Barriers to conducting cancer trials in Canada: an analysis of key informant interviews.

Background: In Canada, there is growing evidence that oncology clinical trials units (ctus) and programs face serious financial challenges. Investment in cancer research in Canada has declined almost 20% in the 5 years since its peak in 2011, and the costs of conducting leading-edge trials are rising. Clinical trials units must therefore be strategic about which studies they open. We interviewed Canadian health care professionals responsible for running cancer trials programs to identify the barriers to sustainability that they face. Methods: One-on-one telephone interviews were conducted with clinicians and clinical research professionals at oncology ctus in Canada. We asked for their perspectives about the barriers to conducting trials at their institutions, in their provinces, and nationwide. Interviews were digitally recorded, transcribed, anonymized, and coded in the NVivo software application (version 11: QSR International, Melbourne, Australia). The initial coding structure was informed by the interview script, with new concepts drawn out and coded during analysis, using a constant comparative approach. Results: Between June 2017 and November 2018, 25 interviews were conducted. Key barriers that participants identified were■ insufficient stable funding to support trials infrastructure and retain staff;■ the need to adopt strict cost-recovery policies, leading to fewer academic trials in portfolios; and■ an overreliance on industry to fund clinical research in Canada. Conclusions: Funding uncertainties have led ctus to increasingly rely on industry sponsorship and more stringent feasibility thresholds to remain solvent. Retaining skilled trials staff can create efficiencies in opening and running studies, with spillover effects of more trials being open to patients. More academic studies are needed to curb industry's influence.

Targeted therapies and clinical trials in ovarian cancer.

Recent advances in molecular profiling have shown that cancers arising from the ovary are phenotypically and genetically heterogeneous. Within histologies, many mutations in druggable targets are uncommon in frequency but mutations leading to activation of specific signal transduction pathways are common. These results support the notion that different targeted agents should be prioritized for testing between and within ovarian cancer histologies. The subsegmentation of ovarian cancers based on molecular features challenge traditional trial designs. Feasibility of accrual and need for data on biological and clinical consequence or target inhibition are leading to trial designs that lump or split patient populations by histology, pathway, gene, and/or mutation. This review summarizes potential therapeutic targets identified from recent molecular profiling studies of ovarian cancers and trial designs to evaluate targeted agents in rare cancer settings.

Reporting practices of pharmacodynamic studies involving invasive research procedures in cancer trials.

BACKGROUND: Tumour biopsy for pharmacodynamic (PD) study is increasingly common in early-phase cancer trials. As they are non-diagnostic, the ethical justification for such procedures rests on their knowledge value. On the premise that knowledge value is related to reporting practices and outcome diversity, we assessed in a sample of recent invasive PD studies within cancer trials. METHODS: We assessed reporting practices and outcomes for PD studies in a convenience sample of cancer trials published from 2000 to 2010 that employed invasive, non-diagnostic tissue procurement. Extracted data were used to measure outcome reporting in individual trials. Using a reporting scale we developed for exploratory purposes, we tested whether reporting varied with study characteristics, such as funding source or drug novelty. RESULTS: Reporting varied widely within and across studies. Some practices were sporadically reported, including results of all planned tests (78% trials reporting), use of blinded histopathological assessment (43% trials reporting), biopsy dimensions (38% trials reporting), and description of patient flow through PD analysis (62%). Pharmacodynamic analysis as a primary end point and mandatory biopsy had statistically significant positive relationships with overall quality of reporting. A preponderance of positive results (61% of the studies described positive PD results) suggests possible publication bias. CONCLUSION: Our results highlight the need for PD-reporting guidelines, and suggest several avenues for improving the risk/benefit for studies involving invasive, non-diagnostic tissue procurement.

Validation of novel imaging methodologies for use as cancer clinical trial end-points.

The success or failure of a clinical trial, of any phase, depends critically on the choice of an appropriate primary end-point. In the setting of phases II and III cancer clinical trials, imaging end-points have historically, and continue presently to play a major role in determining therapeutic efficacy. The primary goal of this paper is to discuss the validation of imaging-based markers as end-points for phase II clinical trials of cancer therapy. Specifically, we outline the issues that must be considered, and the criteria that would need to be satisfied, for an imaging end-point to supplement or potentially replace RECIST- defined tumour status as a phase II clinical trial end-point. The key criteria proposed to judge the utility of a new end-point primarily relate to its ability to accurately and reproducibly predict the eventual phase III end-point for treatment effect, which is usually assessed by a difference between two arms on progression free or overall survival, both at the patient and more importantly at the trial level. As will be demonstrated, the level of evidence required to formally and fully validate a new imaging marker as an appropriate end-point for phase II trials is substantial. In many cases, this level of evidence will only become available by conducting a series of coordinated prospectively designed multicentre clinical trials culminating in a formal meta-analysis. We also include a discussion of situations where flexibility may be required, relative to the ideal rigorous evaluation, to accommodate inevitable real-world feasibility constraints.

Lessons learned from independent central review.

Independent central review (ICR) is advocated by regulatory authorities as a means of independent verification of clinical trial end-points dependent on medical imaging, when the data from the trials may be submitted for licensing applications [Food and Drug Administration. United States food and drug administration guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics. Rockville, MD: US Department of Health and Human Services; 2007; Committee for Medicinal Products for Human Use. European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) guideline on the evaluation of anticancer medicinal products in man. London, UK: European Medicines Agency; 2006; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 21-492 (oxaliplatin). Rockville, MD: US Department of Health and Human Services; 2002; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 21-923 (sorafenib tosylate). Rockville, MD: US Department of Health and Human Services; 2005; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 22-065 (ixabepilone). Rockville, MD: US Department of Health and Human Services; 2007; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 22-059 (lapatinib ditosylate). Rockville, MD: US Department of Health and Human Services; 2007; United States Food and Drug Administration Center for Biologics Evaluation and Research. Approval package for BLA numbers 97-0260 and BLA Number 97-0244 (rituximab). Rockville, MD: US Department of Health and Human Services; 1997; United States Food and Drug Administration. FDA clinical review of BLA 98-0369 (Herceptin((R)) trastuzumab (rhuMAb HER2)). FDA Center for Biologics Evaluation and Research; 1998; United States Food and Drug Administration. FDA Briefing Document Oncology Drugs Advisory Committee meeting NDA 21801 (satraplatin). Rockville, MD: US Department of Health and Human Services; 2007; Thomas ES, Gomez HL, Li RK, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. JCO 2007(November):5210-7]. In addition, clinical trial sponsors have used ICR in Phase I-II studies to assist in critical pathway decisions including in-licensing of compounds [Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. JCO 2007(November):5180-6; Perez EA, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. JCO 2007(August):3407-14; Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. JCO 2007(June):2171-7; Ghassan KA, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. JCO 2006(September):4293-300; Boué F, Gabarre J, GaBarre J, et al. Phase II trial of CHOP plus rituximab in patients with HIV-associated non-Hodgkin's lymphoma. JCO 2006(September):4123-8; Chen HX, Mooney M, Boron M, et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. JCO 2006(July):3354-60; Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. JCO 2006(June):2502-12; Jaffer AA, Lee FC, Singh DA, et al. Multicenter phase II trial of S-1 plus cisplatin in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma. JCO 2006(February):663-7; Bouché O, Raoul JL, Bonnetain F, et al. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Fédération Francophone de Cancérologie Digestive Group Study-FFCD 9803. JCO 2004(November):4319-28]. This article will focus on the definition and purpose of ICR and the issues and lessons learned in the ICR setting primarily in Phase II and III oncology studies. This will include a discussion on discordance between local and central interpretations, consequences of ICR, reader discordance during the ICR, operational considerations and the need for specific imaging requirements as part of the study protocol.

New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

BACKGROUND: Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. FUTURE WORK: A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.

Recommendations for the assessment of progression in randomised cancer treatment trials.

Progression-free survival (PFS) is an increasingly important end-point in cancer drug development. However, several concerns exist regarding the use of PFS as a basis to compare treatments. Unlike survival, the exact time of progression is unknown, so progression times might be over-estimated (or under-estimated) and, consequently, bias may be introduced when comparing treatments. In addition, the assessment of progression is subject to measurement variability which may introduce error or bias. Ideally trials with PFS as the primary end-point should be randomised and, when feasible, double-blinded. All patients eligible for study should be evaluable for the primary end-point and thus, in general, have measurable disease at baseline. Appropriate definitions should be provided in the protocol and data collected on the case-report forms, if patients with only non-measurable disease are eligible and/or clinical, or symptomatic progression are to be considered progression events for analysis. Protocol defined assessments of disease burden should be obtained at intervals that are symmetrical between arms. Independent review of imaging may be of value in randomised phase II trials and phase III trials as an auditing tool to detect possible bias.

A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas.

Standard cytotoxic treatments for neuroendocrine tumours have been associated with limited activity and remarkable toxicity. A phase II study was designed to evaluate the efficacy, safety and pharmacodynamics of temsirolimus in patients with advanced neuroendocrine carcinoma (NEC). Thirty-seven patients with advanced progressive NEC received intravenous weekly doses of 25 mg of temsirolimus. Patients were evaluated for tumour response, time to progression (TTP), overall survival (OS) and adverse events (AE). Twenty-two archival specimens, as well as 13 paired tumour biopsies obtained pretreatment and after 2 weeks of temsirolimus were assessed for potential predictive and correlative markers. The intent-to-treat response rate was 5.6% (95% CI 0.6-18.7%), median TTP 6 months and 1-year OS rate 71.5%. The most frequent drug-related AE of all grades as percentage of patients were: fatigue (78%), hyperglycaemia (69%) and rash/desquamation (64%). Temsirolimus effectively inhibited the phosphorylation of S6 (P=0.02). Higher baseline levels of pmTOR (phosphorylated mammalian target of rapamycin) (P=0.01) predicted for a better response. Increases in pAKT (P=0.041) and decreases in pmTOR (P=0.048) after treatment were associated with an increased TTP. Temsirolimus appears to have little activity and does not warrant further single-agent evaluation in advanced NEC. Pharmacodynamic analysis revealed effective mTOR pathway downregulation.

Phase II study of pegylated liposomal doxorubicin HCl (Caelyx) in combination with cyclophosphamide and vincristine as second-line treatment of patients with small cell lung cancer.

BACKGROUND: Despite chemotherapy and radiotherapy for small cell lung cancer (SCLC), most patients die within 2 years. Response rates for second-line chemotherapy are 15-25%, with a median survival of 5 months. Caelyx, a pegylated liposomal formulation of doxorubicin, may be better tolerated and has activity in SCLC. PATIENTS AND METHODS: Thirty-two patients were enrolled in a phase II study of intravenous Caelyx (35 mg/m2), cyclophosphamide (750 mg/m2) and vincristine (1.2 mg/m2) every 21 days as second-line therapy in SCLC for up to six cycles. RESULTS: Thirty patients were evaluable for response, with a response rate of 10%. Another two had an unconfirmed response. Stable disease (SD) for >or=2 cycles was seen in an additional 53%. Grade 3 or 4 non-hematologic toxicity was seen in 17 (55%) patients (26 [22%] cycles) and included fatigue, mucositis, plantar-palmar erythrodysesthesia, rash and neuropathy. Twelve patients required transfusions. All patients on study have now expired, with a median survival of 28 weeks (7 months). For patients with SD or partial response, median time to progression was 15 weeks. CONCLUSION: The combination of Caelyx, cyclophosphamide and vincristine, despite cyclophosphamide and Caelyx dose reductions, has modest activity in relapsed SCLC with acceptable toxicity.

Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer.

Erlotinib (Tarceva, OSI-774), a potent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR), was evaluated in a phase II study to assess its activity in patients with metastatic colorectal cancer. In all, 38 patients with metastatic colorectal cancer were treated with erlotinib at a continuous daily oral dose of 150 mg. Radiological evaluation was carried out every 8 weeks and tumour biopsies were performed before treatment and on day 8. Of 31 evaluable patients, 19 (61%) had progressive disease and 12 (39%) had stable disease (s.d.). The median time to progression for those patients having s.d. was 123 days (range 108-329 days). The most common adverse events were rash in 34 patients and diarrhoea in 23 patients. Correlative studies were conducted to investigate the effect of erlotinib on downstream signalling. Tumour tissue correlations were based on usable tissue from eight match paired tumour samples pre- and on therapy, and showed a statistically significant decrease in the median intensity of both pEGFR (P=0.008) and phospho-extracellular signal-regulated kinase (ERK) (P=0.008) a week after commencement of treatment. No other statistically significant change in tumour markers was observed. Erlotinib was well tolerated with the most common toxicities being rash and diarrhoea. More than one-third of evaluable patients had s.d. for a minimum of 8 weeks. Correlative studies showed a reduction in phosphorylated EGFR and ERK in tumour tissue post-treatment.

A phase II study of perifosine (D-21226) in patients with previously untreated metastatic or locally advanced soft tissue sarcoma: A National Cancer Institute of Canada Clinical Trials Group trial.

UNLABELLED: BACKGROUND/PATIENTS AND METHODS: 16 adult patients with untreated measurable locally advanced or metastatic inoperable soft tissue sarcoma were treated with oral perifosine, a synthetic alkylphospholipid, believed to inhibit MAP kinase (MAP-K), protein kinase C (PKC), Akt and other regulatory proteins. Perifosine was administered orally in cycles for 21 days out of 28. Loading doses were given day 1 each cycle (900 mg cycle 1, 300 mg cycle 2+) and 150 mg daily was given days 2-21 of each cycle. Cycles were repeated until disease progression, unacceptable toxicity or patient refusal. RESULTS: Seventeen patients were enrolled; 16 and 15 were evaluable for toxicity and response, respectively. A total of 30 cycles of perifosine were administered. Most toxic effects were grade 1 or 2 and commonly included nausea, vomiting, diarrhea, and fatigue (> or =40%). Hematologic toxicity was generally mild. There were no significant biochemical abnormalities due to the drug reported. There were 4 serious adverse events (SAE)-none of which was related to perifosine. No objective responses were seen; 4 patients had stable disease for 1.3 to 8.2 months and the remainder of the patients had progressive disease. CONCLUSIONS: Perifosine when given according to this dosing schedule does not show evidence of activity in a mixed population of adult soft tissue sarcoma patients.

Phase I trial of UCN-01 in combination with topotecan in patients with advanced solid cancers: a Princess Margaret Hospital Phase II Consortium study.

BACKGROUND: 7-Hydroxystaurosporine (UCN-01) inhibits serine-threonine kinases including the Ca2+ and phospholipid-dependent protein kinase C (PKC), CDKs 2, 4, 6, Chk-1 and PDK1. UCN-01 mediates distinct effects in vitro/in vivo: cell cycle arrest in G1, abrogation of G2 arrest by inhibiting chk1, induction of apoptosis and potentiation of cytotoxicity of S-phase-active chemotherapeutics including the topoisomerase 1 inhibitor topotecan (T). This phase I study was designed to determine the maximal tolerated dose (MTD), recommended phase 2 dose (RPTD), toxicity profile, pharmacokinetics and antitumor activity of T and UCN-01 in patients with refractory solid tumors. DESIGN: Both agents were administered every 21 days intravenously through central venous access in escalating doses to eligible patients. On day 1, following antiemetic prophylaxis with dexamethasone and a serotonin type 3(A) receptor (5HT3) inhibitor, UCN-01 was infused over 3 h, followed by T infused over 30 min. On days 2-5, patients received T only. UCN-01 doses were reduced by 50% in cycles 2 and beyond because of its prolonged half-life. RESULTS: Thirty-three patients were entered in three cohorts: Dose Level (DL) 1 (UCN-01 70 mg/m2, T 0.75 mg/m2), three patients; DL 2 (UCN-01 70 mg/m2, T 1.0 mg/m2), 24 patients; DL 3 (UCN-01 90 mg/m2, T 1.0 mg/m2), six patients. All but three patients were PS 0 or 1, median age was 54 years (range, 29-72), 91% were female. Primary tumor types: ovary/peritoneal (23 patients), colon (three patients), salivary gland (two patients), others (five patients). All patients were eligible for adverse event (AE) analysis and 22 patients were eligible for survival and tumor response analysis. Two of six patients had dose limiting toxicity (DLT) at DL 3 (grade 3 N/V; grade 4 neutropenia with infection). One DLT was seen in one patient at DL 2, consisting of grade 4 leukopenia. This cohort was expanded and no further DLTs were observed. Most common drug-related AEs were mild (grade 1-2). Non-hematological grade 3-4 AEs consisted of transient hyperglycemia (4), infection (3), coagulation, fatigue, hypotension, nausea (2), hypomagnesemia, vomiting, headache (1). Hematologic toxicities occurred in 100% of patients. Grade 3-4 hematologic abnormalities included neutropenia (16, including three with infection), leukopenia (11), lymphopenia (7), thrombocytopenia (5). Best response for 22 evaluable patients was PD (8), SD for at least six cycles (12), PR (1: carcinoma of ovary, dose level 2) and one not assessable. Pharmacokinetic analysis confirmed the prolonged half-life of UCN-01 of approximately 15 days. CONCLUSIONS: DLT was observed at DL 3 and RPTD was determined to be DL 2. To date, this combination has been relatively well tolerated with some preliminary evidence of efficacy. A phase II study of this combination in patients with ovarian cancer is underway.

Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To compare the selective matrix metalloproteinase inhibitor BAY 12-9566 with the nucleoside analog gemcitabine in the treatment of advanced pancreatic cancer. METHODS: Patients with advanced pancreatic adenocarcinoma who had not previously received chemotherapy were randomly assigned to receive BAY 12-9566 800 mg orally bid continuously or gemcitabine 1,000 mg/m2 administered intravenously on days 1, 8, 15, 22, 29, 36, and 43 for the first 8 weeks, and then days 1, 8, and 15 of each subsequent 28-day cycle. The primary end point was overall survival; secondary end points were progression-free survival, tumor response, quality of life, and clinical benefit. The planned sample size of the study was 350 patients. Two formal interim analyses were planned. RESULTS: The study was closed to accrual after the second interim analysis on the basis of the recommendation of the National Cancer Institute of Canada Clinical Trials Group Data Safety Monitoring Committee. There were 277 patients enrolled onto the study, 138 in the BAY 12-9566 arm and 139 in the gemcitabine arm. The rates of serious toxicity were low in both arms. The median survival for the BAY 12-9566 arm and the gemcitabine arm was 3.74 months and 6.59 months, respectively (P <.001; stratified log-rank test). The median progression-free survival for the BAY 12-9566 and gemcitabine arms was 1.68 and 3.5 months, respectively (P <.001). Quality-of-life analysis also favored gemcitabine. CONCLUSION: Gemcitabine is significantly superior to BAY 12-9566 in advanced pancreatic cancer.

A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant tumour, which has a poor prognosis. Surgical resection can be curative but most patients are inoperable and most chemotherapy agents have minimal activity in this disease. Seocalcitol, a vitamin D analogue, induces differentiation and inhibits growth in cancer cell lines and in vivo. The vitamin D receptor is expressed in hepatocytes and more abundantly in HCC cells. In total, 56 patients with inoperable advanced HCC were included in an uncontrolled study of oral Seocalcitol treatment for up to 1 year (with possible extension for responders). The dose was titrated according to serum calcium levels. The treatment effect was evaluated by regular CT scans. Out of 33 patients evaluable for tumour response, two had complete response (CR), 12 stable disease and 19 progressive disease. The CRs appeared after 6 and 24 months of treatment, and lasted for 29 and at least 36 months (patient still in remission when data censored). Seocalcitol was well tolerated; the most frequent toxicity was hypercalcaemia and related symptoms. Most patients tolerated a daily dose of 10 micro g of Seocalcitol. This is the first study showing activity, by reduction in tumour dimensions, of a differentiating agent in patients with an advanced bulky, solid tumour. Seocalcitol may have an effect in the treatment of HCC, especially in early disease when a prolonged treatment can be instituted. The survival benefit with or without tumour response should be determined in controlled studies.

Agents targeting ras signaling pathway.

Ras genes encode proteins that activate in an intracellular signaling network controlling differentiation, proliferation and cell survival. Mutated Ras oncogenes encoding proteins that are constitutively active can induce malignancies in a variety of laboratory models. In human malignancies, Ras mutations are common, having been identified in approximately 30% of cancers. Given the importance of Ras and downstream targets Raf and MEK in the development of malignancies and their frequent expression in human cancers, it is not surprising that a variety of agents disrupting signaling through Ras and downstream proteins are under development. These agents can be broadly classified structurally as small molecules and anti-sense oligonucleotides. They can be characterized functionally as those inhibiting Ras protein expression such as the oligodeoxynucleotide ISIS 2503, those inhibiting Ras processing, in particular the farnesyl transferase inhibitors R115777, SCH 66336 and BMS 214662, and those inhibiting downstream effectors Raf, such as ISIS 5132 and MEK, which is inhibited by CI-1040. The purpose of this review is to highlight recent advances in the development of these agents.

Phase II study of pemetrexed disodium, a multitargeted antifolate, and cisplatin as first-line therapy in patients with advanced nonsmall cell lung carcinoma: a study of the National Cancer Institute of Canada Clinical Trials Group.

BACKGROUND: Pemetrexed disodium (Alimta [Eli Lilly and Company, Indianapolis, IN], LY231514, multitargeted antifolate) is a new multitargeted antifolate agent that inhibits multiple enzymes in the folate pathway. Phase II trials showed single-agent response rates of 16% and 23% in untreated patients with nonsmall cell lung carcinoma (NSCLC). This study was undertaken to determine the response to pemetrexed disodium given in combination with cisplatin. METHODS: Previously untreated patients were eligible if they had Stage IIIB or IV NSCLC, performance status 0, 1, or 2, adequate hematology and biochemistry and bidimensionally measurable lesions. Patients with brain metastases or neuropathy higher than Grade 2 were excluded. Pemetrexed disodium 500 mg/m(2) was given over 10 minutes, and cisplatin 75 mg/m(2) with hydration and mannitol diuresis was administered on Day 1 of each 21-day cycle. Dexamethasone 4 mg was taken orally once every 12 hours starting 24 hours before treatment and continuing for 6 doses after treatment. Four patients had detailed pemetrexed disodium pharmacokinetic analysis performed. RESULTS: Between May 1998 and June 1999, 31 patients were treated on the study. There were 20 males and 11 females; median age was 60 years (range, 35-75 years); there were 5 Stage IIIB, 26 Stage IV, 26 performance status 0 or 1, and 5 performance status 2. In 29 patients evaluable for response, there were 13 partial responses (PRs; overall response rate [ORR], 95%; confidence interval [CI]: 26-64%) of median duration 6.1 months (1.6-7.8 months). Three of four evaluable patients with performance status 2 achieved PR, and 11 of 24 evaluable Stage IV patients responded (ORR, 45.8% in Stage IV). Eighteen patients died. The median survival rate was 8.9 months (range, 1-15+ months). A total of 160 courses were delivered (median, 6 for both cisplatin and pemetrexed disodium). Grade 3 and 4 anemia was observed in 5 and 1 patients, respectively, and Grade 3 and 4 granulocytopenia in 7 and 4 patients, respectively. Grade 3 nausea and emesis occurred in only 2 patients, Grade 3/4 diarrhea in 3 patients, and 2 patients had Grade 3 motor neuropathy. Nine patients had Grade 2 infections, and there was one case of febrile neutropenia. Pharmacokinetic results showed C(max), clearance and V(ss) values to be similar to data from single-agent pemetrexed disodium given in the same dose. CONCLUSIONS: The combination of pemetrexed disodium and cisplatin is active against advanced NSCLC and is a well-tolerated convenient outpatient regimen. It deserves further study to compare it with other standard regimens for NSCLC.

Impact of new non-cytotoxics in the treatment of ovarian cancer.

Over the last decade, a number of new cytotoxic chemotherapy agents have shown evidence of antitumor activity in patients with ovarian carcinoma. These agents are currently being evaluated in large multinational randomized trials to determine whether their addition either concurrently or sequentially to standard paclitaxel and carboplatin regimens will result in improved survival. Whether these new combinations will provide additional benefit may be uncertain; however, it is certain that additional toxicity will limit the continued evaluation of the strategy of adding cytotoxics together. New approaches to improve the systemic therapy of ovarian cancer need to be explored. The next decade will see many trials of non-cytotoxics having a wide range of subcellular and extracellular targets. Many of these targets are abnormally expressed in a variety of solid tumors; thus, it is expected that many of these agents will be appropriate to evaluate in patients with ovarian carcinoma. Based on promising data from preclinical and early clinical studies as well as the presumed applicability of these targets to ovarian carcinoma, the inhibitors of growth factor receptors such as epidermal growth factor receptor and inhibitors of angiogenesis are of particular interest. Despite the interest of the investigators, the rapid evaluation of these target-specific non-cytotoxics is limited by the lack of accurate information on the expression of target in ovarian tumors and the relevance of target expression and its modulation to this tumor type. Early clinical trials are being designed to address these concerns; however, the clinical impact of non-cytotoxic agents in epithelial ovarian carcinoma patients must await the completion of randomized evaluations in combination with standard chemotherapeutic regimens.