An E1B 55 kDa gene-deleted adenovirus, Onyx-015, which reportedly selectively replicates in and lyses p53-deficient cells, was administered by a single intratumoral injection to a total of 22 patients with recurrent head and neck cancer. The objectives of this Phase I study were to determine the safety, feasibility, and efficacy of this therapy and determine any correlation to p53 status. Six cohorts were investigated with a dose escalation from 10(7)-10(11) plaque-forming units. Toxicity was assessed using NCIC criteria. Tumor response was assessed by clinical and radiological measurement. Blood samples were taken to detect adenovirus DNA and neutralizing antibody to adenovirus. Tumor biopsies were taken to detect adenovirus by in situ hybridization. Treatment was well tolerated, with the main toxicity being grade 1/2 flu-like symptoms. Dose-limiting toxicity was not reached at the highest dose of 10(11) plaque-forming units. Twenty-one of the 22 patients treated showed an increase in neutralizing antibody to adenovirus. In situ hybridization showed viral replication in 4 of 22 patients treated, all of whom had mutant p53 tumors. Using conventional response criteria, no objective responses were observed. However, magnetic resonance imaging scans were suggestive of tumor necrosis at the site of viral injection in five patients, three of whom were classified using nonconventional criteria as partial responders, and two of whom were classified using nonconventional criteria as minor responders. Of these five cases, four had mutant p53 tumors. The response duration for the three partial responders was 4, 8, and 12 weeks. An additional eight patients had stable disease in the injected tumors lasting from 4-8 weeks. These preliminary results show that intratumoral administration of Onyx-015 is feasible, well tolerated, and associated with biological activity. Further investigation of Onyx-015, particularly with a more frequent injection protocol and in combination with systemic chemotherapy, is warranted.
TPS185 Background: Treatment options for patients (pts) with cancer of unknown primary (CUP) are limited; carboplatin (C) and paclitaxel (P) combination being one of the options. Belinostat (B), is a hydroxamate, class I and II histone deacetylase inhibitor (HDACi) with a broad antineoplastic activity. Phase I and II trials are ongoing in multiple indications and in more than 500 patients the most common adverse events have been nausea, vomiting and fatique. Preclinical data shows synergistic effect when combined with C and P in vitro and in vivo. In a phase I study f or patients with pretreated advanced solid tumors, BelCaP was well-tolerated and active with objective responses seen in pancreatic and rectal cancer pts. A pt with CUP (3 prior chemotherapy regimens) had disease control during 29 mos of treatment. Theref ore, we are conducting a randomized Ph II study (N∼88) of CaP with or without B in CUP pts. Methods: Randomized, global, multicenter phase II trial in 19 centers. Inclusion criteria include: a confirmed diagnosis of CUP, no prior therapy, ECOG PS 0-2, age > 18 years. Eligible patients are randomized to receive either arm A or B. Arm A: BelCaP; B as a 30-min i.v. infusion once daily (1,000 mg/m2) on days 1-3, followed by B 2,000 mg orally once daily on days 4-5, with P (175 mg/m2) administered 2-3 hrs following B on day 3 and C (AUC6) following directly after P, up to 6 cycles. From cycle 7: B 750 mg is administered orally once daily × 14 days. Arm B: P (175 mg/m2) administered day 1 and C (AUC6) following directly after P. Cycles repeated every 3 weeks. Primary endpoint is progression free survival (PFS) and secondary endpoints assess additional efficacy parameters and safety. Response is evaluated according to RECIST criteria. 33 pts have been randomized as of 6 Jan 2009. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration TopoTarget Pfizer Roche, sanofi-aventis TopoTarget
9015 Background: A metaanalysis of 2 pivotal trials evaluated the effect of denosumab treatment in a broad cancer population. Both studies were identically designed and analyzed, comparing denosumab vs ZA in delaying or preventing skeletal-related events (SRE) in patients with bone metastases, one in patients with breast cancer and the other in patients with advanced cancer (except breast or prostate cancer) or multiple myeloma. Methods: The effects of denosumab vs ZA were evaluated with respect to time to first on-study SRE for noninferiority (primary endpoint; synthesis method) and superiority (secondary endpoint, proportional hazards model) and time to first and subsequent SRE (secondary endpoint, superiority; Anderson-Gill approach). Results: Denosumab was superior to ZA in delaying the time to first on-study SRE by 17% (HR 0.83; 95% CI: 0.74, 0.92; P<0.0001 for noninferiority; P = 0.0008 for superiority). Median time to first on-study SRE was 21.1 months for ZA and was not reached for denosumab. Denosumab was also superior to ZA in delaying the time to first and subsequent on-study SRE (multiple event analysis) by 18% (rate ratio 0.82; 95% CI: 0.74, 0.91; P = 0.0003). Denosumab reduced the mean skeletal morbidity rate (SREs/year) vs ZA (0.64 vs 0.80; P = 0.0006). Overall rates of disease progression (HR 1.00; 95% CI: 0.92, 1.08; P = 0.90), survival (HR 0.95; 95% CI: 0.86, 1.05; P = 0.35), adverse events (AEs; 96% denosumab, 97% ZA), and serious AEs (53% denosumab, 56% ZA) were similar in both groups. Osteonecrosis of the jaw occurred in 30 (1.6%) denosumab patients and 25 (1.3%) ZA patients. ZA-treated patients had increased rates of AEs potentially associated with renal toxicity (6.5% denosumab, 9.6% ZA) and with acute phase reactions at 3 days (8.8% denosumab, 21.4% ZA). Conclusions: Denosumab was superior to ZA in delaying or preventing SREs across a broad cancer population with bone metastases. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen, Novartis, Ortho Biotech, Roche, Watson Pharmaceuticals Amgen Amgen, Novartis, Ortho Biotech, Roche, Watson Pharmaceuticals Amgen, Novartis, Ortho Biotech, Watson Pharmaceuticals Novartis
Context: Liposomal encapsulation of drugs can potentially ameliorate toxicities and improve acute and chronic tolerance. The increased uptake of liposomes by colon adenocar-cinoma cell lines may enable DaunoXome to circumvent the p-glycoprotein-mediated anthracycline resistance of colon cancer cells. Purpose: To determine if DaunoXome, liposome- encapsulated daunorubicin, has clinical activity in patients with adenocarcinoma of the colon who failed treatment with a 5-fluorouracil containing regimen. Method: In a Phase II trial, patients with metastatic adenocarcinoma of the colon, whose disease has progressed after receiving one 5-fluorouracil-containing regimen, were treated with DaunoXome 100 mg/m2 repeated every 3 weeks. Results: In this trial 16 patients received 45 courses of therapy. No objective tumor responses were seen. Hematologic toxicities consisted of neutropenia (grade 3 and 4), grade 2 anemia, and grade 2 throm-bocytopenia. Nonhematologic toxicities were mild and manageable. Of the 16 patients, 5 experienced flushing, shortness of breath, chest tightness, and back pain during DaunoXome infusion, which resolved with infusion interruption, diphen-hydramine, and meperidine. Conclusions: DaunoXome is generally well tolerated at a dose of 100 mg/m2 every 3 weeks. Toxicities are mild and reversible. On this schedule DaunoXome does not have significant clinical activity in patients with metastatic adenocarcinoma of the colon who have progressed after one 5-fluorouracil-containing regimen.
Prolonged exposure to topotecan in in vitro and in vivo experiments has yielded the highest antitumor efficacy. An oral formulation of topotecan with a bioavailability of 32-44% in humans enables convenient prolonged administration. Pharmacokinetic/pharmacodynamic relationships from four Phase I studies with different schedules of administration of oral topotecan in 99 adult patients with malignant solid tumors refractory to standard forms of chemotherapy were compared. Topotecan was administered as follows: (a) once daily (o.d.) for 5 days every 21 days (29 patients); (b) o.d. for 10 days every 21 days (19 patients); (c) twice daily (b.i.d.) for 10 days every 21 days (20 patients); and (d) b.i.d. for 21 days every 28 days (31 patients). Pharmacokinetic analysis was performed in 55 patients using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods. Totals of 109, 48, 64, and 59 courses were given, respectively. Dose-limiting toxicity consisted of granulocytopenia for the o.d. x 5-day dosage, a combination of myelosuppression and diarrhea in both of the 10-day schedules, and only diarrhea in the 21-day schedule. Pharmacokinetics revealed a substantial variation of the area under curve (AUC) of topotecan lactone in all of the dose schedules with a mean intrapatient variation of 25.4 +/- 31.0% (o.d. x 5), 34.5 +/- 25.0% (o.d. x 10), 96.5 +/- 70.1% (b.i.d. x 10), and 59.5 +/- 51.0% (b.i.d. x 21). Significant correlations were observed between myelotoxicity parameters and AUC(t) day 1 and AUC(t) per course of topotecan lactone. In all of the studies, similar sigmoidal relationships could be established between AUC(t) per course and the percentage decrease of WBCs. At maximum-tolerated dose level, no significant difference in AUC(t) per course was found [AUC(t) per course was 107.4 +/- 33.7 ng x h/ml (o.d. x 5), 145.3 +/- 23.8 ng x h/ml (o.d. x 10), 100.0 +/- 41.5 ng x h/ml (b.i.d. x 10), and 164.9 +/- 92.2 ng x h/ml (b.i.d. x 21), respectively.] For oral topotecan, the schedule rather than the AUC(t)-per-course seemed to be related to the type of toxicity. Prolonged oral administration resulted in intestinal side effects as a dose-limiting toxicity, and short-term administration resulted in granulocytopenia. On the basis of this pharmacokinetic study, no schedule preference could be expressed, but based on patient convenience, administration once daily for 5 days could be favored.
PURPOSE To evaluate irinotecan (CPT-11; Yakult Honsha, Tokyo, Japan) in patients with metastatic colorectal carcinoma that had recurred or progressed following fluorouracil (5-FU)-based therapy. PATIENTS AND METHODS Patients were treated with irinotecan 125 to 150 mg/m2 intravenously (IV) every week for 4 weeks, followed by a 2-week rest. Forty-eight patients were entered onto the study and all were assessable for toxicity. Forty-three patients completed one full course of therapy and were assessable for response. RESULTS One complete and nine partial responses were observed (response rate, 23%; 95% confidence interval [CI], 10% to 36%). The median response duration was 6 months (range, 2 to 13). The median survival time was 10.4 months and the 1-year survival rate was 46% (95% CI, 39% to 53%). Grade 4 diarrhea occurred in four of the first nine patients (44%) treated on this study at the 150-mg/m2 dose level. The study was amended to reduce the starting dose of irinotecan to 125 mg/m2. At this dose, nine of 39 patients (23%) developed grade 4 diarrhea. Aggressive administration of loperamide also reduced the incidence of grade 4 diarrhea. Grade 4 neutropenia occurred in eight of 48 patients (17%), but was associated with bacteremia and sepsis in only case. CONCLUSION Irinotecan has significant single-agent activity against colorectal cancer that has progressed during or shortly after treatment with 5-FU-based chemotherapy. The incidence of severe diarrhea is reduced by using a starting dose of irinotecan 125 mg/m2 and by initiating loperamide at the earliest signs of diarrhea. These results warrant further clinical evaluation to define the role of irinotecan in the treatment of individuals with colorectal cancer.
