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

Phase 1

Terminated

Conditions: Rectal Cancer
Colo-rectal Cancer

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

Registration Number: NCT00226941

Lead Sponsor: George Albert Fisher

Brief Summary: 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)

Detailed 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 23

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100	Cetuximab	* Cetuximab 250 mg/m² / week * Capecitabine 800 mg/m² * Radiotherapy (XRT) * Oxaliplatin 100 mg/m², Days 2 and 23
Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100	Oxaliplatin	* Cetuximab 250 mg/m² / week * Capecitabine 800 mg/m² * Radiotherapy (XRT) * Oxaliplatin 100 mg/m², Days 2 and 23
Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100	Capecitabine	* Cetuximab 250 mg/m² / week * Capecitabine 800 mg/m² * Radiotherapy (XRT) * Oxaliplatin 100 mg/m², Days 2 and 23
Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100	Radiotherapy	* Cetuximab 250 mg/m² / week * Capecitabine 800 mg/m² * Radiotherapy (XRT) * Oxaliplatin 100 mg/m², Days 2 and 23
Group 1 - Cetuximab + Capecitabine-800 + XRT + Oxaliplatin-100	Diphenhydramine hydrochloride (HCl)	* Cetuximab 250 mg/m² / week * Capecitabine 800 mg/m² * Radiotherapy (XRT) * Oxaliplatin 100 mg/m², Days 2 and 23
Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85	Capecitabine	* Cetuximab 250 mg/m² / week * Capecitabine 700 mg/m² * Radiotherapy (XRT) * Oxaliplatin 85 mg/m², Days 2 and 23
Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85	Radiotherapy	* Cetuximab 250 mg/m² / week * Capecitabine 700 mg/m² * Radiotherapy (XRT) * Oxaliplatin 85 mg/m², Days 2 and 23
Group A - Cetuximab + Capecitabine-800 + XRT	Capecitabine	* Cetuximab 250 mg/m² / week * Capecitabine 800 mg/m² * Radiotherapy (XRT)
Group A - Cetuximab + Capecitabine-800 + XRT	Radiotherapy	* Cetuximab 250 mg/m² / week * Capecitabine 800 mg/m² * Radiotherapy (XRT)
Group A - Cetuximab + Capecitabine-800 + XRT	Diphenhydramine hydrochloride (HCl)	* Cetuximab 250 mg/m² / week * Capecitabine 800 mg/m² * Radiotherapy (XRT)
Group B - Cetuximab + Capecitabine-1000 + XRT	Cetuximab	* Cetuximab 250 mg/m² / week * Capecitabine 1000 mg/m² * Radiotherapy (XRT)
Group B - Cetuximab + Capecitabine-1000 + XRT	Capecitabine	* Cetuximab 250 mg/m² / week * Capecitabine 1000 mg/m² * Radiotherapy (XRT)
Group B - Cetuximab + Capecitabine-1000 + XRT	Radiotherapy	* Cetuximab 250 mg/m² / week * Capecitabine 1000 mg/m² * Radiotherapy (XRT)
Group B - Cetuximab + Capecitabine-1000 + XRT	Diphenhydramine hydrochloride (HCl)	* Cetuximab 250 mg/m² / week * Capecitabine 1000 mg/m² * Radiotherapy (XRT)
Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85	Diphenhydramine hydrochloride (HCl)	* Cetuximab 250 mg/m² / week * Capecitabine 700 mg/m² * Radiotherapy (XRT) * Oxaliplatin 85 mg/m², Days 2 and 23
Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85	Cetuximab	* Cetuximab 250 mg/m² / week * Capecitabine 700 mg/m² * Radiotherapy (XRT) * Oxaliplatin 85 mg/m², Days 2 and 23
Group 2 - Cetuximab + Capecitabine-700 + XRT + Oxaliplatin-85	Oxaliplatin	* Cetuximab 250 mg/m² / week * Capecitabine 700 mg/m² * Radiotherapy (XRT) * Oxaliplatin 85 mg/m², Days 2 and 23
Group A - Cetuximab + Capecitabine-800 + XRT	Cetuximab	* Cetuximab 250 mg/m² / week * Capecitabine 800 mg/m² * Radiotherapy (XRT)

Primary Outcome Measures

Name	Time	Method
Dose-limiting Toxicity (DLT) - Number of DLTs by Treatment Group	10 weeks	Dose-limiting Toxicity (DLT) is the measure used to establish overall Maximum-tolerated dose (MTD) of cetuximab + capecitabine + radiotherapy +/- oxaliplatin. MTD is defined as the highest dose level for which participants have a \< 30% incidence of dose-limiting toxicity (DLT). The outcome is expressed as the number of DLTs by treatment group.
Dose-limiting Toxicity (DLT) - Number of Participants Affected	10 weeks	Dose-limiting Toxicity (DLT) is the measure used to establish overall Maximum-tolerated dose (MTD) of cetuximab + capecitabine + radiotherapy +/- oxaliplatin. MTD is defined as the highest dose level for which participants have a \< 30% incidence of dose-limiting toxicity (DLT). The outcome is expressed as the number of participants experiencing a DLT.

Secondary Outcome Measures

Name	Time	Method
Tumor Downstaging at Surgical Resection	12 to 14 weeks after radiotherapy	Downstaging means a reduction from the stage of disease observed at baseline to the stage of disease after treatment with cetuximab, radiotherapy, oxaliplatin, and capecitabine, as determined at the time of surgical removal of the tumor. Downstaging may be observed as improvements in tumor staging at the primary site of the tumor; in nearby (regional) lymph nodes; or in metastatic disease beyond the regional lymph nodes. This outcome specifically does not include participants that achieved a complete response, nor those that experienced no response or disease progression.
Survival at 5 Years	5 years	Survival at 5 years was assessed as the number of participants alive 5 years after starting treatment.
Time-to-Progression (TTP)	5 years	Time-to-progression was assessed as the time from the date of surgical resection to the appearance of either local disease recurrence or distant metastases by any modality (eg, clinical exam, endoscopy, radiographic imaging). All relapses were to be confirmed by biopsy and pathology review.
Pathologic Response Rate	12 to 14 weeks after radiotherapy	After treatment with capecitabine, cetuximab, radiotherapy, and oxaliplatin, the pathologic response rate was assessed based on the excised tumor taken at the time of surgical resection. Pathologic response rate was determined as the number and proportion of participants who experienced either downstaging of their disease, or complete response (CR, no detectable disease). A participant will be considered to have downstaging of the tumor as a result of the neoadjuvant therapy when the primary tumor (T) stage by pathology isless than the T stage by clinical (endoscopic) evaluation, or when the regional lymph node (N) tumor stage by pathology is less than the N stage by clinical (endoscopic) evaluation.
Overall Survival (OS)	72 months	Overall Survival (OS) was assessed as the mean survival from the date of entry on study though 72 months.