S. Gail Eckhardt

Phase I and Pharmacologic Study of OSI-774, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Advanced Solid Malignancies

PURPOSE To assess the feasibility of administering OSI-774, to recommend a dose on a protracted, continuous daily schedule, to characterize its pharmacokinetic behavior, and to acquire preliminary evidence of anticancer activity. PATIENTS AND METHODS Patients with advanced solid malignancies were treated with escalating doses of OSI-774 in three study parts (A to C) to evaluate progressively longer treatment intervals. Part A patients received OSI-774 25 to 100 mg once daily, for 3 days each week, for 3 weeks every 4 weeks. Part B patients received OSI-774 doses ranging from 50 to 200 mg given once daily for 3 weeks every 4 weeks to establish the maximum tolerated dose (MTD). In part C, patients received this MTD on a continuous, uninterrupted schedule. The pharmacokinetics of OSI-774 and its O-demethylated metabolite, OSI-420, were characterized. RESULTS Forty patients received a total of 123 28-day courses of OSI-774. No severe toxicities precluded dose escalation of OSI-774 from 25 to 100 mg/d in part A. In part B, the incidence of severe diarrhea and/or cutaneous toxicity was unacceptably high at OSI-774 doses exceeding 150 mg/d. Uninterrupted, daily administration of OSI-774 150 mg/d represented the MTD on a protracted daily schedule. The pharmacokinetics of OSI-774 were dose independent; repetitive daily treatment did not result in drug accumulation (at 150 mg/d [average]: minimum steady-state plasma concentration, 1.20 +/- 0.62 microg/mL; clearance rate, 6.33 +/- 6.41 L/h; elimination half-life, 24.4 +/- 14.6 hours; volume of distribution, 136. 4 +/- 93.1 L; area under the plasma concentration-time curve for OSI-420 relative to OSI-774, 0.12 +/- 0.12 microg/h/mL). CONCLUSION The recommended dose for disease-directed studies of OSI-774 administered orally on a daily, continuous, uninterrupted schedule is 150 mg/d. OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease. The precise contribution of OSI-774 to these effects is not known.

Sunitinib: From Rational Design to Clinical Efficacy

Sunitinib (SU011248) is an oral small molecular tyrosine kinase inhibitor that exhibits potent antiangiogenic and antitumor activity. Tyrosine kinase inhibitors such as SU6668 and SU5416 (semaxanib) demonstrated poor pharmacologic properties and limited efficacy; therefore, sunitinib was rationally designed and chosen for its high bioavailability and its nanomolar-range potency against the antiangiogenic receptor tyrosine kinases (RTKs)--vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). Sunitinib inhibits other tyrosine kinases including, KIT, FLT3, colony-stimulating factor 1 (CSF-1), and RET, which are involved in a number of malignancies including small-cell lung cancer, GI stromal tumors (GISTs), breast cancer, acute myelogenous leukemia, multiple endocrine neoplasia types 2A and 2B, and familial medullary thyroid carcinoma. Sunitinib demonstrated robust antitumor activity in preclinical studies resulting not only in tumor growth inhibition, but tumor regression in models of colon cancer, non-small-cell lung cancer, melanoma, renal carcinoma, and squamous cell carcinoma, which were associated with inhibition of VEGFR and PDGFR phosphorylation. Clinical activity was demonstrated in neuroendocrine, colon, and breast cancers in phase II studies, whereas definitive efficacy has been demonstrated in advanced renal cell carcinoma and in imatinib-refractory GISTs, leading to US Food and Drug Administration approval of sunitinib for treatment of these two diseases. Studies investigating sunitinib alone in various tumor types and in combination with chemotherapy are ongoing. The clinical benchmarking of this small-molecule inhibitor of members of the split-kinase domain family of RTKs will lead to additional insights regarding the biology, potential biomarkers, and clinical utility of agents that target multiple signaling pathways in tumor, stromal, and endothelial compartments.

Patient-derived tumour xenografts as models for oncology drug development

Progress in oncology drug development has been hampered by a lack of preclinical models that reliably predict clinical activity of novel compounds in cancer patients. In an effort to address these shortcomings, there has been a recent increase in the use of patient-derived tumour xenografts (PDTX) engrafted into immune-compromised rodents such as athymic nude or NOD/SCID mice for preclinical modelling. Numerous tumour-specific PDTX models have been established and, importantly, they are biologically stable when passaged in mice in terms of global gene-expression patterns, mutational status, metastatic potential, drug responsiveness and tumour architecture. These characteristics might provide significant improvements over standard cell-line xenograft models. This Review will discuss specific PDTX disease examples illustrating an overview of the opportunities and limitations of these models in cancer drug development, and describe concepts regarding predictive biomarker development and future applications.

Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers.

PURPOSE To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer. PATIENTS AND METHODS In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations. RESULTS Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated >or= 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for >or= 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles. CONCLUSION AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing.

Clinical Applications of Metabolomics in Oncology: A Review

Metabolomics, an omic science in systems biology, is the global quantitative assessment of endogenous metabolites within a biological system. Either individually or grouped as a metabolomic profile, detection of metabolites is carried out in cells, tissues, or biofluids by either nuclear magnetic resonance spectroscopy or mass spectrometry. There is potential for the metabolome to have a multitude of uses in oncology, including the early detection and diagnosis of cancer and as both a predictive and pharmacodynamic marker of drug effect. Despite this, there is lack of knowledge in the oncology community regarding metabolomics and confusion about its methodologic processes, technical challenges, and clinical applications. Metabolomics, when used as a translational research tool, can provide a link between the laboratory and clinic, particularly because metabolic and molecular imaging technologies, such as positron emission tomography and magnetic resonance spectroscopic imaging, enable the discrimination of metabolic markers noninvasively in vivo. Here, we review the current and potential applications of metabolomics, focusing on its use as a biomarker for cancer diagnosis, prognosis, and therapeutic evaluation.

Phase I Pharmacologic and Biologic Study of Ramucirumab (IMC-1121B), a Fully Human Immunoglobulin G1 Monoclonal Antibody Targeting the Vascular Endothelial Growth Factor Receptor-2

PURPOSE To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics, and preliminary anticancer activity of ramucirumab (IMC-1121B), a fully human immunoglobulin G(1) monoclonal antibody targeting the vascular endothelial growth factor receptor (VEGFR)-2. PATIENTS AND METHODS Patients with advanced solid malignancies were treated once weekly with escalating doses of ramucirumab. Blood was sampled for PK studies throughout treatment. The effects of ramucirumab on circulating vascular endothelial growth factor-A (VEGF-A), soluble VEGFR-1 and VEGFR-2, tumor perfusion, and vascularity using dynamic contrast-enhanced magnetic resonance imaging were assessed. Results Thirty-seven patients were treated with 2 to 16 mg/kg of ramucirumab. After one patient each developed dose-limiting hypertension and deep venous thrombosis at 16 mg/kg, the next lower dose (13 mg/kg) was considered the MTD. Nausea, vomiting, headache, fatigue, and proteinuria were also noted. Four (15%) of 27 patients with measurable disease had a partial response (PR), and 11 (30%) of 37 patients had either a PR or stable disease lasting at least 6 months. PKs were characterized by dose-dependent elimination and nonlinear exposure consistent with saturable clearance. Mean trough concentrations exceeded biologically relevant target levels throughout treatment at all dose levels. Serum VEGF-A increased 1.5 to 3.5 times above pretreatment values and remained in this range throughout treatment at all dose levels. Tumor perfusion and vascularity decreased in 69% of evaluable patients. CONCLUSION Objective antitumor activity and antiangiogenic effects were observed over a wide range of dose levels, suggesting that ramucirumab may have a favorable therapeutic index in treating malignancies amenable to VEGFR-2 inhibition.

Ligand-Based Targeting of Apoptosis in Cancer: The Potential of Recombinant Human Apoptosis Ligand 2/Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (rhApo2L/TRAIL)

Cancer is a leading cause of premature human death and commands considerable research attention. Apoptosis (type 1 programmed cell death) is critical in maintaining tissue homeostasis in metazoan organisms, and its dysregulation underpins the initiation and progression of cancer. Conventional chemotherapy and radiotherapy can induce apoptosis as a secondary consequence of inflicting cell damage. However, more direct and selective strategies to manipulate the apoptotic process in cancer cells are emerging as potential therapeutic tools. Genetic and biochemical understanding of the cellular signaling mechanisms that control apoptosis has increased substantially during the last decade. These advances provide a strong scientific framework for developing several types of targeted proapoptotic anticancer therapies. One promising class of agents is the proapoptotic receptor agonists. Of these, recombinant human apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL)-an optimized soluble form of an endogenous apoptosis-inducing ligand-is unique in that it activates two related proapoptotic receptors, DR4 and DR5. Preclinical data indicate that rhApo2L/TRAIL can induce apoptosis in a broad range of human cancer cell lines while sparing most normal cell types. In vitro, and in various in vivo tumor xenograft models, rhApo2L/TRAIL exhibits single-agent antitumor activity and/or cooperation with certain conventional and targeted therapies. Preclinical safety studies in nonhuman primates show rhApo2L/TRAIL to be well tolerated. Moreover, early clinical trial data suggest that rhApo2L/TRAIL is generally safe and provide preliminary evidence for potential antitumor activity. Clinical studies are ongoing to assess the safety and efficacy of this novel agent in combination with established anticancer therapies.

Phase I Dose-Escalation Study of Recombinant Human Apo2L/TRAIL, a Dual Proapoptotic Receptor Agonist, in Patients With Advanced Cancer

PURPOSE Apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL)-a member of the tumor necrosis factor cytokine family-induces apoptosis by activating the extrinsic pathway through the proapoptotic death receptors DR4 and DR5. Recombinant human Apo2L/TRAIL (rhApo2L/TRAIL) has broad potential as a cancer therapy. To the best of our knowledge, this is the first in-human clinical trial to assess the safety, tolerability, pharmacokinetics, and antitumor activity of multiple intravenous doses of rhApo2L/TRAIL in patients with advanced cancer. PATIENTS AND METHODS This phase I, open-label, dose-escalation study treated patients with advanced cancer with rhApo2L/TRAIL doses ranging from 0.5 to 30 mg/kg/d, with parallel dose escalation for patients without liver metastases and with normal liver function (cohort 1) and for patients with liver metastases and normal or mildly abnormal liver function (cohort 2). Doses were given daily for 5 days, with cycles repeating every 3 weeks. Assessments included adverse events (AEs), laboratory tests, pharmacokinetics, and imaging to evaluate antitumor activity. RESULTS Seventy-one patients received a mean of 18.3 doses; seven patients completed all eight treatment cycles. The AE profile of rhApo2L/TRAIL was similar in cohorts 1 and 2. The most common AEs were fatigue (38%), nausea (28%), vomiting (23%), fever (23%), anemia (18%), and constipation (18%). Liver enzyme elevations were concurrent with progressive metastatic liver disease. Two patients with sarcoma (synovial and undifferentiated) experienced serious AEs associated with rapid tumor necrosis. Two patients with chondrosarcoma experienced durable partial responses to rhApo2L/TRAIL. CONCLUSION At the tested schedule and dose range, rhApo2L/TRAIL was safe and well tolerated. Dose escalation achieved peak rhApo2L/TRAIL serum concentrations equivalent to those associated with preclinical antitumor efficacy.

Randomized Phase III Study of Exatecan and Gemcitabine Compared With Gemcitabine Alone in Untreated Advanced Pancreatic Cancer

PURPOSE Exatecan mesylate is a hexacyclic, water-soluble, topoisomerase-1 inhibitor. Exatecan has single-agent and combination activity with gemcitabine in advanced pancreatic cancer. A multicenter, randomized, phase III trial comparing exatecan plus gemcitabine versus gemcitabine alone in advanced pancreatic cancer was conducted. PATIENTS AND METHODS Eligibility criteria included Karnofsky performance status > or = 60%, locally advanced or metastatic pancreatic adenocarcinoma, and no prior chemotherapy. Radiation alone for locally advanced disease was permitted. Patients were randomly assigned on a 1:1 basis. For the exatecan plus gemcitabine arm, exatecan 2.0 mg/m2 and gemcitabine 1,000 mg/m2 were administered on days 1 and 8, every 3 weeks. Gemcitabine alone was dosed at 1,000 mg/m2 up to 7 weeks in the first cycle, then once a week for the first 3 weeks of a 4-week cycle. Tumor assessment was performed every 6 weeks. The primary end point was overall survival. An intent-to-treat analysis was used. RESULTS From August 2001 to January 2003, 349 patients were randomly assigned, 175 to exatecan plus gemcitabine and 174 to gemcitabine alone. Twenty-four patients (6.9%) were not treated. The median survival time was 6.7 months for exatecan plus gemcitabine and 6.2 months for gemcitabine alone (P = .52). One complete response (CR; < 1%) and 11 partial responses (PRs; 6.3%) were observed in the exatecan plus gemcitabine treatment group, and one CR (< 1%) and eight PRs (4.6%) were observed in the gemcitabine-alone group. Grade 3 and 4 toxicities were higher for the exatecan plus gemcitabine arm versus the gemcitabine alone arm; neutropenia (30% v 15%) and thrombocytopenia (15% v 4%). CONCLUSION Exatecan plus gemcitabine was not superior to gemcitabine alone with respect to overall survival in the first-line treatment of advanced pancreatic cancer.

Phase II Studies of Modern Drugs Directed Against New Targets: If You Are Fazed, Too, Then Resist RECIST

There is no question that the treatment of cancer 10 years from now will be very different from that employed 10 years ago. Are we at the beginning of a series of rapid breakthroughs, or are we making slow progress? Only time will tell. We have many new “druggable” targets, and maybe the results really will be different from the past, with major advances in the treatment of traditionally refractory malignancies. Let us first briefly recapitulate the history of anticancer agents, to understand that the more things change, the more they stay the same. The pharmacologic management of cancer can be traced back to the Manhattan Project (1945), with a number of laboratories developing alkylating agents. These were clearly targeted agents, directed toward alkylating DNA, albeit in a diffuse manner. The next drugs were the antimetabolites, including the antifols, such as methotrexate, and the purine and pyrimidine analogs, such as 6-mercaptopurine and fluorouracil. Again, these drugs were clearly targeted against specific pathways and even specific enzymes, such as dihydrofolate reductase for methotrexate. Even then, we implicitly understood the concept of biomarkers, and myelosuppression was considered to be pharmacodynamic evidence of effects on the target—DNA. Now, approximately a half century (and hundreds of drugs) later, we are engrossed in a new era of oncology therapeutics, that many call “targeted therapies.” To paraphrase one perennially asked question, why are these drugs different from all other drugs? They are meant to be different because we believe that we can preferentially target the tumor rather than normal tissue. This belief is partially supportable, as particularly exemplified by the fantastic results achieved in chronic myelogenous leukemia with imatinib. The drugs are different because we have identified new signaling pathways and tumor biology, which we must learn and understand. They are different because we can’t remember or spell the generic names. They are not different, however, in that we have always had targets, and we have generally known that we have hit a target (which may be different from the intended target). As one example, estramustine was developed as an estrogen-receptor targeted–alkylating agent. However, it was subsequently demonstrated to be an antimitotic agent with activity in prostate cancer independent of the estrogen receptor. Furthermore, we have demonstrated that targeted agents, both old and new, can exhibit mechanism-based effects on normal tissue (myelosuppression, skin rash, diarrhea) that may or may not be associated with a beneficial effect on the patient. With a plethora of new targets, we also have a plethora of new drugs and sponsors, some of whom only have one drug to develop. There is immense competition among companies for patient resources, particularly in the United States and Europe, though many investigators in Asia and South America are equally inundated with requests for trials. Thus, many sponsors and investigators have attempted to minimize the number of patients treated in early clinical trials because of concerns relating to imbalances in patient resources, and financial incentives to move quickly toward phase III trials. Phase I trials have become smaller, in large part because of the recognition that newer targeted agents are less toxic, and are therefore less likely to result in serious toxic effects. This has led to the widespread adaptation of a variety of accelerated titration designs, which have in common, aggressive dose escalations and small patient cohorts, in the absence of toxicity. Such designs are very efficient for defining the maximum-tolerated dose, but are less useful for obtaining a full understanding of a new agent’s clinical pharmacology. In JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 22 NOVEMBER 15 2004