Neoadjuvant Chemoradiotherapy With CRLX-101 and Capecitabine for Rectal Cancer

This trial will enroll patients with locally advanced rectal cancer (resectable and non-resectable).The phase Ib dose escalation portion of trial is designed to determine the maximum tolerated dose (MTD) of CRLX101 when combined with standard neoadjuvant therapies capecitabine (Cape) and radiation therapy (XRT). CRLX101 is a nanopharmaceutical (NP) formulation of camptothecin. These results will determine the recommended phase II dose (RP2D) for CRLX101 in this setting. The phase II portion of the trial is designed to evaluate the efficacy and safety of CRLX101 at the RP2D, when combined with capecitabine and radiation therapy prior to surgery.

This is an open label, single-arm, multi-center, Phase Ib/II study designed to evaluate CRLX101, which is a NP formulation of camptothecin, dosed in combination with capecitabine and radiation therapy in patients with advanced rectal carcinoma.

The purpose of the Phase Ib portion of this study is to identify the MTD of CRLX101 when added to standard neoadjuvant chemo-radiotherapy. The MTD will be based on the rate of dose-limiting toxicity (DLT) in Phase Ib, and will be assessed via NCI's CTCAE v4.0 toxicity criteria. The MTD will be assigned as the RP2D in this trial.

If CRLX101 can be safely administered in combination with capecitabine and radiation at doses \>/= 9 mg/m\^2 IV in the Phase Ib study, then the trial will proceed to Phase II. Patients in the Phase Ib study will be included in the Phase II outcome analyses when applicable. The phase II study is designed to evaluate the efficacy of this regimen by assessing the rate of pathological complete response (pCR) while monitoring safety and tolerability.

We anticipate accrual of up to 25 patients per year for the Phase II study, with a slightly faster accrual of 2-3 patients per month for Phase Ib given the broader inclusion criteria.

During Phase Ib, we will evaluate the safety and determine the MTD/RP2D of CRLX101 + capecitabine (Cape) and radiation therapy (XRT) in patients with rectal cancer using the traditional 3+3 dose escalation design. Adverse events (AEs) will be evaluated via the CTCAE version 4.0. Patients in Phase Ib will also be followed for pathological response if they have resectable disease.

If CRLX101 can be safely administered in combination with capecitabine and radiation at doses \>/=9 mg/m\^2 IV in the Phase Ib study, then the trial will proceed to Phase II with a primary objective of estimating the rate of pCR. Non-metastatic patients with resectable disease and treated at the MTD/RP2D in Phase Ib will be included in the Phase II study population.

In Phase II, CRLX101 will be administered at the RP2D in combination with capecitabine and radiation in patients with locally advanced rectal cancer for a total of 5-6 weeks, depending on the total radiation dose. A total of 3 doses of CRLX101 will be administered every other week. Surgery will take place at least 6 weeks after the completion of chemoradiotherapy.

For our non-metastatic Phase I patients and our Phase II population, postoperative adjuvant therapy is indicated regardless of whether a pCR is achieved or not. While there are a number of regimens used in the adjuvant setting, national guidelines do not specify one of these regimens over the other. Given the consistent application of adjuvant therapies in this population, we also plan to follow Phase II patients for both disease free survival (DFS) and overall survival (OS).

Eligibility Criteria:
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)