Phase I study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3552-3552 ◽  
Author(s):  
J. P. Machiels ◽  
C. Sempoux ◽  
P. Scalliet ◽  
J. C. Coche ◽  
B. Coster ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Dose Level ◽  
Initial Dose ◽  
External Beam Radiotherapy ◽  
Growth Factor Receptor ◽  
Radiation Dermatitis ◽  
Preoperative Treatment ◽  
Rectal Pain ◽  
Epidermal Growth ◽  
Grade 3

3552 Background: Capecitabine has the potential to replace 5-FU as standard agent in combination with radiotherapy in rectal cancer. Cetuximab is a monoclonal antibody directed against the epidermal growth factor receptor. Both agents are active in the treatment of colorectal cancer and have demonstrated radiosensitising properties. The aim of this study was to assess the feasibility of combining cetuximab and capecitabine with concurrent radiation in the preoperative treatment of patients with rectal cancer. Methods: Twenty patients with rectal cancer (T3-T4 and/or N+, endorectal ultrasound) received radiotherapy (1.8 Gy, 5 days a week over 5 weeks, total dose 45 Gy, 3D conformal technique) in combination with cetuximab (initial dose 400 mg/m2 given one week before the beginning of radiation followed by 250 mg/m2/week for 5 weeks) and 2 different doses of capecitabine for the duration of radiotherapy (650 mg/m2 twice-daily, first dose level; 825 mg/m2 twice-daily, second dose level, including weekends). During treatment all patients were scored weekly using the NCI-CTC v.2.0. Dose-limiting toxicity (DLT) was defined acccording to Dunst (JCO 2002). Six to 8 weeks after the end of chemoradiation surgery was performed. Results: Four and six patients were treated at the first and second dose level of capecitabine, respectively. No DLT occurred at either capecitabine dose. Ten additional patients were treated at the higher dose level. Out of these 20 patients, Grade 3 toxicity included diarrhea (n=2), rectal pain (n=5), ileitis (n=2), radiation dermatitis (n=1) and neutropenia (n=1). The most frequent grade 1/2 side effects were acneiform rash (n=16, 80%), fatigue (n=12, 60%), and diarrhea (n=12, 60%). Until now, 2 pathological complete responses were observed in 19 evaluable patients. Conclusions: Preoperative radiotherapy in combination with capecitabine and cetuximab is feasible and well-tolerated with promising efficacy results. The recommended doses for phase II evaluation are capecitabine 825 mg/m2 twice-daily without interruption during the duration of radiotherapy and cetuximab at an initial dose of 400 mg/m2 followed by 250 mg/m2/week. No significant financial relationships to disclose.

Preliminary results of a phase I study of external beam radiation therapy (EBRT), oxaliplatin (OX), bevacizumab (BV), and capecitabine (CAP) for locally advanced or metastatic adenocarcinoma of the rectum

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3543-3543
Author(s):  
B. Czito ◽  
J. Bendell ◽  
C. Willett ◽  
G. Vaccaro ◽  
M. Morse ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Dose Level ◽  
Infusion Pump ◽  
Locally Advanced ◽  
Radiation Sensitivity ◽  
External Beam Radiation ◽  
Beam Radiation ◽  
Rectal Pain ◽  
Level 1 ◽  
Grade 3

3543 Background: BV, a monoclonal antibody against vascular endothelial growth factor, increases survival when added to first and second line chemotherapy for metastatic colorectal cancer. Preclinical studies suggest BV may enhance tumoral radiation sensitivity. Preliminary studies of OX and 5-FU based chemoradiation therapy for rectal cancer have suggested improved pathologic CR rates compared to 5-FU/ radiation alone. CAP allows fluoropyrimidine treatment without the inconvenience of an infusion pump. We investigated CAP + BV + OX + EBRT for pts with rectal cancer to evaluate for the MTD and preliminary efficacy results. Methods: Pts with adenocarcinoma of the rectum and no prior pelvic irradiation received 5040 cGy EBRT (180 cGy/fx), CAP (625–825 mg/m2 PO BID on EBRT days), BEV (15 mg/kg d1 and 10 mg/kg d8 and d22), and OX (50–75 mg/m2/week during radiation, weeks 1–5) in dose-escalating fashion. DLT was defined as any grade 3 heme tox ≥ 7d, grade 4 heme tox, grade 4 non-heme tox during chemoradiation, or inability to deliver >85% of planned treatment. Pts eligible for surgical resection could have surgery 6–8 wks after treatment completion. After recovery from surgery, patients could be treated with CAP, BV, and OX. Results: 11 patients (5 men/6 women) have been enrolled. All have completed chemoradiation and resection. At dose level 1 (CAP 625 mg/m2 BID, OX 50mg/m2) there were no DLT’s in 3 pts. 1/3 pts had G3 subarachnoid hemorrhage during adjuvant chemotherapy. At dose level 2 (CAP 825 mg/m2, OX 50 mg/m2) 2/2 pts had DLT (1 G4 diarrhea; 1 G2 rectal pain, causing treatment hold for study-defined DLT). 6 more pts were treated at dose level 1. 1pt had DLT of G3 diarrhea. G2 toxicities included diarrhea (3/11), fatigue (2/11), skin changes (2/11), and pain (2/11). 9/11 patients were downstaged. 2/11 patients had pCR at surgery and 2/11 microscopic disease only. Conclusions: CAP + BEV + OX + EBRT is a well-tolerated, active regimen for the treatment of rectal cancer. MTD was determined to be CAP 625 mg/m2 BID + BEV 15 mg/kg d1 + 10 mg/kg d 8 and 22 + OX 50 mg/m2/week. Further study of efficacy at the MTD is warranted. [Table: see text]

scholarly journals Phase I Active Immunotherapy With Combination of Two Chimeric, Human Epidermal Growth Factor Receptor 2, B-Cell Epitopes Fused to a Promiscuous T-Cell Epitope in Patients With Metastatic and/or Recurrent Solid Tumors

2009 ◽  
Vol 27 (31) ◽  
pp. 5270-5277 ◽  
Author(s):  
Pravin T.P. Kaumaya ◽  
Kevin Chu Foy ◽  
Joan Garrett ◽  
Sharad V. Rawale ◽  
Daniele Vicari ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Dose Level ◽  
Stable Disease ◽  
Cell Epitope ◽  
Growth Factor Receptor ◽  
T Cell Epitope ◽  
B Cell Epitopes ◽  
Epidermal Growth

Purpose To evaluate the maximum-tolerated dose (MTD), safety profile, and immunogenicity of two chimeric, B-cell epitopes derived from the human epidermal growth factor receptor (HER2) extracellular domain in a combination vaccine with a promiscuous T-cell epitope (ie, MVF) and nor-muramyl-dipeptide as adjuvant emulsified in SEPPIC ISA 720. Patients and Methods Eligible patients with metastatic and/or recurrent solid tumors received three inoculations on days 1, 22, and 43 at doses of total peptide that ranged from 0.5 to 3.0 mg. Immunogenicity was evaluated by enzyme-linked immunosorbent assay, flow cytometry, and HER2 signaling assays. Results Twenty-four patients received three inoculations at the intended dose levels, which elicited antibodies able to recognize native HER2 receptor and inhibited both the proliferation of HER2-expressing cell lines and phosphorylation of the HER2 protein. The MTD was determined to be the highest dose level of 3.0 mg of the combination vaccine. There was a significant increase from dose level 1 (0.5 mg) to dose level 4 (3.0 mg) in HER2-specific antibodies. Four patients (one each with adrenal, colon, ovarian, and squamous cell carcinoma of unknown primary) were judged to have stable disease; two patients (one each with endometrial and ovarian cancer) had partial responses; and 11 patients had progressive disease. Patients with stable disease received 6-month boosts, and one patient received a 20-month boost. Conclusion The combination vaccines were safe and effective in eliciting antibody responses in a subset of patients (62.5%) and were associated with no serious adverse events, autoimmune disease, or cardiotoxicity. There was preliminary evidence of clinical activity in several patients.

scholarly journals Treatment of Rectal Cancer-Induced Disseminated Carcinomatosis of the Bone Marrow with FOLFOX plus Cetuximab and Panitumumab

2020 ◽  
Vol 13 (1) ◽  
pp. 145-152
Author(s):  
Takehito Ehara ◽  
Masato Kitazawa ◽  
Nao Hondo ◽  
Shugo Takahata ◽  
Yuta Yamamoto ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Bone Marrow ◽  
Poor Prognosis ◽  
Rare Complication ◽  
Growth Factor Receptor ◽  
Initial Condition ◽  
Aortic Lymph Node ◽  
Epidermal Growth ◽  
Node Metastases

Disseminated carcinomatosis of the bone marrow (DCBM) in colorectal cancer is an extremely rare complication with a poor prognosis. Here, we report a case of DCBM due to rectal cancer successfully treated with a combination of FOLFOX and an anti-epidermal growth factor receptor (EGFR) agent. The patient was a 38-year-old man diagnosed with rectal cancer with multiple bone and para-aortic lymph node metastases complicated by disseminated intravascular coagulation (DIC). He first recovered from DIC following cotreatment with FOLOX plus cetuximab; subsequently, the second attack was successfully treated with FOLFOX plus panitumumab. His initial condition was extremely poor, but he survived with two FOLFOX plus anti-EGFR regimens and died 333 days after introduction of chemotherapy.

scholarly journals Intensity-Modulated Radiation Therapy for Rectal Carcinoma Can Reduce Treatment Breaks and Emergency Department Visits

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Salma K. Jabbour ◽  
Shyamal Patel ◽  
Joseph M. Herman ◽  
Aaron Wild ◽  
Suneel N. Nagda ◽  
...  
Keyword(s):  
Emergency Department ◽  
Rectal Cancer ◽  
Radiation Therapy ◽  
Intensity Modulated Radiation Therapy ◽  
Emergency Department Visits ◽  
Long Term Results ◽  
Radiation Dermatitis ◽  
Conformal Radiation Therapy ◽  
Grade 3 ◽  
Chi Square Analysis

Purpose. To compare the acute toxicities of IMRT to 3D-conformal radiation therapy (3DCRT) in the treatment of rectal cancer.Methods and Materials. Eighty-six patients with rectal cancer preoperatively treated with IMRT (n=30) and 3DCRT (n=56) were retrospectively reviewed. Rates of acute toxicity between IMRT and 3DCRT were compared for anorexia, dehydration, diarrhea, nausea, vomiting, weight loss, radiation dermatitis, fatigue, pain, urinary frequency, and blood counts. Fisher's exact test and chi-square analysis were applied to detect statistical differences in incidences of toxicity between these two groups of patients.Results. There were fewer hospitalizations and emergency department visits in the group treated with IMRT compared with 3DCRT (P=0.005) and no treatment breaks with IMRT compared to 20% with 3DCRT (P=0.0002). Patients treated with IMRT had a significant reduction in grade ≥3 toxicities versus grade ≤2 toxicities (P=0.016) when compared to 3DCRT. The incidence of grade ≥3 diarrhea was 9% among 3DCRT patients compared to 3% among IMRT patients (P=0.31).Conclusions. IMRT for rectal cancer can reduce treatment breaks, emergency department visits, hospitalizations, and all grade ≥3 toxicities compared to 3DCRT. Further evaluation and followup is warranted to determine late toxicities and long-term results of IMRT.

A phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of MDX-214, a novel immune-mediated mechanism agent targeting the epithelial growth factor receptor (EGFR), in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2523-2523 ◽  
Author(s):  
C. A. Mita ◽  
K. Papadopoulos ◽  
M. M. Mita ◽  
A. Ricart ◽  
J. Sarantopoulos ◽  
...  
Keyword(s):  
Dose Level ◽  
Immune Cell ◽  
Growth Factor Receptor ◽  
Infusion Reaction ◽  
Maximum Tolerated Dose ◽  
Cell Trafficking ◽  
Fab Fragment ◽  
Immune Mediated ◽  
Grade 3

2523 Background: MDX-214 is a recombinant fusion protein between human EGF and the Fab′ fragment of a fully human anti-CD89 (IgA FcR) MAb. MDX-214 is designed to block EGFR and activate neutrophils via CD89 stimulation, and promotes EGFR+ cell killing in vitro by both mechanisms. Methods: The objectives of this study were to evaluate the safety and tolerability, to determine the maximum tolerated dose (MTD), to characterize the PK, to assess PD markers and to explore the antitumor activity of MDX-214 administered intravenously weekly for 4 weeksin EGFR+ malignancies. PD studies included monitoring immune cell trafficking to tumors by paired In111 WBC scans at the final dose level, MDX-214 saturation of CD89+ neutrophils in blood, as well as EGFR signaling in skin. Pts were permitted only 1 course of therapy. Results: To date, 18 pts (median age 61, range 48–83, 10 M/8 F) have been treated over 4 dose levels at 0.4, 1, 4 and 10 mg/m2, respectively. Tumor types included renal (4), colorectal (2), pancreatic (2), head/neck (2), tracheal, parotid, esophageal, breast, anal, thyroid, hepatocellular, and skin carcinomas. DLT was encountered at 10 mg/m2 with one grade 3 reversible infusion reaction of rigors, erythema and transient hypoxemia. In the 6 pts treated at this dose level, 2 additional pts experienced grade 2 infusion reactions despite premedication, and one grade 2 hypotension. The MTD was therefore 4 mg/m2. Other grade 1–2 toxicities included nausea/vomiting (9), diarrhea (2), fatigue (4), headache (4). There were 7 pts with stable disease at 6 weeks. The serum half-life was < 30 min but neutrophil-bound MDX-214 was detectable for 24 h. In111 WBC scans are under analysis. Conclusion: Weekly administration of MDX-214, a novel immune mediated therapeutic strategy targeting EGFR is feasible with an MTD of 4 mg/m2. This dose results in neutrophil labeling with MDX-214 for over 24 hours, and may permit activated neutrophil localization at tumor sites. Accrual at the MTD is ongoing. [Table: see text]

Incorporation of bevacizumab (B) and erlotinib (Er) with induction (Ind) and concurrent (Conc) carboplatin (Cb)/paclitaxel (P) and 74 Gy of thoracic radiotherapy in stage III non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7528-7528
Author(s):  
M. A. Socinski ◽  
T. E. Stinchcombe ◽  
J. S. Halle ◽  
D. T. Moore ◽  
W. J. Petty ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase Ii ◽  
Growth Factor Receptor ◽  
Conformal Radiotherapy ◽  
Vascular Endothelial ◽  
Treatment Paradigm ◽  
Epidermal Growth ◽  
Grade 3 ◽  
Endothelial Growth Factor ◽  
Pet Scans

7528 Background: Therapies directed at both the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathways have been shown to improve survival in NSCLC and also have radiosensitizing properties. Methods: Pts receive Ind Cb (AUC 6), P (225 mg/m2) and B (15 mg/kg) on d1 and 22. PET scans are done pre- and post-I. On day 43, pts receive weekly Cb (AUC 2 x 7) and P (45 mg/m2 x 7) with 74 Gy (2 Gy/d) of thoracic conformal radiotherapy (TCRT). Cohort I (n=5) received B at 10 mg/kg q2wks during C therapy. Cohorts II and III (both n=5) received the same dose of B as in cohort I but also received Er at 100 mg and 150 mg po Tuesday - Friday of each week of C therapy, respectively. The primary endpoint is PFS at 1 year. All histologies are allowed including squamous (SQ) (an early stopping rule is in place for pulmonary hemorrhagic (PH) complications in SQ pts). Results: Thus far, 31 eligible PS 0–1 pts have been accrued (med age 62 yrs, range 41–74, 19 non- squamous, 12 SQ, 63% IIIA, 37% IIIB). Ind CbP + B has been well tolerated (1 gr 3 hypertension). No PH during Ind has been seen (including the 12 SQ cell pts). Response after Ind, 37% PR, 59% SD, 4% PD. Tumor volumes and PET SUVs have significantly decreased comparing pre- and post-Ind studies (p=0.0001 and p=0.0002, respectively). Cohort II has been expanded as the phase II regimen. To date, 25 of 26 (96%) pts have achieved the dose of 74 Gy (1 pt stopped at 60 Gy due to ILD). During Conc therapy, the principal toxicity has been esophagitis (53.8% gr 2, 19.2% gr 3). One grade 3 PH occurred in 1 SQ pt. One gr 5 late (> 2 mos after treatment) PH occurred in a SQ pt. Overall response rate following treatment - 68.2% (95% CI, 45–86%). The PFS at 1 year is 58% (95% CI, 34–76%) with an estmated 1-year overall survival rate of 79% (95% CI, 53–92%) which compares favorably to our historical experience. Conclusions: Preliminarily, we conclude that 1) Incorporation of B and E into this treatment paradigm appears feasible, 2) Esophagitis remains the primary toxicity, 3) Phase II accrual continues but early analysis of survival appears promising. Further details regarding the TCRT parameters and toxicity will be presented. [Table: see text]

A phase III randomized, double-blind, placebo-controlled trial of the epidermal growth factor receptor inhibitor gefitinb in completely resected stage IB-IIIA non-small cell lung cancer (NSCLC): NCIC CTG BR.19.

2010 ◽  
Vol 28 (18_suppl) ◽  
pp. LBA7005-LBA7005 ◽  
Author(s):  
G. D. Goss ◽  
I. Lorimer ◽  
M. S. Tsao ◽  
C. J. O'Callaghan ◽  
K. Ding ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Complete Resection ◽  
Phase Iii ◽  
Stage Ib ◽  
Study Results ◽  
Epidermal Growth ◽  
Grade 3

LBA7005 Background: In meta-analyses, platinum-based adjuvant (adj) chemotherapy (CT) in completely resected NSCLC increased cure rate by ∼5%. At BR.19 initiation, adj study results with third-generation agents were unavailable. Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, showed activity in monotherapy trials. We report a trial of adj gefitinib versus placebo after complete resection of NSCLC. Methods: Patients (pts) with stage IB-IIIA NSCLC were stratified by sex, stage, histology, post-op radiation, and after Jan 2003, adj CT. Pts were randomized to gefitinib 250 mg or placebo daily x 2 years. Study endpoints included overall survival (OS), disease free survival (DFS), toxicity, preplanned correlative studies. Study closed prematurely in Apr. 2005. Trial committee and NCIC CTG staff remained blinded to study drug. Results: 503 pts randomized (Sep 2002-Apr 2005); median age 67, males 54%, PS 0 54%; stage IB 49%, II 38%, III 13%; adenocarcinoma 59%, squamous 28%; ever smokers 89%; adj CT 17%; lobectomy 82%. Commonest grade 3/4 toxicities = fatigue 5%, rash 4% and diarrhea 5%. grade 3+ pneumonitis in 7 (1.4%) pts and led to death in 1. Median follow-up is 4.7 yrs; median treatment time is 4.8 mos. For gefitinib versus placebo, median DFS is 4.2 yrs versus not yet reached (NYR) HR1.22 (95% C.I. 0.93-1.61), p=0.15 and median OS 5.1 yrs versus NYR HR 1.24 (95% C.I. 0.94-1.64), p=0.14. In multivariate analysis, tumor size >4cm was predictive of poor DFS (p<0.0001) and never smoking for better OS with gefitinib (p=0.02). Results for KRAS and EGFR copy are available on 350 and 348 pts respectively. KRAS mutations were neither prognostic HR 1.12 (95% C.I. 0.67-1.86), p=0.66 nor predictive of gefitinib benefit (p = 0.16) on OS. EGFRcopy whether low/high polysomy or amplification was neither prognostic (p=0.77) nor predictive of OS benefit from gefitinib. Conclusions: Adjuvant gefitinib after complete resection of early stage NSCLC did not confer DFS or OS advantage in overall population. KRAS and EGFR copy were neither prognostic nor predictive of benefit from gefitinib. EGFR mutational analysis will be presented. [Table: see text]

A phase I dose-escalation study of TAS-102 in patients (pts) with refractory metastatic colorectal cancer (mCRC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3631-3631 ◽  
Author(s):  
Manish R. Patel ◽  
Johanna C. Bendell ◽  
Robert J. Mayer ◽  
Fabio M. Benedetti ◽  
Lee S. Rosen
Keyword(s):  
Dose Level ◽  
Initial Dose ◽  
Acquired Resistance ◽  
Median Number ◽  
Dose Escalation Study ◽  
Significant Survival ◽  
Phase 2 Study ◽  
Study Results ◽  
Grade 3 ◽  
Number Of Treatment

3631 Background: TAS-102 is an oral combination of a novel antimetabolite 5-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI) that prevents degradation of FTD. In preclinical studies, TAS-102 is effective against human colorectal tumors with innate and acquired resistance to 5FU. A Japanese randomized phase 2 study demonstrated a significant survival improvement of TAS-102 over placebo in refractory mCRC (HR=0.56 p=0.0011, EMCC2011). The present study was conducted to determine the MTD of TAS-102 in Western pts with refractory mCRC. Methods: Pts with mCRC who had received at least 2 lines of chemotherapy including a fluoropyrimidine, irinotecan and oxaliplatin were enrolled at an initial dose level of 30 mg/m2 BID days 1- 5 and days 8-12 every 4wks using a standard 3+3 design. A second dose level of 35 mg/m2, which was the MTD for Japanese pts, was the maximal targeted dose in this study. Results: 12 pts received TAS-102 (30/35 mg/m2=3/9, M/F=7/5, Age 44-75, PS0/1=8/4). Pts received a median of 3 prior regimens for metastatic disease. No DLT was observed in the initial dose level (0/3) and one DLT (grade 3 febrile neutropenia) was observed at 35mg/m2 (1/9). Other drug-related ≥ grade 3 toxicities observed in cycle 1 included neutropenia at 58% (7/12). To date, a median number of treatment cycles at the MTD has not been reached as 5 pts are still receiving therapy (range 1-3+ cycles). Conclusions: Western patients with refractory mCRC showed the same MTD as Japanese pts (35 mg/m2 BID, days 1- 5 and days 8-12 every 4wks) and the safety profile was consistent between the populations. The trial has entered an expansion phase to assess further safety and preliminary efficacy. A phase 3 trial is being planned.

A single-institution phase II trial of five fractions of radiotherapy followed by four courses of FOLFOX chemotherapy as preoperative therapy for rectal adenocarcinoma.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 553-553 ◽  
Author(s):  
Robert J. Myerson ◽  
Parag J Parikh ◽  
Benjamin Tan ◽  
Steven Hunt ◽  
James W Fleshman ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Residual Disease ◽  
Rectal Adenocarcinoma ◽  
Standard Of Care ◽  
Response Rates ◽  
Cytotoxic Agents ◽  
Preoperative Treatment ◽  
Local Response ◽  
Grade 3 ◽  
Folfox Chemotherapy

553 Background: Preoperative radiotherapy (RT) with 5FU chemotherapy (CT) is a standard of care for cT3-4 rectal cancer. Studies incorporating additional cytotoxic agents have resulted in increased morbidity with little benefit. We evaluate a template that seeks to (1) include the known benefits of preoperative RT on local response/control, (2) provide for preoperative multi-drug CT, (3) avoid the morbidity of concurrent RT and multi-drug CT. Methods: Patients with cT3-4, any N, any M rectal cancer were eligible. Patients were confirmed to be candidates for surgery, provided the response was sufficient. Preoperative treatment was 5 fractions RT (25 Gy to involved mesorectum, 20 Gy to elective nodes), followed by 4 cycles of mFOLFOX6. Postoperative CT was at the discretion of the medical oncologist. The principal objectives are to demonstrate that this regimen can achieve T stage down staging (ypT < cT) and acute grade 3+ gastrointestinal (GI) morbidity equal to or better than historical controls. Results: Accrual opened late 2009, with 60 patients enrolled through 8/2011. Forty-six have had sufficient time to proceed to surgery with 4 having grade 3 preoperative GI morbidity. Two cases are inevaluable for response: one withdrew consent prior to CT and one received no surgery due to progression of cM1 disease (with local response). The 44 evaluable cases included 4 cT4 and 40 cT3; 32 (73%) cN+, 4 cM1. At surgery 33 (75%) had ypT0-2 residual disease including 13 (30%) ypT0, 14 (32%) were ypN+. Cases were sub-analyzed by whether disease was too advanced for the upcoming ACOSOG preoperative FOLFOX vs. 5FU-RT trial. By ACOSOG eligibility, response rates were (eligible first, ineligible second) ypT0: 10/22 (45%) vs. 3/22 (14%) (p = 0.05), ypT0-2: 19/22 (86%) vs. 14/22 (64%) (p = NS). Conclusions: This regimen achieves high response rates with acceptable morbidity. The response for ACOSOG eligible cases meets pre-determined stopping criteria for proceeding to a randomized trial. Our successor study will randomize to this regimen vs. FOLFOX alone for ACOSOG eligible cases, while initially continuing as a single arm trial for ACOSOG ineligible cases.

A phase II trial of gemcitabine (G), cisplatin (C), and nab-paclitaxel (N) in advanced biliary tract cancers (aBTCs): Updated survival analysis.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 350-350
Author(s):  
Rachna T. Shroff ◽  
Milind M. Javle ◽  
Lianchun Xiao ◽  
Ahmed Omar Kaseb ◽  
Gauri R. Varadhachary ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase Ii ◽  
Initial Dose ◽  
Hypothesis Test ◽  
Progression Free Survival ◽  
Median Number ◽  
Controlled Study ◽  
Grade 3 ◽  
Bayesian Hypothesis Test ◽  
Md Anderson

350 Background: BTCs are often diagnosed at an advanced stage and have a poor prognosis. The standard therapy for aBTCs is the combination of GC. However, the median overall survival (mOS) is dismal at 11.7 months (mos) with a median progression free survival (mPFS) of 8 mos. Methods: A single arm, phase II study was conducted at MD Anderson and Mayo Clinic Arizona. Patients (pts) with aBTC were treated at initial dose level of G/C/N (in mg/m2) at 1000/25/125 (n = 30) which was reduced to lower doses due to grade 3/4 hematological (heme) toxicity (tox) - G/C/N: 800/25/100 (n = 30). Cycles were q21 days with restaging q3 cycles until progression. PFS was the primary endpoint (endpt). Using a Bayesian hypothesis test-based design, we assumed mPFS of 8 mos under the null hypothesis (H0), 10 mos under the alternative (H1). Secondary endpts included mOS, RECIST v1.1 response rate (RR), safety and CA19-9 response. Results: 60 pts were enrolled with 51 being response-evaluable having received more than 1 cycle of therapy (age: median 60 yrs [range 31-77], ECOG PS 0/1 (22/38), M/F (33/27), intrahepatic cholangiocarcinoma/extrahepatic/gallbladder (38/9/13). Median follow-up was 14 mos and median number of treatment (trmt) cycles = 5.24. Pts at initial dose level had significant grade 3/4 heme tox: neutropenia, febrile neutropenia, anemia, and thrombocytopenia leading to trmt discontinuation in 6/30 pts. After dose reduction to G/C/N (in mg/m2) at 800/25/100, trmt was better tolerated with only 3 pts experiencing grade 4 heme tox. Non-heme tox were grade 3 in 19 pts: nausea/vomiting, diarrhea, thromboembolic event/CVA, hypokalemia, constipation, cystitis, LFT elevations. The mPFS = 11.4 mos (95% CI: 6.1, 16.1) and mOS = 19.2 (95%CI: 13.6, NA), 1-year survival rate 67.6%. 51 pts evaluable for response: disease control rate (PR+CR+SD)-84.3% and RR-39%. 12 unresectable cases were operated post trmt with 1 pathologic CR. Conclusions: The combination of GCN was well tolerated at adjusted doses and demonstrates encouraging efficacy having met its mPFS endpt and an impressive mOS higher than historical control. These results merit evaluating GC +/-N in a randomized controlled study. Clinical trial information: NCT02392637.

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