Neoadjuvant Chemoradiotherapy With CRLX-101 and Capecitabine for Rectal Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by UNC Lineberger Comprehensive Cancer Center
Sponsor:
Collaborator:
Cerulean Pharma Inc.
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT02010567
First received: December 9, 2013
Last updated: July 10, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Rectal Cancer
Drug: CRLX101
Drug: Capecitabine
Radiation: Radiotherapy
Procedure: Surgery
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase Ib/II Study of Neoadjuvant Chemoradiotherapy With CRLX-101 and Capecitabine for Locally Advanced Rectal Cancer

Resource links provided by NLM:


Further study details as provided by UNC Lineberger Comprehensive Cancer Center:

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    Primary Objective Phase Ib: MTD (RP2D) is based on the rate of dose-limiting toxicity (DLT) using CTCAE v4.0 toxicity criteria.

  • Pathological complete response (pCR) [ Time Frame: 6 years ] [ Designated as safety issue: No ]
    Primary Objective Phase II: Pathological response will be made based on 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.


Secondary Outcome Measures:
  • Pathological response rate [ Time Frame: 8 years ] [ Designated as safety issue: No ]
    Phase Ib and Phase II - For resectable patients who do not meet criteria for a pCR, the extent of response to preoperative therapy will be graded using the Tumor Regression Grade (TRG) schema. Pathologic response will include pCR+moderate response.

  • Number of subjects with adverse events [ Time Frame: 8 years ] [ Designated as safety issue: Yes ]
    Phase Ib and Phase II - Safety will be the reported adverse event (AE) profile characterized by NCI CTCAE v4.0.

  • Disease-free survival (DFS) [ Time Frame: 6 years ] [ Designated as safety issue: No ]
    Phase II only - DFS will be defined as the time from surgical resection until disease recurrence or death as a result of any cause.

  • Overall survival (OS) [ Time Frame: 6 years ] [ Designated as safety issue: Yes ]
    Phase II only - OS is defined as the time from surgical resection until death

  • Disease-free survival (DFS) and overall survival (OS) based on pathological complete response (pCR). [ Time Frame: 6 years ] [ Designated as safety issue: No ]
    Phase II only - a comparison of DFS and OS 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.OS is defined as the time from surgical resection until death


Estimated Enrollment: 71
Study Start Date: December 2013
Estimated Study Completion Date: December 2022
Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: CLRX101 MTD/RP2D
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
CRLX101 is an experimental nanoparticle formulation of the anticancer agent camptothecin manufactured by Cerulean Pharma Inc..
Drug: Capecitabine
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.
Other Name: Xeloda
Radiation: Radiotherapy

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 PTV1 and PTV2 shall be no less than 95% of the protocol specified dose for that volume.

Other Names:
  • Intensity Modulated Radiation Therapy
  • IMRT
Experimental: Chemoradiotherapy + Surgery
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
CRLX101 is an experimental nanoparticle formulation of the anticancer agent camptothecin manufactured by Cerulean Pharma Inc..
Drug: Capecitabine
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.
Other Name: Xeloda
Radiation: Radiotherapy

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 PTV1 and PTV2 shall be no less than 95% of the protocol specified dose for that volume.

Other Names:
  • Intensity Modulated Radiation Therapy
  • IMRT
Procedure: Surgery
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.
Other Names:
  • Resection
  • Surgical resection

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/m2 IV in the Phase Ib study, then the trial will proceed to Phase II. Patients in the Phase Ib study with resectable disease and treated at the RP2D will be included in the Phase II study population. 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/m2 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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. ECOG performance score ≤ 2
  2. Phase Ib and II: surgical candidates, with moderate to high-risk pathologically-confirmed rectal cancer (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)
    • ANC < 1,500/mm3
    • Platelet count < 100,000/mm3
    • ALT and 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
    • 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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02010567

Contacts
Contact: Maureen Tynan, RN (919)966-4432 maureen_tynan@med.unc.edu
Contact: Julie White, RN (919)966-4432 julie_white@med.unc.edu

Locations
United States, Indiana
Indiana University Simon Cancer Center Recruiting
Indianapolis, Indiana, United States, 46202
Principal Investigator: Bert O'Neil, MD         
United States, North Carolina
University of North Carolina Recruiting
Chapel Hill, North Carolina, United States, 27599
Rex Cancer Center at Rex Hospital Recruiting
Raleigh, North Carolina, United States, 27607
Principal Investigator: Jeremiah Boles, MD         
Principal Investigator: Courtney Bui, MD         
Wake Forest University Comprehensive Cancer Center Not yet recruiting
Winston-Salem, North Carolina, United States, 27157
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
Cerulean Pharma Inc.
Investigators
Principal Investigator: Andrew Wang, MD UNC Lineberger Comprehensive Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT02010567     History of Changes
Other Study ID Numbers: LCCC 1315
Study First Received: December 9, 2013
Last Updated: July 10, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by UNC Lineberger Comprehensive Cancer Center:
rectal cancer
colorectal cancer
locally advanced rectal cancer
locally advanced rectal cancer (resectable)
locally advanced rectal cancer (non-resectable)
chemoradiotherapy
nanopharmaceuticle
CLX101
camptothecin
capecitabine

Additional relevant MeSH terms:
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Capecitabine
Fluorouracil
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 18, 2014