The genetic basis for cancer treatment decisions.

Personalized cancer medicine is based on increased knowledge of the cancer mutation repertoire and availability of agents that target altered genes or pathways. Given advances in cancer genetics, technology, and therapeutics development, the timing is right to develop a clinical trial and research framework to move future clinical decisions from heuristic to evidence-based decisions. Although the challenges of integrating genomic testing into cancer treatment decision making are wide-ranging and complex, there is a scientific and ethical imperative to realize the benefits of personalized cancer medicine, given the overwhelming burden of cancer and the unprecedented opportunities for advancements in outcomes for patients.

Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02.

Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination.

Rare cancers: a sea of opportunity.

Rare cancers, as a collective, account for around a quarter of all cancer diagnoses and deaths. Historically, they have been divided into two groups: cancers defined by their unusual histogenesis (cell of origin or differentiation state)--including chordomas or adult granulosa cell tumours--and histologically defined subtypes of common cancers. Most tumour types in the first group are still clinically and biologically relevant, and have been disproportionately important as sources of insight into cancer biology. By contrast, most of those in the second group have been shown to have neither defining molecular features nor clinical utility. Omics-based analyses have splintered common cancers into a myriad of molecularly, rather than histologically, defined subsets of common cancers, many of which have immediate clinical relevance. Now, almost all rare cancers are either histomolecular entities, which often have pathognomonic mutations, or molecularly defined subsets of more common cancers. The presence of specific genetic variants provides rationale for the testing of targeted drugs in rare cancers. However, in addition to molecular alterations, it is crucial to consider the contributions of both mutation and cell context in the development, biology, and behaviour of these cancers. Patients with rare cancers are disadvantaged because of the challenge of leading clinical trials in this setting due to poor accrual. However, the number of patients with rare cancers will only increase as more molecular subsets of common cancers are identified, necessitating a shift in the focus of clinical trials and research into these cancer types, which, by epidemiological definitions, will become rare tumours.

Feasibility of real time next generation sequencing of cancer genes linked to drug response: results from a clinical trial.

The successes of targeted drugs with companion predictive biomarkers and the technological advances in gene sequencing have generated enthusiasm for evaluating personalized cancer medicine strategies using genomic profiling. We assessed the feasibility of incorporating real-time analysis of somatic mutations within exons of 19 genes into patient management. Blood, tumor biopsy and archived tumor samples were collected from 50 patients recruited from four cancer centers. Samples were analyzed using three technologies: targeted exon sequencing using Pacific Biosciences PacBio RS, multiplex somatic mutation genotyping using Sequenom MassARRAY and Sanger sequencing. An expert panel reviewed results prior to reporting to clinicians. A clinical laboratory verified actionable mutations. Fifty patients were recruited. Nineteen actionable mutations were identified in 16 (32%) patients. Across technologies, results were in agreement in 100% of biopsy specimens and 95% of archival specimens. Profiling results from paired archival/biopsy specimens were concordant in 30/34 (88%) patients. We demonstrated that the use of next generation sequencing for real-time genomic profiling in advanced cancer patients is feasible. Additionally, actionable mutations identified in this study were relatively stable between archival and biopsy samples, implying that cancer mutations that are good predictors of drug response may remain constant across clinical stages.

Minding the gaps: assessing and addressing clinical research core competencies across a network of Canadian cancer centres.

The Canadian Cancer Clinical Trials Network (3CTN, the Network), established in 2014 to address the decline in academic cancer clinical trials' (ACCT) activity, has successfully achieved incremental year-over-year accrual targets as well as implemented recognized performance measures and supports for improving efficiency and quality of trial activities at member sites across Canada. As part of efforts to address ongoing challenges of staff recruitment, retention, and turnover in academic institutions that have been more recently exacerbated by the pandemic, the Network's Performance Strategy Sub-Committee (PSC) oversaw surveys of site clinical research professionals intended to capture workforce development status and identify knowledge gaps using the Joint Task Force Core Competency Framework (JTF CCF) as the standard basis for assessment. Accountable to the 3CTN Management Committee, the PSC consists of clinical research operations experts across Canada responsible for overseeing implementation and monitoring progress of this initiative. Staff at 3CTN's adult sites evaluated and reported trial personnel core competencies and gaps according to each domain/leveled competency statement of the framework. The most frequently noted competency gaps were in the domains of: Investigational Product Development and Regulation (28%); Scientific Concepts and Research Design (16%); and Study and Site Management (14%). Reported data was compiled and represented in the 3CTN Core Competency Report, developed as a web-based, interactive tool enabling members and stakeholders to filter data to enumerate and quantify workforce competency gaps at their site, within their node of affiliated sites, or across the national Network. Concurrently, an environmental scan and review of education resources was conducted and reviewed by the PSC. Embedded links to curated learning and development resources were incorporated into the report and associated with each domain/leveled competency statement to provide ready access to high-quality learning and development resources where needed. In the remaining years of its current strategic plan, 3CTN will continue to monitor, develop collaborative initiatives to target prioritized clinical research competency gaps and create opportunities for ongoing assessment and reporting by sites to capture changes in workforce core competencies over time.

Predictive factors for epidermal growth factor receptor inhibitors--the bull's-eye hits the arrow.

Studies have shown that epidermal growth factor receptor (EGFR) signaling is important to normal development and neoplastic transformation, and that EGFR inhibition reduces cancer cell proliferation. The promising response rates of the EGFR inhibitor gefitinib in patients with chemotherapy-refractory non-small cell lung cancer (NSCLC) led to its approval for clinical use. However, there was little understanding of why gefitinib was effective in only some NSCLC patients. Two recent studies have identified somatic mutations in EGFR that confer its sensitivity to gefitinib in vitro and correlate strongly with patients' clinical response to the inhibitor.

The Impact of COVID-19 on Academic Cancer Clinical Trials in Canada and the Initial Response from Cancer Centers.

The COVID-19 pandemic resulted in temporary holds placed on new trial startups, patient recruitment and follow up visits for trials which contributed to major disruptions in cancer center trial unit operations. To assess the impact, the Canadian Cancer Clinical Trials Network (3CTN) members participated in regional meetings and a survey to understand the impact of the pandemic to academic cancer clinical trials (ACCT) activity, cancer trial unit operations and supports needed for post-pandemic recovery. Trial performance and recruitment data collected from 1 April 2020-31 March 2021 was compared to the same period in previous years. From 1 April-30 June 2020, patient recruitment decreased by 67.5% and trial site activations decreased by 81% compared to the same period in 2019. Recovery to reopening and recruitment of ACCTs began after three months, which was faster than initially projected. However, ongoing COVID-19 impacts on trial unit staffing and operations continue to contribute to delayed trial activations, lower patient recruitment and may further strain centers' capacity for participation in academic-sponsored trials.

Ridaforolimus: a promising drug in the treatment of soft-tissue sarcoma and other malignancies.

Ridaforolimus (deforolimus; AP23573; MK-8669) is a novel sirolimus derivative manufactured by ARIAD Pharmaceuticals and acquired by Merck. It is a small-molecule kinase inhibitor of the mTOR in clinical development for the treatment of cancer. Both intravenous and oral formulations of the agent are being tested in cancer clinical trials. In preclinical and clinical studies, ridaforolimus exhibited significant antitumor activity with acceptable safety and tolerability. With single-agent ridaforolimus, mucositis and myelosuppression were dose-limiting toxicities. In advanced soft-tissue sarcoma, single-agent ridaforolimus was associated with a 29% clinical benefit rate and 2% partial response rate. A Phase III trial has recently been reported to have met its primary end point.

Advancing Academic Cancer Clinical Trials Recruitment in Canada.

The Canadian Cancer Clinical Trials Network (3CTN) was established in 2014 to address the decline in academic cancer clinical trials (ACCT) activity. Funding was provided to cancer centres to conduct a Portfolio of ACCTs. Larger centres received core funding and were paired with smaller centres to enable support and sharing of resources. All centres were eligible for incentive-based funding for recruitment above pre-3CTN baseline. Established performance measures were collected and tracked. The overall recruitment target was 50% above pre-3CTN baseline by Year 4. An analysis was completed to identify predictive success factors and descriptive statistics were used to summarize site characteristics and outcomes. From 2014-2018, a total of 11,275 patients were recruited to 559 Portfolio trials, an overall increase of 59.6% above pre-3CTN baseline was observed in Year 4. Twenty-five (51%) adult centres met the Year 4 recruitment target and the overall recruitment target was met within three years. Three factors that correlated with sites' achieving recruitment targets were: time period, region and number of baseline trials. 3CTN was successful in meeting its objectives and will continue to support ACCTs and member cancer centres, monitor performance over time and seek continued funding to ensure success, better trial access and outcomes for patients.

CRAFT-A Proposed Framework for Decentralized Clinical Trials Participation in Canada.

Canada's vast geography, and centralized delivery of cancer care and clinical trials create barriers for trial participation for patients in remote and rural settings. The development and implementation of a framework that enables safe and regulatory compliant trial participation through local healthcare providers would benefit Canadian patients, clinicians, trial sponsors and the health care system. To address this issue, representatives of Canada's cancer clinical trial community met to identify key challenges and develop recommendations for remote patient participation in trials. A structured literature review identified remote/rural trial delivery models. A panel of expert stakeholders reviewed the models and participated in a workshop to assess health system readiness, identify needed processes, tools and mechanisms, and develop recommendations for a Canadian framework for decentralized clinical trial conduct. The Canadian Remote Access Framework for clinical Trials (CRAFT) represents a risk-based approach used by site investigators to delegate responsibilities for a given trial to satellite health centres within a hub-and-spoke "trial cluster". The Framework includes specific recommendations to ensure research experience, capacity, regulatory compliance and patient safety. Canada's cancer care and telemedicine systems can be leveraged to enable broader access to clinical trials for patients who are geographically remote from cancer centres. CRAFT's risk-based framework is based on other successful models of remote trial patient management and is in the pilot implementation phase in Canada.

A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group.

BACKGROUND: Accurate grading of dermatologic adverse events (AE) due to epidermal growth factor receptor (EGFR) inhibitors (EGFRIs) is necessary for drug toxicity determinations, interagent comparisons, and supportive care trials. The most widely used severity grading scale, the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE v4.0), was not designed specifically for this class of agents and may result in underreporting and poor grading of distinctive adverse events. We believe a class-specific grading scale is needed to help standardize assessment and improve reporting of EGFRI-associated dermatologic AEs. METHODS: The Multinational Association of Supportive Care in Cancer (MASCC) Skin Toxicity Study Group conducted an international multidisciplinary meeting that included 20 clinicians and researchers from academic centers and government agencies. Experts from different disciplines presented current information specific to EGFRI-induced dermatologic toxicities: grading scale development, pharmacovigilance safety reporting, health-related quality of life, patient reporting, and pharmacology. Group discussions, literature reviews, and professional expertise established the theoretical foundation for the proposed grading scale. RESULTS: A new grading system is proposed for the most common events associated with EGFRI-induced dermatologic AEs: papulopustular reaction or acneiform rash, nail changes, erythema, pruritus, xerosis, hair changes, telangiectasias, hyperpigmentation, mucositis, flushing, radiation dermatitis, hyposalivation, and taste changes. The proposed scale maintains consistency with the grading principles and language of the existing CTCAE version 4.0 and MedDRA terminology and includes relevant patient-reported health-related quality of life factors. CONCLUSIONS: A grading scale specific to EGFR inhibitor dermatologic AEs is presented for formal integration into future versions of CTCAE and for validation in clinical trial settings. The study group designed this scale to detect and report EGFRI-related toxicities with greater sensitivity, specificity, and range than the scales currently used. This scale should serve as a foundation for efforts to perform objective interdrug comparisons and assessments of supportive care treatment strategies more effectively than with current methods.

Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study.

BACKGROUND: Epidermal growth factor receptor (EGFR) is a validated target in squamous-cell carcinoma of the head and neck, but in patients with recurrent or metastatic disease, EGFR targeting agents have displayed modest efficacy. Vascular endothelial growth factor (VEGF)-mediated angiogenesis has been implicated as a mechanism of resistance to anti-EGFR therapy. In this multi-institutional phase I/II study we combined an EGFR inhibitor, erlotinib, with an anti-VEGF antibody, bevacizumab. METHODS: Between April 15, 2003, and Jan 27, 2005, patients with recurrent or metastatic squamous-cell carcinoma of the head and neck were enrolled from seven centres in the USA and were given erlotinib (150 mg daily) and bevacizumab in escalating dose cohorts. The primary objectives in the phase I and II sections, respectively, were to establish the maximum tolerated dose and dose-limiting toxicity of bevacizumab when administered with erlotinib and to establish the proportion of objective responses and time to disease progression. Pretreatment serum and tissues were collected and analysed by enzyme-linked immunosorbent assay and immunofluorescence quantitative laser analysis, respectively. This study was registered with ClinicalTrials.gov, number NCT00055913. FINDINGS: In the phase I section of the trial, ten patients were enrolled in three successive cohorts with no dose-limiting toxic effects noted. 46 patients were enrolled in the phase II section of the trial (including three patients from the phase I section) on the highest dose of bevacizumab (15 mg/kg every 3 weeks). Two additional patients were accrued beyond the protocol-stipulated 46, leaving a total of 48 patients for the phase II assessment. The most common toxic effects of any grade were rash and diarrhoea (41 and 16 of 48 patients, respectively). Three patients had serious bleeding events of grade 3 or higher. Seven patients had a response, with four showing a complete response allowing rejection of the null hypothesis. Median time of overall survival and progression-free survival (PFS) were 7.1 months (95% CI 5.7-9.0) and 4.1 months (2.8-4.4), respectively. Higher ratios of tumour-cell phosphorylated VEGF receptor-2 (pVEGFR2) over total VEGFR2 and endothelial-cell pEGFR over total EGFR in pretreatment biopsies were associated with complete response (0.704 vs 0.386, p=0.036 and 0.949 vs 0.332, p=0.036, respectively) and tumour shrinkage (p=0.007 and p=0.008, respectively) in a subset of 11 patients with available tissue. INTERPRETATION: The combination of erlotinib and bevacizumab is well tolerated in recurrent or metastatic squamous-cell carcinoma of the head and neck. A few patients seem to derive a sustained benefit and complete responses were associated with expression of putative targets in pretreatment tumour tissue.

Phase I/II study of sorafenib in combination with erlotinib for recurrent glioblastoma as part of a 3-arm sequential accrual clinical trial: NABTC 05-02.

BACKGROUND: Receptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) and their downstream signaling pathways such as the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway play important roles in glioblastoma (GBM). This study investigated the safety, pharmacokinetics, and efficacy of sorafenib (Ras/Raf/MAPK inhibitor) in combination with erlotinib (EGFR inhibitor) for treatment of recurrent GBMs. METHODS: Patients with recurrent GBM were eligible. A novel sequential accrual trial design was used, where patients were sequentially accrued into separate treatment arms in phase I and phase II investigations to optimize recruitment efficiency. In phase I, a standard 3 + 3 format was used to identify dose-limiting toxicities (DLTs), determine maximum tolerated dose (MTD), and investigate pharmacokinetics. Phase II followed a 2-stage design with the primary endpoint being 6-month progression-free survival (PFS6). RESULTS: Sixteen patients were recruited for phase I, and the MTD was determined to be sorafenib 200 mg twice daily and erlotinib 100 mg once daily. DLTs include Grade 3 hypertension, Grade 3 elevated liver transaminases, and Grade 4 elevated lipase. While erlotinib did not affect sorafenib levels, sorafenib reduced erlotinib levels. In phase II, 3 of 19 stage 1 participants were progression free at 6 months. This did not meet the predetermined efficacy endpoint, and the trial was terminated. CONCLUSION: This study identified the MTD and DLTs for sorafenib and erlotinib combination therapy for recurrent GBMs; however, efficacy data did not meet the primary endpoint. This study also demonstrates the feasibility of a novel sequential accrual clinical trial design that optimizes patient recruitment for multiarm studies, which is particularly effective for multicenter clinical trials.

Strategies for optimizing combinations of molecularly targeted anticancer agents.

The rapid emergence of hundreds of new agents that modulate an ever-growing list of cancer-specific molecular targets offers tremendous hope for cancer patients. However, evaluating targeted agents individually, in combination with standard treatments, and in combination with other targeted agents presents significant development challenges. Because the number of possible drug combinations is essentially limitless, a strategy for determining the most promising combinations and prioritizing their evaluation is crucial. Here, we consider the crucial elements of a development strategy for targeted-agent combinations. Issues that pose challenges to the rational preclinical and clinical evaluation of such combinations will be described, and possible approaches to overcoming these challenges will be discussed.

Epidermal growth factor receptor inhibitors in non-small cell lung cancer.

Aberrant epidermal growth factor receptor (EGFR) signalling contributes to neoplastic transformation and EGFR inhibition by antibodies and small molecules inhibits cancer cell proliferation and survival. In previously treated patients with non-small cell lung cancer, the administration of gefitinib and erlotinib are associated with objective tumour response rates of 8-19%. However, only erlotinib has been shown definitively to improve patient survival. The likelihood of benefit may be determined by the presence of specific genotypic abnormalities in EGFR or downstream pathway components. Additional evaluation to determine optimal dose/schedule of the agents combined with standard treatments and with other targeted agents in appropriately selected patients are areas of active research.

Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Children's Oncology Group Study.

PURPOSE: Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors. PATIENTS AND METHODS: Gefitinib (150, 300, 400, or 500 mg/m2) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28). RESULTS: Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m2 and elevated ALT and AST in one patient treated with 400 mg/m2. The maximum-tolerated dose was 400 mg/m2/d. The most frequent non-dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing's sarcoma had a partial response. Disease stabilized for 8 to > or = 60 weeks in two patients with Wilms' tumor and two with brainstem glioma (one exophytic). At 400 mg/m2, the median peak gefitinib plasma concentration was 2.2 microg/mL (range, 1.2 to 3.6 microg/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m2 (range, 3.8 to 24.8 L/h/m2) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults. CONCLUSION: Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.

Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE: We conducted a two-phase clinical trial in patients with progressive malignant glioma (MG). The first phase of this trial was designed to determine the dose of O6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O6-BG. In addition, plasma concentrations of O6-BG and O6-benzyl-8-oxoguanine were evaluated after O6-BG. PATIENTS AND METHODS: For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O6-BG infusion at 120 mg/m2 followed by a continuous infusion at an initial dose of 30 mg/m2/d for 48 hours. The dose of the continuous infusion of O6-BG escalated until tumor AGT was depleted. Once the O6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O6-BG infusion, was escalated until the MTD was determined. RESULTS: The O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m2 with dose-limiting toxicities limited to myelosuppression. CONCLUSION: This study provides the foundation for a phase II trial of O6-BG plus temozolomide in temozolomide-resistant MG.

Therapeutic targets: MTOR and related pathways.

The mammalian target of rapamycin (mTOR), a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, has a central role in controlling malignant cellular growth. As a result, mTOR is viewed as an important target for anticancer drug development. Inhibitors of mTOR currently under evaluation in cancer clinical trials are rapamycin (also known as sirolimus, Wyeth) and derivatives temsirolimus (CCI-779, Wyeth), everolimus, (RAD001, Novartis Pharma AG), and AP23573 (Ariad Pharmaceuticals). Preclinical studies suggest that sensitivity to mTOR inhibitors may correlate with activation of the PI3K pathway and/or with aberrant expression of cell cycle regulatory or anti-apoptotic proteins. Clinical trial results show that mTOR inhibitors are well tolerated and may induce prolonged stable disease and tumor regressions in cancer patients. Future research should evaluate optimal, schedule, patient selection, and combination strategies for this novel class of agents.