Neoadjuvant Chemoradiotherapy With CRLX-101 and Capecitabine for Rectal Cancer

NCT02010567 | Terminated Phase 1 Results DMC

• 1 other identifier: LCCC 1315
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 6

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.

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

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (6)

• Pathological Response Rate

  12 weeks

• Number of Participants With Grade 3 or Higher, Treatment-related Toxicities

  12 weeks

• Disease-free Survival (DFS) Rate

  An average of 2.6 years (full range 2.1 to 3.1 years)

• Overall Survival (OS) Rate

  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).

  an average of 2.6 years (full range 2.1 to 3.1 years)

Study Arms (2)

CLRX101 MTD/RP2D

EXPERIMENTAL

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; Drug: Capecitabine; Radiation: Radiotherapy

Chemoradiotherapy + Surgery

EXPERIMENTAL

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; Drug: Capecitabine; Radiation: Radiotherapy; Procedure: Surgery

Interventions

CRLX101 DRUG

CRLX101 is an experimental nanoparticle formulation of the anticancer agent camptothecin manufactured by Cerulean Pharma Inc..

CLRX101 MTD/RP2D; Chemoradiotherapy + Surgery

Capecitabine DRUG

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.

Also known as: Xeloda

CLRX101 MTD/RP2D; Chemoradiotherapy + Surgery

Radiotherapy RADIATION

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.

Also known as: Intensity Modulated Radiation Therapy, IMRT

CLRX101 MTD/RP2D; Chemoradiotherapy + Surgery

Surgery PROCEDURE

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.

Also known as: Resection, Surgical resection

Chemoradiotherapy + Surgery

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• UNC Lineberger Comprehensive Cancer Center: lead
• Cerulean Pharma Inc.: collaborator

Study Sites (6)

Rocky Mountain Cancer Center

Denver, Colorado, 80218, United States

Location

Indiana University Simon Cancer Center

Indianapolis, Indiana, 46202, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

Rex Cancer Center at Rex Hospital

Raleigh, North Carolina, 27607, United States

Location

Wake Forest University Comprehensive Cancer Center

Winston-Salem, North Carolina, 27157, United States

Location

Swedish Cancer Institute

Seattle, Washington, 98104, United States

Location

Related Publications (2)

• Sanoff HK, Moon DH, Moore DT, Boles J, Bui C, Blackstock W, O'Neil BH, Subramaniam S, McRee AJ, Carlson C, Lee MS, Tepper JE, Wang AZ. Phase I/II trial of nano-camptothecin CRLX101 with capecitabine and radiotherapy as neoadjuvant treatment for locally advanced rectal cancer. Nanomedicine. 2019 Jun;18:189-195. doi: 10.1016/j.nano.2019.02.021. Epub 2019 Mar 8.

  PMID: 30858085 DERIVED

• Tian X, Nguyen M, Foote HP, Caster JM, Roche KC, Peters CG, Wu P, Jayaraman L, Garmey EG, Tepper JE, Eliasof S, Wang AZ. CRLX101, a Nanoparticle-Drug Conjugate Containing Camptothecin, Improves Rectal Cancer Chemoradiotherapy by Inhibiting DNA Repair and HIF1alpha. Cancer Res. 2017 Jan 1;77(1):112-122. doi: 10.1158/0008-5472.CAN-15-2951. Epub 2016 Oct 26.

  PMID: 27784746 DERIVED

Related Links

• Lineberger Comprehensive Cancer Center website

MeSH Terms

Conditions

Rectal Neoplasms; Colorectal Neoplasms

Interventions

IT-101; Capecitabine; Radiotherapy; Radiotherapy, Intensity-Modulated; Surgical Procedures, Operative

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases; Colonic Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Therapeutics; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted

Limitations and Caveats

Follow-up of participants was ended early, resulting in few or no observed events (progression or death) for all survival endpoints.

Results Point of Contact

• Title: Robin Johnson
• Organization: UNC Lineberger

robin_v_johnson@med.unc.edu

919-966-1125

Study Officials

• Andrew Wang, MD

  UNC Lineberger Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 9, 2013
• First Posted: December 12, 2013
• Study Start: December 1, 2013
• Primary Completion: September 16, 2016
• Study Completion: June 25, 2019
• Last Updated: November 3, 2020
• Results First Posted: November 14, 2017

Record last verified: 2020-10

Locations

US (6)