-CR29 | -The QLQ-CR29 contains 29 questions, including items in 4 scales (urinary frequency, blood/mucus in stools, stool frequency, body image) and 19 single items (urinary incontinence, dysuria, abdominal pain, buttock pain, bloating, dry mouth, hair loss, taste, anxiety, weight, flatulence, fecal incontinence, sore skin, embarrassment, stoma care problems, sexual interest for men, sexual interest for women, impotence, dyspareunia). There are 11 items allocated for specific sub-populations, including males, females, and stoma patients. Scores of the QLQ-CR29 can be linearly transformed to provide a score from 0 to 100, with higher scores representing higher levels of functioning on the functional scales, greater degrees of symptomatology on the symptom scales and improved QOL on the global QOL scale | Prior to start of radiation therapy, 1-2 weeks post radiation therapy, 3 months post radiation therapy, 6 months post radiation therapy, 9 months post radiation therapy and 12 months post radiation therapy | 
| Frequency of acute adverse events as measured by CTCAE v 5.0 |  | From start of treatment through 3 months after completion of radiation therapy (estimated to be 3 months and 1 week) | 
| Frequency of late adverse events as measured by CTCAE v 5.0 |  | From 3 month post-completion of radiation therapy to 12 months post-completion of radiation therapy |