Trial Information

A Phase II/III Trial of Neoadjuvant FOLFOX, With Selective Use of Combined Modality Chemoradiation Versus Preoperative Combined Modality Chemoradiation for Locally Advanced Rectal Cancer Patients Undergoing Low Anterior Resection With Total Mesorectal Excision

OBJECTIVES:

Primary

- To assure that neoadjuvant oxaliplatin, leucovorin calcium, and fluorouracil (FOLFOX)
followed by selective use of combined modality therapy with fluorouracil (5FUCMT) group
(Group 1) maintains the current high rate of pelvic R0 resection and is consistent with
non-inferiority for time to local recurrence (TLR). (Phase II)

- To compare neoadjuvant FOLFOX followed by Selective use of 5FUCMT (Group 1) to standard
5FUCMT (Group 2) with respect to the proportion of patients who achieve a pathologic
complete response (pCR) at the time of surgical resection. (Phase III)

- To compare bowel function in patients randomized to the neoadjuvant FOLFOX followed by
selective use of 5FUCMT vs standard 5FUCMT at approximately 1 and 2 years
postoperatively.

- To evaluate the feasibility of implementing the PRO-CTCAE in an NCI-sponsored treatment
trial.

- To evaluate the feasibility of implementing the PRO-CTCAE at Alliance sites.

- To evaluate the feasibility of patients self-reporting symptoms during treatment by
using the PRO-CTCAE.

- To prospectively use Molecular Inversion Probe (MIP) array technology and MALDI-TOF
mass spectrometry-based genotyping to identify copy number aberrations and somatic
mutations that mediate tumor formation using formalin-fixed, paraffin-embedded (FFPE)
tumor tissue from patients participating in the current study.

- To determine whether germline genetic variants in candidate genes of interest are
associated with response and/or toxicity to platinum and 5FU-based chemotherapy.

Secondary

- To determine if the neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) is
non-inferior to the standard group 5FUCMT (Group 2) with respect to the proportion of
patients who achieve a pCR at the time of surgical resection.

- To determine if the neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) is
non-inferior to the standard 5FUCMT (Group 2) with respect to overall survival.

- To evaluate and compare the adverse event profile and surgery complications between the
two groups.

- To estimate the proportion of patients in the selective group (Group 1) who receive
pre-operative 5FUCMT, post-operative 5FUCMT, and either pre- or post-operative 5FUCMT.

- To compare sexual function separately within men and within women between groups at
approximately 1 and 2 years post-operatively.

- To compare bladder function between groups at approximately 1 and 2 years
post-operatively.

- To compare health-related quality of life between groups at 1 and 2 years
post-operatively.

- To assess the correlation between bladder, bowel, and sexual function and quality of
life. (Exploratory)

- To investigate factors associated with bladder, bowel, and sexual dysfunction.
(Exploratory)

- To compare bladder and bowel function over time between genders. (Exploratory)

- To perform subgroup analyses based on other sociodemographic factors. (Exploratory)

- To evaluate and compare patients' self-reported symptom burden during treatment between
groups using the PRO-CTCAE system.

- To evaluate whether exposure to patient-reported symptoms influences CTCAE symptom
reporting by research staff. (Exploratory)

- To correlate the MIP array copy number and mutational data from patients with locally
advanced rectal cancer with clinical outcome in each treatment cohort (the clinical
outcomes include pathologic complete response, time to recurrence, time to pelvic
recurrence, and overall survival).

- To identify immune markers for response to neoadjuvant chemotherapy or chemoradiation
using very well-established, validated immunologic assays.

- To investigate the ability of neoadjuvant FOLFOX or chemoradiation to augment
anti-tumor immunity against rectal cancer.

- To identify novel immune targets in rectal cancer.

- To determine whether germline genetic variants in candidate genes of interest are
associated with response and/or toxicity to radiation therapy.

- To assess whether genetic-risk variants identified in genome-wide association studies
of colorectal cancer susceptibility are associated with rectal cancer clinical outcome
and response to therapy.

OUTLINE: This is a multicenter, phase II study followed by a phase III study. Patients are
stratified according to ECOG performance status (0 or 1 vs 2). Patients are randomized to 1
of 2 treatment arms.

- Group 1 (FOLFOX): Patients receive neoadjuvant chemotherapy comprising oxaliplatin IV
over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV
continuously on days 1-2. Treatment repeats every 14 days for 6 courses in the absence
of disease progression or unacceptable toxicity. Patients with at least 20% of tumor
regression undergo low-anterior resection (LAR) with total mesorectal excision (TME).
Patients with less than 20% of tumor regression undergo chemoradiation as in group 1
before proceeding to LAR with TME.

- Group 2 (5FUCMT): Patients receive fluorouracil IV continuously 7 days a week for 5.5
weeks or capecitabine orally (PO) twice daily (BID) 5 days a week for 5.5 weeks.
Patients also undergo 3-dimensional conformal or intensity-modulated radiation therapy
5 days a week for approximately 5.5 weeks. Patients then undergo LAR with TME.

Patients in both groups may receive adjuvant chemotherapy comprising FOLFOX and/or 5FUCMT.

Patients undergo blood sample collection at baseline and periodically during study for
genotyping and immunologic studies. Paraffin-embedded tissue samples from primary tumor are
also collected for aberration and somatic mutation studies by molecular inversion probe
(MIP) array and mass spectrometry-based genotyping.

Patients complete the Bowel Function Index, the Prostate Health-Related Quality-of-Life
(QOL) and the International Prostate Symptom Score (IPSS) questionnaires, the EuroQOL5D-5L
(EQ5D) questionnaire, and the International Index of Erectile Function (IIEF) or Female
Sexual Function Index (FSFI) questionnaire at baseline, and periodically during study.

After completion of study treatment, patient are followed up for up to 8 years.