A Phase 1-2 Trial of Cetuximab in Combination With Oxaliplatin, Capecitabine, and Radiation Therapy Followed by Surgery for Locally-advanced Rectal Cancer

George Albert Fisher

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Colo-rectal Cancer; Rectal Cancer

Treatments: Drug: Oxaliplatin; Radiation: Radiotherapy; Drug: Cetuximab; Drug: Diphenhydramine hydrochloride (HCl); Drug: Capecitabine

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT00226941

95054 (Other Identifier)

IRB-12426

COR0001 (Other Identifier)

Details and patient eligibility

About

The objectives of this study are to:

1. To assess dose-limiting toxicities (DLTs) of capecitabine +/- oxaliplatin in a combination regimen with capecitabine and radiotherapy (Phase 1)

2. To determine the maximum-tolerated dose (MTD) when capecitabine

   • oxaliplatin in a combination regimen with capecitabine and radiotherapy (Phase 1)

3. To determine the pathologic response rate of cetuximab +/- oxaliplatin in combination with capecitabine and radiotherapy (Phase 2)

Full description

Part of the treatment plan for this study is surgical removal of the tumor that is planned to occur 6 to 8 weeks after completion of radiotherapy (XRT). This study consists of 2 distinct phases (Phase 1 and Phase 2).

In Phase 1, the objectives are to

1. Assess dose-limiting toxicities (DLTs) and
2. Determine a maximum-tolerated dose (MTD)

The Phase 1 endpoints are assessed on an initial cohort of patients after the completion of the chemo-radiotherapy regimen at defined timepoints that precede surgery.

Phase 2 is the efficacy assessment portion of this study. In Phase 2, the objective is to accrue an expansion cohort. Efficacy assessments for phase 2 are to be assessed across all study participants at the time of, or after, surgery, as measured by the pathologic response rate; downstaging; and survival at 5 years from the start of treatment.

Enrollment: 23 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

INCLUSION CRITERIA

• Histologically-confirmed adenocarcinoma of the rectum. Clinical stages T3; T4; or N1 as determined by endoscopic ultrasound; or a rectal CT or MRI scan are eligible, including T3 N0; T3 N1; T4 N0; T4 N1; T1-4 N1. Rectal cancers are defined as those whose distal border extends to within 12 cm of the anal verge.

• Age ≥ 18

• Karnofsky performance status (KPS) ≥ 70

• Leukocyte count > 3,500 x 10e6/µL

• Platelet count > 100,000/µL

• Serum glutamic-oxaloacetic transaminase (SGOT) < 2.5 x institutional upper limits of normal (ULN)

• Serum glutamic-pyruvic transaminase (SGPT) < 2.5 x ULN

• Alkaline phosphatase < 2.5 x ULN

• Total bilirubin < 1.5x ULN

• Creatinine:

  • Within normal institutional limits
  • OR
  • Creatinine clearance > 60 mL/min/1.73 m2 (if serum creatinine levels above institutional normal)

• Ability to swallow pills without difficulty

• Women of child-bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG), within 72 hours prior to the start of study medication

• Women of child-bearing potential must be using an adequate method of contraception to avoid pregnancy throughout the treatment

EXCLUSION CRITERIA

• Metastatic (M1) or stage IV disease

• Prior history of treatment with cetuximab or other therapy targeting EGFR

• Prior history of anti-cancer murine monoclonal antibody therapy

• Prior pelvic or whole abdominal radiotherapy

• Uncontrolled intercurrent illness including, but not limited to:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness / social situations that would limit compliance with study requirements

• Patients with a concurrent malignancy or previous malignancy within 5 years of screening will be excluded from this study (EXCEPTION: concurrent or previous non-melanoma skin cancer, hematolymphoid malignancy or carcinoma in-situ of the cervix may be allowed at the investigator's discretion)

• Inability to sign written consent

• Pregnant or breastfeeding

• Unwilling or unable to use effective contraception in self or partner for the entire study period and for up to 4 weeks after the study

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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23 participants in 4 patient groups

Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100

Experimental group

Description:

* Cetuximab 250 mg/m² / week * Capecitabine 800 mg/m² * Radiotherapy (XRT) * Oxaliplatin 100 mg/m², Days 2 and 23

Treatment:

Drug: Diphenhydramine hydrochloride (HCl)

Drug: Capecitabine

Drug: Cetuximab

Radiation: Radiotherapy

Drug: Oxaliplatin

Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85

Experimental group

Description:

* Cetuximab 250 mg/m² / week * Capecitabine 700 mg/m² * Radiotherapy (XRT) * Oxaliplatin 85 mg/m², Days 2 and 23

Treatment:

Drug: Diphenhydramine hydrochloride (HCl)

Drug: Capecitabine

Drug: Cetuximab

Radiation: Radiotherapy

Drug: Oxaliplatin

Group A - Cetuximab + Capecitabine-800 + XRT

Experimental group

Description:

* Cetuximab 250 mg/m² / week * Capecitabine 800 mg/m² * Radiotherapy (XRT)

Treatment:

Drug: Diphenhydramine hydrochloride (HCl)

Drug: Capecitabine

Drug: Cetuximab

Radiation: Radiotherapy

Group B - Cetuximab + Capecitabine-1000 + XRT

Experimental group

Description:

* Cetuximab 250 mg/m² / week * Capecitabine 1000 mg/m² * Radiotherapy (XRT)

Treatment:

Drug: Diphenhydramine hydrochloride (HCl)

Drug: Capecitabine

Drug: Cetuximab

Radiation: Radiotherapy