Neoadjuvant Chemoradiotherapy With CRLX-101 and Capecitabine for Rectal Cancer

Study Overview
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Brief Summary
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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
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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).

Official Title
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Phase Ib/II Study of Neoadjuvant Chemoradiotherapy With CRLX-101 and Capecitabine for Locally Advanced Rectal Cancer

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: CRLX101
* Drug: Capecitabine
* Radiation: Radiotherapy
* Procedure: Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance score ≤ 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 Age ≥18 years old Women of childbearing potential (WOCBP) must have negative pregnancy test within 7 days prior to D1 of treatment Recommendation to undergo concurrent chemoradiation, as determined by the treating physician Ability to swallow oral medications 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 Informed consent reviewed and signed Exclusion Criteria: Patients meeting any of the following exclusion criteria will not be able to participate in this study: 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®) 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. 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 Known dihydropyrimidine dehydrogenase (DPD) deficiency History of Gilbert's syndrome Those who require therapeutic anticoagulation with coumarin-derivative anticoagulants Unable to provide informed consent Receiving any other concurrent cytotoxic, biologic agent(s) or investigational agent 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. Previous pelvic radiation therapy Prior treatment with a topoisomerase I inhibitor (i.e. irinotecan, topotecan)

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CLRX101 MTD/RP2D<br>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. | Drug: CRLX101<br>* CRLX101 is an experimental nanoparticle formulation of the anticancer agent camptothecin manufactured by Cerulean Pharma Inc..<br>Drug: Capecitabine<br>* 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.<br>* Other names: Xeloda;Radiation: Radiotherapy<br>* 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.<br>* Other names: IMRT;|
| Experimental: Chemoradiotherapy + Surgery<br>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. | Drug: CRLX101<br>* CRLX101 is an experimental nanoparticle formulation of the anticancer agent camptothecin manufactured by Cerulean Pharma Inc..<br>Drug: Capecitabine<br>* 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.<br>* Other names: Xeloda;Radiation: Radiotherapy<br>* 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.<br>* Other names: IMRT;Procedure: Surgery<br>* 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.<br>* Other names: Surgical resection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of CRLX101 When Added to Standard Neoadjuvant Chemoradiotherapy Consisting of Capecitabine + Radiotherapy in Locally Advanced Rectal Cancer | The MTD is the highest dose of CRLX101 at which ≤1 out of 6 patients had a dose limiting toxicity (DLT) using CTCAE v4.0 toxicity criteria. DLTs include Grade (G) >3 neutropenia for ≥7 days; G 3 or 4 neutropenia with fever; G 4 anemia not related to cancer-associated bleeding; G 4 thrombocytopenia or G 3 with clinically significant bleeding; G ≥3 nausea or vomiting >48 hours despite anti-emetics; G 2 cystitis not resolved within 14 days; second G 2 cystitis; G 3 or 4 cystitis; diarrhea requiring dose reduction; Any other non-hematologic toxicity G ≥3 requiring a dose reduction (G ≥3 infusion-related reactions were not a DLT unless they recur despite slowing down the infusion); Other CRLX101 related treatment emergent adverse effect (TEAE) that requires patient withdrawal prior to completing all doses; Radiotherapy interruption due to TEAEs ≥5 days; or Dose interruption or reduction of capecitabine due to TEAE that results in <50% of the scheduled capecitabine dose for entire course | 12 weeks | 
| Pathological Complete Response (pCR) Rate | Primary Objective Phase II: Pathological response will be made based on microscopic assessment of the surgical specimen at the primary treatment site. A pCR must include no gross or microscopic tumor identified anywhere within the surgical specimen. This must include:No evidence of malignant cells in the primary tumor specimen and No lymph nodes that contain tumor. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Response Rate | Pathologic response will be made based on microscopic assessment of the surgical specimen at the primary treatment site, including regional nodes and any peritumoral satellite nodules in the specimen, and categorized as outlined below as per the American Joint Committee on Cancer (AJCC) Cancer Staging Manual 7th edition.Determination of pathological response will be reported by the local pathologist. Pathologic Complete Response (pCR): No gross or microscopic tumor identified anywhere within the surgical specimen. This must include: No evidence of malignant cells in the primary tumor specimen and No lymph nodes that contain tumor. Moderate response: Single cells or small groups of cancer cells Minimal response: Residual cancer outgrown by fibrosis Poor response:Minimal or no tumor kill; extensive residual cancer | 12 weeks | 
| Number of Participants With Grade 3 or Higher, Treatment-related Toxicities | Toxicity profile of CRLX101 when combined with capecitabine + radiotherapy to treat patients with locally advanced rectal cancer. Phase Ib and Phase II - Safety is the reported adverse event (AE) profile characterized by NCI CTCAE v4.0. The profile was limited to grade 3 or higher, treatment related AEs. | 12 weeks | 
| Disease-free Survival (DFS) Rate | Phase II only - DFS will be defined as the time from surgical resection until disease recurrence or death as a result of any cause, reported as the count of participants still alive without recurrence at the end of study follow-up. | An average of 2.6 years (full range 2.1 to 3.1 years) | 
| Overall Survival (OS) Rate | Phase II only - OS is defined as the time from surgical resection until death reported as the count of participants still alive at the end of study follow-up. | an average of 2.6 years (full range 2.1 to 3.1 years) | 
| Disease-free Survival (DFS) Rate Based on Pathological Complete Response (pCR). | Phase II only - a comparison of DFS for patients who achieve pCR and those who do not. DFS will be defined as the time from surgical resection until disease recurrence or death as a result of any cause, reported as the count of participants still alive without recurrence at the end of study follow-up. | an average of 2.6 years (full range 2.1 to 3.1 years) | 
| Overall Survival (OS) Based on Pathological Complete Response (pCR). | Phase II only - a comparison of OS for patients who achieve pCR and those who do not. OS is defined as the time from surgical resection until death reported as the count of participants still alive at the end of study follow-up. | an average of 2.6 years (full range 2.1 to 3.1 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rectal cancer, colorectal cancer, locally advanced rectal cancer, locally advanced rectal cancer (resectable), locally advanced rectal cancer (non-resectable), chemoradiotherapy, nanopharmaceutical, CLRX101, camptothecin, capecitabine