A Phase I/ II Feasibility Study of Intravenous Cetuximab in Combination with 5 days Weekly Oral Capecitabine and Preoperative Radiotherapy in Rectal Cancer (XERXES)

Background Preoperative Long-course chemoradiation (LCCRT) is the standard-of-care in locally advanced rectal cancer (LARC). This phase I/II trial in two sequential studies aimed to evaluate the activity and safety of the anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab administered weekly-prior to, and following LCCRT. 
 
Patients and Methods All patients had magnetic resonance imaging (MRI) defined cT3/cT4 or node-positive rectal adenocarcinoma and treatment with LCCRT (capecitabine 825 mg/m2 bid on Monday-Friday for 5 weeks during radiotherapy [45Gy in 25 daily fractions] followed by total mesorectal excision (TME). In Phase I patients received weekly induction cetuximab 400mg/m2 loading, then 250mg/m2 once weekly for 4 weeks prior to standard LCCRT. In phase II 10 patients were randomised to receive: arm A standard LCCRT alone or arm B (sandwich) LCCRT with additional induction cetuximab 250mg/m2 weekly prior to LCCRT and consolidation for 5 weeks following. 
 
Results In Phase I all 12 patients proceeded to surgery with a single pCR (8%) reported. This pCR rate together with acceptable compliance (100%) and toxicity (4 Grade 3 toxicities, 2 skin rash, 1 pain and 1 pulmonary embolus) and the absence of severe surgical complications allowed continuation to phase II. In Phase II, 10 patients were recruited and five patients were randomly assigned to each treatment arm. One additional patient allocated cetuximab/CRT chose to withdraw from the trial and received no treatment. In Arm B 4/5 patients proceeded to surgery with one pCR compared to three of five patients proceeding to surgery with two achieving pCR in Arm A. The Trial closed after studies in metastatic disease reported efficacy depended on selection according to K-RAS/NRAs mutational status. 
 
Conclusions: In unselected patients without enrichment according to KRAS/NRAS/BRAF status, the addition of induction and consolidation cetuximab to pre-operative LCCRT provided modest efficacy with good compliance and manageable toxicity.


Introduction
Randomized phase III trials have confirmed that preoperative long-course chemoradiation (LCCRT) with concurrent fluoropyrimidines significantly reduces local recurrence in LARC and is now the standard of care [1,2]. Yet, not all patients respond, and achieving better local control has not impacted on the frequency of metastases and disease-free (DFS) or overall survival (OS) [3,4]. Hence, investigators have aspired both to enhance radio-sensitivity and to target potential micrometastases early by integrating additional neoadjuvant cytotoxic and molecularlytargeted treatments into LCCRT. This strategy also aims to increase down-staging and pathological complete response (pCR) rates, thereby potentially avoiding radical surgery with a 'watch and wait' management.
Integration of additional cytotoxic agents into standard LCCRT regimens has often been accompanied by excess acute toxicity with minimal increases in efficacy. Randomized phase III trials (STAR-01, EGFR-targeted monoclonal antibodies are effective in metastatic colorectal cancer (mCRC) and significantly prolong PFS [12,13], investigators have examined the addition of EGFR targeted therapies in combination with LCCRT in LARC. The molecular rationale has been previously reviewed in depth [14].
Cetuximab is a chimeric immunoglobulin G1 monoclonal antibody directed against EGFR, which is responsible for cell differentiation, proliferation, and survival. Pre-clinical studies demonstrate hypoxia may upregulate EGFR [15]. Landmark trials in squamous cell cancer of the head and neck (SCHN) showed the addition of cetuximab combined with radiotherapy, improved both loco-regional control and median OS [16] compared to patients who received radiation alone.
Early clinical studies in rectal cancer provided inconsistent response results for EGFR expression and cetuximab and radiation [9,11,17]. Phase I trials demonstrated an acceptable toxicity profile (Grade 3 diarrhoea in 15-20%) but no obvious increase in down-staging [18,19].
A subsequent randomised phase II study of cetuximab and 5-FU chemoradiation, showed similar pCR rates for patients in the cetuximab arm to patients on the standard LCCRT control arm without cetuximab [25].
Even when analysed for KRAS wild-type participants, studies showed no difference in PCR rates or outcomes [26][27][28]. Hence, the benefit of cetuximab in addition to concurrent single or doublet chemotherapy in rectal cancer CRT remains uncertain.
Hence, the integration of cetuximab as consolidation was proposed after the completion of LCCRT in the interval before surgery [22]. Other investigators also suggested efficacy of radiation might be enhanced by cetuximab-induced inhibition of repopulation during the latter phase of radiotherapy [29].
This present study aimed to investigate the strategy of the addition of induction, concurrent and consolidation cetuximab to capectabine-based LCCRT in a phase I/ II sequential study. However, accumulating evidence of poor efficacy (in terms of pCR) and in light of the widely held hypothesis that cetuximab can lead to G1 or G2/M cell cycle arrest, the phase II protocol was amended to examine a novel cetuximab induction and consolidation 'sandwich' approach to avoid concurrent administration. The design of our Phase II trial was amended. In the revised design patients were randomly assigned in a 1:1 ratio to a standard treatment arm A (radiotherapy and capecitabine without cetuximab) or to receive weekly induction cetuximab x 4 before and after capecitabine LCCRT (but not concurrently) in Arm B.

Trial Design
( Figure 1). There were no stratification factors.
This study is registered at controlled-trials.com, number 26715889. mg/m 2 weekly for 5 weeks following LCCRT.

Endpoint Measurements and Data Analysis
The

Statistical Analysis/Sample Size
No formal sample calculation was done for the phase 1b design. The sample size required for the phase II study was based on a Fleming single stage design [32].
It was assumed that the pCR rate in historical controls was 8%. With an 80% power and 5% one sided significance level, 24 patients were required to detect an expected pCR rate of >=25% in the cetuximab 'sandwich' regimen. Therefore, if at least 5 patients achieved pCR, then this would be seen as sufficient to warrant further investigation of this regimen. A noncomparative randomised design was added to this study to allow a descriptive comparison between the experimental regimen and the control group and therefore a further 24 patients were randomised to a control group.

Results
Pre-treatment characteristics for both trials are shown in Table 1, confirming these were locally advanced cancers according to MRI criteria, and that they were well balanced in the randomised phase II. In the phase I trial, compliance to capecitabine in LCCRT was excellent with no reductions for toxicity.
Compliance to cetuximab was also acceptable. One patient stopped cetuximab with toxicity, and two patients had a delay (one for administrative reasons).
Compliance to irradiation was acceptable ( Table 2).
All 12 patients enrolled in the phase I proceeded to surgery with a single pCR (8%) reported. With a median follow-up of 42 months, five patients recurred (liver (1), lung (1), brain (1), loco-regional and spleen (1) and loco-regional/nodal/lung (1) and 3 patients died due to rectal cancer; 1 patient died due to Rectal cancer + Chemo related SAE (Renal Failure and Pneumonia).
In the randomised phase II, 10 patients were recruited and randomly assigned to Group A (5) and group B (5) before the early closure of the trial on 11 th September 2012. This was on the recommendation of the Trial steering Committee due to emerging data from other phase II trials reporting on selection for cetuximab according to KRAS mutation status. One patient allocated cetuximab/CRT chose to withdraw from the trial and received no treatment. Hence the analysis is based on 9 patients.
In the phase II a range of adverse events were reported at Grade 3 and below (  (2), intercurrent illness (1) and toxicity (1).
One of 5 patients in the control arm and 2 of 3 in the cetuximab arm achieved a pCR (3/10 on ITT and 3/7 who underwent surgery Not reported for WHO performance status 0 (0%) 0 (0%) 1 (20%)