Trial of the Efficacy and Safety of Short and Long Course Radiation Therapy With/Without BMX-001

Study Overview
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Brief Summary
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In this Phase 2 study, we will conduct an efficacy and safety study of the combination of investigational drug BMX-001, with short-course radiotherapy (SCRT) or long-course chemoradiotherapy (LCCRT) as part of total neoadjuvant therapy in newly diagnosed rectal adenocarcinoma (RAC) patients.

Detailed Description
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In this trial, we will enroll patients in two cohorts: Cohort 1: A 6 patient safety lead-in for patients receiving capecitabine prior to beginning a randomized trial for the Long Course Chemo-radiation (LCCRT) cohort. There will be trial stopping rules to review safety and PK data prior to initiating the randomized trial of patients receiving LCCRT. Cohort 2: The Randomized Short Course Radiation (SCRT) cohort. Cohort 1 and 2 will begin enrolling concurrently. Cohort 1 will have a safety lead-in of patients receiving LCCRT (with capecitabine). Cohort 2 will begin with the randomized study of patients receiving SCRT, while the LCCRT cohort is going through the safety lead-in portion. There are stopping rules for the LCCRT cohort 1 pending PK analysis as well as an AE review from the treatment period plus 1 week post BMX-001 treatment for the 6 patients prior to moving on with the randomized portion of the study for the LCCRT cohort. All patients in the safety lead-in portion of the trial will receive BMX-001 (A loading dose of 28 mg/subject followed by maintenance doses of 14 mg/subject twice a week) with either SCRT or LCCRT. Patients will receive 3 cycles of FOLFOX or 2 cycles of CAPOX and then be assigned to SCRT or LCCRT prior to randomization. Patients will be randomized (stratified by gender) to BMX-001 or no BMX-001. The randomized trial in each cohort will involve SCRT or LCCRT with or without BMX-001. After conclusion of radiation, patients will then receive 6 more cycles of FOLFOX or 4 more cycles of CAPOX. Skin, GI, and GU symptoms will be measured on the day of screening, before and after RT.

Official Title
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A Randomized Phase 2 Trial of the Efficacy and Safety of Short and Long Course Radiation Therapy With and Without BMX-001 as Part of Total Neoadjuvant Therapy in Patients With Newly Diagnosed Locally Advanced Rectal Adenocarcinoma

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: BMX-001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with pathologically confirmed locally advanced rectal adenocarcinoma who will be receiving total neoadjuvant therapy regimen with curative intent. AJCC stage II to III rectal adenocarcinoma that will require total neoadjuvant therapy. Adult, age > or equal to 18 years (for Nebraska, age of consent is ≥19 years old) ECOG Performance Status 0-2 or Karnofsky Performance Status (KPS) ≥ 60% Hemoglobin ≥ 9.0 g/dl, ANC ≥ 1,500 /dl, platelets ≥ 100,000 /dl (The use of transfusion or other intervention to achieve Hgb > 9.0 g/dl is acceptable) Serum SGOT and bilirubin ≤ 1.5 times upper limit of normal Adequate renal function defined as follows: 1)Serum creatinine < 1.5 mg/dl within 2 weeks prior to enrollment or 2)Creatinine clearance (CC) ≥ 50 ml/min within 2 weeks prior to enrollment determined by 24-hour collection or estimated by Cockcroft-Gault formula: CCr male = [(140 - age) x (wt in kg)]/[(Serum Cr mg/dl) x (72)], CCr female = 0.85 x (CrCl male) 8. Signed, written informed consent prior to completing any study specific procedures 9. Negative pregnancy test for women of child-bearing potential within 48 hours prior to first dose of BMX-001 10. Women of childbearing potential and male participants must agree to use two forms of a medically effective means of birth control throughout their participation in the treatment phase of the study and until 12 months following the last study treatment 11. Chest/Abdominal/Pelvic (CAP) CT/ pelvic MRI done within 8 weeks of trial initiation Exclusion Criteria: Breast-feeding or pregnant Active infection requiring IV antibiotics 7 days before enrollment Prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ, basal cell or carcinoma of the skin, invasive cancers with a 5-year disease-free interval, resected cancer of the bladder or low-grade (Gleason 6 or less) prostate cancer Prior history of rectal adenocarcinoma (RAC) Prior history of pelvic radiotherapy for any other type of malignancy Known hypersensitivity or contraindication to any agent in FOLFOX or CAPOX regimen. Because corticosteroids are anti-inflammatory and could interrupt oxidative stress, patients will be excluded unless they are on stable or decreasing corticosteroids dose at the time of randomization. Patients on oral coumarin-derivative anticoagulant therapy will not be allowed to receive capecitabine concurrently unless they have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. BMX-001 Specific Exclusion Criteria (Subjects meeting any of the following criteria are ineligible for study entry) Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mmHg) Active or history of postural hypotension and autonomic dysfunction within the past year Known hypersensitivity to BMX-001 Clinically significant (i.e. active) cardiovascular disease or cerebrovascular disease, for example cerebrovascular accidents ≤ 6 months prior to study enrollment, myocardial infarction ≤ 6 months prior to study enrollment, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment History or evidence upon physical/neurological examination of central nervous system disease (e.g. seizures) unrelated to cancer unless adequately controlled by medication or potentially interfering with protocol treatment Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to start of study treatment A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 milliseconds (ms) (CTCAE grade 1) using the specific/usual choice by clinical center for correction factor. A history of additional risk factors for Torsades de Pointes (TdP) (e.g., congestive heart failure, hypokalemia, known family history of Long QT Syndrome). Note: Inclusion of Women and Minorities Both men and women and members of all races and ethnic groups are eligible for this trial.

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: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Short Chemo-Radiation Therapy (SCRT) + BMX-001 | Drug: BMX-001<br>* Loading dose of 28 mg per subject, followed by maintenance doses of 14 mg per subject twice per week.<br>|
| No Intervention: Arm B<br>Short Chemo-Radiation Therapy (SCRT) | |
| Experimental: Arm C<br>Long Course Chemo-Radiation Therapy (LCCRT) + BMX-001 | Drug: BMX-001<br>* Loading dose of 28 mg per subject, followed by maintenance doses of 14 mg per subject twice per week.<br>|
| No Intervention: Arm D<br>Long Course Chemo-Radiation Therapy (LCCRT) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of BMX-001 as measured by Grade 3 and above associated with gastrointestinal Toxicities | Grade 3 and above radiation-associated gastrointestinal, genitourinary, skin and hematologic toxicity (SCRT or LCCRT) including frequency, severity and duration of rectal bleeding, rectal pain, diarrhea, dysuria, hematuria, urinary frequency, radiation dermatitis and thrombocytopenia | Three weeks (During and 2 weeks after RT) | 
| Efficacy of BMX-001 as measured by Grade 3 and above associated with genitourinary Toxicities | Grade 3 and above radiation-associated gastrointestinal, genitourinary, skin and hematologic toxicity (SCRT or LCCRT) including frequency, severity and duration of rectal bleeding, rectal pain, diarrhea, dysuria, hematuria, urinary frequency, radiation dermatitis and thrombocytopenia | Three weeks (During and 2 weeks after RT) | 
| Efficacy of BMX-001 as measured by Grade 3 and above associated with skin Toxicities | Grade 3 and above radiation-associated gastrointestinal, genitourinary, skin and hematologic toxicity (SCRT or LCCRT) including frequency, severity and duration of rectal bleeding, rectal pain, diarrhea, dysuria, hematuria, urinary frequency, radiation dermatitis and thrombocytopenia | Three weeks (During and 2 weeks after RT) | 
| Efficacy of BMX-001 as measured by Grade 3 and above associated with hematologic Toxicities | Grade 3 and above radiation-associated gastrointestinal, genitourinary, skin and hematologic toxicity (SCRT or LCCRT) including frequency, severity and duration of rectal bleeding, rectal pain, diarrhea, dysuria, hematuria, urinary frequency, radiation dermatitis and thrombocytopenia | Three weeks (During and 2 weeks after RT) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radiation