Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial.

BACKGROUND: Treatment options for patients with relapsed or refractory lymphoma and multiple myeloma are limited. CUDC-907 is an oral, first-in-class, small molecule that is designed to inhibit both histone deacetylase (HDAC) and PI3K enzymes, which are members of common oncogenic pathways in haematological malignancies. We aimed to assess overall safety and preliminary activity in this dose-escalation study of CUDC-907 monotherapy in patients with relapsed or refractory lymphoma and multiple myeloma. METHODS: This open-label, first-in-man, phase 1 trial recruited adult patients (aged ≥18 years) with lymphoma or multiple myeloma who were refractory to or had relapsed after two or more previous regimens, from four US cancer centres. CUDC-907 was orally administered in a standard 3 + 3 dose-escalation design at four different dosing schedules, to which participants were sequentially assigned as follows: once daily, intermittently (twice or three times weekly; simultaneous enrolment), and daily for 5 days followed by a 2-day break (5/2), in 21-day cycles. Dosing started at 30 mg for the once-daily schedule and 60 mg for other schedules, escalating in 30 mg increments. Patients continued to receive CUDC-907 until disease progression or until other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose, assessed in patients who received at least 66% of cycle 1 doses without modification and those who had a dose-limiting toxicity (DLT) in cycle 1 irrespective of dose modification. We assessed safety in all patients who received at least one dose of study drug. This ongoing trial is registered at ClinicalTrials.gov, number NCT01742988. FINDINGS: Between Jan 23, 2013, and July 27, 2015, we enrolled 44 patients, of whom ten were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to three-times-weekly (MTD 150 mg), and seven to the 5/2 dosing schedule (MTD 60 mg). 37 (84%) patients had discontinued study drug as a result of progressive disease or clinical signs of progressive disease at the data cutoff. Four DLTs occurred in three of 40 DLT-evaluable patients (diarrhoea and hyperglycaemia in one patient on 60 mg once daily, hyperglycaemia in one patient on 150 mg twice weekly, and diarrhoea in one patient on 150 mg three times weekly); no DLTs were reported in patients on the 5/2 schedule. Grade 3 or worse adverse events occurred in 19 (43%) of 44 patients, the most common of which were thrombocytopenia (in nine [20%] of 44 patients), neutropenia (three [7%]), and hyperglycaemia (three [7%]). 11 (25%) of 44 patients had serious adverse events, three of which were regarded as treatment related (epistaxis and the DLTs of diarrhoea and hyperglycaemia). Adverse events led to dose reductions in six (14%) patients and treatment discontinuation in seven (16%). Five (14%) of 37 response-evaluable patients achieved an objective response (two complete responses and three partial responses). All five responses occurred in the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; n=9), and three occurred in those with transformed follicular lymphoma DLBCL (n=5). 21 (57%) of 37 response-evaluable patients had stable disease, including those with DLBCL, Hodgkin's lymphoma, and multiple myeloma. On the basis of these findings, we selected CUDC-907 60 mg on the 5/2 dosing schedule as the recommended phase 2 dose. INTERPRETATION: The safety and tolerability profile of CUDC-907 and the promising preliminary evidence of response support continued development of CUDC-907 at the 60 mg 5/2 dosing schedule, alone and in combination with other therapies. A dose-expansion trial of this dose in patients with refractory and relapsed DLBCL in particular, is ongoing. FUNDING: Curis, Inc, and the Leukemia and Lymphoma Society.

Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis.

BACKGROUND: Observational studies and randomized trials have reported increased cardiovascular risk associated with cyclooxygenase-2 inhibitors. Prior placebo-controlled randomized studies had limited ability to assess the relationship of either celecoxib dose or pretreatment cardiovascular status to risk associated with celecoxib. Our aim was to assess the cardiovascular risk associated with celecoxib in 3 dose regimens and to assess the relationship between baseline cardiovascular risk and effect of celecoxib on cardiovascular events. METHODS AND RESULTS: We performed a patient-level pooled analysis of adjudicated data from 7950 patients in 6 placebo-controlled trials comparing celecoxib with placebo for conditions other than arthritis with a planned follow-up of at least 3 years. Patients were administered celecoxib in 3 dose regimens: 400 mg QD, 200 mg BID, or 400 mg BID. From the pooled data, we calculated a hazard ratio for all dose regimens combined and individual hazard ratios for each dose regimen and examined whether celecoxib-related risk was associated with baseline cardiovascular risk. The primary end point was the combination of cardiovascular death, myocardial infarction, stroke, heart failure, or thromboembolic event. With 16,070 patient-years of follow-up, the hazard ratio for the composite end point combining the tested doses was 1.6 (95% CI, 1.1 to 2.3). The risk, which increased with dose regimen (P=0.0005), was lowest for the 400-mg-QD dose (hazard ratio, 1.1; 95% CI, 0.6 to 2.0), intermediate for the 200-mg-BID dose (hazard ratio, 1.8; 95% CI, 1.1 to 3.1), and highest for the 400-mg-BID dose (hazard ratio, 3.1; 95% CI, 1.5 to 6.1). Patients at highest baseline risk demonstrated disproportionately greater risk of celecoxib-related adverse events (P for interaction=0.034). CONCLUSIONS: We observed evidence of differential cardiovascular risk as a function of celecoxib dose regimen and baseline cardiovascular risk. By further clarifying the extent of celecoxib-related cardiovascular risk, these findings may help guide treatment decisions for patients who derive clinical benefit from selective cyclooxygenase-2 inhibition.

Celecoxib for the prevention of sporadic colorectal adenomas.

BACKGROUND: Studies showing that drugs that inhibit cyclooxygenase-2 (COX-2) reduce the number of colorectal adenomas in animals and patients with familial adenomatous polyposis suggest that COX-2 inhibitors may also prevent sporadic colorectal neoplasia. METHODS: We randomly assigned patients who had adenomas removed before study entry to receive placebo (679 patients) or 200 mg (685 patients) or 400 mg (671 patients) of celecoxib twice daily. Randomization was stratified for the use of low-dose aspirin. Follow-up colonoscopies were performed at one and three years after randomization. The occurrence of newly detected colorectal adenomas was compared among the groups with the life-table extension of the Mantel-Haenszel test. RESULTS: Follow-up colonoscopies were completed at year 1 in 89.5 percent of randomized patients, and at year 3 in 75.7 percent. The estimated cumulative incidence of the detection of one or more adenomas by year 3 was 60.7 percent for patients receiving placebo, as compared with 43.2 percent for those receiving 200 mg of celecoxib twice a day (risk ratio, 0.67; 95 percent confidence interval, 0.59 to 0.77; P<0.001) and 37.5 percent for those receiving 400 mg of celecoxib twice a day (risk ratio, 0.55; 95 percent confidence interval, 0.48 to 0.64; P<0.001). Serious adverse events occurred in 18.8 percent of patients in the placebo group, as compared with 20.4 percent of those in the low-dose celecoxib group (risk ratio, 1.1; 95 percent confidence interval, 0.9 to 1.3; P=0.5) and 23.0 percent of those in the high-dose group (risk ratio, 1.2; 95 percent confidence interval, 1.0 to 1.5; P=0.06). As compared with placebo, celecoxib was associated with an increased risk of cardiovascular events (risk ratio for the low dose, 2.6; 95 percent confidence interval, 1.1 to 6.1; and risk ratio for the high dose, 3.4; 95 percent confidence interval, 1.5 to 7.9). CONCLUSIONS: These findings indicate that celecoxib is an effective agent for the prevention of colorectal adenomas but, because of potential cardiovascular events, cannot be routinely recommended for this indication. (ClinicalTrials.gov number, NCT00005094 [ClinicalTrials.gov].).

A multicenter study of prevalence and risk factors for aberrant crypt foci.

BACKGROUND & AIMS: Aberrant crypt foci (ACF) are the putative precursor of colorectal adenomas. However, there are limited data available on the prevalence and risk factors for ACF. METHODS: Subjects from the Prostate, Lung, Colorectal and Ovarian cancer screening trial were recruited for an ACF study, with subjects with adenoma history being oversampled. By using a standardized protocol of magnified chromoendoscopy with methylene blue staining (up to the middle rectal fold), ACF were photo-documented and removed for histologic evaluation. RESULTS: A total of 505 (66% male; 55% > or =70 y) subjects from 4 institutions were examined; 42% had no adenoma, 32% had nonadvanced distal adenoma, and 25% had advanced distal adenoma at the baseline Prostate, Lung, Colorectal and Ovarian cancer screening trial examination (8.2 years before ACF examination on average). A total of 68% of this population had 1 or more ACF, 43% had 1 to 3, 19% had 4 to 6, and 5% had 7 or more. Baseline adenoma status was not associated with ACF prevalence (range, 66%-69%) or mean number of ACF (range, 3.1-3.5). Of 143 endoscopic ACF examined histologically, 68.5% were confirmed to be ACF. In a logistic model, current (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.2-5.6) and former smoking (OR, 1.6; 95% CI, 1.1-2.5) were associated with higher ACF prevalence; a body mass index greater than 30 was associated with lower prevalence (OR, 0.53; 95% CI, 0.35-0.8). Age, sex, family history of colorectal cancer, and aspirin/nonsteroidal anti-inflammatory drug use were not associated significantly with ACF prevalence. CONCLUSIONS: ACF prevalence and number were not associated with adenoma history, and only 68.5% of endoscopic ACF were confirmed histologically. These results raise concern about the use of ACF as a surrogate marker of colorectal cancer risk.

The Translational Research Working Group developmental pathways: introduction and overview.

The Translational Research Working Group (TRWG) was created as a national initiative to evaluate the current status of the National Cancer Institute's investment in translational research and envision its future in an inclusive, representative, and transparent manner. To clarify the challenges facing translational research and facilitate its deliberations, the TRWG conceptualized translational research as a set of developmental processes or pathways focused on various clinical goals. Drawing on the collective knowledge of the TRWG members, six pathways were derived, with two addressing the development of tools designed to characterize an individual's cancer-related health status (biospecimen-based and image-based assessment modalities) and four addressing the development of interventions intended to change cancer-related health status (drugs or biological agents, immune response modifiers, interventive devices, and life-style alterations). The pathways, which share a number of common structural elements, are graphically represented by schematic flowcharts that capture relevant contingencies, decision points, and interdependencies. They are conceived not as comprehensive descriptions of the corresponding real-world processes but as tools designed to serve specific purposes including research program management and research project management, coordination of research efforts, and professional and lay education and communication. Further development of the pathways is encouraged, as is application of the pathway concept to translational research on other diseases.

Statins in esophageal cancer cell lines: promising lead?

Barrett's-associated esophageal adenocarcinoma (BEAC) is an important health concern in many western populations owing to its increasing incidence and the paucity of effective treatments. Statins have recently been suggested to induce anticancer effects against a variety of cancers in several, but not all, in vitro, in vivo, and epidemiologic studies. In the accompanying article by Ogunwobi and Beales, three statins were shown to inhibit proliferation and stimulate apoptosis in two EAC cell lines. These effects were achieved by reducing Ras, extracellular signal-regulated kinase (ERK), and protein kinase B (Akt)-related cellular signaling. Although these results are promising, they are clearly preliminary, and much additional work is needed to confirm or refute the potential anticancer effects of statins in human BEAC. In addition, the work of Ogunwobi and Beales highlights the importance of developing better, more predictive in vitro and in vivo models of BEAC, and of taking promising, low-risk agents, such as statins, into early-phase therapeutic and preventive clinical trials involving cancer patients and patients with Barrett's metaplasia/dysplasia, respectively.

Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers.

Upregulation of MYC is a common driver event in human cancers, and some tumors depend on MYC to maintain transcriptional programs that promote cell growth and proliferation. Preclinical studies have suggested that individually targeting upstream regulators of MYC, such as histone deacetylases (HDAC) and phosphoinositide 3-kinases (PI3K), can reduce MYC protein levels and suppress the growth of MYC-driven cancers. Synergy between HDAC and PI3K inhibition in inducing cancer cell death has also been reported, but the involvement of MYC regulation is unclear. In this study, we demonstrated that HDAC and PI3K inhibition synergistically downregulates MYC protein levels and induces apoptosis in "double-hit" (DH) diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, CUDC-907, a small-molecule dual-acting inhibitor of both class I and II HDACs and class I PI3Ks, effectively suppresses the growth and survival of MYC-altered or MYC-dependent cancer cells, such as DH DLBCL and BRD-NUT fusion-positive NUT midline carcinoma (NMC) cells, and MYC protein downregulation is an early event induced by CUDC-907 treatment. Consistently, the antitumor activity of CUDC-907 against multiple MYC-driven cancer types was also demonstrated in animal models, including DLBCL and NMC xenograft models, Myc transgenic tumor syngeneic models, and MYC-amplified solid tumor patient-derived xenograft (PDX) models. Our findings suggest that dual function HDAC and PI3K inhibitor CUDC-907 is an effective agent targeting MYC and thus may be developed as potential therapy for MYC-dependent cancers. Mol Cancer Ther; 16(2); 285-99. ©2016 AACR.

What is the future of oncology? National Cancer Institute initiatives to improve research, development, and implementation in cancer prevention and treatment.

To improve the efficiency and effectiveness with which we bring novel cancer treatment and prevention strategies into routine clinical use, the National Cancer Institute has commissioned the Clinical Trials Working Group to restructure its activities related to clinical trials. A total of 22 initiatives have been developed and are being implemented under the rubrics of Coordination, Prioritization/Scientific Quality, Standardization, Operational Efficiency, and Integrated Management. A similar model was recently applied to the newly formed Translational Research Working Group, which will focus on more efficient translation of scientific discoveries arising from the laboratory, clinic, or population into early phase clinical testing.

Can animal models help us select specific compounds for cancer prevention trials?

Animal models provide unparalleled mechanistic insights into cancer development and potential opportunity for cancer prevention. Nevertheless, species differ markedly with regard to dietary exposures, cancer development, drug effects, and toxicity thresholds; therefore, testing in a single animal system may not predict human responses. Although replication of human cancer in animal models remains inexact, more than two decades of research have clearly yielded significant gains, as is evident in agents tested--and in certain cases, approved--for the prevention of epithelial cancers. Research efficiencies achievable through preliminary testing in genetically engineered and carcinogen-induced animal models enable us to probe genetic and signaling pathways that drive normal and neoplastic processes, and thereby figure prominently in decision trees for agent development.

Prevention and therapy of colorectal cancer.

Colorectal cancer is expected to affect more than 146,000 and kill more than 57,000 Americans in 2004. Increased understanding of carcinogenesis is transforming clinical approaches to all stages of this disease. During the last 5 years, four new drugs have been approved for colorectal cancer treatment, and substantial progress has been made in identifying and developing agents that prevent or delay carcinogenesis. These advances substantiate target-driven approaches to cancer prevention and treatment, and provide fruitful opportunities for future investigations.

Irreversible ototoxicity associated with difluoromethylornithine.

Difluoromethylornithine (DFMO) is a potent, irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in the synthesis of polyamines that promote cellular proliferation. DFMO has been tested as a potential cancer therapeutic and chemopreventive agent in clinical trials. Reversible hearing loss is a recognized toxicity of DFMO that usually occurs at doses above 2 g/m(2)/d, and generally when the cumulative dose exceeds 250 g/m(2). In a recently completed Barrett's esophagus chemoprevention trial, a participant developed a 15-dB decrease in hearing at frequencies of 250, 2,000, and 3,000 Hz in the right ear and a > or =20-dB decrease in hearing at 4,000 to 6,000 Hz in the left ear after taking 0.5 g/m(2)/d DFMO for approximately 13 weeks (cumulative dose of 45 g/m(2)). The threshold shifts persisted 7 months after DFMO was discontinued. There was no obvious impact on the participant's clinical hearing, but these findings were consistent with irreversible hearing loss. This is the first case reported of irreversible ototoxicity in a clinical trial participant receiving DFMO and, thus, trial participants should be made aware of this small but important risk.

The role of cyclooxygenase inhibitors in cancer prevention.

Carcinogenesis results from the long-term accumulation of genetic and epigenetic aberrations at the molecular level, which are under constant selection pressure for growth advantage. Recognizing that cancer is the result of this long-term, multi-step process provides opportunities for molecularly targeted cancer prevention. Ideally, chemopreventive agents should be low in toxicity, morbidity, and cost. Several individual agents and agent combinations are currently under evaluation in the U.S. National Cancer Institute s (NCI) chemoprevention agent development program. Nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase (COX) -1 and -2 are among the most promising classes of agents for targeted molecular prevention.

Chemoprevention of nonmelanoma skin cancer: experience with a polyphenol from green tea.

Nonmelanoma skin cancer is extremely common and is increasing in incidence. It would be very useful to have forms of therapy that would prevent precancerous changes from going on to form cancer, or to reverse the precancerous changes. Epidemiologic evidence in humans, in vitro studies on human cells, and clinical experiments in animals have identified polyphenol compounds found in tea to be possibly useful in reducing the incidence of various cancers, including skin cancer. To examine the potential for a polyphenol from green tea, epigallocatechin gallate, to act as a chemopreventive agent for nonmelanoma skin cancer, a randomized, double-blind, placebo-controlled phase II clinical trial of topical epigallocatechin gallate in the prevention of nonmelanoma skin cancer was performed.

Epidemiology and prevention of colorectal cancer.

CRC, the second-leading cause of cancer death in the United States, is a highly preventable disease. Ironically, available and effective screening technologies are not consistently applied, even as new ones are developed. This discordance between preventive opportunity and practice conveys a sobering message regarding nontechnologic issues that must be addressed if the promise of CRC prevention is to be realized. Our response to this message will determine the public health impact of cancer prevention. In the 1980s, cancer chemoprevention was regarded as scientific speculation. Within the last decade, however, cancer has been recognized as a late, nonobligate stage of carcinogenesis, a chronic process that provides time and targets for preventive intervention. Further advances are emerging out of rigorous clinical testing, which remains the limiting factor in transforming ingenious concepts into useful tools for the prevention of CRC. The challenges and rewards of participation in chemoprevention research--both as patients and health care providers-have never been greater.

Mechanisms and applications of non-steroidal anti-inflammatory drugs in the chemoprevention of cancer.

Biological and chemical irritants can be the cause of irritation in a variety of organ sites. It is becoming well understood that chronic irritation in any form can initiate and accelerate the cancer process in these same organs. This understanding comes in part from the many epidemiologic studies which point out that chronic inflammation correlates with increased risk of developing cancer in that organ which is affected. One of the hallmarks of chronic irritation is the increased activity in the arachidonic acid pathway which provides many of the necessary inflammatory biochemical mediators to this process. Arachidonic acid metabolism diverges down two main pathways, the cyclooxygenase (COX) and the lipoxygenase (LOX) pathways. The COX pathway leads to prostaglandin and thromboxane production and the LOX pathway leads to the leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs). These classes of inflammatory molecules exert profound biological effects which enhance the development and progression of human cancers. A large number of synthetic drugs and natural products have been discovered that block many of these key pathways. Much experimental evidence in animals has shown that inhibition of the key enzymes which drive these pathways can, in fact, prevent, slow or reverse the cancer process. The data are convincing in a number of organ sites including colon, breast, lung, bladder and skin. More recently, double-blinded randomize clinical trials in humans have shown the prevention of colonic polyps by anti-inflammatory agents. These studies have primarily used non-steroidal anti-inflammatory drugs (NSAIDS) which block the COX pathways. Recent preclinical studies indicate that the LOX pathway also may be an important target for cancer prevention strategy. The expression of high levels of these enzymes in cancerous tissues make them an obvious first target for cancer prevention strategies. As newer more specific drugs are developed with few adverse effects this important prevention strategy may become a reality.

Chemoprevention of skin cancer.

OBJECTIVES: To discuss the principles, science, and roles of nurses related to skin cancer chemoprevention. DATA SOURCES: Journal articles and federal government reports. CONCLUSIONS: The skin is a model organ for investigating cancer prevention processes that may be relevant to other organs as well. Agents that selectively target molecular hallmarks of skin carcinogenesis are under intense clinical and preclinical investigation. IMPLICATIONS FOR NURSING PRACTICE: Nurses play key roles in coordinating clinical trials, stimulating public awareness, and ensuring access to and acceptance of new agents. Nurses play a role in translational research by bridging the gap between technologic development and patient care.

Phase I dose-escalation study of MEDI-573, a bispecific, antiligand monoclonal antibody against IGFI and IGFII, in patients with advanced solid tumors.

PURPOSE: This phase I, multicenter, open-label, single-arm, dose-escalation, and dose-expansion study evaluated the safety, tolerability, and antitumor activity of MEDI-573 in adults with advanced solid tumors refractory to standard therapy or for which no standard therapy exists. EXPERIMENTAL DESIGN: Patients received MEDI-573 in 1 of 5 cohorts (0.5, 1.5, 5, 10, or 15 mg/kg) dosed weekly or 1 of 2 cohorts (30 or 45 mg/kg) dosed every 3 weeks. Primary end points included the MEDI-573 safety profile, maximum tolerated dose (MTD), and optimal biologic dose (OBD). Secondary end points included MEDI-573 pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor activity. RESULTS: In total, 43 patients (20 with urothelial cancer) received MEDI-573. No dose-limiting toxicities were identified, and only 1 patient experienced hyperglycemia related to treatment. Elevations in levels of insulin and/or growth hormone were not observed. Adverse events observed in >10% of patients included fatigue, anorexia, nausea, diarrhea, and anemia. PK evaluation demonstrated that levels of MEDI-573 increased with dose at all dose levels tested. At doses >5 mg/kg, circulating levels of insulin-like growth factor (IGF)-I and IGFII were fully suppressed. Of 39 patients evaluable for response, none experienced partial or complete response and 13 had stable disease as best response. CONCLUSIONS: The MTD of MEDI-573 was not reached. The OBD was 5 mg/kg weekly or 30 or 45 mg/kg every 3 weeks. MEDI-573 showed preliminary antitumor activity in a heavily pretreated population and had a favorable tolerability profile, with no notable perturbations in metabolic homeostasis.

A randomized, double-blind, placebo-controlled phase II clinical trial of lovastatin for various endpoints of melanoma pathobiology.

On the basis of large cardiovascular clinical trials of lipid-lowering agents that showed a considerable decrease in the incidence of primary melanomas in the active agent arm, we have carried out a randomized, double-blind clinical trial examining the impact of lovastatin on various biomarkers of melanoma pathogenesis. Subjects with at least two clinically atypical nevi were randomized to receive oral lovastatin or placebo for a 6-month period. Clinical, histopathologic, and molecular biomarkers were evaluated for change in the two groups. Eighty subjects were randomized, evaluable, and included in the analyses. Lovastatin showed no benefit in comparison with placebo in the primary endpoint of decreasing the level of histopathologic atypia, nor in any of the secondary endpoints of decreasing clinical atypia, impact on nevus number, nor in showing significant changes in any of the molecular biomarkers. There were no significant differences in adverse event profiles for lovastatin compared with placebo. The lovastatin arm did show a significant and considerable decrease in total serum cholesterol and serum low-density lipoprotein (LDL) levels compared with placebo, an expected result. This finding bolsters confidence in subject compliance. Given the results of this trial, it is concluded that if lovastatin were to lower the incidence of melanoma, it would appear not to be doing so by reversing atypia of precursor atypical nevi over the 6-month time frame studied. Further research into the pathogenesis of melanoma and in other potential chemopreventive agents is needed.