A phase II multicentre study of ziv-aflibercept in combination with cisplatin and pemetrexed in patients with previously untreated advanced/metastatic non-squamous non-small cell lung cancer.

BACKGROUND: This study evaluated the efficacy and safety of ziv-aflibercept in combination with cisplatin and pemetrexed in non-small cell lung cancer (NSCLC). METHODS: This single arm, multicentre phase II trial enrolled patients with previously untreated, locally advanced or metastatic non-squamous NSCLC. Patients received intravenous ziv-aflibercept 6 mg kg(-1), pemetrexed 500 mg m(-2), and cisplatin 75 mg m(-2), every 21 days for up to six cycles. Maintenance administration of ziv-aflibercept was to continue until disease progression, intolerable toxicity or other cause for withdrawal. The co-primary end points were objective response rate (ORR) and progression-free survival (PFS). Planned sample size was 72 patients. RESULTS: The study was closed prematurely because of three confirmed and two suspected cases of reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 patients were enrolled. Median age was 61.5 years; 55% were male, 86% Caucasian and 50% had Eastern Cooperative Oncology Group performance status (ECOG PS)=0. A median of four cycles of ziv-aflibercept was administered. The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69%) and fatigue (67%), with hypertension (36%) as the most common grade 3/4 TEAE. Of the 38 evaluable patients, ORR was 26% and median PFS was 5 months. CONCLUSION: Cases of RPLS had been observed in other studies in the ziv-aflibercept clinical development programme but the rate observed in this study was higher than previously observed. This might be related to declining renal function and/or hypertension. Although ORR and PFS were in accordance with most historical first-line NSCLC studies, this combination of ziv-aflibercept/cisplatin/pemetrexed will not be further explored in NSCLC.

Impact of hemoglobin levels on outcomes of adjuvant chemotherapy in resected non-small cell lung cancer: the JBR.10 trial experience.

BACKGROUND: Cisplatin-induced anemia may correlate with adverse events, poor quality of life (QoL), decreased adjuvant chemotherapy (ACT) dose intensity, shorter relapse-free survival (RFS) or overall survival (OS). METHODS: The JBR.10 trial demonstrated significantly longer survival with adjuvant cisplatin and vinorelbine (n=242) compared to observation (n=240) in patients with resected NSCLC [Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005;352(25):2640-2]. This exploratory analysis evaluates the predictive value of baseline (in all patients) and during-treatment (in ACT arm only) hemoglobin (Hb) levels on OS and RFS when adjusted for prognostic factors. Baseline (in all patients) and during treatment (in ACT arm only) Hb levels were also correlated with adverse events, QoL, morbidity and ACT dose intensity. RESULTS: Baseline Hb did not predict RFS or OS. However, there was a trend to shorter OS (p=0.1) when baseline Hb was <120g/L. Lower baseline Hb predicted increased hospitalization (p=0.04) and worse QoL (SOB item, p=0.03) but had no impact on adverse events or dose intensity. There was a trend to longer RFS (p=0.08) in patients with lower nadir during-treatment Hb and to longer OS (p=0.06) and RFS (p=0.08) in patients with maximum during-treatment Hb drop >30% that was not maintained when ACT dose intensity was included in the model. Maximum during-treatment Hb drop >30% correlated with increased lethargy (p=0.003) and worse QoL (fatigue item, p=0.07). CONCLUSIONS: Lower baseline and during-treatment Hb levels seem associated with poorer QoL, fatigue and increased hospitalization. There is a trend for shorter OS in patients with lower baseline Hb levels.

Non-platinum based combination chemotherapy: phase I and II trials of docetaxel plus gemcitabine, vinorelbine, or irinotecan.

Non-platinum combination regimens have been developed for advanced non--small cell lung cancer using the novel and active agents docetaxel, gemcitabine, vinorelbine, and irinotecan. The aim of these combinations is to equal or exceed the survival benefits achieved with cisplatin doublets while minimizing toxicity. Of the docetaxel-based combinations, gemcitabine has been the most extensively studied. In a 317-patient randomized trial, docetaxel plus gemcitabine achieved a response rate of 34%, similar to the 32% response rate seen in patients randomized to docetaxel plus cisplatin. One-year survival rates were 38% and 42%, respectively. While being equally active, the docetaxel/gemcitabine combination was associated with significantly less neutropenia and gastrointestinal adverse events than the cisplatin-containing regimen. Phase II trials of docetaxel plus vinorelbine have reported response rates of up to 51% and 1-year survival in up to 60% of patients without significant peripheral neuropathy. Docetaxel plus irinotecan is also active in advanced non--small cell lung cancer and has shown similar efficacy to docetaxel plus cisplatin in a randomized trial. The adverse event profile of docetaxel/irinotecan is different from that of cisplatin-based regimens. Both non-platinum and platinum combination regimens have an important role to play in the treatment of non--small cell lung cancer. Semin Oncol 28 (suppl 9):15-20.

Multi-institutional phase I/II trial of oral bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with advanced non-small-cell lung cancer.

PURPOSE: Bexarotene (Targretin; Ligand Pharmaceuticals, Inc, San Diego, CA) is a retinoid-X-receptor (RXR)-selective retinoid with preclinical antitumor activity in squamous cell cancers. In this phase I/II trial, we combined bexarotene with cisplatin and vinorelbine in the treatment of patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-three patients who had stage IIIB NSCLC with pleural effusion or stage IV NSCLC and had received no prior therapy received bexarotene in combination with cisplatin (100 mg/m2) and vinorelbine (alternating doses of 30 mg/m2 and 15 mg/m2). In the phase I portion, the daily dose of bexarotene was escalated in cohorts of three patients from 150 mg/m2 to 600 mg/m2, beginning 1 week before the start of the cisplatin-vinorelbine regimen. Once the maximum-tolerated dose (MTD) of bexarotene was determined, the study entered the phase II portion. Response rate was the primary end point; median survival time and 1-year survival rate were secondary end points. RESULTS: In the phase I portion, the daily MTD of bexarotene was determined to be 400 mg/m2. Eight of 43 patients exhibited major responses. Seven (25%) of the 28 patients in the phase II portion responded to treatment. The median survival time in the phase II portion was 14 months; nine (32%) of the 28 patients were still alive at a minimum follow-up of 2 years. One-year and projected 3-year survival rates were 61% and 30%, respectively. The most common grade 3 and 4 adverse events were hyperlipemia, leukopenia, nausea, vomiting, pneumonia, dyspnea, anemia, and asthenia. Grade 3 and 4 laboratory abnormalities with incidences greater than 5% were decreased hemoglobin levels and WBC, absolute neutrophil, and absolute lymphocyte counts and increased prothrombin time and creatinine and amylase levels. Of the two cases of pancreatitis, one required hospitalization and both were associated with increased triglyceride levels. There was one death secondary to renal insufficiency unrelated to bexarotene treatment. CONCLUSION: In patients with advanced NSCLC, bexarotene with cisplatin and vinorelbine yielded acceptable phase II response rates (25%) and was associated with better-than-expected survival (14-month median survival time; 61% 1-year, 32% 2-year, and 30% projected 3-year survival rates). The regimen should be studied in larger clinical trials.

Docetaxel (Taxotere) shows survival and quality-of-life benefits in the second-line treatment of non-small cell lung cancer: a review of two phase III trials.

The potential benefits of docetaxel (Taxotere; Aventis, Antony, France) to patients with previously-treated non-small cell lung cancer have been evaluated in two prospective randomized phase III trials. In one study, patients with stage IIIB/IV non-small cell lung cancer who had failed previous cisplatin-based chemotherapy were randomized to receive either docetaxel (100 or 75 mg/m2, once every 3 weeks) or best supportive care. Median survival was significantly longer for patients treated with docetaxel 75 mg/m2 (7.5 months v 4.6 months) as was 1-year survival (37% v 11%). A second trial, also in platinum-pretreated patients, randomized patients to docetaxel 100 mg/m2, docetaxel 75 mg/m2, or vinorelbine/ifosfamide. Median survival was similar across the three study groups. Thirty-two percent of patients assigned to docetaxel 75 mg/m2 and 21% to docetaxel 100 mg/m2, were alive at 1 year, versus 19% on the vinorelbine/ifosfamide arm. Docetaxel offers clinically meaningful benefits in the second-line setting. The recommended dose is 75 mg/m2 once every 3 weeks. The adverse events observed were predictable, tolerable, and manageable. These phase III trials showed that docetaxel provided clinical benefits to patients with non-small cell lung cancer.

The retinoids and cancer prevention mechanisms.

Carcinogenesis is a multistep process that converts normal cells into malignant cells. Once transformed, malignant cells acquire the ability to invade and metastasize, leading to clinically evident disease. During this continuum from normal to metastatic cells, carcinogenic steps can be arrested or reversed through pharmacological treatments, known as cancer chemoprevention. Chemoprevention strategies represent therapeutic interventions at early stages of carcinogenesis, before the onset of invasive cancer. Effective chemoprevention should reduce or avoid the clinical consequences of overt malignancies by treating early neoplastic lesions before development of clinically apparent signs or symptoms. Preclinical, clinical, and epidemiological data provide considerable support for cancer chemoprevention as an attractive therapeutic strategy. This clinical approach was validated in the recent tamoxifen randomized trial, demonstrating that a selective estrogen receptor modulator reduces the risk of breast cancer in women at high risk for this malignancy. Derivatives of vitamin A, the retinoids, have reported activity in treating specific premalignant lesions and reducing incidence of second primary tumors in patients with prior head and neck, lung or liver cancers. Whether the retinoids will prevent primary cancers at these sites is not yet known. Notably, a carotenoid (beta-carotene) was shown as inactive in primary prevention of lung cancers in high-risk individuals. This underscores the need for relevant in vitro models to identify pathways signaling chemopreventive effects. These models should assess the activity of candidate chemoprevention agents before the conduct of large and costly prevention trials. An improved understanding of cancer prevention mechanisms should aid in the discovery of new therapeutic targets and chemoprevention agents. Ideally, these agents should have tolerable clinical toxicities suitable for chronic administration to individuals at high risk for developing primary or second cancers. This article reviews what is now known from clinical and preclinical studies about the retinoids as cancer prevention agents.

Docetaxel and gemcitabine: a nonplatinum combination for non small-cell lung cancer.

The 1990s have introduced a number of novel chemotherapeutic agents with activity in non small-cell lung carcinoma. Docetaxel and gemcitabine appear to be two of the most active new agents. Their use in non small-cell lung carcinoma has been associated with improvements in survival, palliation of symptoms, and maintenance of quality of life when compared to best supportive care. Options for treatment of non small-cell lung carcinoma after platinum have been limited. These newer agents have substantial activity in this subset of patients. This review focuses on the current data using the combination of docetaxel and gemcitabine in the fight against non small-cell lung carcinoma.

Docetaxel (Taxotere) in combination chemotherapy and in association with thoracic radiotherapy for the treatment of non-small-cell lung cancer. Thoracic Oncology Program.

Docetaxel is one of the most active single agents for the treatment of non-small-cell lung cancer. Given the preclinical indications for synergy and the lack of cross-resistance with other active agents in this disease, clinical trials of docetaxel combinations have been undertaken. Phase I and II clinical trials of docetaxel in combination with cisplatin, carboplatin, gemcitabine, vinorelbine, or thoracic radiation for patients with non-small-cell lung cancer were reviewed. The endpoint for phase I trials was to define the phase II doses for the docetaxel combinations where overall response rates, median and one year survival were the endpoints. Five phase I-II studies of docetaxel and cisplatin have reported response rates ranging from 21% to 48%. Median survival times ranged from 8 to 13 months, and one-year survivals from 32% to 58%. Combining docetaxel with vinorelbine resulted in a 37% response rate and a median survival of 9.4 months. Docetaxel in combination with gemcitabine produced a response rate of 53%. The adverse events of these combinations were manageable. Responses have also been reported in studies of docetaxel administered with carboplatin or thoracic radiation therapy. Combinations of docetaxel with platinum, vinorelbine, gemcitabine, and radiation were active in non-small-cell lung cancer with acceptable adverse effects. Phase III trials are currently in progress to further define the role of docetaxel combinations in the first-line treatment of this disease.

A brief historical review of the development of chemotherapy for the treatment of advanced non-small cell lung cancer: why we should look beyond platinum.

We are approaching the end of the fifth decade and the most productive period in the development of chemotherapy for the treatment of advanced non-small cell lung cancer. We began this decade by establishing cisplatin-based combination chemotherapy regimens of the 1980s as effective at improving survival for patients with advanced disease. The observed improvement in survival from these trials appears to be primarily attributed to cisplatin. Furthermore, this decade, unlike the prior, has identified an abundance of novel active agents for the treatment of this disease. Vinorelbine, gemcitabine, docetaxel, paclitaxel, and irinotecan are all new chemotherapeutic agents which have shown promising activity in this disease. In contrast to the cisplatin-based chemotherapy trials of the 1980s, these newer chemotherapeutic agents when given in combination with cisplatin add to the survival outcomes for these patients. With these survival advances has come a focus on chemotherapy-induced adverse events, lung cancer symptom management, and overall quality of life. The results of the cisplatin combination trials will be discussed.

Modulation of apoptosis signaling pathways and cell cycle regulation.

Apoptosis can be described as multiple pathways converging from numerous different initiating events and insults, such as anticancer agents. These pathways converge on a common irreversible execution phase in which proteases and nucleases digest the doomed cell. Counteracting the signals to die are a variety of pathways that enhance cell survival and that may become constitutively active as a result of oncogenic transformation. Studies of apoptosis have identified many cellular factors that play a role in the decision as to whether a cell lives or dies. These factors include the p53 tumor suppressor, the Bcl-2 family of proteins, and a variety of intracellular signal transduction pathways, all of which may provide novel therapeutic targets. It also is possible to take advantage of the defect in cell cycle regulation that occurs in cells with mutant p53; such cells are susceptible to agents that inhibit DNA damage-induced cell cycle checkpoints at S and G2 phase. Cell cycle perturbation occurs following treatment with all anticancer drugs and a knowledge of the kinetics of such events should facilitate design of synergistic rather than antagonistic schedules. These concepts have been developed in cell culture models and it is essential to determine whether the mechanisms defined also occur in patients receiving therapy. Accordingly, tumors need to undergo serial biopsies during therapy and be analyzed for perturbation in cell cycle or apoptosis-regulating proteins. The results of such studies should facilitate the rational design of chemotherapy combinations.

The future beyond platinum for the treatment of advanced non-small cell lung cancer.

The development of chemotherapy for advanced non-small cell lung cancer has been most productive in its fifth decade. We began this decade by establishing cisplatin-based combination chemotherapy regimens of the 1980s as effective at improving survival for patients with advanced disease. The observed improvement in survival from these trials appears to be primarily attributed to cisplatin. Furthermore, this decade, unlike the prior, has identified an abundance of novel active agents for the treatment of this disease. Vinorelbine, gemcitabine, docetaxel, paclitaxel, and irinotecan are all new chemotherapeutic agents which have shown promising activity and their cisplatin combinations have further advanced survival for these patients. In contrast to the cisplatin-based chemotherapy trials of the 1980s, these newer chemotherapeutic agents, when given in combination with cisplatin, add to the survival outcomes for patients with advanced non-small cell lung cancer. With these survival advances has come a focus on chemotherapy-induced adverse events, lung cancer symptom management, and overall quality of life. Is it feasible to use these novel chemotherapeutic drugs as single-agents, sequentially or as nonplatinum combinations to prolong survival, minimize adverse events, control symptoms, and improve the quality of life for patients with this disease? The goal of this symposium will be to present the results of the single-agent and nonplatinum combination studies of these newer therapies with a focus on survival, symptom management, and quality of life. This symposium is intended to introduce the next decade of care for advanced non-small cell lung cancer, namely "Non-platinum-Based Chemotherapy."

Phase I study of the sequential administration of edatrexate and paclitaxel in patients with advanced solid tumors.

BACKGROUND: The antifolate edatrexate and the microtubule-stabilizing agent paclitaxel have both demonstrated single-agent activity in lung and breast cancer. In vitro, the sequential combination of edatrexate followed by paclitaxel produced synergistic antitumor effects. This trial was designed to find the maximum tolerated doses of edatrexate and paclitaxel when given every two weeks utilizing this sequential schedule. PATIENTS AND METHODS: Thirty-four patients with solid tumors received edatrexate intravenously on days 1 and 15 and paclitaxel intravenously as a three-hour infusion on days 2 and 16 of each 28-day cycle. Edatrexate was escalated from 40 to 120 mg/m2 and the paclitaxel dose fixed at 135 mg/m2. When the maximum-tolerated dose was not reached, edatrexate was fixed at 120 mg/m2 and paclitaxel escalated to 175 and 210 mg/m2. RESULTS: All 34 patients were assessable. The maximum tolerated doses were 120 mg/m2 of edatrexate and 210 mg/m2 of paclitaxel. Grade 3 myalgia, peripheral neuropathy, leukopenia, and an infusion-related reaction occurred. Eight patients with non-small-cell lung cancer and one with bladder cancer achieved major objective responses. CONCLUSIONS: The recommended phase II doses are 120 mg/m2 of edatrexate days 1 and 15 and 175 mg/m2 of paclitaxel as a three-hour infusion days 2 and 16 of a 28 day cycle. These results warrant phase II trials of the combination leading to phase III studies comparing the two drugs to a single agent to confirm the preclinical evidence of synergy.

Daily paclitaxel and thoracic radiation therapy for non-small cell lung cancer: preliminary results.

Platinum-based combination chemotherapy plus thoracic radiation prolongs survival for patients with stage III non-small cell lung cancer. Paclitaxel demonstrates significant clinical antitumor activity in this disease and potentiates the effects of ionizing radiation by arresting cells at the sensitive G2/M cell cycle phase. The optimal schedule of paclitaxel administered concomitantly with thoracic radiation has not been established. The preliminary results of this phase I trial, which was designed to define the dose-limiting adverse event and the maximum tolerated dose of paclitaxel administered daily before each fraction of thoracic radiation, are being presented. Twenty-nine patients with inoperable clinical stage II to IIIB non-small cell lung cancer received two 21-day cycles of primary chemotherapy with carboplatin and paclitaxel. Six weeks from the initiation of therapy, daily paclitaxel was administered intravenously over 1 hour without premedication before 68 Gy of thoracic radiation in 34 fractions. Twenty-six patients completed concomitant daily paclitaxel with radiation and are evaluable for toxicity. Early radiation esophagitis was the dose-limiting toxicity at the 15 mg dose level. A daily paclitaxel dose of 10 mg or 6 mg/m2 and 68 Gy of thoracic radiotherapy are recommended for further study. Preliminary data from this dose-escalation trial suggest that this combined modality treatment with concurrent radiation and daily paclitaxel following primary induction therapy for stage II to III non-small cell lung cancer is feasible. The observed adverse effects within the radiation field suggest active radiosensitization by low-dose daily paclitaxel.

New options in the treatment of non-small cell lung cancer.

The options for treating non-small cell lung cancer (NSCLC) were expanded by the introduction of the taxanes. As a single agent, docetaxel produced response rates ranging from 15 to 22% in evaluable patients in the second-line setting, with median duration of responses ranging from 5.6 to 7.5 months. To confirm the results observed in the phase II studies, a phase III trial was conducted. Three-hundred and seventy-three patients with advanced NSCLC who had failed prior platinum-based chemotherapy were randomized to receive docetaxel 100 mg/m2, docetaxel 75 mg/m2 or a reference arm consisting of vinorelbine or ifosfamide. Efficacy, safety and quality of life (using the Lung Cancer Symptom Scale) were assessed. Data from this study are forthcoming and may confirm the benefits provided by the inclusion of docetaxel in the second-line treatment of NSCLC. Docetaxel is also an active single agent in the first-line setting, with response rates ranging from 24 to 38% in evaluable patients, with a median survival of 6-13 months. Based on the single-agent activity, it was logical to evaluate the efficacy of docetaxel in combination with other active agents. As such, docetaxel has been studied in with numerous other agents such as vinorelbine, gemcitabine, platinums, etc. Notably cisplatin and carboplatin has shown promising rates of response and response duration in phase II trials. These combinations have now entered randomized phase III study.

New oral chemotherapeutic agents for lung cancer.

Anticancer treatment has recently shifted to include a broad range of antineoplastic therapies. Old agents are continuously being re-evaluated, and new mechanisms of treatment are rapidly being explored and developed. At the same time, the patient's perceived quality of life, adverse effects of therapy, time demands, and healthcare costs have become paramount in the treatment process. Lung cancer is the most common cause of cancer death in the USA, and because many of the patients are older or debilitated, these issues become all the more important. The oral administration of anticancer therapy offers both quality-of-life and healthcare cost advantages. Oral forms of 3 new cytotoxic agents and 2 novel oral therapies are discussed. Vinorelbine, a vinca alkaloid, has well documented activity in non-small cell lung cancer. Myelosuppression is dose limiting; neurotoxicity is rare. Satraplatin (JM-216), an oral platinum derivative, shows activity in lung cancer with a favourable adverse effect profile, with no neurotoxicity or nephrotoxicity. The oral topoisomerase I inhibitor topotecan may be ideal for obtaining long term low plasma drug concentrations, which appears to maximise efficacy. LGD-1069 is a retinoid X receptor agonist that modulates cell proliferation, and BAY-129566, a matrix metalloproteinase inhibitor, appears to interrupt both the processes of angiogenesis and metastasis. LGD-1069 and BAY-129566 are nontraditional anticancer agents which may be used in conjunction with chemotherapy, other modalities, or in prevention. These 5 agents will be discussed with particular reference to recent developments in the treatment of lung cancer.

Do newer chemotherapeutic agents improve survival in non-small cell lung cancer?

Cisplatin-based chemotherapy regimens used in the 1980s led to a small but significant prolongation of survival for patients with advanced non-small cell lung cancer (NSCLC), achieving median survival of approximately 7 months compared with the 4 months seen with best supportive care. Vinorelbine, docetaxel, and gemcitabine are new drugs with promising activity in NSCLC. For each of these drugs, median survivals in excess of 7 months have been reported in single-agent studies. When they are used in combination with cisplatin, 10-month median survivals have been achieved. In addition, docetaxel appears capable of inducing responses and prolonging survival when used as second-line therapy in patients who have failed platinum therapy. The combination of these new agents with cisplatin or with each other may further improve survival prospects for patients with advanced NSCLC.

Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer.

PURPOSE: The population pharmacokinetic/pharmacodynamic (PK/PD) approach was prospectively integrated in the clinical development of docetaxel to assess the PK profile in a large population of patients and investigate systemic exposure as a prognostic factor for clinical outcome. PATIENTS AND METHODS: PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limited-sampling schedules. Bayesian estimates of clearance (CL), area under the concentration-time curve (AUC), and peak and duration of plasma levels greater than threshold levels were used as measures of exposure. PD data included for efficacy, response rate, time to first response, and time to progression (TTP) in breast cancer and non-small-cell lung cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention. PK/PD analysis was conducted using logistic and Cox multivariate regression models. RESULTS: PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were assessable for PK (640 patients). First-course docetaxel AUC was a significant predictor (P = .0232) of TTP in NSCLC (n = 151). Docetaxel CL was a strong independent predictor (P < .0001) of both grade 4 neutropenia and febrile neutropenia (n = 582). Cumulative dose was the strongest predictor (P < .0001) of the time to onset of fluid retention (n = 631). However, the duration of exposure over 0.20 micromol/L (0.16 microg/mL) at first course was an independent predictor (P = .0029). Few patients (n = 25, 4%) received the recommended dexamethasone premedication. CONCLUSION: First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulative in nature. Patients with elevated hepatic enzymes have a 27% reduction in docetaxel CL and are at a higher risk of toxicity. A starting dose of 75 mg/m2 is currently being evaluated in this population. Prospective implementation of large-scale population PK/PD evaluation is feasible in early drug development and this approach generates clinically relevant findings.

Initial clinical trial of a selective retinoid X receptor ligand, LGD1069.

PURPOSE: The retinoid response is mediated by nuclear receptors, including retinoic acid receptors (RARs) and retinoid "X" receptors (RXRs). All-trans retinoic acid (RA) binds only RARs, while 9-cis RA is an agonist for both RARs and RXRs. Recently, LGD1069 was identified as a highly selective RXR agonist with low affinity for RARs. We undertook a dose-ranging study to examine the safety, clinical tolerance, and pharmacokinetics of LGD1069 in patients with advanced cancer. PATIENTS AND METHODS: Fifty-two patients received. LGD1069 administered orally once daily at doses that ranged from 5 to 500 mg/m2 for 1 to 41 weeks. Treatment proceeded from a starting dose of 5 mg/m2. Pharmacokinetic sampling was performed on selected patients on days 1, 15, and 29. RESULTS: Reversible, asymptomatic increases in liver biochemical tests were the most common dose-limiting adverse effect. Less prominent reactions included leukopenia, hypertriglyceridemia, and hypercalcemia. Characteristic retinoid toxicities, such as cheilitis, headache, and myalgias/arthralgias, were mild or absent. Two patients with cutaneous T-cell lymphoma experienced major antitumor responses. Pharmacokinetic studies obtained in 27 patients at eight dose levels showed that the day 1 area under the plasma concentration-times-time curves (AUCs) were proportional to dose. At all doses studied, the day 1 AUCs were similar to those on days 15 and 29, indicating a lack of induced metabolism. CONCLUSION: LGD1069 is a unique compound that exploits a newly identified pathway of retinoid receptor biology that may be relevant to tumor-cell proliferation and apoptosis. Further investigation of this drug is warranted. Based on the results of this study, a dose of 300 mg/m2 is recommended for single-agent trials.