Mace L. Rothenberg

Background: To demonstrate the noninferiority of capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid and oxaliplatin (FOLFOX-4) as second-line therapy in patients with metastatic colorectal cancer after prior irinotecan-based chemotherapy. Patients and methods: A total of 627 patients were randomly assigned to receive XELOX (n = 313) or FOLFOX-4 (n = 314) following disease progression/recurrence or intolerance to irinotecan-based chemotherapy. The primary end point was progression-free survival (PFS). Results: PFS for XELOX was noninferior to FOLFOX-4 [hazard ratio (HR) = 0.97; 95% confidence interval (CI) 0.83–1.14] in the intention-to-treat (ITT) population. Median PFS was 4.7 months with XELOX versus 4.8 months with FOLFOX-4. The robustness of the primary analysis was supported by multivariate and subgroup analyses. Median overall survival in the ITT population was 11.9 months with XELOX versus 12.5 months with FOLFOX-4 (HR = 1.02; 95% CI 0.86–1.21). Treatment-related grade 3/4 adverse events occurred in 50% of XELOX- and 65% of FOLFOX-4-treated patients. Whereas grade 3/4 neutropenia (35% versus 5% with XELOX) and febrile neutropenia (4% versus < 1%) were more common with FOLFOX-4, grade 3/4 diarrhea (19% versus 5% with FOLFOX-4) and grade 3 hand–foot syndrome (4% versus < 1%) were more common with XELOX. Conclusion: XELOX is noninferior to FOLFOX-4 when administered as second-line treatment in patients with metastatic colorectal cancer.

5011 Background: We conducted a Phase I trial of S and B to study inhibition of the vascular endothelial growth factor (VEGF) pathway at both the ligand (B) and receptor (S), and platelet derived growth factor receptor (S) in mRCC. Methods: Pts with measurable mRCC, adequate organ function, and PS 0–1 were eligible. Cohorts of at least 6 pts were enrolled to define the MTD and DLT of B given IV q 2wks and S po QD on 28-day cycles. Response and toxicity were assessed after 2 cycles. Initial doses were S at 200mg BID and B at 5 mg/kg with modification based on observed toxicities. High dose pyridoxine was administered in some cohorts attempting to ameliorate hand-foot syndrome (HFS) symptoms. Results: 47/48 pts completed their 1^st response evaluation. Median age was 61 yrs (35–83 ); M/F: 40/8; PS: 0/1= 32/16; 41 clear cell, 7 non-clear cell; 41 had prior nephrectomy; 6 prior IFN and 9 prior IL-2. The table summarizes dose levels explored and toxicities. Toxicities included PUD, rash, weight loss, proteinuria, hypertension, and HFS with no evidence of microangiopathy. Three pts had late vascular events after >12 mos of treatment (TIA, AMI) Pryidoxine did not ameliorate HFS. Only 4/48 pts stopped therapy due to toxicities. MTD was S 200 mg PO QD and B 5 mg/kg IV Q 2 wks. 46/48 pts were evaluable for response. Twenty-one of 46 (46%) had PR by RECIST, including 2 pts with sarcomatoid RCC. Additionally, 23 pts had SD and 1 PD at 1^st eval.with 1 dying from disease progression prior to 1^st eval. Median time to progression (TTP) was 11.2 months with 10 pts (21%) progression-free at 18 mos. Conclusions: While toxicities led to a MTD with lower doses of each agent, B + S had impressive antitumor activity based on both OR and TTP. B appears to significantly increase S-related toxicity, especially HFS. We have opened a Phase II trial with correlative and PK studies for S and B to investigate the mechanism of enhanced S-related toxicity. The combination has been incorporated into E2804 (BeST) a multi-arm Phase II trial of combination regimens. The study was supported by U01 CA099177 and CTEP-NCI.

2504 Background: SJG-136 is a pyrrolobenzodiazepine dimer that forms DNA crosslinks and has demonstrated a broad antitumor activity. Daily x 5 schedule led to edema and delayed liver toxicity (AACR/EORTC/NCI 2006). We report results of a daily x 3 schedule with dexamethasone premedication (dex) and diuretic support. Methods: Pts with refractory solid tumors received SJG-136 IV daily x 3, every 21 days, starting dose 20 μg/m²/day and 3+3 design with fixed-dose increments. Pts received dex on D -1 to 3 of each cycle and followed a diuresis protocol with spironolactone (S). Pharmacokinetics was assessed on Days 1 and 3 of Cycle 1 and 2 using a sensitive HPLC/MS/MS assay. Single cell gel electrophoresis (comet) was used to detect DNA crosslinks in PBMCs. Results: 14 pts (8M, 6F) were enrolled. Median age: 55 (range: 41–81), median PS: 1 (0–1), median # of prior regimens: 3 (1–5). Dose levels tested (μg/m²/day): 20 (3 pt), 25 (3 pt), 30 (6 pts), 35 (2 pts). DLT/Toxicity: DLT was Gr 3 soft tissue edema, dyspnea, fatigue in one and Gr 3 transaminitis in the second pt at the 35 μg/m²/day. Gr 1 edema occurred during Cycles 2–4 in 4 additional pts treated at the 30 μg/m²/day dose level. This was manageable with diuretics without need for dose interruption. Other toxicities: hypophosphatemia, hypoalbuminemia, myalgias. No significant myelosuppression was observed. MTD/RPTD: 30 μg/m²/day daily x 3 q 21 days. Pharmacokinetics: The PK analysis revealed dose-dependent increases in AUC and Cmax on Day 1 of Cycle 1. In some patients, repeated SJG-136 dosing appeared to induce substantial changes in the PK parameters of SJG-136, in particular, volume of distribution (V_ss). Pharmacodynamics: DNA crosslinks were detectable in PBMCs on D3. Responses: 2 PR (ovarian CA, poorly dif. CA) by RECIST. 1 pt with SD for 4.5 months (leiomyosarcoma), 2 pts with SD (SCLC, bladder) > 3 months. Conclusions: The RPTD of SJG-136 administered on a daily x 3 basis is 30 μg/m²/day. At this dose 2 out of 6 pts achieved PR. The premedication with dex and S diuresis can successfully manage the delayed hepatotoxicity and soft tissue edema. Day 3 increase in V_ss may correlate with subsequent development of significant soft tissue edema. DNA crosslinks were detectable in PBMCs on Day 3. Supported by NIH U01 CA099177, M01 RR00095 and CRUK C2259/A3083. No significant financial relationships to disclose.

Purpose: To identify the maximum tolerated dose (MTD) and describe dose-limiting toxicities (DLT) of pemetrexed and oxaliplatin given on a once-every-2-week schedule in patients with metastatic cancer. Patients and methods: Twenty-five patients were enrolled. Due to toxicities observed at the first dose level in unselected patients, a second MTD was determined in patients who had received zero to two prior chemotherapy regimens. Results: DLT was observed at dose level 1—pemetrexed 400 mg/m² and oxaliplatin 85 mg/m²—in the form of grade 3 fatigue in two of six patients. Enrollment was then limited to lightly pretreated patients and DLT was observed at dose level 2—pemetrexed 500 mg/m² and oxaliplatin 85 mg/m²—in the form of neutropenic fever in one of five patients. Complete response was confirmed in one patient (squamous cell carcinoma of the head and neck) and partial response was confirmed in three patients. Conclusions: The combination of pemetrexed and oxaliplatin can be safely administered at doses of 400 to 500 mg/m² of pemetrexed and 85 mg/m² in patients without extensive prior therapy and 300 and 85 mg/m², respectively, every 2 weeks in patients with more extensive prior therapy. Based on promising results observed in this study, a phase II trial in patients with recurrent head and neck cancer has been initiated.

Learning Objectives: After completing this course, the reader should be able to: Discuss recent progress in the treatment of patients with advanced colorectal cancer.Define the continuum-of-care approach and how it may differ from our current approach to the treatment of patients with advanced colorectal cancer.Identify key factors in treatment selection for patients with advanced colorectal cancer.Explain the impact of each active drug in the treatment of advanced colorectal cancer and the impact of treatment with multiple agents over the course of the disease.CME Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com

Purpose The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor–alpha (TGFα). Patients and Methods One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome. Results Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% ± 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance. Conclusion Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.

3095 Background: The thioxanthone analog, SR271425, is a novel cytotoxic DNA-interacting agent with a broad spectrum of antitumor activity in preclinical murine tumor models. This clinical trial aims to determine tolerability and toxicities of SR271425 as a 1-hour single intravenous dose repeated weekly for 2 weeks followed by 1 week rest, to determine the maximum tolerated dose (MTD), recommended phase II dose (RPIID), and to assess its pharmacokinetic profile. Methods: A modified Fibonacci dose escalation design is being used. A single intravenous dose of SR271425 is administered over 1-hour weekly for 2 weeks, followed by 1 week rest, in a variety of refractory solid tumors. Of note, in the rabbit model, QTc prolongation, related to Cmax, has been reported at doses >660mg/m². Therefore, all patients are undergoing cardiology assessment with serial ECGs, which are assessed by a central reviewer. Results: To date, 17 patients have been treated at 5 dose levels (ranges, 64–675 mg/m²/week). The mean age is 53 (range 24 -74 years) and ECOG performance status is 0–2. Grade 1–2 toxicities including QTc prolongation, nausea/vomiting/ constipation, and fatigue have been observed. The pharmacokinetics of SR271425 following weekly dosing were consistent with that observed previously in a single dose ascending study with SR271425. Both Cmax and AUC (day 1) increased in a dose dependent manner. As would be predicted from the drugs short half-life (6.7 h), no systemic accumulation was observed as assessed by Cmax and C_6h values on Day 1 versus Day 8. Stable disease has been observed in 3 patients. Conclusions: Preliminary data on this ongoing study suggests that SR271425 administered at split, weekly doses will likely allow greater cumulative exposure without significant toxicity.

2106 Background: MST-997 is a novel taxane with greater apparent potency in preclinical models than paclitaxel, and antitumor activity in cells that express low to moderate MDR1 levels. Pharmacokinetic (PK) and toxicity profiles also appear improved relative to conventional taxanes. Methods: This phase 1 dose-escalation study is designed to determine the safety and tolerability of IV MST-997 (in Intralipid) given weekly, and define the dose for phase 2 studies. Key eligibility criteria include adult subjects with refractory solid tumors; ECOG of 0 - 2; adequate hematologic, hepatic, and renal function. Dose escalation proceeded using accelerated dose titration with 1 or 2 subjects treated at initial dose levels. Cohorts were expanded to 3 subjects when related adverse events (AEs) ≥ grade 2 were observed. Planned dose levels are 5, 10, 20, 30, and 40 mg/m² with PK analysis performed following the first drug dose. No premedications are given prior to MST-997 administration. Results: To date, 9 subjects (ECOG 0 -1) have been treated at dose levels of 5 to 30 mg/m². Tumor types have included NSCLC, bladder, ovarian, pancreas, carcinoid, biliary, sarcoma and thyroid. One (1) patient developed a dose limiting toxicity (DLT) at the 30 mg/m² dose level (grade 3 fatigue). Other grade 3 and 4 AEs that did not meet the criteria for a DLT have included: neutropenia (1) and pain (1). No complete or partial responses have been observed. Disease stabilization (per modified RECIST criteria) was seen in 3 subjects: pancreatic (with decreased Ca 19–9; unconfirmed), carcinoid, and ovarian cancers. Plasma concentrations from 4 patients receiving doses ranging from 5 to 30 mg/m² suggest that MST-997 has a moderate clearance, ranging from 18 to 51 L/h; a high V_ss, with values ranging from 940 to 2160 L; and a long t_1/2, with values ranging from 13 to 71 h. C_max and AUC values appeared to increase with dose level. Conclusions: MST-997 administered in an intralipid formulation appears well tolerated when given weekly in doses up to 30 mg/m². Dose escalation is ongoing with a maximum tolerated dose confirmatory cohort planned. Additional phase 1 studies with MST-997 are also planned. No significant financial relationships to disclose.