Robert A. Beckman

Antibody constructs in cancer therapy : Protein engineering strategies to improve exposure in solid tumors

Whereas over 85% of human cancers are solid tumors, of the 8 monoclonal antibodies (mAbs) currently approved for cancer therapy, 25% are directed at solid tumor surface antigens (Ags). This shortfall may be due to barriers to achieving adequate exposure in solid tumors. Advancements in tumor biology, protein engineering, and theoretical modeling of macromolecular transport are currently enabling identification of critical physical properties for antitumor Abs. It is now possible to structurally modify Abs or even replace full Abs with a plethora of Ab constructs. These constructs include Fab and Fab′2 fragments, scFvs, multivalent scFvs (e.g., diabodies and tribodies), minibodies (e.g., scFv‐CH3 dimers), bispecific Abs, and camel variable functional heavy chain domains. The purpose of the article is to provide investigators with a conceptual framework for exploiting the recent scientific advancements. The focus is on 2 properties that govern tumor exposure: 1) physical properties that enable penetration of and retention by tumors, and 2) favorable plasma pharmacokinetics. It is demonstrated that manipulating molecular size, charge, valence, and binding affinity can optimize these properties. These manipulations hold the key to promoting tumor exposure and to ultimately creating successful Ab therapies for solid tumors. Cancer 2007.

Phase I Pharmacologic and Pharmacodynamic Study of the Gamma Secretase (Notch) Inhibitor MK-0752 in Adult Patients With Advanced Solid Tumors

PURPOSEnAberrant Notch signaling has been implicated in the pathogenesis of many human cancers. MK-0752 is a potent, oral inhibitor of γ-secretase, an enzyme required for Notch pathway activation. Safety, maximum-tolerated dose, pharmacokinetics (PKs), pharmacodynamics, and preliminary antitumor efficacy were assessed in a phase I study of MK-0752.nnnPATIENTS AND METHODSnMK-0752 was administered in three different schedules to patients with advanced solid tumors. Hair follicles were collected at higher dose levels to assess a gene signature of Notch inhibition.nnnRESULTSnOf 103 patients who received MK-0752, 21 patients received a continuous once-daily dosing at 450 and 600 mg; 17 were dosed on an intermittent schedule of 3 of 7 days at 450 and 600 mg; and 65 were dosed once per week at 600, 900, 1,200, 1,500, 1,800, 2,400, 3,200, and 4,200 mg. The most common drug-related toxicities were diarrhea, nausea, vomiting, and fatigue. PKs (area under the concentration-time curve and maximum measured plasma concentration) increased in a less than dose proportional manner, with a half-life of approximately 15 hours. Significant inhibition of Notch signaling was observed with the 1,800- to 4,200-mg weekly dose levels, confirming target engagement at those doses. One objective complete response and an additional 10 patients with stable disease longer than 4 months were observed among patients with high-grade gliomas.nnnCONCLUSIONnMK-0752 toxicity was schedule dependent. Weekly dosing was generally well tolerated and resulted in strong modulation of a Notch gene signature. Clinical benefit was observed, and rational combination trials are currently ongoing to maximize clinical benefit with this novel agent.

Cancers Exhibit a Mutator Phenotype: Clinical Implications

Malignancies are characterized by mutations. We have hypothesized that the thousands of mutations in most human cancers do not result from the low mutation rates exhibited by normal human cells. Instead, cancer cells express a mutator phenotype (i.e., the mutation rate in the cancer cells is much greater than that in normal cells). We consider the following points: (a) Mutations in genes that govern genetic stability could be the cause of a mutator phenotype exhibited by human cancers. (b) A mutator phenotype increases the efficiency of acquiring mutations including those associated with cancer. (c) Recent experimental evidence indicates that human tumors contain a vast array of both clonal mutations and nonexpanded (random) mutations. (d) The presence of nonexpanded mutations in tumors has fundamental clinical implications for cancer risk assessment, grading, and prognosis including the rapid emergence of resistance to chemotherapeutic agents. Lastly, (e) if a mutator phenotype drives carcinogenesis, drugs that target mutator pathways might prevent cancer by delay.

Phase I Evaluation of a Fully Human Anti–αv Integrin Monoclonal Antibody (CNTO 95) in Patients with Advanced Solid Tumors

Purpose: A fully human monoclonal antibody to anti–αv integrins (CNTO 95) has been shown to inhibit angiogenesis and tumor growth in preclinical studies. We assessed the safety and pharmacokinetics of CNTO 95 in patients with advanced refractory solid tumors. Experimental Design: In this phase I trial, CNTO 95 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg) was infused on days 0, 28, 35, and 42, and clinical assessments, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and [18F]-2-fluorodeoxyglucose positron emission tomography (FDG-PET) were done. Patients achieving stable disease or better were eligible for extended dosing every 3 weeks for up to 12 months. Results: Among the 24 enrolled patients, CNTO 95 was associated with one episode of grade III and four episodes of grade II infusion-related fever (all responded to acetaminophen). Of the six patients who received extended dosing, one patient (10.0 mg/kg), with cutaneous angiosarcoma, had a 9-month partial response. Pre- and post-treatment lesion biopsies confirmed tumor cell αv integrin expression, as well as CNTO 95 penetration of the tumor and localization to tumor cells in association with reduced bcl-2 expression. A lesion in one patient (10.0 mg/kg) with stable ovarian carcinosarcoma was no longer detectable by FDG-PET by day 49. Exposure to CNTO 95 seemed to increase in a greater-than-dose-proportional manner; dose-dependent mean half-life ranged from 0.26 to 6.7 days. Conclusions: CNTO 95 was generally well tolerated. Six patients received extended therapy, including one patient with a prolonged response. Biopsy data confirmed tumor localization and pharmacodynamic activity.

Efficiency of carcinogenesis with and without a mutator mutation

Carcinogenesis involves the acquisition of multiple genetic changes altering various cellular phenotypes. These changes occur within the fixed time period of a human lifespan, and mechanisms that accelerate this process are more likely to result in clinical cancers. Mutator mutations decrease genome stability and, hence, accelerate the accumulation of random mutations, including those in oncogenes and tumor suppressor genes. However, if the mutator mutation is not in itself oncogenic, acquiring that mutation would add an extra, potentially time-consuming step in carcinogenesis. We present a deterministic mathematical model that allows quantitative prediction of the efficiency of carcinogenesis with and without a mutator mutation occurring at any time point in the process. By focusing on the ratio of probabilities of pathways with and without mutator mutations within cell lineages, we can define the frequency or importance of mutator mutations in populations independently of absolute rates and circumvent the question of whether mutator mutations are “necessary” for cancers to evolve within a human lifetime. We analyze key parameters that predict the relative contribution of mutator mutants in carcinogenesis. Mechanisms of carcinogenesis involving mutator mutations are more likely if they occur early. Involvement of mutator mutations in carcinogenesis is favored by an increased initial mutation rate, by greater fold-increase in mutation rate due to the mutator mutation, by increased required steps in carcinogenesis, and by increased number of cell generations to the development of cancer.

Integrating predictive biomarkers and classifiers into oncology clinical development programmes

The future of drug development in oncology lies in identifying subsets of patients who will benefit from particular therapies, using predictive biomarkers. These technologies offer hope of enhancing the value of cancer medicines and reducing the size, cost and failure rates of clinical trials. However, examples of the failure of predictive biomarkers also exist. In these cases the use of biomarkers increased the costs, complexity and duration of clinical trials, and narrowed the treated population unnecessarily. Here, we present methods to adaptively integrate predictive biomarkers into clinical programmes in a data-driven manner, wherein these biomarkers are emphasized in exact proportion to the evidence supporting their clinical predictive value. The resulting programme demands value from predictive biomarkers and is designed to optimally harvest this value for oncology drug development.

Phase I Study of U3-1287, a Fully Human Anti-HER3 Monoclonal Antibody, in Patients with Advanced Solid Tumors

Purpose: HER3 is a key dimerization partner for other HER family members, and its expression is associated with poor prognosis. This first-in-human study of U3-1287 (NCT00730470), a fully human anti-HER3 monoclonal antibody, evaluated its safety, tolerability, and pharmacokinetics in patients with advanced solid tumor. Experimental Design: The study was conducted in 2 parts: part 1—sequential cohorts received escalating doses (0.3–20 mg/kg) of U3-1287 every 2 weeks, starting 3 weeks after the first dose; part 2—additional patients received 9, 14, or 20 mg/kg U3-1287 every 2 weeks, based on observed tolerability and pharmacokinetics from part 1. Recommended phase II dose, adverse event rates, pharmacokinetics, and tumor response were determined. Results: Fifty-seven patients (part 1: 26; part 2: 31) received U3-1287. As no dose-limiting toxicities were reported, the maximum-tolerated dose was not reached. The maximum-administered dose was 20 mg/kg every 2 weeks. The most frequent adverse events related to U3-1287 were fatigue (21.1%), diarrhea (12.3%), nausea (10.5%), decreased appetite (7.0%), and dysgeusia (5.3%). No patient developed anti-U3-1287 antibodies. In these heavily pretreated patients, stable disease was maintained 9 weeks or more in 19.2% in part 1 and 10 weeks or more in 25.8% in part 2. Conclusion: U3-1287 treatment was well tolerated, and some evidence of disease stabilization was observed. Pharmacokinetic data support U3-1287 dosing of 9 to 20 mg/kg every 2 to 3 weeks. Combination studies of U3-1287 are ongoing. Clin Cancer Res; 19(11); 3078–87. ©2013 AACR.

Impact of genetic dynamics and single-cell heterogeneity on development of nonstandard personalized medicine strategies for cancer

Cancers are heterogeneous and genetically unstable. Current practice of personalized medicine tailors therapy to heterogeneity between cancers of the same organ type. However, it does not yet systematically address heterogeneity at the single-cell level within a single individual’s cancer or the dynamic nature of cancer due to genetic and epigenetic change as well as transient functional changes. We have developed a mathematical model of personalized cancer therapy incorporating genetic evolutionary dynamics and single-cell heterogeneity, and have examined simulated clinical outcomes. Analyses of an illustrative case and a virtual clinical trial of over 3 million evaluable “patients” demonstrate that augmented (and sometimes counterintuitive) nonstandard personalized medicine strategies may lead to superior patient outcomes compared with the current personalized medicine approach. Current personalized medicine matches therapy to a tumor molecular profile at diagnosis and at tumor relapse or progression, generally focusing on the average, static, and current properties of the sample. Nonstandard strategies also consider minor subclones, dynamics, and predicted future tumor states. Our methods allow systematic study and evaluation of nonstandard personalized medicine strategies. These findings may, in turn, suggest global adjustments and enhancements to translational oncology research paradigms.

Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer.

Tigatuzumab is the humanized version of the agonistic murine monoclonal antibody TRA‐8 that binds to the death receptor 5 and induces apoptosis of human cancer cell lines via the caspase cascade. The combination of tigatuzumab and gemcitabine inhibits tumor growth in murine pancreatic xenografts. This phase 2 trial evaluated the efficacy of tigatuzumab combined with gemcitabine in 62 chemotherapy‐naive patients with histologically or cytologically confirmed unresectable or metastatic pancreatic cancer. Patients received intravenous tigatuzumab (8 mg/kg loading dose followed by 3 mg/kg weekly) and gemcitabine (1000 mg/m2 once weekly for 3 weeks followed by 1 week of rest) until progressive disease (PD) or unacceptable toxicity occurred. The primary end point was progression‐free survival (PFS) at 16 weeks. Secondary end points included objective response rate (ORR) (complete responses plus partial responses), duration of response, and overall survival (OS). Safety of the combination was also evaluated. Mean duration of treatment was 18.48 weeks for tigatuzumab and 17.73 weeks for gemcitabine. The PFS rate at 16 weeks was 52.5% (95% confidence interval [CI], 39.3–64.1%). The ORR was 13.1%; 28 (45.9%) patients had stable disease and 14 (23%) patients had PD. Median PFS was 3.9 months (95% CI, 2.2–5.4 months). Median OS was 8.2 months (95% CI, 5.1–9.6 months). The most common adverse events related to tigatuzumab were nausea (35.5%), fatigue (32.3%), and peripheral edema (19.4%). Tigatuzumab combined with gemcitabine was well tolerated and may be clinically active for the treatment of chemotherapy‐naive patients with unresectable or metastatic pancreatic cancer.

Negative Clonal Selection in Tumor Evolution

Development of cancer requires the acquisition of multiple oncogenic mutations and selection of the malignant clone. Cancer evolves within a finite host lifetime and mechanisms of carcinogenesis that accelerate this process may be more likely to contribute to the development of clinical cancers. Mutator mutations are mutations that affect genome stability and accelerate the acquisition of oncogenic mutations. However, mutator mutations will also accelerate the accumulation of mutations that decrease cell proliferation, increase apoptosis, or affect other key fitness parameters. These “reduced-fitness” mutations may mediate “negative clonal selection,” i.e., selective elimination of premalignant mutator clones. Target reduced-fitness loci may be “recessive” (both copies must be mutated to reduce fitness) or “dominant” (single-copy mutation reduces fitness). A direct mathematical analysis is applied to negative clonal selection, leading to the conclusion that negative clonal selection against mutator clones is unlikely to be a significant effect under realistic conditions. In addition, the relative importance of dominant and recessive reduced-fitness mutations is quantitatively defined. The relative predominance of mutator mutations in clinical cancers will depend on several variables, including the tolerance of the genome for reduced-fitness mutations, particularly the number and potency of dominant reduced-fitness loci.