Conditions: Rectal Cancer
Keywords: rectal cancer colorectal cancer locally advanced rectal cancer locally advanced rectal cancer (resectable) locally advanced rectal cancer (non-resectable) chemoradiotherapy nanopharmaceutical CLRX101 camptothecin capecitabine
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
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.

Detailed description:
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).

Arms:
arm 1: 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. arm 2: 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.

Interventions: intervention 1: CRLX101 intervention 2: Capecitabine intervention 3: Radiotherapy intervention 4: Surgery
Intervention descriptions: intervention 1: CRLX101 is an experimental nanoparticle formulation of the anticancer agent camptothecin manufactured by Cerulean Pharma Inc.. intervention 2: Capecitabine is an oral fluoropyrimidine pro-drug, metabolically converted to 5-fluorouracil after administration. It is indicated as adjuvant treatment in patients with stage III colorectal cancer (Dukes' C colon cancer), and as first-line treatment of metastatic colorectal cancer. intervention 3: This protocol allows physician discretion as to the use of Intensity Modulated Radiation Therapy (IMRT) or 3D conformal planning techniques.

Radiation begins on Day1 of neoadjuvant chemotherapy and continues for 28 (if \<T4) or 30 (T4 disease) consecutive weekdays. Patient will receive 1.8 Gy daily fractions of radiotherapy without a break except for weekends and holidays.

Dose is to be prescribed to an isodose surface that encompasses the planning target volume (PTV) and that satisfies the dose uniformity guidelines below. The minimum dose to PTV 1 and PTV 2 shall be no less than 95% of the protocol specified dose for that volume. intervention 4: Surgery will take place at least 6 weeks post completion of chemoradiotherapy in patients with resectable disease; tissue from surgical resection will be preserved for correlative studies in those patients who do not achieve a pCR.

Protocol document: