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Neoadjuvant Chemoradiotherapy With CRLX-101 and Capecitabine for Rectal Cancer

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ClinicalTrials.gov Identifier: NCT02010567
Recruitment Status : Active, not recruiting
First Posted : December 12, 2013
Results First Posted : November 14, 2017
Last Update Posted : January 8, 2019
Sponsor:
Collaborator:
Cerulean Pharma Inc.
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

Tracking Information
First Submitted Date  ICMJE December 9, 2013
First Posted Date  ICMJE December 12, 2013
Results First Submitted Date  ICMJE October 13, 2017
Results First Posted Date  ICMJE November 14, 2017
Last Update Posted Date January 8, 2019
Study Start Date  ICMJE December 2013
Actual Primary Completion Date September 16, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 29, 2018)
  • Maximum Tolerated Dose (MTD) of CRLX101 When Added to Standard Neoadjuvant Chemoradiotherapy Consisting of Capecitabine + Radiotherapy in Locally Advanced Rectal Cancer [ Time Frame: 12 weeks ]
    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
  • Pathological Complete Response (pCR) Rate [ Time Frame: 12 weeks ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 9, 2013)
  • Maximum tolerated dose (MTD) [ Time Frame: 2 years ]
    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 ]
    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.
Change History Complete list of historical versions of study NCT02010567 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 29, 2018)
  • Pathological Response Rate [ Time Frame: 12 weeks ]
    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
  • Number of Participants With Grade 3 or Higher, Treatment-related Toxicities [ Time Frame: 12 weeks ]
    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.
  • Disease-free Survival (DFS) [ Time Frame: 6 years ]
    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 ]
    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 ]
    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
Original Secondary Outcome Measures  ICMJE
 (submitted: December 9, 2013)
  • Pathological Response Rate [ Time Frame: 8 years ]
    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 ]
    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 ]
    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 ]
    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 ]
    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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Neoadjuvant Chemoradiotherapy With CRLX-101 and Capecitabine for Rectal Cancer
Official Title  ICMJE Phase Ib/II Study of Neoadjuvant Chemoradiotherapy With CRLX-101 and Capecitabine for Locally Advanced Rectal Cancer
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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Rectal Cancer
Intervention  ICMJE
  • 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 PTV 1 and PTV 2 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
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: CRLX101
    • Drug: Capecitabine
    • Radiation: Radiotherapy
  • 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.
    Interventions:
    • Drug: CRLX101
    • Drug: Capecitabine
    • Radiation: Radiotherapy
    • Procedure: Surgery
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: October 13, 2017)
32
Original Estimated Enrollment  ICMJE
 (submitted: December 9, 2013)
71
Estimated Study Completion Date  ICMJE September 16, 2021
Actual Primary Completion Date September 16, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02010567
Other Study ID Numbers  ICMJE LCCC 1315
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party UNC Lineberger Comprehensive Cancer Center
Study Sponsor  ICMJE UNC Lineberger Comprehensive Cancer Center
Collaborators  ICMJE Cerulean Pharma Inc.
Investigators  ICMJE
Principal Investigator: Andrew Wang, MD UNC Lineberger Comprehensive Cancer Center
PRS Account UNC Lineberger Comprehensive Cancer Center
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP