A Phase II Study with Lead-In Safety Cohort of 5-Fluorouracil, Oxaliplatin, and Lapatinib in Combination with Radiation Therapy as Neoadjuvant Treatment for Patients with Localized HER2-Positive Esophagogastric Adenocarcinomas.

LESSONS LEARNED: Neoadjuvant 5-fluorouracil, oxaliplatin, and lapatinib in combination with radiation therapy is safe for neoadjuvant treatment for patients with localized human epidermal growth receptor 2-positive esophagogastric adenocarcinoma.Evaluation of this drug combination in a larger patient pool would allow for more accurate analysis of its efficacy. BACKGROUND: The optimal design of neoadjuvant chemoradiation for the treatment of localized esophagogastric cancers is the subject of much debate. In this nonrandomized trial, we evaluated neoadjuvant 5-fluorouracil (5-FU), oxaliplatin, and lapatinib in combination with radiation therapy as neoadjuvant treatment for patients with localized human epidermal growth receptor 2 (HER2)-positive esophagogastric adenocarcinomas. METHODS: Patients received neoadjuvant 5-FU (225 mg/m2 continuous intravenous infusion, days 1-42), oxaliplatin (85 mg/m2 intravenously [IV], days 1, 15, and 29), and lapatinib (six patients, 1,000 mg p.o., days 1-42; six patients, 750 mg p.o., days 1-42) plus radiation (1.8 Gy/day Monday through Friday for 50.4 Gy total). Following restaging, eligible patients underwent definitive resection, and pathologic response to neoadjuvant therapy was assessed. Planned enrollment was 42 patients. The primary endpoint was the pathologic complete response (pCR) rate. RESULTS: Twelve patients (median age 64 years; 67% male) received a median of 5.6 weeks of treatment (range: 1.1-8.4). The pCR rate was 8%; four of the 12 patients underwent tumor resection and one patient had a pCR, with pathologic partial response in the remaining three. The most common lapatinib-related adverse events included (all grades) nausea (67%) and diarrhea (58%), although these were all grade 1 or 2. Enrollment was halted due to low accrual. CONCLUSION: The treatment regimen was determined to be safe. The study was terminated early due to low accrual.

A phase I dose escalation study of NK012, an SN-38 incorporating macromolecular polymeric micelle.

PURPOSE: This study evaluated the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) and recommended phase II dose (RD) of NK012, a macromolecular polymeric micelle formulation of SN-38 (the active metabolite of irinotecan). PATIENTS AND METHODS: Patients with previously treated advanced solid tumors and acceptable organ function were administered NK012 as a 30-min infusion every 21 or 28 days without premedications. Patients were screened for UGT1A1 *28 polymorphism prior to enrollment. Patients homozygous for UGT1A1*28 allele (*28/*28 genotype patients) were treated at a reduced dose level with the potential for dose escalation based on toxicities. Pharmacokinetic samples were obtained during cycles 1 and 2. RESULTS: Thirty-nine patients were enrolled, and thirty-eight patients were treated with NK012. NK012 was escalated from 9 to 37 mg/m(2) in patients with UGT1A1*28 allele genotype of wt/wt and wt/*28. The MTD/RD of a Q21D regimen was determined to be 28 mg/m(2) where the dose-limiting toxicity is myelosuppression, which appears to be cumulative and limits timely subsequent dosing. Based on delayed neutrophil recovery, the NK012 dose of 28 mg/m(2) administered on an every 28 days schedule was confirmed as the RD. Gastrointestinal toxicities were mild, with no grade 3 diarrhea reported. The T1/2z value of polymer-unbound SN-38 was significantly prolonged compared to that of SN-38 metabolized from CPT-11, indicating a sustained high systemic SN-38 concentration. Six patients had confirmed partial responses. Eighteen additional patients had stable disease as their best response to treatment. CONCLUSIONS: The recommended phase II dose of NK012 for UGT1A1 wt/wt and wt/*28 genotype patients is 28 mg/m(2) every 28 days. Additional clinical development as a single agent in specific patient populations or in combination with other chemotherapy agents is warranted.

Phase II study of biweekly pemetrexed and gemcitabine in patients with previously untreated advanced non-small cell lung cancer.

INTRODUCTION: Pemetrexed and gemcitabine are safe and active non-small cell lung cancer (NSCLC) therapies when administered every 3 weeks. Biweekly scheduling was studied in this phase II trial. METHODS: The primary objective was to assess the overall response rate in chemotherapy-naive patients with unresectable stage III/IV NSCLC. Patients received 500 mg/m(2) of pemetrexed intravenously and 1500 mg/m(2) of gemcitabine intravenously every 2 weeks for 8 to 12 cycles with restaging every 4 cycles. Patients also received supplemental folate/B12 therapy. Entry criteria included the following: all non-small cell histologies, measurable disease, Eastern Cooperative Oncology Group 0 to 2, and informed consent. RESULTS: Seventy-two patients were enrolled. Baseline characteristics included the following: median age: 66 years (41-85 years); male/female: 65%/35%; Eastern Cooperative Oncology Group 0/1/2: 19%/67%/14%; and histology: adenocarcinoma (36%), large cell (18%), squamous (13%), and mixed or not specified (34%). The median number of cycles was 7 (range, 1-12). The most common (> or =5%) grade 3/4 toxicities were as follows: neutropenia (47%), leukopenia (31%), fatigue (25%), dyspnea (18%), pain (11%), and anemia (8%). Complete/partial responses for all patients: 1 patient/18 patients, respectively, for an overall response rate of 26% (95% confidence interval, 17-38%). Thirty-nine percentage of patients had stable disease, and 21% had disease progression (10 patients were not evaluable). Median progression-free survival was 6.2 months. One-year overall survival was 37.5%. CONCLUSION: Biweekly administration of pemetrexed and gemcitabine seems to be well tolerated with activity comparable with other first-line NSCLC regimens. Further study addressing whether biweekly scheduling could be an effective strategy to shorten overall treatment duration will require a randomized design.

Phase II study of capecitabine in combination with thalidomide in patients with metastatic breast cancer.

We examined the toxicity/efficacy of capecitabine with thalidomide, administered over 21-day cycles, in 24 previously treated metastatic breast cancer (MBC) patients. This regimen was poorly tolerated: grade 3/4 neutropenia (13%); grade 3 nausea (22%), vomiting (17%), and diarrhea (13%); and grade 2/3 hand-foot syndrome (38%). In addition, the response rate was lower than expected: partial response (13%), stable disease (17%), and progressive disease at first evaluation (35%). The median time to progression and overall survival were 2.7 and 11.0 months, respectively. These results do not support further investigation of thalidomide for MBC. The role of angiogenesis inhibition in breast cancer treatment should continue to be defined using more efficacious and specific inhibitors.

A phase II trial of gemcitabine/carboplatin with or without trastuzumab in the first-line treatment of patients with metastatic breast cancer.

PURPOSE: The purpose of this study was to evaluate the efficacy and toxicity of the combination of gemcitabine and carboplatin (and with trastuzumab in patients with HER2-positive disease) as first-line treatment for patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Seventy-four patients who had received no previous chemotherapy for MBC were enrolled. Patients with HER2-negative breast cancer received treatment with gemcitabine 1000 mg/m(2) intravenously (I.V.) on days 1 and 8 and carboplatin area under the curve (AUC) 5 I.V. on day 1. Cycles were repeated every 21 days. Patients with HER2-positive disease also received trastuzumab 8-mg/kg I.V. loading dose, then 6 mg/kg I.V. every 21 days. After the first 29 patients were treated, the carboplatin dose was lowered to AUC 4. Patients were re-evaluated every 6 weeks; responses were measured using Response Evaluation Criteria in Solid Tumors criteria. RESULTS: In patients with HER2-negative disease, gemcitabine/carboplatin produced a 34% major response rate; an additional 28% of patients had stable disease > or = 6 months (overall disease control rate, 62%). Gemcitabine/carboplatin/trastuzumab produced an overall response rate of 66%, with a disease control rate of 77%. Grade 3/4 myelosuppression was common, even after reduction of the carboplatin dose. Only 3 patients treated with the lower dose regimen developed neutropenia and fever, but platelet and red blood cell transfusions were necessary in 24% and 40% of patients, respectively. Trastuzumab did not add to hematologic toxicity. Severe nonhematologic toxicity was uncommon. CONCLUSION: Gemcitabine/carboplatin and gemcitabine/carboplatin/trastuzumab are active first-line regimens for patients with MBC. The gemcitabine/carboplatin combination causes more grade 3/4 myelosuppression than other standard combination regimens for MBC; however, severe nonhematologic toxicity is minimal.

A phase II feasibility trial of dose-dense docetaxel followed by doxorubicin/cyclophosphamide as adjuvant or neoadjuvant treatment for women with node-positive or high-risk node-negative breast cancer.

PURPOSE: Dose-dense adjuvant chemotherapy with doxorubicin/cyclophosphamide (AC) followed by paclitaxel has improved results compared with standard dosing at 3-week intervals. Because docetaxel might be more active than paclitaxel in the treatment of metastatic breast cancer, we explored the feasibility of substituting docetaxel for paclitaxel in dose-dense adjuvant therapy. PATIENTS AND METHODS: Seventy-six patients with node-positive breast cancer received treatment with 4 cycles of docetaxel followed by 4 cycles of AC administered with pegfilgrastim at 2-week intervals. When treatment proved difficult for the first 33 patients, 2 additional cohorts were treated: first, with a reduction of pegfilgrastim and dexamethasone prophylaxis doses (cohort 2) and then with a reduction of docetaxel from 100 mg/m2 to 75 mg/m2 (cohort 3). RESULTS: Treatment with dose-dense docetaxel at 100 mg/m2 resulted in unacceptable toxicity (24% of patients required hospitalization) and compromised subsequent dosing of AC as a result of neutropenia on the day of scheduled treatment. Only 21 patients (40%) who received docetaxel 100 mg/m2 were able to receive all 8 doses at full dose and on schedule. Reduction of docetaxel to 75 mg/m2 allowed 74% of patients to receive all 8 doses as scheduled. Delivery of AC as scheduled occurred in 82% of patients who received docetaxel 75 mg/m2 versus 40% when docetaxel 100 mg/m2 was administered. CONCLUSION: Full-dose docetaxel is difficult to administer as part of this dose-dense treatment regimen. Docetaxel 75 mg/m2 can be administered with improved subsequent delivery of 4 courses of dose-dense AC. Until comparative clinical studies are available, docetaxel should not be substituted for paclitaxel in dose-dense adjuvant chemotherapy for patients with high-risk breast cancer.

The patents-based pharmaceutical development process: rationale, problems, and potential reforms.

The pharmaceutical industry is facing substantial criticism from many directions, including financial barriers to access to drugs in both developed and developing countries, high profits, spending on advertising and marketing, and other issues. Underlying these criticisms are fundamental questions about the value of the current patent-based drug development system. Six major problems with the patent system are (1) recovery of research costs by patent monopoly reduces access to drugs; (2) market demand rather than health needs determines research priorities; (3) resources between research and marketing are misallocated; (4) the market for drugs has inherent market failures; (5) overall investment in drug research and development is too low, compared with profits; and (6) the existing system discriminates against US patients. Potential solutions fall into 3 categories: change in drug pricing through either price controls or tiered pricing; change in drug industry structure through a "buy-out" pricing system or with the public sector acting as exclusive research funder; and change in development incentives through a disease burden incentive system, orphan drug approaches, or requiring new drugs to demonstrate improvement over existing products prior to US Food and Drug Administration approval. We recommend 4 complementary reforms: (1) having no requirement to test new drug products against existing products prior to approval but requiring rigorous comparative postapproval testing; (2) international tiered pricing and systematic safeguards to prevent flow-back; (3) increased government-funded research and buy-out for select conditions; and (4) targeted experiments using other approaches for health conditions in which there has been little progress and innovation over the last few decades.

TRIPS and the global pharmaceutical market.

This paper reviews the international controversy over patents and access to drugs in developing countries and explores the implications of the 1995 Trade-Related Aspects of Intellectual Property Rights (TRIPS) agreement, the 2001 Doha Declaration, and the 2003 agreement preceding the Cancun meeting. These agreements do not resolve the important funding issues that developing countries confront as they seek access to drugs. Also, the international debate and its resolution will complicate the importing of foreign pharmaceuticals into the United States and strengthen pressures both for expanding public support of U.S. drug purchases and, in the long run, for political control of U.S. pharmaceutical pricing.

Combination treatment with weekly docetaxel and gemcitabine for advanced non-small-cell lung cancer in elderly patients and patients with poor performance status: results of a Minnie Pearl Cancer Research Network phase II trial.

The purpose of this study was to evaluate the feasibility, toxicity, and efficacy of the combination of weekly docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer (NSCLC) who are either elderly or have poor performance status (PS). Patients with stage IIIB or IV NSCLC who had received no previous chemotherapy and were = 70 years of age were eligible for this clinical trial. Patients < 70 years of age were also eligible if they had poor PS or were considered poor candidates for standard platinum-based combination chemotherapy regimens. All patients received chemotherapy with gemcitabine 800 mg/m2 and docetaxel 30 mg/m2, both drugs administered by 30-minute intravenous infusions on days 1, 8, and 15. Treatment courses were repeated every 28 days. Patients were reevaluated after completion of 2 treatment courses; responding patients continued treatment until disease progression or for a maximum of 6 courses. Between August 1999 and June 2000, 64 patients (73% with stage IV disease) were treated at 17 participating sites in the Minnie Pearl Cancer Research Network. Eighteen of 64 patients enrolled (28%) had objective response to treatment; an additional 25 patients (39%) had stable disease. Median survival was 7 months, with 1- and 2-year survival rates of 30% and 17%, respectively. Treatment was well tolerated by most patients. Grade 3/4 leukopenia occurred in 7 patients (11%), but no patient required hospitalization for neutropenia/fever. One patient developed fatal bilateral pneumonitis, which was possibly treatment-related. The combination of weekly docetaxel/gemcitabine is active and relatively well tolerated in most patients with advanced age or poor PS with advanced NSCLC. A randomized comparison of this regimen versus single-agent weekly docetaxel is in progress.

Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network.

PURPOSE: To assess the efficacy and toxicity of first-line single-agent rituximab, followed by re-treatment with rituximab at 6-month intervals, in previously untreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). PATIENTS AND METHODS: Forty-four previously untreated patients with CLL/SLL received rituximab 375 mg/m2 weekly for 4 consecutive weeks. All patients were required to have one or more indications for treatment. Patients with objective response or stable disease continued to receive identical 4-week rituximab courses at 6-month intervals, for a total of four courses. RESULTS: The objective response rate after the first course of rituximab was 51% (4% complete responses). Twenty-eight patients received one or more additional courses of rituximab. At present, the overall response rate is 58%, with 9% complete responses. After a median follow-up of 20 months, the median progression-free survival (PFS) time was 18.6 months, and the 1- and 2-year PFS rates were 62% and 49%, respectively. Treatment was well tolerated, with only two episodes of grade 3 to 4 infusion-related toxicity. No cumulative toxicity or opportunistic infections occurred. CONCLUSION: Single-agent rituximab, used at a standard dose and schedule, is active in the first-line treatment of patients with CLL/SLL, producing substantially higher response rates than previously reported in relapsed or refractory patients (51% v 13%, respectively). Re-treatment with rituximab at 6-month intervals is well tolerated. The PFS time of 18.6 months in patients with CLL/SLL seems shorter than the 36- to 40-month median PFSs previously reported with first-line plus maintenance rituximab in patients with follicular lymphoma. Additional follow-up is required to fully assess the impact of this treatment strategy.

Patents, genomics, research, and diagnostics.

Two kinds of currently available genomic patents may significantly interfere with medical research: (1) patents such as those on specific single nucleotide polymorphisms (SNPs), which may include claims that control the inference of phenotypic characteristics from specific genotypes, and (2) patents on computer-based genomic information, databases, or manipulation procedures. These will create more serious encumbrances than will patents on expressed sequence tags (ESTs). Two approaches should be considered vis-à-vis these genomic patents: (1) Reconsideration and redefinition of the recent extensions of patentable subject matter into more and more intangible areas. This could be pursued by legislation or by test litigation to seek Supreme Court reversal of certain of the decisions of the Court of Appeals for the Federal Circuit (CAFC). (2) A narrow legislative exemption protecting the ability to use SNPs and phenotypic-genotypic relationships in medical research, including contexts in which medical research and clinical practice are substantially intertwined.

A phase I trial of weekly paclitaxel plus prolonged oral eniluracil/5-fluorouracil in patients with refractory malignancies.

PURPOSE: This phase I study was conducted to determine the dose-limiting toxicity (DLT), maximum-tolerated doses, and recommended phase II doses of the combination of weekly intravenous paclitaxel and oral eniluracil/5-fluorouracil (5-FU). PATIENTS AND METHODS: Patients received paclitaxel i.v. over 1 hour weekly for four consecutive weeks of each cycle. Oral eniluracil/5-FU was administered orally twice daily for 28 consecutive days starting on day 1 of each cycle. Cycles were repeated every 35 days. Patients were accrued at six different dosing combinations. Weekly paclitaxel doses ranged from 60 mg/m(2) to 80 mg/m(2), and oral eniluracil/5-FU doses ranged from 8.0/0.8 mg/m(2) to 11.5/1.15 mg/m(2) twice daily. RESULTS: Thirty-seven patients received 126 cycles of therapy. Myelosuppression was minimal at all dose levels, with no grade 4 neutropenia or thrombocytopenia reported. DLT was reported in three out of six patients enrolled at the highest dose level and consisted of grade 3 diarrhea (two patients) and grade 3 mucositis (one patient). No DLTs were reported in patients enrolled at lower dose levels. One complete response and three partial responses were reported in patients with taxane-resistant metastatic breast cancer. CONCLUSION: The combination of paclitaxel and eniluracil/5-FU was generally well tolerated. The recommended doses for further phase II testing are paclitaxel 80 mg/m(2) i.v. weekly for 4 weeks plus eniluracil/ 5-FU 10.0/1.0 mg/m(2) orally twice daily on days 1-28 with cycles repeated every 35 days.

Prospective randomized study of four novel chemotherapy regimens in patients with advanced nonsmall cell lung carcinoma: a minnie pearl cancer research network trial.

BACKGROUND: The authors compared the toxicity, response rate, and progression free survival of four chemotherapy regimens for patients with advanced (Stage IIIB and IV) nonsmall cell lung carcinoma. METHODS: A total of 267 patients entered this randomized Phase II trial on one of four arms: paclitaxel, carboplatin, and gemcitabine (Arm A); paclitaxel, carboplatin, and vinorelbine (Arm B); paclitaxel and gemcitabine (Arm C); and gemcitabine and vinorelbine (Arm D). Patient characteristics were similar in all treatment arms. At the time of tumor progression, patients were removed from study and were treated at the discretion of their physician. RESULTS: Patients received a median of four courses of chemotherapy in all arms, and there was no difference in the dose delivered. There were no statistical differences in response rates (range, 32-45%), median progression free survival (range, 4.9-6.6 months), or progression free survival at 1 year (range, 8-19%). Actuarial survival in all four arms was not different, with a median survival ranging from 8.7 months to 10.7 months and a 1-year survival rate of 38-44%. Each arm was compared with a historic control with a median survival of 8 months. Arm D (gemcitabine and vinorelbine) approached significance at the 0.05 level. CONCLUSIONS: Two-drug combinations containing the newer drugs without a platinum drug were less toxic than three-drug, platinum-based regimens. There were no significant differences in objective response rates or progression free survival when the four regimens were compared. The two-drug combination of gemcitabine and vinorelbine was the least toxic and, thus, may be superior. A Phase III trial comparing combined gemcitabine and vinorelbine with combined paclitaxel, carboplatin, and gemcitabine is ongoing.

Research-tool patents: issues for health in the developing world.

The patent system is now reaching into the tools of medical research, including gene sequences themselves. Many of the new patents can potentially preempt large areas of medical research and lay down legal barriers to the development of a broad category of products. Researchers must therefore consider redesigning their research to avoid use of patented techniques, or expending the effort to obtain licences from those who hold the patents. Even if total licence fees can be kept low, there are enormous negotiation costs, and one "hold-out" may be enough to lead to project cancellation. This is making it more difficult to conduct research within the developed world, and poses important questions for the future of medical research for the benefit of the developing world. Probably the most important implication for health in the developing world is the possible general slowing down and complication of medical research. To the extent that these patents do slow down research, they weaken the contribution of the global research community to the creation and application of medical technology for the benefit of developing nations. The patents may also complicate the granting of concessional prices to developing nations - for pharmaceutical firms that seek to offer a concessional price may have to negotiate arrangements with research-tool firms, which may lose royalties as a result. Three kinds of response are plausible. One is to develop a broad or global licence to permit the patented technologies to be used for important applications in the developing world. The second is to change technical patent law doctrines. Such changes could be implemented in developed and developing nations and could be quite helpful while remaining consistent with TRIPS. The third is to negotiate specific licence arrangements, under which specific research tools are used on an agreed basis for specific applications. These negotiations are difficult and expensive, requiring both scientific and legal skills. But they will be an unavoidable part of international medical research.

Gemcitabine, carboplatin, and paclitaxel for patients with carcinoma of unknown primary site: a Minnie Pearl Cancer Research Network study.

PURPOSE: To evaluate the efficacy and toxicity of the novel chemotherapy combination that includes gemcitabine, carboplatin, and paclitaxel in the treatment of patients with carcinoma of unknown primary site. PATIENTS AND METHODS: One hundred twenty patients were treated with the following regimen, administered every 21 days for a planned four courses: gemcitabine 1,000 mg/m(2) intravenously (i.v.) on days 1 and 8, carboplatin at an estimated area under the concentration-time curve of 5 mg min/mL i.v. on day 1, and paclitaxel 200 mg/m(2) i.v. on day 1. After four courses, stable and responding patients were given weekly paclitaxel 70 mg/m(2) i.v. for 6 weeks for three 8-week courses. All patients had relatively poor prognostic features. Sixty-three patients had well-differentiated adenocarcinoma, 56 patients had poorly differentiated carcinoma, and 104 patients had performance status of 0 or 1. RESULTS: Twenty-eight (25%) of 113 assessable patients (95% confidence interval, 22% to 30%) had major objective responses to treatment. Response rates were similar in the two major histologic types. Response rate did not seem to be improved by continued therapy with weekly paclitaxel. The median progression-free survival time was 6 months. Median survival for the entire group was 9 months, and the actuarial survival at 1 and 2 years was 42% and 23%, respectively. CONCLUSION: Combination chemotherapy with gemcitabine, carboplatin, and paclitaxel followed by weekly paclitaxel is an active and tolerable treatment for patients with carcinoma of unknown primary site. The survival seen in this poor-prognosis group of patients in this multicenter community-based trial is notable and similar to other taxane-based regimens for these patients. Study of additional combinations or sequences of newer drugs, as well as the exploration of targeted biologic agents for patients with an identified target in their tumors, is warranted.