Eric H. Rubin

Risk factors for high-dose cytarabine neurotoxicity: an analysis of a cancer and leukemia group B trial in patients with acute myeloid leukemia.

PURPOSEnWe analyzed pretreatment characteristics of patients with postremission acute myeloid leukemia (AML) treated with high-dose cytarabine (HIDAC) during a recent Cancer and Leukemia Group B (CALGB) trial to determine risk factors associated with HIDAC neurotoxicity.nnnPATIENTS AND METHODSnOne hundred seventy-six patients received at least one course of HIDAC as part of a CALGB protocol designed to determine the optimal dose of cytarabine (ara-C) for postremission treatment of AML. HIDAC consisted of 3 g/m2 ara-C infused over 3 hours at 12-hour intervals on days 1, 3, and 5. The pretreatment characteristics of 170 patients were available for risk analyses.nnnRESULTSnEighteen patients (10%) experienced neurotoxicity. Univariate analyses demonstrated associations between the occurrence of neurotoxicity and elevated serum creatinine, age, and alkaline phosphatase (AP). Multivariate analysis showed that these variables were independent risk factors. These findings were used to construct a risk model with the following parameters: creatinine greater than or equal to 1.2 mg/dL, age greater than or equal to 40 years, and AP greater than or equal to 3 x normal. Seventeen of 46 (37%) patients with two or more of these criteria developed neurotoxicity compared with one of 124 (1%) patients with one or none. The sensitivity and specificity of this model were 94% and 81%, respectively.nnnCONCLUSIONnWe conclude that patients with two or more of the following parameters may be at increased risk for HIDAC neurotoxicity: (creatinine greater than or equal to 1.2 mg/dL, age greater than or equal to 40, and AP greater than or equal to 3 x normal). However, this model should be confirmed by analysis of additional groups of patients treated with HIDAC.

Drug development and clinical trials--the path to an approved cancer drug.

Advances in our understanding of cancer biology have led to the discovery of a spectrum of new therapeutic targets. However, despite remarkable progress in the identification and characterization of novel mechanisms of the oncogenic process, the success rate for approval of oncology drugs remains low relative to other therapeutic areas. Innovative preclinical and clinical approaches, such as the use of advanced genomic technologies, as well as branched adaptive clinical trial designs, have the potential to accelerate the development and approval of highly effective oncology drugs, along with a matching diagnostic test to identify those patients most likely to benefit from the new treatment. To maximize the effectiveness of these new strategies, close collaboration between academic, industry, and regulatory agencies will be required. In this Review, we highlight new approaches in preclinical and clinical drug development that will help accelerate approval of drugs, and aim to provide more-effective treatments alongside companion diagnostic tests to ensure the right treatment is given to the right patient.

Antitumor activity in ras-driven tumors by blocking akt and mek

Purpose: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. Experimental Design: We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. Results: Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug–drug interactions. Clinical antitumor activity included RECIST 1.0–confirmed partial responses in non–small cell lung cancer and low-grade ovarian carcinoma. Conclusion: Responses in KRAS-mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748). Clin Cancer Res; 21(4); 739–48. ©2014 AACR.

Clinical pharmacology profile of vorinostat, a histone deacetylase inhibitor

PurposeVorinostat is a histone deacetylase inhibitor that has demonstrated preclinical activity in numerous cancer models. Clinical activity has been demonstrated in patients with a variety of malignancies. Vorinostat is presently indicated for the treatment of patients with advanced cutaneous T cell lymphoma (CTCL). Clinical investigation is ongoing for therapy of other solid tumors and hematological malignancies either as monotherapy or in combination with other chemotherapeutic agents. This review summarizes the pharmacokinetic properties of vorinostat.MethodsMonotherapy pharmacokinetic data across a number of pharmacokinetic studies were reviewed, and data are presented. In addition, literature review was performed to obtain published Phase I and II pharmacokinetic combination therapy data to identify and characterize potential drug interactions with vorinostat. Pharmacokinetic data in special populations were also reviewed.ResultsThe clinical pharmacology profile of vorinostat is favorable, exhibiting dose-proportional pharmacokinetics and modest food effect. There appear to be no major differences in the pharmacokinetics of vorinostat in special populations, including varying demographics and hepatic dysfunction. Combination therapy pharmacokinetic data indicate that vorinostat has a low propensity for drug interactions.ConclusionsVorinostat’s favorable clinical pharmacology and drug interaction profile aid in the ease of administration of vorinostat for the treatment of advanced CTCL and will be beneficial in continued assessment for other oncologic indications. Although a number of studies have been conducted to elucidate the detailed pharmacokinetic profile of vorinostat, more rigorous assessment of vorinostat pharmacokinetics, including clinical drug interaction studies, will be informative.

Reports from the 2010 Clinical and Translational Cancer Research Think Tank meeting: design strategies for personalized therapy trials.

It has long been evident that cancer is a heterogeneous disease, but only relatively recently have we come to realize the extent of this heterogeneity. No single therapy is effective for every patient with tumors having the same histology. A clinical strategy based on a single-therapy approach results in overtreatment for the majority of patients. Biomarkers can be considered as knives that dissect the disease ever more finely. The future of clinical research will be based on learning whether certain therapies are more appropriate than others for biomarker-defined subsets of patients. Therapies will eventually be tailored to narrow biomarker subsets. The ability to determine which therapies are appropriate for which patients requires information from biological science as well as empirical evidence from clinical trials. Neither is easy to achieve. Here we describe some nascent approaches for designing clinical trials that are biomarker-based and adaptive. Our focus is on adaptive trials that address many questions at once. In a way, these clinical experiments are themselves part of a much larger experiment: learning how (or whether it is possible) to design experiments that match patients in small subsets of disease with therapies that are especially effective and possibly even curative for them. Clin Cancer Res; 18(3); 638–44. ©2012 AACR.

A phase I dose-escalation study of oral MK-2206 (allosteric AKT inhibitor) with oral selumetinib (AZD6244; MEK inhibitor) in patients with advanced or metastatic solid tumors.

3004 Background: The PI3K-Akt and RAF/MEK/ERK pathways represent two of the most frequently activated growth factor signaling pathways in human cancer. Inhibition of both pathways could yield greater benefits than inhibiting either pathway alone. The objectives of this phase I study were to examine the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of the novel combination of MK-2206 with selumetinib. This investigational study represents a new approach to early-stage drug development with the collaboration of two pharmaceutical companies co-developing early stage targeted agent combinations ( NCT01021748 ).nnnMETHODSnEligible patients with advanced solid tumors were treated with MK-2206 either every other day (QOD) or once weekly (QW), in combination with selumetinib administered continuously either once daily (QD) or twice daily (BID).nnnRESULTSnTo date, 33 patients have been treated on five dose levels. In the MK-2206 QOD dosing schedule, dose-limiting Grade 3 macular skin rash was reported in 2/3 evaluable patients at MK-2206 45 mg QOD with selumetinib 75mg BID; the tolerable dose was MK-2206 45 mg QOD with selumetinib 75 mg QD. For QW MK-2206, dose-limiting acneiform rash (n=1), stomatitis (n=1) and detached retinal pigment epithelium (n=1) were observed in 3/7 evaluable patients treated at MK-2206 90 mg QW with selumetinib 75mg BID; dose reduction to MK-2206 90mg QW/ selumetinib 50 mg BID was not tolerated due to dose-limiting acneiform rash in 2/ 4 evaluable patients. An intermediate dose of MK-2206 90mg once weekly with selumetinib 75mg QD was tolerable. Preliminary assessment of PK/PD data suggest no apparent drug-drug interactions with the PK profile of each drug administered in this combination.nnnCONCLUSIONSnMK2206 at 45 mg QOD, or 90 mg QW is well tolerated in combination with selumetinib 75 mg QD in patients with advanced cancer.

Cancer Progress Report 2014

Americans are more likely to survive a cancer diagnosis today than at any other time in history. In fact, thanks to the incredible strides that have been made in biomedical research, the percentage of the U.S. population living with, through, or beyond cancer has more than tripled since the U.S.

The BATTLE-2 Study: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non–Small-Cell Lung Cancer

PURPOSEnBy applying the principles of real-time biopsy, biomarker-based, adaptively randomized studies in non-small-cell lung cancer (NSCLC) established by the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, we conducted BATTLE-2 (BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer), an umbrella study to evaluate the effects of targeted therapies focusing on KRAS-mutated cancers.nnnPATIENTS AND METHODSnPatients with advanced NSCLC (excluding sensitizing EGFR mutations and ALK gene fusions) refractory to more than one prior therapy were randomly assigned, stratified by KRAS status, to four arms: (1) erlotinib, (2) erlotinib plus MK-2206, (3) MK-2206 plus AZD6244, or (4) sorafenib. Tumor gene expression profiling-targeted next-generation sequencing was performed to evaluate predictive and prognostic biomarkers.nnnRESULTSnTwo hundred patients, 27% with KRAS-mutated (KRAS mut+) tumors, were adaptively randomly assigned to erlotinib (n = 22), erlotinib plus MK-2206 (n = 42), MK-2206 plus AZD6244 (n = 75), or sorafenib (n = 61). In all, 186 patients were evaluable, and the primary end point of an 8-week disease control rate (DCR) was 48% (arm 1, 32%; arm 2, 50%; arm 3, 53%; and arm 4, 46%). For KRAS mut+ patients, DCR was 20%, 25%, 62%, and 44% whereas for KRAS wild-type patients, DCR was 36%, 57%, 49%, and 47% for arms 1, 2, 3, and 4, respectively. Median progression-free survival was 2.0 months, not different by KRAS status, 1.8 months for arm 1, and 2.5 months for arms 2 versus arms 3 and 4 in KRAS mut+ patients (P = .04). Median overall survival was 6.5 months, 9.0 and 5.1 months for arms 1 and 2 versus arms 3 and 4 in KRAS wild-type patients (P = .03). Median overall survival was 7.5 months in mesenchymal versus 5 months in epithelial tumors (P = .02).nnnCONCLUSIONnDespite improved progression-free survival on therapy that did not contain erlotinib for KRAS mut+ patients and improved prognosis for mesenchymal tumors, better biomarker-driven treatment strategies are still needed.

The BATTLE Trial: A Bold Step toward Improving the Efficiency of Biomarker-Based Drug Development

Successful completion of the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, reported in this issue of Cancer Discovery, is an important advance in the effort to improve clinical trial approaches to the simultaneous development of new therapeutics with matching diagnostic tests so that patients most likely to benefit from these therapies can be identified.

Rendering the 3 + 3 Design to Rest: More Efficient Approaches to Oncology Dose-Finding Trials in the Era of Targeted Therapy

Selection of the maximum tolerated dose (MTD) as the recommended dose for registration trials based on a dose-escalation trial using variations of an MTD/3 + 3 design often occurs in the development of oncology products. The MTD/3 + 3 approach is not optimal and may result in recommended doses that are unacceptably toxic for many patients and in dose reduction/interruptions that might have an impact on effectiveness. Instead of the MTD/3 + 3 approach, the authors recommend an integrated approach. In this approach, typically an adaptive/Bayesian model provides a general framework to incorporate and make decisions for dose escalation based on nonclinical data, such as animal efficacy and toxicity data; clinical data, including pharmacokinetics/pharmacodynamics data; and dose/exposure–response data for efficacy and safety. To improve dose-ranging trials, model-based estimation, rather than hypothesis testing, should be used to maximize and integrate the information gathered across trials and doses. This approach may improve identification of optimal recommended doses, which can then be confirmed in registration trials. Clin Cancer Res; 22(11); 2623–9. ©2016 AACR. See all articles in this CCR Focus section, “New Approaches for Optimizing Dosing of Anticancer Agents.”