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

Overview

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

Detailed description

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.

Interventions

• Drug Capecitabine
  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.
• Device Initial Dose of Radiation before Dose Escalation
  50 Gy over 25 frac.
• Device Cohort A: Dose Escalation Radiation
  Cohort A will receive 14 Gy boost for a total of 64 Gy over 32 total fractions.
• Device Cohort B: Dose Escalation Radiation
  Cohort B will receive 18 Gy boost for a total of 68 Gy over 34 total fractions.
• Device Cohort C: Dose Escalation Radiation
  Cohort C will receive 22 Gy boost for a total of 72 Gy over 36 total fractions.
• Drug FOLFOX
  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.)

Primary outcome measures

• The number of subjects in Cohort A with serious adverse events during radiation. [Time frame: Up to 11.5-week period]
• The number of subjects in Cohort B with serious adverse events during radiation. [Time frame: Up to 11.5-week period]
• The number of subjects in Cohort C with serious adverse events during radiation. [Time frame: Up to a 12.1-week period.]

Secondary outcome measures (12)

• The number of subjects in Cohort A with a complete clinical response (CCR) to treatment. [Time frame: 31.5 weeks]
• The number of subjects in Cohort B with a complete clinical response (CCR) to treatment. [Time frame: 31.5 weeks]
• The number of subjects in Cohort C with a complete clinical response (CCR) to treatment. [Time frame: 32.1 weeks]
• The number of subjects in Cohort A with a noncomplete response (NCR) to treatment. [Time frame: 31.5 weeks]
• The number of subjects in Cohort B with a noncomplete response (NCR) to treatment. [Time frame: 31.5 weeks]
• The number of subjects in Cohort C with a noncomplete response (NCR) to treatment. [Time frame: 32.1 weeks]
• Circulating tumor deoxyribonucleic acid (ctDNA) [Time frame: Baseline, 12.1 weeks, 32 weeks, one year and two years.]
• The number of subjects with dose-limiting toxicities in Cohort A. [Time frame: 11.5-week period]
• The number of subjects with dose-limiting toxicities in Cohort B. [Time frame: 11.5-week period]
• The number of subjects with dose-limiting toxicities in Cohort C. [Time frame: 12.1- week period]
• Change from baseline in the EQ-5D-SL quality of life questionnaire [Time frame: Baseline and up to 12.1 weeks.]
• Change from baseline in the Memorial Sloan Kettering Bowel Function Index (MSKCC BFI) Score [Time frame: Baseline and up to 12.1 weeks.]

Eligibility criteria

Inclusion criteria

• Age ≥ 18.
• Pathologically confirmed (histologic or cytological), adenocarcinoma of the rectum.
• Determined on staging evaluation to be clinical stage I, II or III.
• No concerning unequivocal or biopsy-proven metastatic disease. Patients are eligible with either no evidence of distant metastatic disease, or "equivocal" evidence of distant metastatic disease, as judged by the multidisciplinary tumor board. This "equivocal" definition can include small lung or liver lesions that are not able to be radiographically characterized otherwise.
• Eastern Cooperative Oncology Group (ECOG) status 0-2 within 45 days of study entry.
• History/physical examination, including collection of weight and vital signs within 45 days prior to start of treatment.
• MR of the rectum is mandatory for staging and follow-up.
• Chest CT scan within 45 days prior to study entry.
• Radiation treatment planning abdominal CT. A mandatory pelvic MR will be done as a simulation (SIM) (ideally with interpretation). The CT SIM will not be done with interpretation. Ability to undergo abdominal MR scans for staging and radiation planning and follow-up is mandatory.
• Laboratory values (CBC, Chem24) 45 days prior to treatment as follows:

• Carcinoembryonic antigen (CEA) (any value).
• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3.
• Platelets ≥50,000 cells/mm3.
• Hemoglobin ≥ 8.0 g/dl. (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable.)
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 4 x upper limit of normal.
• Total bilirubin < 2 x upper normal mg/dL.
• Alkaline phosphatase < 4 x upper limit of normal.
• Not on hemodialysis.
• Ability to swallow oral medications.
• Patients must be determined by medical oncology to be a candidate for systemic chemotherapy.
• Patients must provide study-specific informed consent prior to study entry.
• Negative serum pregnancy test (if applicable).
• Women of childbearing potential and male participants who are sexually active must practice adequate contraception.

Exclusion criteria

• Biopsy-proven distant metastatic disease or high clinical concern for metastatic disease and tumor conference consensus of stage IV disease.
• Prior invasive malignancy (except nonmelanomatous skin cancer, noninvasive breast cancer (DCIS), or prostate cancer under active surveillance). Other malignancies are allowed if patient has been disease free for a minimum of three years
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.
• Any major surgery within 28 days prior to study entry, except colonic stent placement, intestinal diversion without resection or vascular access insertion.
• Severe, active comorbidity, defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalization within the last six months.
• Transmural myocardial infarction within three months prior to study entry.
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration.
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration.
• Uncontrolled malabsorption syndrome significantly affecting gastrointestinal function.
• Any unresolved intestinal obstruction.
• Acquired immune deficiency syndrome (AIDS), based upon current Centers for Disease Control and Prevention (CDC) definition. Note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because patients receiving antiretroviral therapy may experience possible pharmacokinetic interactions with required treatment medications, such as capecitabine.
• Absence of any significant medical comorbidity which would preclude the consideration of major intestinal surgery.
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception during the course of the study and for women three months after study therapy is completed and for men six months after study therapy is completed. This exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
• Participation in another interventional clinical treatment trial while on study (observational trials are permitted).
• Patients taking nonprotocol-specified chemotherapy agents or immune-modulating agents for other medical conditions are not permitted to participate in this trial. Any medication questions should be reviewed by the PI.
• Poor functional status such that patients are not able to be positioned for radiation treatments.
• Gadolium allergy.
• If age over 60, history of hypertension, diabetes or liver transplant, and glomerular filtration rate (GFR) at enrollment is < 30.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Froedtert & the Medical College of Wisconsin — Milwaukee

Identifiers

NCT: NCT04808323 · PRO00040139

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗