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1.  Dose-Levels and First Signs of Efficacy in Contemporary Oncology Phase 1 Clinical Trials 
PLoS ONE  2011;6(3):e16633.
Purpose
Phase 1 trials play a crucial role in oncology by translating laboratory science into efficient therapies. Molecular targeted agents (MTA) differ from traditional cytotoxics in terms of both efficacy and toxicity profiles. Recent reports suggest that higher doses are not essential to produce the optimal anti-tumor effect. This study aimed to assess if MTA could achieve clinical benefit at much lower dose than traditional cytotoxics in dose seeking phase 1 trials.
Patients and Methods
We reviewed 317 recent phase 1 oncology trials reported in the literature between January 1997 and January 2009. First sign of efficacy, maximum tolerated dose (MTD) and their associated dose level were recorded in each trial.
Results
Trials investigating conventional cytotoxics alone, MTA alone and combination of both represented respectively 63.0% (201/317), 23.3% (74/317) and 13.7% (42/317) of all trials. The MTD was reached in 65.9% (209/317) of all trials and was mostly observed at the fifth dose level. First sign of efficacy was less frequently observed at the first three dose-levels for MTA as compared to conventional cytotoxics or combinations regimens (48.3% versus 63.2% and 61.3%). Sign of efficacy was observed in the same proportion whatever the treatment type (73–82%). MTD was less frequently established in trials investigating MTA alone (51.3%) or combinations (42.8%) as compared to conventional cytotoxic agents (75.6%).
Conclusion
First sign of efficacy was less frequently reported at the early dose-levels and MTD was less frequently reached in trials investigating molecular targeted therapy alone. Similar proportion of trials reported clinical benefit.
doi:10.1371/journal.pone.0016633
PMCID: PMC3056556  PMID: 21415927
2.  Case Example of Dose Optimization Using Data From Bortezomib Dose-Finding Clinical Trials 
Journal of Clinical Oncology  2016;34(12):1395-1401.
Purpose
The current dose-finding methodology for estimating the maximum tolerated dose of investigational anticancer agents is based on the cytotoxic chemotherapy paradigm. Molecularly targeted agents (MTAs) have different toxicity profiles, which may lead to more long-lasting mild or moderate toxicities as well as to late-onset and cumulative toxicities. Several approved MTAs have been poorly tolerated during long-term administration, leading to postmarketing dose optimization studies to re-evaluate the optimal treatment dose. Using data from completed bortezomib dose-finding trials, we explore its toxicity profile, optimize its dose, and examine the appropriateness of current designs for identifying an optimal dose.
Patients and Methods
We classified the toxicities captured from 481 patients in 14 bortezomib dose-finding studies conducted through the National Cancer Institute Cancer Therapy Evaluation Program, computed the incidence of late-onset toxicities, and compared the incidence of dose-limiting toxicities (DLTs) among groups of patients receiving different doses of bortezomib.
Results
A total of 13,008 toxicities were captured: 46% of patients’ first DLTs and 88% of dose reductions or discontinuations of treatment because of toxicity were observed after the first cycle. Moreover, for the approved dose of 1.3 mg/m2, the estimated cumulative incidence of DLT was > 50%, and the estimated cumulative incidence of dose reduction or treatment discontinuation because of toxicity was nearly 40%.
Conclusions
When considering the entire course of treatment, the approved bortezomib dose exceeds the conventional ceiling DLT rate of 20% to 33%. Retrospective analysis of trial data provides an opportunity for dose optimization of MTAs. Future dose-finding studies of MTAs should take into account late-onset toxicities to ensure that a tolerable dose is identified for future efficacy and comparative trials.
doi:10.1200/JCO.2015.66.0662
PMCID: PMC5070578  PMID: 26926682
3.  Withdrawal of anticancer therapy in advanced disease: a systematic literature review 
BMC Cancer  2015;15:892.
Background
Current guidelines set out when to start anticancer treatments, but not when to stop as the end of life approaches. Conventional cytotoxic agents are administered intravenously and have major life-threatening toxicities. Newer drugs include molecular targeted agents (MTAs), in particular, small molecule kinase-inhibitors (KIs), which are administered orally. These have fewer life-threatening toxicities, and are increasingly used to palliate advanced cancer, generally offering additional months of survival benefit. MTAs are substantially more expensive, between £2-8 K per month, and perceived as easier to start than stop.
Methods
A systematic review of decision-making concerning the withdrawal of anticancer drugs towards the end of life within clinical practice, with a particular focus on MTAs. Nine electronic databases searched. PRISMA guidelines followed.
Results
Forty-two studies included. How are decisions made? Decision-making was shared and ongoing, including stopping, starting and trying different treatments. Oncologists often experienced ‘professional role dissonance’ between their self-perception as ‘treaters’, and talking about end of life care. Why are decisions made? Clinical factors: disease progression, worsening functional status, treatment side-effects. Non-clinical factors: physicians’ personal experience, values, emotions. Some patients continued treatment to maintain ‘hope’, often reflecting limited understanding of palliative goals. When are decisions made? Limited evidence reveals patients’ decisions based upon quality of life benefits. Clinicians found timing withdrawal particularly challenging. Who makes the decisions? Decisions were based within physician-patient interaction.
Conclusions
Oncologists report that decisions around stopping chemotherapy treatment are challenging, with limited evidence-based guidance outside of clinical trial protocols. The increasing availability of oral MTAs is transforming the management of incurable cancer; blurring boundaries between active treatment and palliative care. No studies specifically addressing decision-making around stopping MTAs in clinical practice were identified. There is a need to develop an evidence base to support physicians and patients with decision-making around the withdrawal of these high cost treatments.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1862-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1862-0
PMCID: PMC4641339  PMID: 26559912
Molecular targeted agents; Treatment decision-making; End of life; Palliative care
4.  Dosing targeted and cytotoxic two‐drug combinations: Lessons learned from analysis of 24,326 patients reported 2010 through 2013 
International Journal of Cancer  2016;139(9):2135-2141.
Combining agents has the potential to attenuate resistance in metastatic cancer. However, knowledge of appropriate starting doses for novel drug combinations in clinical trials and practice is lacking. Analysis of 372 published studies was used to ascertain safe starting doses for doublets involving a cytotoxic and targeted agent. Phase I–III adult oncology clinical trial publications (January 1, 2010 to December 31, 2013) were identified (PubMed). The dose of drug used in each combination was compared to the single agent recommended dose [FDA‐approved/recommended phase 2 dose (RP2D)/maximum tolerated dose (MTD)]. Dose percentages were calculated as: (safe dose of drug in combination/dose of drug as single agent at FDA/RP2D/MTD) × 100. Additive dose percentages were the sum of the dose percentage for each drug. A total of 24,326 patients (248 drug combinations) were analyzed. In 38% of studies, both drugs could be administered at 100% of their FDA‐approved/RP2D/MTD dose. The lowest safe additive dose percentage was 41% with poly‐ADP ribose polymerase (PARP) or histone deacetylase inhibitors as the targeted agents; 82%, in the absence of these agents; and 97%, with an antibody in the combination. If one drug was administered at 100% of the single agent dose, the lowest safe dose percentage for the second drug was 17% (cytotoxic at 100%) or 36% (targeted at 100%) of the FDA‐approved/RP2D/MTD dose. The current findings can help inform safe starting doses for novel two‐drug combinations (cytotoxic and targeted agents) in the context of clinical trials and practice.
What's new?
Cytotoxic and targeted cancer drugs act through distinct mechanisms, and when used in combination they can potentially augment therapeutic effectiveness while minimally impacting toxicity. However, whereas algorithms for safe starting doses for new single‐agent therapies are well established, there are few guidelines for combination therapies. Here, analyses of data from published Phase I–III clinical trials shows that about 38% of patients tolerated combinations in which both drugs were administered at full starting doses. In the majority of patients, significant dose reductions were required to guard against toxicity. Intrapatient dose escalation is possible, however, potentially allowing for increased efficacy.
doi:10.1002/ijc.30262
PMCID: PMC5096042  PMID: 27389805
targeted therapy; cytotoxic chemotherapy; maximum tolerated dose; recommended Phase 2 dose; precision medicine
5.  Early phase clinical trials to identify optimal dosing and safety 
Molecular oncology  2014;9(5):997-1007.
The purpose of early stage clinical trials is to determine the recommended dose and toxicity profile of an investigational agent or multi-drug combination. Molecularly targeted agents (MTAs) and immunotherapies have distinct toxicities from chemotherapies that are often not dose dependent and can lead to chronic and sometimes unpredictable side effects. Therefore utilizing a dose escalation method that has toxicity based endpoints may not be as appropriate for determination of recommended dose, and alternative parameters such as pharmacokinetic or pharmacodynamic outcomes are potentially appealing options. Approaches to enhance safety and optimize dosing include improved preclinical models and assessment, innovative model based design and dose escalation strategies, patient selection, the use of expansion cohorts and extended toxicity assessments. Tailoring the design of phase I trials by adopting new strategies to address the different properties of MTAs is required to enhance the development of these agents. This review will focus on the limitations to safety and dose determination that have occurred in the development of MTAs and immunotherapies. In addition, strategies are proposed to overcome these challenges to develop phase I trials that can more accurately define the recommended dose and identify adverse events.
doi:10.1016/j.molonc.2014.07.025
PMCID: PMC4329110  PMID: 25160636
Phase I trials; recommended phase 2 dose; toxicity
6.  Bayesian dose-finding designs for combination of molecularly targeted agents assuming partial stochastic ordering 
Statistics in Medicine  2014;34(5):859-875.
Molecularly targeted agent (MTA) combination therapy is in the early stages of development. When using a fixed dose of one agent in combinations of MTAs, toxicity and efficacy do not necessarily increase with an increasing dose of the other agent. Thus, in dose-finding trials for combinations of MTAs, interest may lie in identifying the optimal biological dose combinations (OBDCs), defined as the lowest dose combinations (in a certain sense) that are safe and have the highest efficacy level meeting a prespecified target. The limited existing designs for these trials use parametric dose–efficacy and dose–toxicity models. Motivated by a phase I/II clinical trial of a combination of two MTAs in patients with pancreatic, endometrial, or colorectal cancer, we propose Bayesian dose-finding designs to identify the OBDCs without parametric model assumptions. The proposed approach is based only on partial stochastic ordering assumptions for the effects of the combined MTAs and uses isotonic regression to estimate partially stochastically ordered marginal posterior distributions of the efficacy and toxicity probabilities. We demonstrate that our proposed method appropriately accounts for the partial ordering constraints, including potential plateaus on the dose–response surfaces, and is computationally efficient. We develop a dose-combination-finding algorithm to identify the OBDCs. We use simulations to compare the proposed designs with an alternative design based on Bayesian isotonic regression transformation and a design based on parametric change-point dose–toxicity and dose–efficacy models and demonstrate desirable operating characteristics of the proposed designs. © 2014 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.
doi:10.1002/sim.6376
PMCID: PMC4359011  PMID: 25413162
Bayesian isotonic regression transformation; dose–efficacy surface; dose–toxicity surface; matrix ordering; plateau; post processing
7.  Phase I Oncology Studies: Evidence That in the Era of Targeted Therapies, Patients on Lower Doses Do Not Fare Worse 
PURPOSE
To safely assess new drugs, cancer patients in initial cohorts of phase I oncology studies receive low drug doses. Doses are successively increased until the maximum tolerated dose (MTD) is determined. Since traditional chemotherapy is often more effective near the MTD, ethical concerns have been raised regarding administration of low drug doses to phase I patients. However, a substantial portion of oncology trials now investigate targeted agents, which may have different dose-response relationships than cytotoxic chemotherapies.
EXPERIMENTAL DESIGN
Twenty-four consecutive trials treating 683 patients between 10-01-2004 and 6-30-2008 at MD Anderson Cancer Center were analyzed. Patients were assigned to a low-dose (≤25% MTD), medium-dose (25–75% MTD), or high-dose (≥75% MTD) group, and groups were compared for response rate, time-to-treatment-failure, progression-free survival, overall survival, and toxicity. To remove negatively biasing data from the high-dose group, in a second analysis patients treated above the MTD were excluded (high-dose group = 75–100% MTD). 97.7% of patients received targeted agents.
RESULTS
Even when excluding patients above the MTD, there was an early trend favoring the low- versus high-dose group in time-to-treatment-failure, with 32.9% versus 25.2% of patients on therapy at 3 months (p=0.08). Additionally, the low-dose group fared at least as well as the other groups in all other outcomes, including response rate, progression-free survival, overall survival, and toxicity.
CONCLUSIONS
These data may help alleviate concerns that patients who receive low drug doses on contemporary phase I oncology trials fare worse, and suggest targeted agents may have different dose-response relationships than cytotoxic chemotherapies.
doi:10.1158/1078-0432.CCR-09-2684
PMCID: PMC2822881  PMID: 20145187
8.  A survey of new oncology drug approvals in the USA from 2010 to 2015: a focus on optimal dose and related postmarketing activities 
The maximally tolerated dose (MTD) of cytotoxic agents has historical precedence in treating cancer, as it was believed that dose and therapeutic effect are intrinsically linked and that the MTD would provide greatest therapeutic value. With molecularly targeted agents, the premise of preventing toxicity to normal tissues while modulating tumor growth provides a potential for an increased therapeutic window. Results from these targeted agents suggest we are entering an era of chronic cancer management, which will require design of regimens with long-term tolerability. A corresponding switch from MTD-based (toxicity-driven) dosing strategies to alternative paradigms is also expected. The challenge with these targeted agents is to fully understand the complex relationship between pharmacokinetics, pharmacodynamics, and safety and efficacy in early-stage trials, so that the optimal dose and schedule for registration trials may be identified. This review provides a systematic survey of the applications submitted to the United States Food and Drug Administration (FDA) for oncology indications, from 2010 through early 2015, and summarizes the dose selection rationale for registrational trials, the relationship of the MTD to outcomes of the final label dose, the postmarketing requirements or commitments related to dose optimization activities, the role of biomarkers, and typical exposure–response modeling methods.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-015-2931-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s00280-015-2931-4
PMCID: PMC4767861  PMID: 26811176
Oncology; Dose selection; Pharmacokinetics; Modeling; Pharmacodynamics; Maximum tolerated dose; Food and Drug Administration
9.  Antitumor Activity of Rapamycin in a Phase I Trial for Patients with Recurrent PTEN-Deficient Glioblastoma 
PLoS Medicine  2008;5(1):e8.
Background
There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population.
Methods and Findings
Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN) loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR), we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation) varied substantially. Tumor cell proliferation (measured by Ki-67 staining) was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test) but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test).
Conclusions
Rapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors. The short-term treatment endpoints used in this neoadjuvant trial design identified the importance of monitoring target inhibition and negative feedback to guide future clinical development.
Trial registration: http://www.ClinicalTrials.gov (#NCT00047073).
In a Phase I clinical trial Charles Sawyers and colleagues investigated the role of rapamycin in patients with PTEN-deficient glioblastoma.
Editors' Summary
Background.
Glioblastoma is a highly malignant tumor of the brain. As with other tumors, it can result from a number of different molecular changes. Traditional chemotherapy does little more than contain these tumors, and cannot cure it. An alternative approach to the treatment of such tumors is to target specific molecular changes in the tumor. Obviously such targeted treatment will work only in patients who have the specific molecular defect being targeted. Hence, traditional clinical trials, which include a large variety of different patients and tumors with different genetic changes, may be an inappropriate way to test how effective targeted treatments are.
One specific change that has been identified in around 40% of patients with glioblastoma is inactivation of a gene known as PTEN, which acts as a tumor suppressor gene. When PTEN is inactivated it has previously been shown to make cells more sensitive to a class of drugs known as mTOR inhibitors—one of which is rapamycin (trade name Sirolimus). mTOR is a protein that is involved in the regulation of a number of cellular processes including growth and proliferation. Drugs active against mTOR are currently being tested for effectiveness against other cancers and as immunosuppressive agents.
Why Was This Study Done?
This was a Phase I study—that is, the earliest type of a drug study that is done in humans—which aimed to look at the safety of rapamycin in a selected group of patients who were undergoing surgery after recurrence of glioblastoma, and whose tumors did not express PTEN. In addition, the authors also wanted to assess the feasibility of incorporating detailed molecular studies of the action of this drug into such a Phase I study and whether these molecular studies could predict whether patients were more or less likely to respond to rapamycin.
What Did the Researchers Do and Find?
A total of 15 patients were treated with rapamycin at differing doses for one week before surgery and then again after surgery until there was evidence that the tumors were progressing. There was no evidence of very severe toxicity in any of the patients, though there were some adverse effects that required treatment. When samples from the patients were tested after surgery, seven of them showed a reduction in how rapidly the tumor cells divided, and this reduction was associated with how much inhibition there was of mTOR. Two of these patients showed evidence on scans of a reduction in tumor mass. Cells from tumors that appeared resistant to rapamycin in patients were sensitive to rapamycin in tissue culture, suggesting that the lack of response was due to the drug not being able to penetrate the tumor. A second, unfortunate effect of rapamycin was to cause activation of another intracellular protein, Akt, in some patients; when this activation occurred, patients had a shorter time between surgery and a return of their disease.
What Do These Findings Mean?
The detailed molecular studies within this Phase I trial allow a better understanding of how this targeted drug works. These findings suggest that the rapamycin can reduce the proliferation rate of glioblastoma cells, and that this reduction appears to be related to how well the drug is able to penetrate the tumor and inhibit mTOR. However, in some patients the activation of a second pathway can speed up the course of the disease, so further trials should incorporate inhibitors of this second pathway.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050008.
The US National Cancer Institute provides information on all aspects of cancer (in English and Spanish)
The UK charity Cancerbackup provides information on brain tumors
Wikipedia has a page on mTOR (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.0050008
PMCID: PMC2211560  PMID: 18215105
10.  Clinical Development of VEGF Signaling Pathway Inhibitors in Childhood Solid Tumors 
The Oncologist  2011;16(11):1614-1625.
The clinical development of vascular endothelial growth factor signaling pathway inhibitors in pediatric solid tumors is reviewed. Challenges and considerations for future trials of antiangiogenic agents in children and adolescents are discussed.
Learning Objectives
After completing this course, the reader will be able to: Identify the mechanism, specificity, relative potency, dosing schedule, important pharmacokinetic characteristics, and agent-specific side effects of the VEGF signaling pathway inhibitors currently in pediatric development.Describe the different concerns between children and adults regarding the common class side effects of the VEGF pathway inhibitors.
This article is available for continuing medical education credit at CME.TheOncologist.com
Angiogenesis is a target shared by both adult epithelial cancers and the mesenchymal or embryonal tumors of childhood. Development of antiangiogenic agents for the pediatric population has been complicated by largely theoretical concern for toxicities specific to the growing child and prioritization among the many antiangiogenic agents being developed for adults. This review summarizes the mechanism of action and preclinical data relevant to childhood cancers and early-phase clinical trials in childhood solid tumors. Single-agent adverse event profiles in adults and children are reviewed with emphasis on cardiovascular, bone health, and endocrine side effects. In addition, pharmacological factors that may be relevant for prioritizing clinical trials of these agents in children are reviewed. Considerations for further clinical evaluation should include preclinical data, relative potency, efficacy in adults, and the current U.S. Food and Drug Administration approval status. Toxicity profiles of vascular endothelial growth factor (VEGF) signaling pathway inhibitors may be age dependent and ultimately, their utility in the treatment of childhood cancer will require combination with standard cytotoxic drugs or other molecularly targeted agents. In combination studies, toxicity profiles, potential drug interactions, and late effects must be considered. Studies to assess the long-term impact of VEGF signaling pathway inhibitors on cardiovascular, endocrine, and bone health in children with cancer are imperative if these agents are to be administered to growing children and adolescents with newly diagnosed cancers.
doi:10.1634/theoncologist.2011-0148
PMCID: PMC3233297  PMID: 22042784
Angiogenesis inhibitors; Childhood cancer; VEGF; Drug development
11.  Effect of Folic Acid and Vitamin B12 on Pemetrexed Antifolate Chemotherapy in Nutrient Lung Cancer Cells 
BioMed Research International  2013;2013:389046.
Pemetrexed (MTA) is a multitargeted antifolate drug approved for lung cancer therapy. Clinically, supplementation with high doses of folic acid (FA) and vitamin B12 (VB12) lowers MTA cytotoxicities. An antagonistic effect of FA/VB12 on MTA efficacy has been proposed. However, patients who receive FA/VB12 show better tolerance to MTA with improved survival. The aims of this study are to investigate the modulation of FA and VB12 on MTA drug efficacy in human nonsmall cell lung cancer (NSCLC) cell lines. The sensitivities of cells, apoptosis, and MTA-regulated proteins were characterized to determine the possible effects of high doses of FA and VB12 on MTA efficacy. MTA has the lowest efficacy under 10% serum conditions. However, supplementation with FA and VB12 individually and additively reversed the insensitivity of NSCLC cells to MTA treatment with 10% serum. The enhanced sensitivities of cells following FA/VB12 treatment were correlated with increasing apoptosis and were specific to MTA but not to 5-fluorouracil (5-FU). Enhanced sensitivity was also associated with p21WAF1/Cip1 expression level. Our results revealed no antagonistic effect of high doses of FA/VB12 on MTA efficacy in cancer cells grown in nutrient medium. Furthermore, these data may partially explain why supplementation of FA and VB12 resulted in better survival in MTA-treated patients.
doi:10.1155/2013/389046
PMCID: PMC3747471  PMID: 23984356
12.  Effective Treatment of Advanced Human Melanoma Metastasis in Immunodeficient Mice Using Combination Metronomic Chemotherapy Regimens 
Statement of translational relevance
Despite significant efforts over the last two decades aimed at improving the efficacy of standard treatment (maximum tolerated dose (MTD) of dacarbazine), there has been no significant increase in the median survival of patients suffering from metastatic melanoma. Given the lack of success achieved, a rethinking of alternative treatment strategies is needed. Using preclinical models of advanced melanoma metastasis, we show that metronomic chemotherapeutic combinations results in improved survival, which is achieved with minimal toxicity. These results compare favorably with minimal effectiveness achieved by MTD dacarbazine therapy (alone or in combination with other chemotherapeutic agents or a VEGFR-blocking antibody), often accompanied by higher toxicity. Successes in preclinical setting of metastatic breast cancer have led to a clinical trial to examine the efficacy of metronomic therapy. A similar extension of the metronomic chemotherapeutic combinations presented here into the clinical setting of melanoma metastasis may be warranted.
Purpose
The development of effective therapeutic approaches for treatment of metastatic melanoma remains an immense challenge. Present therapies offer minimal benefit. While dacarbazine (DTIC) chemotherapy remains the standard therapy, it mediates only low response rates, usually of short duration, even when combined with other chemotherapeutic agents. Thus, new therapeutic strategies are urgently needed.
Experimental design
Using a newly developed preclinical model, we evaluated the efficacy of various doublet metronomic combination chemotherapy against established, advanced melanoma metastasis and compared these to the standard maximum tolerated dose (MTD) DTIC (alone or in combination with chemotherapeutic agents or VEGFR-blocking antibody)
Results
Whereas MTD DTIC therapy did not cause significant improvement in median survival, a doublet combination of low-dose metronomic (LDM) vinblastine (Vbl) and LDM cyclophosphamide (CTX) induced a significant increase in survival with only minimal toxicity. Furthermore, we show that the incorporation of the LDM Vbl/LDM CTX combination with a LDM DTIC regimen also results in a significant increase in survival, but not when combined with MTD DTIC therapy. We also show that a combination of metronomic Vbl therapy and a VEGFR2-blocking antibody (DC101) results in significant control of metastatic disease and that the combination of LDM Vbl/DC101 and LDM DTIC induced a significant improvement in median survival.
Conclusions
The effective control of advanced metastatic melanoma achieved by these metronomic-based chemotherapeutic approaches warrants clinical consideration of this treatment concept given the recent results of a number of metronomic-based chemotherapy clinical trials.
doi:10.1158/1078-0432.CCR-08-3275
PMCID: PMC2743327  PMID: 19622578
melanoma; spontaneous metastasis; vinblastine; cyclophosphamide; DC101; metronomic chemotherapy
13.  Perspectives on the Design of Clinical Trials Combining Transarterial Chemoembolization and Molecular Targeted Therapy 
Liver Cancer  2012;1(3-4):168-176.
Transarterial chemoembolization (TACE) moderately prolongs the survival of patients with intermediate-stage hepatocellular carcinoma. Molecular targeted therapy (MTT) may improve the efficacy of TACE. However, the findings of clinical trials evaluating the efficacy of a combination of TACE and MTT are conflicting. We hypothesized that this disparity can be prevented using alternative study designs. In this review, we classify the pertinent issues of study designs into five domains: primary endpoints, patients, TACE procedures, timing of randomization, and drug administration. Furthermore, we discuss the methods for increasing the success rate by minimizing potentially confounding factors within these five domains. Transarterial chemoembolization (TACE) is the current standard therapy for patients with Barcelona Clinic Liver Cancer (BCLC) intermediate-stage hepatocellular carcinoma (HCC) [1, 2, 3]. The survival benefit of TACE is supported by the results of meta-analysis of clinical trials comparing TACE with other conservative treatments in patients with inoperable HCC [4]. The results showed that the median survival of patients improved from approximately 16 to 20 months following TACE [4, 5]. Although advances in TACE techniques and the use of new embolization agents may improve the efficacy of TACE [6, 7], other approaches are needed to further improve the outcome in HCC patients treated using TACE. Molecular targeted therapy (MTT) has improved the survival of patients with advanced-stage HCC [5, 8]. Therefore, combining MTT and TACE may additionally improve the survival in patients with intermediate-stage HCC. Many molecular targeted agents (MTA) are currently undergoing evaluation in randomized trials (table 1). However, the designs of these trials differ significantly. The results of two trials combining sorafenib and TACE were recently reported. Both trials failed to demonstrate a therapeutic benefit of the combination therapy for time to tumor progression (TTP) or overall survival (OS) [9, 10]. However, specific subgroups of patients who received treatment for more than 6 months exhibited significantly better survival (table 2). Because median survival can be greater than 2 years in patients with intermediate-stage HCC, it is likely that an extended exposure period is necessary for MTA effects to reach the biological threshold at which survival benefit becomes measurable. Therefore, early discontinuation of study drug treatment may significantly undermine the statistical power of efficacy analysis in randomized trials (fig. 1). Clinical trials should be designed to minimize confounding factors that could lead to early discontinuation of study drug [1, 2, 3, 11, 12]. Factors that are crucial in this regard can be categorized into five domains: (1) selection of primary endpoints, (2) selection of patient population, (3) selection of TACE procedures, (4) timing of randomization, and (5) study drug administration. In this review we discuss the confounding effects potentially associated with each domain and the possible interactions among domains in trials combining TACE and MTA. We also discuss strategies that can help improve sensitivity and accuracy measurements of MTA efficacy.
doi:10.1159/000343830
PMCID: PMC3760466  PMID: 24159581
Clinical trial; Hepatocellular carcinoma; Transarterial chemoembolization
14.  Oncolytic herpes viruses, chemotherapeutics, and other cancer drugs 
Oncolytic Virotherapy  2013;2:57-74.
Oncolytic viruses are emerging as a potential new way of treating cancers. They are selectively replication-competent viruses that propagate only in actively dividing tumor cells but not in normal cells and, as a result, destroy the tumor cells by consequence of lytic infection. At least six different oncolytic herpes simplex viruses (oHSVs) have undergone clinical trials worldwide to date, and they have demonstrated an excellent safety profile and intimations of efficacy. The first pivotal Phase III trial with an oHSV, talimogene laherparepvec (T-Vec [OncoVexGM-CSF]), is almost complete, with extremely positive early results reported. Intuitively, therapeutically beneficial interactions between oHSV and chemotherapeutic and targeted therapeutic drugs would be limited as the virus requires actively dividing cells for maximum replication efficiency and most anticancer agents are cytotoxic or cytostatic. However, combinations of such agents display a range of responses, with antagonistic, additive, or, perhaps most surprisingly, synergistic enhancement of antitumor activity. When synergistic interactions in cancer cell killing are observed, chemotherapy dose reductions that achieve the same overall efficacy may be possible, resulting in a valuable reduction of adverse side effects. Therefore, the combination of an oHSV with “standard-of-care” drugs makes a logical and reasonable approach to improved therapy, and the addition of a targeted oncolytic therapy with “standard-of-care” drugs merits further investigation, both preclinically and in the clinic. Numerous publications report such studies of oncolytic HSV in combination with other drugs, and we review their findings here. Viral interactions with cellular hosts are complex and frequently involve intracellular signaling networks, thus creating diverse opportunities for synergistic or additive combinations with many anticancer drugs. We discuss potential mechanisms that may lead to synergistic interactions.
doi:10.2147/OV.S52601
PMCID: PMC4918355  PMID: 27512658
combination studies; herpes simplex virus; oncolytic virus; virotherapy
15.  Clinical studies with MTA. 
British Journal of Cancer  1998;78 (Suppl 3):35-40.
MTA (LY231514), a multi-targeted antifolate, is a classical antifolate undergoing intracellular polyglutamation. Polyglutamated MTA is a potent thymidylate synthase (TS) inhibitor and inhibits other folate-dependent enzymes, including dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. Multifocal antifolates may overcome antifolate resistance, but it is not known whether the anti-tumour activity of MTA depends on its TS inhibition, its primary locus of action, or whether other loci contribute. MTA was examined in three phase I trials using different schedules: a 10-min i.v. infusion given once every 3 weeks, once weekly for 4 weeks every 6 weeks or daily for 5 days every 3 weeks. Dose-limiting toxicities were neutropenia and thrombocytopenia. Other consistently seen side-effects, which were manageable, included mucositis, skin rashes and transient elevations of transaminases. Toxicity was highly schedule dependent: the recommended dose for the 3-weekly schedule (600 mg m(-2)) was 30 times that for the daily x 5 schedule (4 mg m(-2)day(-1)). The 3-weekly dosing schedule was chosen for phase II evaluation. Phase II trials are underway to investigate the activity and toxicity of MTA in several tumour types, including colorectal, pancreas, breast, bladder and non-small-cell lung cancer (NSCLC) Further phase I trials will investigate MTA in combination with other agents, including gemcitabine, cisplatin, 5-fluorouracil and folate. Preliminary phase II trials results are encouraging; responses were seen in colorectal, pancreas, NSCLC and breast cancer.
PMCID: PMC2062802  PMID: 9717989
16.  Pharmacokinetics and Toxicity of Sodium Selenite in the Treatment of Patients with Carcinoma in a Phase I Clinical Trial: The SECAR Study 
Nutrients  2015;7(6):4978-4994.
Background: Sodium selenite at high dose exerts antitumor effects and increases efficacy of cytostatic drugs in multiple preclinical malignancy models. We assessed the safety and efficacy of intravenous administered sodium selenite in cancer patients’ refractory to cytostatic drugs in a phase I trial. Patients received first line of chemotherapy following selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits. Materials and Methods: Thirty-four patients with different therapy resistant tumors received iv sodium selenite daily for consecutive five days either for two weeks or four weeks. Each cohort consisted of at least three patients who received the same daily dose of selenite throughout the whole treatment. If 0/3 patients had dose-limiting toxicities (DLTs), the study proceeded to the next dose-level. If 2/3 had DLT, the dose was considered too high and if 1/3 had DLT, three more patients were included. Dose-escalation continued until the maximum tolerated dose (MTD) was reached. MTD was defined as the highest dose-level on which 0/3 or 1/6 patients experienced DLT. The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite. The secondary endpoint was primary response evaluation. Results and Conclusion: MTD was defined as 10.2 mg/m2, with a calculated median plasma half-life of 18.25 h. The maximum plasma concentration of selenium from a single dose of selenite increased in a nonlinear pattern. The most common adverse events were fatigue, nausea, and cramps in fingers and legs. DLTs were acute, of short duration and reversible. Biomarkers for organ functions indicated no major systemic toxicity. In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m2 under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.
doi:10.3390/nu7064978
PMCID: PMC4488827  PMID: 26102212
sodium selenite; carcinoma; pharmacokinetics; maximum tolerated dose
17.  Targeting of Interferon-Beta to Produce a Specific, Multi-Mechanistic Oncolytic Vaccinia Virus 
PLoS Medicine  2007;4(12):e353.
Background
Oncolytic viruses hold much promise for clinical treatment of many cancers, but a lack of systemic delivery and insufficient tumor cell killing have limited their usefulness. We have previously demonstrated that vaccinia virus strains are capable of systemic delivery to tumors in mouse models, but infection of normal tissues remains an issue. We hypothesized that interferon-beta (IFN-β) expression from an oncolytic vaccinia strain incapable of responding to this cytokine would have dual benefits as a cancer therapeutic: increased anticancer effects and enhanced virus inactivation in normal tissues. We report the construction and preclinical testing of this virus.
Methods and Findings
In vitro screening of viral strains by cytotoxicity and replication assay was coupled to cellular characterization by phospho-flow cytometry in order to select a novel oncolytic vaccinia virus. This virus was then examined in vivo in mouse models by non-invasive imaging techniques. A vaccinia B18R deletion mutant was selected as the backbone for IFN-β expression, because the B18R gene product neutralizes secreted type-I IFNs. The oncolytic B18R deletion mutant demonstrated IFN-dependent cancer selectivity and efficacy in vitro, and tumor targeting and efficacy in mouse models in vivo. Both tumor cells and tumor-associated vascular endothelial cells were targeted. Complete tumor responses in preclinical models were accompanied by immune-mediated protection against tumor rechallenge. Cancer selectivity was also demonstrated in primary human tumor explant tissues and adjacent normal tissues. The IFN-β gene was then cloned into the thymidine kinase (TK) region of this virus to create JX-795 (TK−/B18R−/IFN-β+). JX-795 had superior tumor selectivity and systemic intravenous efficacy when compared with the TK−/B18R− control or wild-type vaccinia in preclinical models.
Conclusions
By combining IFN-dependent cancer selectivity with IFN-β expression to optimize both anticancer effects and normal tissue antiviral effects, we were able to achieve, to our knowledge for the first time, tumor-specific replication, IFN-β gene expression, and efficacy following systemic delivery in preclinical models.
Stephen Thorne and colleagues describe, in a mouse model, an oncolytic vaccinia virus with interferon-dependent cancer selectivity that allows tumor-specific replication; it also expresses the IFN-β gene and hence has efficacy against tumors.
Editors' Summary
Background.
Normally, throughout life, cell division (which produces new cells) and cell death are carefully balanced to keep the body in good working order. But sometimes cells acquire changes (mutations) in their genetic material that allow them to divide uncontrollably to form cancers—disorganized masses of cells. Cancers can develop anywhere in the body and, as they develop, their cells acquire other genetic changes that enable them to move and start new tumors (metastases) elsewhere. Chemotherapy drugs kill rapidly dividing cancer cells but, because some normal cells are also sensitive to these drugs, it is hard to destroy the cancer without causing serious side effects. Consequently, researchers are trying to develop “targeted” therapies that attack the changes in cancer cells that allow them to divide uncontrollably but leave normal cells unscathed. One promising class of targeted therapies is oncolytic viruses. These viruses make numerous copies of themselves inside cancer cells (but not inside normal cells). Eventually the cancer cell bursts open (lyses), releases more of the therapeutic agent, and dies.
Why Was This Study Done?
Existing oncolytic viruses have two major disadvantages: they have to be injected directly into tumors, and therefore they can't destroy distant metastases; and they don't kill cancer cells particularly efficiently. In this study, the researchers have tried to adapt vaccinia virus (a virus that infects humans and which has recently been shown to kill tumor cells when injected into the bloodstream) in two ways: to both infect cancer cells selectively and then to kill them effectively.
They hypothesized that putting a gene that causes expression of a protein called interferon-beta (IFN-β) in a particular virus strain that is itself incapable of responding to IFN-β might achieve these aims. Human cells infected with viruses usually release IFNs, which induce an antiviral state in nearby cells. But vaccinia virus makes anti-IFN proteins that prevent IFN release. If the viral genes that encode these proteins are removed from the virus, the virus cannot spread through normal cells. However, many cancer cells have defective IFN signaling pathways so the virus can spread through them. IFN-β expression by the virus, however, should improve its innate anticancer effects because IFN-β stops cancer cells dividing, induces an antitumor immune response, and stops tumors developing good blood supplies.
What Did the Researchers Do and Find?
The researchers selected a vaccinia virus strain called WR-delB18R in which the B18R gene, which encodes an anti-IFN protein, had been removed from the virus. (WR is a wild-type virus.) In laboratory experiments, IFN treatment blocked the spread of WR-delB18R in normal human cells but not in human tumor cells. After being injected into the veins of tumor-bearing mice, WR-delB18R was rapidly cleared from normal tissues but persisted in the tumors. A single injection of WR-delB18R directly into the tumor killed most of the tumor cells. A similar dose injected into a vein was less effective but nevertheless increased the survival time of some of the mice by directly killing the tumor cells, by targeting the blood supply of the tumors, and by inducing antitumor immunity. Finally, when the researchers inserted the IFN-β gene into this WR-delB18R, the new virus—JX-795—was much better at killing tumors after intravenous injection than either WR or WR-delB18R.
What Do These Findings Mean?
These findings indicate that the vaccinia virus can be adapted so that it replicates only in tumor cells and kills these cells effectively after intravenous injection. In particular, they show that the strategy adopted by the researchers both optimizes the anticancer effects of the virus and minimizes viral replication in normal tissues. JX-795 is a promising oncolytic virus, therefore, particularly since vaccinia virus has been safely used for many years to vaccinate people against smallpox. Nevertheless, it will be some years before JX-795 can be used clinically. Vaccinia virus constructs like this need to be tested extensively in the laboratory and in animals before any attempt is made to test them in people and, even if they passes all these preclinical tests with flying colors, only clinical trials will reveal whether they can treat human cancer. Several related strains of vaccinia virus are currently undergoing clinical testing.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/:10.1371/journal.pmed.0040353.
The US National Cancer Institute provides information on all aspects of cancer (in English and Spanish)
CancerQuest, from Emory University, provides information on all aspects of cancer (in several languages)
The UK charity Cancerbackup also provides information on all aspects of cancer
Wikipedia has a page on oncolytic viruses (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
A short interview about oncolytic viruses with researcher Dr. John Bell is available on the Insidermedicine Web site
The Oncolytic virus Web page provides lists of oncolytic viruses classified by type
doi:10.1371/journal.pmed.0040353
PMCID: PMC2222946  PMID: 18162040
18.  Evaluation of rodent-only toxicology for early clinical trials with novel cancer therapeutics 
British Journal of Cancer  1999;81(5):760-768.
Preclinical toxicology studies are performed prior to phase I trials with novel cancer therapeutics to identify a safe clinical starting dose and potential human toxicities. The primary aim of this study was to evaluate the ability of rodent-only toxicology studies to identify a safe phase I trial starting dose. In addition, the ability of murine studies to predict the quantitative and qualitative human toxicology of cancer therapeutics was studied. Data for 25 cancer drugs were collated for which the preclinical and clinical routes and schedules of administration were either the same (22/25), or closely matched. The maximum tolerated dose/dose lethal to 10% of mice (MTD/LD10) was identified for 24 drugs, and in patients the maximum administered dose (MAD) was associated with dose-limiting toxicity (DLT) in initial clinical trials with 20 compounds. In addition, for 13 agents, the toxicity of the drug at one-tenth the mouse MTD/LD10 was also investigated in rats, following repeated administration (20 doses). A phase I trial starting dose of one-tenth the mouse MTD/LD10 (mg m–2) was, or would have been, safe for all 25 compounds. With the exception of nausea and vomiting, which cannot be assessed in rodents, other common DLTs were accurately predicted by the murine studies (i.e. 7/7 haematological and 3/3 neurological DLTs). For two of the 13 drugs studied in rats, repeated administration of one-tenth the mouse MTD/LD10 was toxic, leading to a reduction in the phase I trial starting dose; however, one-tenth the mouse MTD/LD10 was subsequently tolerated in patients. For the 20 drugs where clinical DLT was reached, the median ratio of the human MAD to the mouse MTD/LD10 was 2.6 (range 0.2–16) and the median ratio of the clinical starting dose to the MAD was 35 (range 2.3–160). In contrast, in 13 subsequent phase I trials with 11 of the initial 25 drugs, the median ratio of the clinical starting dose to the MAD was 2.8 (range 1.6–56), emphasizing the value of early clinical data in rapidly defining the dose range for therapeutic studies. For all 25 drugs studied, rodent-only toxicology provided a safe and rapid means of identifying the phase I trial starting dose and predicting commonly encountered DLTs. This study has shown that the routine use of a non-rodent species in preclinical toxicology studies prior to initial clinical trials with cancer therapeutics is not necessary. © 1999 Cancer Research Campaign
doi:10.1038/sj.bjc.6690761
PMCID: PMC2374299  PMID: 10555743
phase I trials; preclinical toxicology; starting dose
19.  Phase 1/1b Study of Lonafarnib and Temozolomide in Patients With Recurrent or Temozolomide Refractory Glioblastoma 
Cancer  2013;119(15):2747-2753.
BACKGROUND
Lonafarnib is an oral selective farnesyltransferase inhibitor, a class of drugs which have shown activity in preclinical glioma models. Temozolomide (TMZ) is an alkylating agent that is the first-line chemotherapy for glioblastoma.
METHODS
The current study combined the cytotoxic agent TMZ with the cytostatic agent lonafarnib for patients with recurrent glioblastoma to establish a maximum tolerated dose (MTD) of the combination and its preliminary efficacy. Three dose cohorts of lonafarnib were studied in the phase 1 component of the trial (100 mg twice daily [bid], 150 mg bid, and 200 bid) with dose-dense schedule of TMZ (150 mg/m2 daily) administered in an alternating weekly schedule. After establishing the MTD of lonafarnib, a subsequent expansion phase 1b was undertaken to evaluate efficacy, primarily measured by 6-month progression-free survival (PFS-6).
RESULTS
Fifteen patients were enrolled into the phase 1 component and 20 patients into the phase 1b component. The MTD of lonafarnib in combination with TMZ was 200 mg bid. Among the patients enrolled into the study, 34 were eligible for 6-month progression evaluation and 35 patients were evaluable for time-to-progression analysis. The PFS-6 rate was 38% (95% confidence interval [CI] = 22%, 56%) and the median PFS was 3.9 months (95% CI = 2.5, 8.4). The median disease-specific survival was 13.7 months (95% CI = 8.9, 22.1). Hematologic toxicities, particularly lymphopenia, were the most common grade 3 and 4 adverse events. There were no treatment-related deaths.
CONCLUSIONS
These results demonstrate that TMZ can be safely combined with a farnesyltransferase inhibitor and that this regimen is active, although the current study cannot determine the relative contributions of the 2 agents or the contribution of the novel administration schedule.
doi:10.1002/cncr.28031
PMCID: PMC4001735  PMID: 23633392
glioblastoma; recurrent; lonafarnib; temozolomide; farnesyltransferase inhibitor
20.  Choice of Starting Dose for Biopharmaceuticals in First-in-Human Phase I Cancer Clinical Trials 
The Oncologist  2015;20(6):653-659.
All biotechnology-derived products (BDPs) with sufficient nonclinical and clinical data were identified to assess the safety of one-sixth highest nonseverely toxic dose (HNSTD) in advanced cancer first-in-human (FIH) trials. Using one-sixth HNSTD might reduce the number of dose escalations needed to reach the recommended dose in FIH studies and thus the number of patients treated at subtherapeutic doses and limit unnecessary exposure to high drug levels.
Background.
First-in-human (FIH) trials of low-molecular-weight anticancer agents conventionally derive a safe start dose (SD) from one-tenth the severely toxic dose in 10% of rodents or one-sixth the highest nonseverely toxic dose (HNSTD) in nonrodent species. No consensus has been reached on whether this paradigm can be safely applied to biotechnology-derived products (BDPs).
Materials and Methods.
A comprehensive search was conducted to identify all BDPs (excluding immune checkpoint inhibitors and antibody drug conjugates) with sufficient nonclinical and clinical data to assess the safety of hypothetical use of one-sixth HNSTD in an advanced cancer FIH trial.
Results.
The search identified 23 BDPs, of which 21 were monoclonal antibodies. The median ratio of the maximum tolerated or maximum administered dose (MTD or MAD) to the actual FIH SD was 36 (range, 8–500). Only 2 BDPs reached the MTD. Hypothetical use of one-sixth HNSTD (allometrically scaled to humans) would not have exceeded the MTD or MAD for all 23 BDPs and would have reduced the median ratio of the MTD or MAD to a SD to 6.1 (range, 3.5–55.3). Pharmacodynamic (PD) markers were included in some animal toxicology studies and were useful to confirm the hypothetical SD of one-sixth HNSTD.
Conclusion.
One-sixth HNSTD would not have resulted in unacceptable toxicities in the data available. Supporting its use could reduce the number of dose escalations needed to reach the recommended dose. A low incidence of toxicities in animals and humans underscores the need to identify the pharmacokinetic and PD parameters to guide SD selection of BDPs for FIH cancer trials.
Implications for Practice:
Start dose (SD) for biotechnology-derived products (BDPs) can be safely derived from one-sixth the highest nonseverely toxic dose in nonrodent species and may reduce the number of dose escalations needed to reach the recommended dose in first-in-human studies while limiting unnecessary exposure to high drug levels in humans. The use of this type of SD could improve the design of phase I studies of BDPs by making them more efficient. The role of preclinical pharmacodynamic markers was useful in confirming the hypothetical SD, and attempts should be explored in future animal studies to identify such parameters.
doi:10.1634/theoncologist.2015-0008
PMCID: PMC4571794  PMID: 25964306
Starting dose; Biotechnology derived products; Animal toxicology studies; Phase I clinical trials; Highest nonseverely toxic dose
21.  Clinical benefit in Phase-I trials of novel molecularly targeted agents: does dose matter? 
British Journal of Cancer  2009;100(9):1373-1378.
Phase-I trials traditionally involve dose-escalation to determine the maximal tolerated dose (MTD). With conventional chemotherapy, efficacy is generally deemed to be dose-dependent, but the same may not be applicable to molecularly targeted agents (MTAs). We analysed consecutive patients included in Phase-I trials at the Royal Marsden Hospital from 5 January 2005 to 6 June 2006. We considered only trials of monotherapy MTAs in which the MTD was defined. Three patient cohorts (A, B, and C) were identified according to the dose received as a percentage of the final trial MTD (0–33%, 34–65%, >66%). Potential efficacy was assessed using the non-progression rate (NPR), that is, complete/partial response or stable disease for at least 3 months by RECIST. A total of 135 patients having progressive disease before enrolment were analysed from 15 eligible trials. Median age was 57 years (20–86); male : female ratio was 1.8 : 1. Cohort A, B, and C included 28 (21%), 22 (16%), and 85 (63%) patients; NPR at 3 and 6 months was 21% and 11% (A), 50% and 27% (B), 31% and 14% (C), respectively, P=0.9. Median duration of non-progression (17 weeks; 95% CI=13–22) was not correlated with the MTD level, P=0.9. Our analysis suggests that the potential for clinical benefit is not confined to patients treated at doses close to the MTD in Phase-I trials of MTAs.
doi:10.1038/sj.bjc.6605030
PMCID: PMC2694416  PMID: 19401696
Phase-I trial; molecularly targeted agents; maximal tolerated dose; non-progression rate; clinical benefit
22.  Breast Cancer Cell Lines Exhibit Differential Sensitivities to Microtubule-targeting Drugs Independent of Doubling Time 
Anticancer research  2015;35(11):5845-5850.
Background
Microtubule-targeting agents (MTAs) are a mainstay in breast cancer treatment, yet patient responses differ. The underlying mechanisms of these differences are unknown. While MTAs are mitotic inhibitors, recent evidence highlights that non-mitotic effects of these drugs can contribute to their anticancer effects. It is critical to identify the non-mitotic mechanisms that could contribute to differences among MTAs. However, it is not clear whether rapidly dividing cells in culture are optimal tools to address these mechanistic questions in interphase cells.
Materials and Methods
Detailed concentration response curves for five MTAs in a panel of diverse breast cancer cell lines were generated.
Results
Substantial differences among both drugs and cell lines, consistent with the clinical scenario, were observed. Importantly, these differences do not correlate with cell doubling time.
Conclusion
The interphase actions of MTAs are critical to the full spectrum of their effects in cancer cells, even in cell culture models.
PMCID: PMC4812601  PMID: 26504006
Microtubule; microtubule destabilizer; eribulin; paclitaxel; docetaxel; vinorelbine; ixabepilone
23.  Pediatric phase I trial of oral sorafenib and topotecan in refractory or recurrent pediatric solid malignancies 
Cancer Medicine  2015;5(2):294-303.
Abstract
Targeted kinase inhibitors and camptothecins have shown preclinical and clinical activity in several cancers. This trial evaluated the maximum tolerated dose (MTD) and dose‐limiting toxicities of sorafenib and topotecan administered orally in pediatric patients with relapsed solid tumors. Sorafenib was administered twice daily and topotecan once daily on days 1–5 and 8–12 of each 28‐day course. The study utilized a standard 3 + 3 dose escalation design. Three dose levels (DL) were evaluated: (1) sorafenib 150 mg/m2 and topotecan 1 mg/m2; (2) sorafenib 150 mg/m2 and topotecan 1.4 mg/m2; and (3) sorafenib 200 mg/m2 and topotecan 1.4 mg/m2. Pharmacokinetics were ascertained and treatment response assessed. Thirteen patients were enrolled. DL2 was the determined MTD. Grade 4 thrombocytopenia delaying therapy for >7 days was observed in one of six patients on DL2, and grade 4 neutropenia that delayed therapy in two of three patients on DL3. A patient with preexisting cardiac failure controlled with medication developed a transient drop in the left ventricular ejection fraction that improved when sorafenib was withheld. Sorafenib exposure with or without topotecan was comparable, and the concentration‐time profiles for topotecan alone and in combination with sorafenib were similar. One objective response was noted in a patient with fibromatosis. We determined MTD to be sorafenib 150 mg/m2 twice daily orally on days 1–28 combined with topotecan 1.4 mg/m2 once daily on days 1–5 and 8–12. While these doses are 1 DL below the MTD of the agents individually, pharmacokinetic studies suggested adequate drug exposure without drug interactions. The combination had limited activity in the population studied.
doi:10.1002/cam4.598
PMCID: PMC4735769  PMID: 26714427
Combination; pediatric cancer; phase I; sarcoma; sorafenib; topotecan
24.  6-Thioguanine: A Drug With Unrealized Potential for Cancer Therapy 
The Oncologist  2014;19(7):760-765.
This review suggests that the full potential of 6-thioguanine (6-TG) in cancer therapy may not have been reached. The authors contrast 6-TG and the more widely used 6-mercaptopurine; discuss 6-TG metabolism, pharmacokinetics, dosage and schedule; and summarize many of the early studies that have shown infrequent but nevertheless positive results with 6-TG treatment. The combination of 6-TG and a natural compound, methylthioadenosine (MTA), may provide selective treatment of cancers that have lost the gene methylthioadenosine phosphorylase (MTAP). Administration of MTA decreases 6-TG toxicity to normal host tissues, thus permitting use of increased therapeutic doses of 6-TG. Combinations of 6-TG with other agents, such as methotrexate or pralatrexate, may also enhance therapeutic effects in MTAP-deficient tumors.
Sixty years ago, 6-thioguanine (6-TG) was introduced into the clinic. We suggest its full potential in therapy may not have been reached. In this paper, we contrast 6-TG and the more widely used 6-mercaptopurine; discuss 6-TG metabolism, pharmacokinetics, dosage and schedule; and summarize many of the early studies that have shown infrequent but nevertheless positive results with 6-TG treatment of cancers. We also consider studies that suggest that combinations of 6-TG with other agents may enhance antitumor effects. Although not yet tested in man, 6-TG has recently been proposed to treat a wide variety of cancers with a high frequency of homozygous deletion of the gene for methylthioadenosine phosphorylase (MTAP), often codeleted with the adjacent tumor suppressor CDKN2A (p16). Among the cancers with a high frequency of MTAP deficiency are leukemias, lymphomas, mesothelioma, melanoma, biliary tract cancer, glioblastoma, osteosarcoma, soft tissue sarcoma, neuroendocrine tumors, and lung, pancreatic, and squamous cell carcinomas. The method involves pretreatment with the naturally occurring nucleoside methylthioadenosine (MTA), the substrate for the enzyme MTAP. MTA pretreatment protects normal host tissues, but not MTAP-deficient cancers, from 6-TG toxicity and permits administration of doses of 6-TG that are much higher than can now be safely administered. The combination of MTA/6-TG has produced substantial shrinkage or slowing of growth in two different xenograft human tumor models: lymphoblastic leukemia and metastatic prostate carcinoma with neuroendocrine features. Further development and a clinical trial of the proposed MTA/6-TG treatment of MTAP-deficient cancers seem warranted.
doi:10.1634/theoncologist.2014-0178
PMCID: PMC4077447  PMID: 24928612
Chemotherapy; Denovo purine synthesis; 6-thioguanine; Folate antagonists
25.  Safety and efficacy of targeted agents in metastatic kidney cancer patients with renal dysfunction 
Anti-cancer drugs  2011;22(8):794-800.
Background:
Multiple molecularly targeted agents (MTAs) have been approved for the management of metastatic renal cell carcinoma(mRCC). Sunitinib and M-TOR inhibitors (temsirolimus, everolimus) are primarily metabolized in the liver, while the metabolism of bevacizumab is unclear. There are limited data on the toxicity profile and efficacy of these agents in patients with renal impairment(RI). This is clinically relevant especially since about one third of mRCC patients have renal dysfunction.
Methods:
The primary objective was to assess the safety and efficacy of targeted agents in mRCC patients with RI. Medical records of patients with mRCC at Wayne State University started on sunitinib, temsirolimus, everolimus or bevacizumab were reviewed. Patients with a calculated creatinine clearance(CrCl) of ≤60ml/min were deemed to have RI. Data on safety and efficacy of MTA therapy were collected and analyzed with respect to renal function.
Results:
RI was observed in 33% of our mRCC patients. The incidence of toxicities, responses, time to progression(TTP), and overall survival(OS) were not significantly different in patients with RI compared to patients with normal renal function. Patients with RI had larger median increases in blood pressure with sunitinib and bevacizumab, increased incidence of thyroid dysfunction with sunitinib, and increased incidence of rash and dose interruptions with m-TOR inhibitors, than did patients with normal renal function.
Conclusions:
RI was commonly observed in our mRCC patients. MTAs are well tolerated and efficacy appears to be maintained in patients with RI. Vigilant monitoring of hypertension would be recommended for pts receiving sunitinib and bevacizumab.
doi:10.1097/CAD.0b013e328346af0d
PMCID: PMC3149855  PMID: 21799472
renal dysfunction; kidney cancer; sunitinib; temsirolimus; bevacizumab; everolimus

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