Neoadjuvant Chemoradiotherapy With CRLX-101 and Capecitabine for Rectal Cancer

Inclusion Criteria:

1. Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2
2. Phase Ib and II: surgical candidates, with moderate to high-risk pathologically-confirmed rectal cancer (Tumor (T) and Nodal (N) stage cT3-4N0 or cT1-4N+); clinical staging by endoscopic ultrasound (EUS) or magnetic resonance imaging (MRI) is permitted.

   Phase Ib only:
   * Patients with metastatic rectal cancer are allowed if their primary site meets other eligibility criteria and chemoradiotherapy is recommended as initial therapy for symptom palliation by the multidisciplinary treating team
   * Patients with locally advanced unresectable rectal cancer are allow provided:

     * There is no evidence of recto-vaginal, recto-vesicular, recto-intestinal fistulization
     * Standard dose and schedule chemoradiotherapy is recommended as initial therapy by the multidisciplinary treating team
3. Age ≥18 years old
4. Women of childbearing potential (WOCBP) must have negative pregnancy test within 7 days prior to D1 of treatment
5. Recommendation to undergo concurrent chemoradiation, as determined by the treating physician
6. Ability to swallow oral medications
7. As determined by the enrolling physician or protocol designee, ability of the patient to understand and comply with study procedures for the entire length of the study
8. Informed consent reviewed and signed

Exclusion Criteria:

Patients meeting any of the following exclusion criteria will not be able to participate in this study:

1. Grade 2 or higher diarrhea at baseline unless deemed by the investigator to be caused by laxatives prescribed for symptomatic partial obstruction (e.g. MiraLAX®)
2. Not deemed a candidate for concurrent chemoradiation for medical reasons, such as uncontrolled infection (including HIV), uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.
3. Specific laboratory exclusion values, including:

   * Hemoglobin \< 10.0 g/dL for males and ≤ 9.0 g/dL for females (transfusion allowed to achieve or maintain levels)
   * Absolute neutrophil count (ANC) \< 1,500/mm3
   * Platelet count \< 100,000/mm3
   * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \> 2.5 times upper level of normal (ULN)
   * Alkaline phosphatase \> 2.5 times ULN
   * Total bilirubin \> 1.5 times ULN
   * Creatinine clearance \< 50 mL/min
   * International normalized ratio (INR) \>2
4. Known dihydropyrimidine dehydrogenase (DPD) deficiency
5. History of Gilbert's syndrome
6. Those who require therapeutic anticoagulation with coumarin-derivative anticoagulants
7. Unable to provide informed consent
8. Receiving any other concurrent cytotoxic, biologic agent(s) or investigational agent
9. Patients with a "currently active" second malignancy other than non-melanoma skin cancers, non-invasive bladder cancer, "low risk" adenocarcinoma of the prostate and carcinoma in situ of the cervix. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for ≥ 2 years.
10. Previous pelvic radiation therapy
11. Prior treatment with a topoisomerase I inhibitor (i.e. irinotecan, topotecan)