Clinical Trials

OBJECTIVES:

     Primary

       -  To compare disease-free survival of patients with resected stage III colon cancer treated with adjuvant FOLFOX chemotherapy comprising oxaliplatin, fluorouracil, and leucovorin calcium with versus without celecoxib.

     Secondary

       -  To contribute to an international prospective pooled analysis comparing disease-free survival of patients treated with these regimens.

       -  To compare overall survival at 3 years of patients treated with these regimens.

       -  To contribute to an international prospective pooled analysis comparing disease-free survival of patients treated with 6 versus 12 courses of FOLFOX chemotherapy.

       -  To assess toxicities of celecoxib as maintenance adjuvant therapy in these patients.

       -  To assess differences in cardiovascular-specific events in patients treated with versus without celecoxib.

       -  To evaluate differences in toxicities, particularly cumulative peripheral neuropathy, in patients treated with 6 versus 12 courses of FOLFOX chemotherapy.

     OUTLINE: This is a multicenter study. Patients are stratified according to number of positive lymph nodes* (1-3 vs 4 or more) and concurrent regular low-dose of aspirin (yes vs no). Patients are randomized to 1 of 4 treatment arms.

     NOTE: *Patients with N1c-only disease (i.e., no positive nodes but N1c disease by AJCC 7) should be stratified to 1-3 nodes.

       -  Arm I: Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 46-48 hours (FOLFOX) on day 1. Patients also receive oral celecoxib once daily on days 1-14 beginning on day 1 of course 2 of FOLFOX. Courses repeat every 14 days for 12 courses in the absence of disease progression or unacceptable toxicity.

       -  Arm II: Patients receive FOLFOX as in arm I and oral placebo once daily on days 1-14 beginning on day 1 of course 2. Courses repeat every 14 days for 12 courses in the absence of disease progression or unacceptable toxicity.

       -  Arm III: Patients receive FOLFOX and celecoxib as in arm I. Courses repeat every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity.

       -  Arm IV: Patients receive FOLFOX and placebo as in arm II. Courses repeat every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity.

     In all arms, treatment with celecoxib or placebo continues for 3 years in the absence of disease progression or unacceptable toxicity.

     Blood and tissue samples maybe collected for biomarker analysis and pharmacogenomic studies.

     After completion of study therapy, patients are followed up every 3 months for 1 year, every 6 months for years 2-3, and then annually for 3 years.

PRIMARY OBJECTIVES:

     I. The proportion of subjects with an adenoma recurrence at the 1-year follow-up colonoscopy exam. This adenoma recurrence rate for difluoromethylornithine (DFMO) (eflornithine) + aspirin will be compared to double placebo to see if there is improvement in the adenoma recurrence rate in this patient population.

     SECONDARY OBJECTIVES:

     I. To determine the relative tolerability and safety of the treatment regimens administered for 12 months.

     II. To determine the effect of the study drugs (aspirin [acetylsalicylic acid] + DFMO) and placebo with respect to proliferation (Ki67 labeling index), apoptosis (caspase-3 expression assay), and drug effect markers (COX-1, -2, polyamines, PGE2) from adenomas, aberrant crypt focus (ACF) and normal-appearing mucosa using pre- and 12-month post-intervention tissue biopsy samples.

     III. To estimate the percentage change in rectal ACF number, as determined by magnifying colonoscopy in subjects treated for 12 months with placebo or study drugs (aspirin +DFMO) by comparing % change in drug versus placebo arms.

     IV. To characterize ACF based on three criteria (ACF size [crypt number < 50 or >= 50], crypt morphology characteristics, and histology) of ACF and to correlate such characteristics with the intervention (vs placebo). Also, to evaluate the natural history of ACF over 1-year on placebo.

     V. To correlate the 12-month measurements of ACF size (# crypts/ACF), number, morphology, and histopathology with the adenoma recurrence data at 12 and 36 months; correlate the 12-month % (and actual) change in ACF size and number with the 12- and 36-month adenoma recurrence rate; and correlate the adenoma recurrence data at 1 year with the adenoma recurrence data at 3 years.

     TERTIARY OBJECTIVES:

     I. To explore the effects of the study agents on a focused panel of tissue biomarkers in pre- and post-intervention biopsy samples from recurrent adenomas, rectal ACF, and adjacent normal-appearing mucosa among subjects enrolled in the phase II clinical trial.

     II. To determine if cleaved capase-3 expression can improve the detection of apoptotic cells by recognizing cellular commitment to apoptosis prior to late nuclear morphologic features and correlate with apoptotic regulatory proteins, histology, and treatment response.

     III. To determine the effects of aspirin on its biochemical targets COX-1, -2, and prostaglandin E2, and polyamine levels in subjects receiving DFMO.

     IV. To examine COX-2-dependent genes (i.e., Bcl-2 and DR5) in adenomas and ACF that have been shown to regulate the intrinsic mitochondrial and extrinsic death receptor-mediated apoptotic pathways in vitro and in vivo.

     V. To perform expression profiling of adenomas or ACF and to relate such date to ACF histology, size/morphology, modulation by chemopreventive agents, and subsequent adenoma recurrence rates.

     OUTLINE: Patients are randomized to 1 of 2 treatment arms.

     ARM I: Patients receive acetylsalicylic acid orally (PO) once daily and eflornithine PO twice daily on days 1-28.

     ARM II: Patients receive placebo PO three times daily on days 1-28.

     Treatment repeats every 28 days for 12 months in the absence of disease progression or unacceptable toxicity.

     After completion of study treatment, patients are followed at 6, 12, and 36 months.

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.

OBJECTIVES:

     Primary

       -  To test the hypothesis that laparoscopic-assisted resection is not inferior to open resection, based on a composite primary endpoint of oncologic factors that are indicative of a safe and feasible surgical resection, in patients with stage IIA, IIIA, or IIIB rectal cancer.

     Secondary

       -  To compare the patient-related benefit of laparoscopic-assisted resection vs open resection, in terms of blood loss, length of stay, and utilization of pain medication.

       -  To compare the disease-free survival and local pelvic recurrence at 2 years.

       -  To compare the quality of life, sexual function, and bowel and stoma function.

     OUTLINE: This is a multicenter study. Patients are stratified according to site of primary tumor (high vs middle vs low rectum), registering surgeon, and planned operative procedure (low anterior resection vs abdominal perineal resection). Patients are randomized to 1 of 2 treatment arms.

       -  Arm I: Patients undergo open laparotomy and rectal resection.

       -  Arm II: Patients undergo laparoscopic-assisted rectal resection. Quality of life is assessed periodically using EORTC Quality of Life Questionnaires (EORTC QLQ-C30 and -CR38), the Linear Analog Self-Assessment (LASA), the Stoma Quality of Life Scale (SQOLS), and the Mayo Bowel Function Questionnaire (MBFQ).

     After completion of study treatment, patients are followed periodically for up to 5 years.