Improving attribution of adverse events in oncology clinical trials.

Attribution of adverse events (AEs) is critical to oncology drug development and the regulatory process. However, processes for determining the causality of AEs are often sub-optimal, unreliable, and inefficient. Thus, we conducted a toxicity-attribution workshop in Silver Springs MD to develop guidance for improving attribution of AEs in oncology clinical trials. Attribution stakeholder experts from regulatory agencies, sponsors and contract research organizations, clinical trial principal investigators, pre-clinical translational scientists, and research staff involved in capturing attribution information participated. We also included patients treated in oncology clinical trials and academic researchers with expertise in attribution. We identified numerous challenges with AE attribution, including the non-informative nature of and burdens associated with the 5-tier system of attribution, increased complexity of trial logistics, costs and time associated with AE attribution data collection, lack of training in attribution for early-career investigators, insufficient baseline assessments, and lack of consistency in the reporting of treatment-related and treatment-emergent AEs in publications and clinical scientific reports. We developed recommendations to improve attribution: we propose transitioning from the present 5-tier system to a 2-3 tier system for attribution, more complete baseline information on patients' clinical status at trial entry, and mechanisms for more rapid sharing of AE information during trials. Oncology societies should develop recommendations and training in attribution of toxicities. We call for further harmonization and synchronization of recommendations regarding causality safety reporting between FDA, EMA and other regulatory agencies. Finally, we suggest that journals maintain or develop standardized requirements for reporting attribution in oncology clinical trials.

First-in-Human, First-in-Class Phase I Trial of the Anti-CD47 Antibody Hu5F9-G4 in Patients With Advanced Cancers.

PURPOSE: To evaluate the safety, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 (5F9), a humanized IgG4 antibody that targets CD47 to enable phagocytosis. PATIENTS AND METHODS: Adult patients with solid tumors were treated in four cohorts: part A, to determine a priming dose; part B, to determine a weekly maintenance dose; part C, to study a loading dose in week 2; and a tumor biopsy cohort. RESULTS: Sixty-two patients were treated: 11 in part A, 14 in B, 22 in C, and 15 in the biopsy cohort. Part A used doses that ranged from 0.1 to 3 mg/kg. On the basis of tolerability and receptor occupancy studies that showed 100% CD47 saturation on RBCs, 1 mg/kg was selected as the priming dose. In subsequent groups, patients were treated with maintenance doses that ranged from 3 to 45 mg/kg, and most toxicities were mild to moderate. These included transient anemia (57% of patients), hemagglutination on peripheral blood smear (36%), fatigue (64%), headaches (50%), fever (45%), chills (45%), hyperbilirubinemia (34%), lymphopenia (34%), infusion-related reactions (34%), and arthralgias (18%). No maximum tolerated dose was reached with maintenance doses up to 45 mg/kg. At doses of 10 mg/kg or more, the CD47 antigen sink was saturated by 5F9, and a 5F9 half-life of approximately 13 days was observed. Strong antibody staining of tumor tissue was observed in a patient at 30 mg/kg. Two patients with ovarian/fallopian tube cancers had partial remissions for 5.2 and 9.2 months. CONCLUSION: 5F9 is well tolerated using a priming dose at 1 mg/kg on day 1 followed by maintenance doses of up to 45 mg/kg weekly.

Two phase I, pharmacokinetic, and pharmacodynamic studies of DFP-10917, a novel nucleoside analog with 14-day and 7-day continuous infusion schedules.

Purpose DFP-10917 is a novel deoxycytidine analog with a unique mechanism of action. Brief exposure to high concentrations of DFP-10917 inhibits DNA polymerase resulting in S-phase arrest, while prolonged exposure to DFP-10917 at low concentration causes DNA fragmentation, G2/M-phase arrest, and apoptosis. DFP-10917 demonstrated activity in tumor xenografts resistant to other deoxycytidine analogs. Experimental design Two phase I studies assessed the safety, pharmacokinetic, pharmacodynamic and preliminary efficacy of DFP-10917. Patients with refractory solid tumors received DFP-10917 continuous infusion 14-day on/7-day off and 7-day on/7-day off. Enrollment required age > 18 years, ECOG Performance Status 0-2 and adequate organ function. Results 29 patients were dosed in both studies. In 14-day infusion, dose-limiting toxicities (DLT) consisting of febrile neutropenia and thrombocytopenia occurred at 4.0 mg/m2/day. At 3.0 mg/m2/day, 3 patients experienced neutropenia in cycle 2. The dose of 2.0 mg/m2/day was well tolerated in 6 patients. In 7-day infusion, grade 4 neutropenia was DLT at 4.0 mg/m2/day. The maximum tolerated dose was 3 mg/m2/day. Other toxicities included nausea, vomiting, diarrhea, neutropenia, and alopecia. Eight patients had stable disease for >12 weeks. Paired comet assays performed for 7 patients showed an increase in DNA strand breaks at day 8. Pharmacokinetic data showed dose-proportionality for steady-state concentration and AUC of DFP-10917 and its primary metabolite. Conclusion Continuous infusion of DFP-10917 is feasible and well tolerated with myelosuppression as main DLT. The recommended doses are 2.0 mg/m2/day and 3.0 mg/m2/day on the 14-day and 7-day continuous infusion schedules, respectively. Preliminary activity was suggested. Pharmacodynamic data demonstrate biological activity at the tested doses.

Therapeutic Targeting of the Macrophage Immune Checkpoint CD47 in Myeloid Malignancies.

In recent years, immunotherapies have been clinically investigated in AML and other myeloid malignancies. While most of these are focused on stimulating the adaptive immune system (including T cell checkpoint inhibitors), several key approaches targeting the innate immune system have been identified. Macrophages are a key cell type in the innate immune response with CD47 being identified as a dominant macrophage checkpoint. CD47 is a "do not eat me" signal, overexpressed in myeloid malignancies that leads to tumor evasion of phagocytosis by macrophages. Blockade of CD47 leads to engulfment of leukemic cells and therapeutic elimination. Pre-clinical data has demonstrated robust anti-cancer activity in multiple hematologic malignancies including AML and myelodysplastic syndrome (MDS). In addition, clinical studies have been underway with CD47 targeting agents in both AML and MDS as monotherapy and in combination. This review will describe the role of CD47 in myeloid malignancies and pre-clinical data supporting CD47 targeting. In addition, initial clinical data of CD47 targeting in AML/MDS will be reviewed, and including the first-in-class anti-CD47 antibody magrolimab.

CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin's Lymphoma.

BACKGROUND: The Hu5F9-G4 (hereafter, 5F9) antibody is a macrophage immune checkpoint inhibitor blocking CD47 that induces tumor-cell phagocytosis. 5F9 synergizes with rituximab to eliminate B-cell non-Hodgkin's lymphoma cells by enhancing macrophage-mediated antibody-dependent cellular phagocytosis. This combination was evaluated clinically. METHODS: We conducted a phase 1b study involving patients with relapsed or refractory non-Hodgkin's lymphoma. Patients may have had diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma. 5F9 (at a priming dose of 1 mg per kilogram of body weight, administered intravenously, with weekly maintenance doses of 10 to 30 mg per kilogram) was given with rituximab to determine safety and efficacy and to suggest a phase 2 dose. RESULTS: A total of 22 patients (15 with DLBCL and 7 with follicular lymphoma) were enrolled. Patients had received a median of 4 (range, 2 to 10) previous therapies, and 95% of the patients had disease that was refractory to rituximab. Adverse events were predominantly of grade 1 or 2. The most common adverse events were anemia and infusion-related reactions. Anemia (an expected on-target effect) was mitigated by the strategy of 5F9 prime and maintenance dosing. Dose-limiting side effects were rare. A selected phase 2 dose of 30 mg of 5F9 per kilogram led to an approximate 100% CD47-receptor occupancy on circulating white and red cells. A total of 50% of the patients had an objective (i.e., complete or partial) response, with 36% having a complete response. The rates of objective response and complete response were 40% and 33%, respectively, among patients with DLBCL and 71% and 43%, respectively, among those with follicular lymphoma. At a median follow-up of 6.2 months among patients with DLBCL and 8.1 months among those with follicular lymphoma, 91% of the responses were ongoing. CONCLUSIONS: The macrophage checkpoint inhibitor 5F9 combined with rituximab showed promising activity in patients with aggressive and indolent lymphoma. No clinically significant safety events were observed in this initial study. (Funded by Forty Seven and the Leukemia and Lymphoma Society; ClinicalTrials.gov number, NCT02953509 .).

Population pharmacokinetic analysis of oxaliplatin in adults and children identifies important covariates for dosing.

PURPOSE: To characterize the determinants of variability for oxaliplatin pharmacokinetics including age, renal function, and hepatic function in children and adults. METHODS: Oxaliplatin pharmacokinetic data were combined from phase I and II clinical trials: three pediatric trials (Peds1-3) and two adult NCI organ dysfunction studies (Hepatic and Renal). A population pharmacokinetic model was developed utilizing platinum ultrafiltrate concentrations to characterize changes in oxaliplatin disposition with age and organ dysfunction along with other potential sources of oxaliplatin pharmacokinetic variability. RESULTS: A total of 1,508 concentrations from 186 children and adults were used in the study. The data were well described by a three-compartment model. Serum creatinine (SCR) was an independent predictor of clearance (CL) while age was an independent predictor of volume of distribution. Although age was a significant covariate on CL in the univariate analysis, age effects on CL were entirely accounted for by SCR. Gender, hepatic function, and race had no effect on CL or volume of distribution. Median CL values were 0.58 (Hepatic), 0.34 (Renal), 0.78 (Peds1), 0.74 (Peds2), and 0.81 (Peds3) (L/h/kg(0.75)). Monte Carlo simulations of the final model with 130 mg/m(2) yielded median AUC values of: 14.2 (2-6 years), 16.8 (6-12 years), 16.5 (12-18 years), and 17.3 (>18 years) (µg h/mL). CONCLUSIONS: Renal function had the greatest effect on CL with a small age effect seen on the distribution of oxaliplatin. Young pediatric patients had higher CL values than adults as a result of better renal function.

A phase 1, dose-escalation, pharmacokinetic and pharmacodynamic study of BIIB021 administered orally in patients with advanced solid tumors.

PURPOSE: BIIB021 is the first oral, synthetic, non-geldanamycin-based HSP90 inhibitor that showed activity in preclinical models at low nanomolar concentrations. We performed a phase 1 trial of BIIB021 administered to subjects with advanced solid tumors. EXPERIMENTAL DESIGN: Sixty patients received BIIB021 capsules orally on days 1, 4, 8, 11, 15, and 18 of each course in schedule 1, and on days 1, 4, 8, 11, 15, 18, 22, and 25 of each course in schedule 2. The treatment schedules were repeated every 28 days. In addition to determining the MTD, we evaluated pharmacokinetics of BIIB021 and pharmacodynamic effects of BIIB021 [Hsp70, HER2 extracellular domain (HER2-ECD)]. RESULTS: The MTD was 700 mg twice weekly when BIIB021 was dosed for 3 weeks out of each 4-week course. The MTD for continuous dosing regimen was established at 600 mg twice weekly. Gastrointestinal (nausea, vomiting), hot flashes, and neurologic (dizziness) events characterize the safety profile of BIIB021 dosed twice weekly, with events mostly mild or moderate. Plasma exposure to BIIB021 was dose-dependent. Cmax occurred at approximately 90 minutes and t1/2 was approximately 1 hour across dosing cohorts of 25 to 800 mg BIIB021 twice weekly. The biologic activity of BIIB021 was demonstrated in serum, PBMCs, and tumor tissue. Hsp70 levels were increased (>150% from baseline) and serum HER2-ECD was significantly decreased (>15% inhibition from baseline). CONCLUSIONS: BIIB021 twice weekly, given with or without the 1 of 4-week rest period was tolerated in subjects with advanced solid tumors at doses that are pharmacodynamically active.

Utilizing pharmacokinetics/pharmacodynamics modeling to simultaneously examine free CCL2, total CCL2 and carlumab (CNTO 888) concentration time data.

The chemokine ligand 2 (CCL2) promotes angiogenesis, tumor proliferation, migration, and metastasis. Carlumab is a human IgG1κ monoclonal antibody with high CCL2 binding affinity. Pharmacokinetic/pharmacodynamic data from 21 cancer patients with refractory tumors were analyzed. The PK/PD model characterized the temporal relationships between serum concentrations of carlumab, free CCL2, and the carlumab-CCL2 complex. Dose-dependent increases in total CCL2 concentrations were observed and were consistent with shifting free CCL2. Free CCL2 declined rapidly after the initial carlumab infusion, returned to baseline within 7 days, and increased to levels greater than baseline following subsequent doses. Mean predicted half-lives of carlumab and carlumab-CCL2 complex were approximately 2.4 days and approximately 1 hour for free CCL2. The mean dissociation constant (KD ), 2.4 nM, was substantially higher than predicted by in vitro experiments, and model-based simulation revealed this was the major factor hindering the suppression of free CCL2 at clinically viable doses.

Metabolism of patupilone in patients with advanced solid tumor malignancies.

A phase 1, open-label, non-randomized, single center study was conducted to determine the pharmacokinetics, distribution, metabolism, elimination, and mass balance of patupilone in patients with advanced solid tumors. Five patients with advanced solid tumors received 10 mg/m(2) (1.1 MBq) of (14) C-radiolabeled patupilone at cycle 1 as a 20-minute intravenous infusion every 3 weeks until disease progression. Sequential samples of blood/plasma were taken for 3 weeks and urine and fecal samples were collected for seven days after the first dose of patupilone. Patupilone blood levels decreased rapidly after the infusion. The compound showed a large volume of distribution (Vss: 2242 L). The main radiolabeled component in blood was patupilone itself, accompanied by the lactone hydrolysis products that are unlikely to contribute to the pharmacological effect of patupilone. The blood clearance of patupilone was relatively low at 14 L/h. The administered radioactivity dose was excreted slowly (46 % of dose up to 168 h) but ultimately accounted for 91 % of the dose by extrapolation. The fecal excretion of radioactivity was 2-3 times higher than the urinary excretion consistent with hepato-biliary elimination. Three patients had progressive disease and two patients had stable disease as their best response. Patupilone was generally well tolerated in patients with advanced solid tumors with no newly occurring safety events compared to previous clinical studies. In adult solid tumor patients, intravenous radiolabeled patupilone undergoes extensive metabolism with fecal excretion of radioactive metabolites predominating over renal excretion.

Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer.

BACKGROUND: CC-chemokine ligand 2 (CCL2) promotes tumor growth by angiogenesis, macrophage infiltration and tumor invasion, and distant metastasis. Carlumab (CNTO 888) is a human IgG1κ mAb with high affinity and specificity for human CCL2. Preclinical data suggest carlumab may offer clinical benefit to cancer patients. METHODS: In a phase 2, open-label study, patients with metastatic castration-resistant prostate cancer (CRPC) previously treated with docetaxel received a 90-min infusion of 15 mg/kg carlumab q2w. The primary endpoint was response rate: change from baseline in skeletal lesions, extraskeletal lesions, and PSA values. Secondary endpoints included overall response rate (CR + PR) by RECIST, OS, PSA response, safety, pharmacodynamics, pharmacokinetics, immunogenicity. RESULTS: Forty-six patients were treated with 6 median (range 1, 26) doses. One patient had SD >6 months. There were no PSA or RECIST responses. Fourteen (34 %) patients had SD ≥ 3 months. Median OS was 10.2 (95 % CI: 5.2, not estimable) months. Twelve (39 %) patients reported improved pain scores. AEs occurred in 43 (93 %) patients, including 27 (59 %) with grade ≥ 3 AEs. Common grade ≥ 3 AEs were back (11 %) and bone (9 %) pain. Twenty (43 %) patients experienced SAEs, including pneumonia, spinal cord compression, back pain. No patient developed antibodies to carlumab. Steady-state serum concentrations were achieved after 3 repeated doses and were above the 10-µg/mL target concentration. Suppression of free CCL2 serum concentrations was briefly observed following each dose but was not sustained. CONCLUSION: Carlumab was well-tolerated but did not block the CCL2/CCR2 axis or show antitumor activity as a single agent in metastatic CRPC.

Using pharmacokinetic and pharmacodynamic data in early decision making regarding drug development: a phase I clinical trial evaluating tyrosine kinase inhibitor, AEE788.

PURPOSE: In this first-in-human study of AEE788, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), HER-2, and VEGFR-2, a comprehensive pharmacodynamic program was implemented in addition to the evaluation of safety, pharmacokinetics, and preliminary efficacy of AEE788 in cancer patients. EXPERIMENTAL DESIGN: Patients with advanced, solid tumors received escalating doses of oral AEE788 once daily. Primary endpoints were to determine dose-limiting toxicities (DLTs) and maximum-tolerated dose (MTD). A nonlinear model (Emax model) was used to describe the relationship between AEE788 exposure and target-pathway modulation in skin and tumor tissues. RESULTS: Overall, 111 patients were treated (25 to 550 mg/day). DLTs included rash and diarrhea; MTD was 450 mg/day. Effects on biomarkers correlated to serum AEE788 concentrations. The concentration at 50% inhibition (IC(50)) for EGFR in skin (0.033 µmol/L) and tumor (0.0125 µmol/L) were similar to IC(50) in vitro suggesting skin may be surrogate tissue for estimating tumor EGFR inhibition. No inhibition of p-MAPK and Ki67 was observed in skin vessels at ≤ MTD. Hence, AEE788 inhibited EGFR, but not VEGFR, at doses ≤ MTD. A total of 16 of 96 evaluable patients showed a >10% shrinkage of tumor size; one partial response was observed. CONCLUSION: Our pharmacodynamic-based study showed effective inhibition of EGFR, but not of VEGFR at tolerable AEE788 doses. Emax modeling integrated with biomarker data effectively guided real-time decision making in the early development of AEE788. Despite clinical activity, target inhibition of only EGFR led to discontinuation of further AEE788 development.

Pharmacokinetics and safety of bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction: phase I NCI Organ Dysfunction Working Group Study NCI-6432.

PURPOSE: The proteasome inhibitor bortezomib undergoes oxidative hepatic metabolism. This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations. EXPERIMENTAL DESIGN: Patients received bortezomib on days 1, 4, 8, and 11 of 21-day cycles. Patients were assigned to four hepatic function groups based on the National Cancer Institute Organ Dysfunction Working Group classification. Those with normal function received bortezomib at the 1.3 mg/m(2) standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m(2), respectively, up to a 1.3 mg/m(2) maximum. Serial blood samples were collected for 24 hours postdose on days 1 and 8, cycle 1, for bortezomib plasma concentration measurements. RESULTS: Sixty-one patients were treated, including 14 with normal hepatic function and 17, 12, and 18 with mild, moderate, and severe impairment, respectively. Mild hepatic impairment did not alter dose-normalized bortezomib exposure (AUC(0-tlast)) or C(max) compared with patients with normal function. Mean dose-normalized AUC(0-tlast) was increased by approximately 60% on day 8 in patients with moderate or severe impairment. CONCLUSIONS: Patients with mild hepatic impairment do not require a starting dose adjustment of bortezomib. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m(2).

A phase I pharmacokinetic study of bexarotene with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC).

PURPOSE: Preclinical data suggest that the synthetic retinoid bexarotene may be an effective chemopreventive agent and that it may act synergistically in combination with platinum-based chemotherapy. The primary objective of this study was to determine whether repeated doses of bexarotene capsules affect pharmacokinetic parameters of paclitaxel or carboplatin in patients with advanced non-small cell lung cancer. METHODS: Patients received treatment with paclitaxel (200 mg/m(2)) and carboplatin to provide a target AUC of 6 mg min/mL (day 1) every 3 weeks. Continuous oral bexarotene therapy (400 mg/m(2)/day) was initiated on Day 4, and patients started lipid-lowering therapy prior to beginning chemotherapy. Blood sampling to characterize the pharmacokinetic profiles of the chemotherapeutic agents with or without bexarotene was performed during cycle 1 (without concomitant bexarotene) and during cycle 2 (with concomitant bexarotene). RESULTS: An analysis of drug concentration data from 16 patients indicated that bexarotene did not affect the pharmacokinetics of paclitaxel, free carboplatin, or total carboplatin concentrations. However, both maximal plasma concentrations and total exposure of bexarotene increased by 80% in the presence of paclitaxel-carboplatin by an, as of yet, unexplained mechanism. The toxicities observed resembled those of either the chemotherapy regimen or bexarotene alone, and there was no evidence for an enhancement of any drug-related toxicity with the combined treatment. CONCLUSIONS: The administration of bexarotene, paclitaxel, and carboplatin is feasible and safe; however, the increased bexarotene plasma concentrations and exposure warrant further investigation if this combination is to be utilized clinically.

The effect of bexarotene on atorvastatin pharmacokinetics: results from a phase I trial of bexarotene plus chemotherapy in patients with advanced non-small cell lung cancer.

PURPOSE: Bexarotene (Targretin(®) capsules) is a retinoid-X-receptor agonist and an inducer of CYP3A4-mediated metabolism. This phase I trial evaluated the pharmacokinetic (PK) and drug-drug interactions of bexarotene with chemotherapy and a lipid-lowering agent (atorvastatin or fenofibrate). This trial was run in parallel with phase III trials of the combinations to determine whether repeated doses of bexarotene capsules affect the pharmacokinetics (PK) of the chemotherapeutic or the lipid-lowering agents. METHODS: Patients (n = 48) with advanced non-small cell lung cancer were treated with repetitive cycles of either paclitaxel/carboplatin or cisplatin/vinorelbine chemotherapy, bexarotene (400 mg/m(2)/day) administered continuously starting on day 4 of chemotherapy, and a lipid-lowering drug, either atorvastatin or fenofibrate, starting at least 5 days before chemotherapy due to hypertriglyceridemia induced by bexarotene. Extensive plasma sampling to characterize the PK profiles of the lipid-lowering drugs, relevant chemotherapy agents was performed on day 1 (without bexarotene) and during chemotherapy cycles 2 or 3 (with bexarotene). RESULTS: Here, we report the drug-drug interactions between the lipid-lowering agents and bexarotene. Mean atorvastatin clearance and dose-corrected AUC values were reduced by nearly 50% with the addition of concomitant bexarotene. As fenofibrate was less effective at controlling hypertriglyceridemia, too few patients received this agent to make any meaningful conclusions about drug-drug interactions. CONCLUSIONS: A drug-drug interaction was seen in this trial with bexarotene co-administration leading to a significant reduction in the AUC of atorvastatin. The likely mechanism for this interaction is through induction of CYP3A4 by bexarotene given the role of this enzyme in the metabolism of atorvastatin. Knowledge of this interaction is important for optimizing lipid management with atorvastatin for patients receiving bexarotene.

Heat shock proteins: a potential anticancer target.

Heat shock proteins (Hsp) are highly conserved proteins and their expression is dependent on the level of various cellular stresses. Hsp work as a molecular chaperon for several cellular proteins and have cytoprotective roles. Their function is essential for normal cell viability and growth. Hsp90 interacts with proteins mediating cell signaling involved in essential processes such as proliferation, cell cycle control, angiogenesis and apoptosis. The naturally occurring Hsp90 inhibitor geldanamycin (GA) was the first to demonstrate anticancer activity but its significant toxicity profile in pre-clinical models precluded its clinical development. Subsequent, several Hsp90 inhibitors have been developed and underwent clinical development with favorable safety profiles. Several initial clinical studies have shown promising anticancer activity of Hsp90 inhibitors mainly in breast cancer, non small cell lung carcinoma (NSCLC), gastrointestinal stromal tumors (GIST) and various hematological malignancies. The universal involvement of Hsp90 in multiple oncogenic processes makes Hsp90 inhibitors ideal compounds to be explored as a single agent or in combination with other anticancer therapies.

Tesetaxel, a new oral taxane, in combination with capecitabine: a phase I, dose-escalation study in patients with advanced solid tumors.

PURPOSE: This phase I study was conducted primarily to determine the maximum tolerated dose (MTD) of tesetaxel, a novel, orally active, semisynthetic microtubule inhibitor of the taxane class, administered with oral capecitabine to patients with advanced solid tumors. METHODS: During each 21-day cycle, patients were to receive tesetaxel on Day 1 and capecitabine twice daily on Days 1 through 14. The starting dose was tesetaxel 18 mg/m(2) and capecitabine 1,250 mg/m(2)/day. These doses were increased based on tolerability during the first cycle according to the protocol-specified dose-escalation scheme. Response was evaluated every other treatment cycle according to RECIST. Serial blood samples were collected during the first and second cycles to explore possible pharmacokinetic drug interactions. RESULTS: Twenty-seven patients were enrolled and treated. The most frequently reported dose-limiting toxicities were neutropenia and febrile neutropenia, with individual patients experiencing dose-limiting stomatitis and diarrhea. The MTD for the treatment regimen was defined as tesetaxel 27 mg/m(2) and capecitabine 2,500 mg/m(2)/day. The most common ≥ Grade 3 treatment-related adverse events included leukopenia (44% of patients) and neutropenia (41%). Of 22 evaluable patients, the best overall response was stable disease in 82% and progressive disease in 18%. No meaningful pharmacokinetic drug interactions were apparent. CONCLUSIONS: The results of this study demonstrate that these two orally active agents can be combined at the individual MTD of each drug with acceptable toxicity. These data further support the continued clinical development of tesetaxel both as a single agent and in combination with other active cancer therapeutics.

Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study.

PURPOSE: To determine the toxicities, pharmacokinetics, pharmacodynamics, and maximum tolerated dose of bortezomib in patients with renal impairment and to develop dosing guidelines for such a patient population. PATIENTS AND METHODS: Sixty-two adult cancer patients received intravenous bortezomib at 0.7-1.5 mg/m(2) on days 1, 4, 8, and 11 every 3 weeks. Patients were stratified by 24-h creatinine clearance (CrCl) normalized to body surface area (BSA) 1.73 m(2) into five cohorts: normal renal function (≥ 60 ml/min/1.73 m(2)); mild dysfunction (40-59 ml/min/1.73 m(2)); moderate dysfunction (20-39 ml/min/1.73 m(2)); severe dysfunction (<20 ml/min/1.73 m(2)); and dialysis. Dose escalation was planned for the four cohorts with renal dysfunction. Plasma bortezomib concentrations and blood 20S proteasome inhibition were assayed. RESULTS: Bortezomib escalation to the standard 1.3 mg/m(2) dose was well tolerated in all patients with CrCl ≥ 20 ml/min/1.73 m(2); 0.7 mg/m(2) was tolerated in three patients with severe renal dysfunction (<20 ml/min/1.73 m(2)). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3 mg/m(2) in four patients. Decreased CrCl did not affect bortezomib pharmacokinetics or pharmacodynamics. Bortezomib-related side-effects were neither more common nor severe in patients with renal dysfunction versus those with normal renal function. CONCLUSION: Bortezomib 1.3 mg/m(2) is well tolerated, and dose reductions are not necessary in patients with renal dysfunction. Extrapolation from clinical and pharmacologic data suggests patients with severe renal dysfunction, including dialysis patients, can receive bortezomib at the full dose established to be clinically effective in the general patient population.

Phase I study of E7820, an oral inhibitor of integrin alpha-2 expression with antiangiogenic properties, in patients with advanced malignancies.

PURPOSE: This phase I study was conducted to characterize the safety profile, pharmacokinetics, pharmacodynamics, dose-limiting toxicity (DLT), and the maximum-tolerated dose of E7820, a novel oral sulfonamide derivative with antiangiogenic properties, when administered to patients with advanced solid malignancies. PATIENTS AND METHODS: Patients received single daily doses of E7820 orally for 28 days in cycle 1, followed by a 7-day no-treatment period, after which time-uninterrupted daily dosing ensued. The starting dose of E7820 was 10 mg/d, which was increased to 20, 40, 70, 100, and 200 mg/d in cohorts of new patients. RESULTS: Thirty-seven patients [21 male; median age 65 (40-82] were enrolled. At 100 mg/d, 1 patient experienced a DLT consisting of grade 3 neutropenia, thrombocytopenia, and elevated liver enzymes. At the 200-mg dose level, 2 patients experienced grade 4 thrombocytopenia and neutropenia. No partial or complete responses were observed; 8 patients had stable disease (≥ 4 months), including 5 patients with protracted stable disease exceeding 6 months. Mean time to maximum plasma concentration values ranged from 1 to 12 hours, whereas mean terminal half-life values ranged from 5.6 to 8.6 hours. Flow cytometric analysis of platelet integrin α-2 expression showed a sustained greater than 50% decrease beyond day 28 in 3 of 4 patients at 200 mg, whereas moderate (<30%) decreases were observed at 70- and 100-mg dose levels. CONCLUSIONS: The recommended phase II dose of E7820 is 100 mg/d, based on a fasting schedule. E7820 downregulates integrin α-2 expression in surrogate tissues (platelets) and is associated with stable disease in a wide variety of heavily pretreated malignancies.

Effects of patupilone on the pharmacokinetics and pharmacodynamics of warfarin in patients with advanced malignancies: a phase I clinical trial.

Patupilone is a novel microtubule-targeting cytotoxic agent, which exerts its antitumor effect through microtubule stabilization. Pharmacokinetics, pharmacodynamics, and safety of warfarin when administered concomitantly with patupilone were investigated, and antitumor activity was assessed. This was a phase I, two-center, drug-drug interaction study. In the core phase of the study, treatment consisted of warfarin 20 mg orally (days 1 and 29) and patupilone 10 mg/m(2) i.v. (days 8 and 29). Patients benefiting from patupilone treatment continued treatment every 3 weeks (extension phase) until progression of disease, death, or unacceptable toxicity. Seventeen patients were treated (core phase, 17; extension, 9). The geometric mean ratios (comedication/monotherapy) for C(max) and area under the curve(0-168) of warfarin were near unity and their 90% confidence intervals were within the equivalence limits of 0.80 and 1.25. The half-life, plasma clearance, and International Normalized Ratio (INR) of warfarin were not affected by patupilone coadministration. The most common adverse events were diarrhea, nausea, vomiting, abdominal pain, anorexia, dehydration, asthenia, and peripheral neuropathy. Five (29.4%) patients experienced grade 3 study drug-related adverse events (diarrhea, 17.6%; increased INR, 11.8%; dehydration, 5.9%; and neutropenia, 5.9%). One patient with triple-negative breast cancer (estrogen receptor, progesterone receptor, and HER2/neu negative) had a partial response (35% decrease in tumor measurements by Response Evaluation Criteria in Solid Tumors), and 11 had stable disease for 6 weeks or more (≥12 weeks, 6 patients). The pharmacokinetics and pharmacodynamics of warfarin were not affected by patupilone coadministration, suggesting that patupilone has no clinically relevant effect on CYP2C9 metabolism. Patupilone showed antitumor activity in triple-negative breast cancer.

Phase 1 study of AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, in combination with chemotherapy in adults with advanced solid tumors.

PURPOSE: To evaluate the safety, pharmacokinetics, and antitumor activity of AMG 386, an investigational selective angiopoietin 1/2-neutralizing peptibody, in combination with FOLFOX-4 (F), carboplatin/paclitaxel (C/P), or docetaxel (D), in adult patients with advanced solid tumors. EXPERIMENTAL DESIGN: Three cohorts of patients (F, n = 6; C/P, n = 8; D, n = 12) received one full cycle of chemotherapy alone during the pretreatment phase, followed by administration of AMG 386 10 mg/kg i.v. weekly in combination with chemotherapy until disease progression or intolerance. Safety and tolerability, tumor response, pharmacokinetic profiles, and biomarkers were assessed. RESULTS: Twenty-six patients were enrolled; 22 received treatment with AMG 386. No dose-limiting toxicities or grade 3 or 4 adverse events related to AMG 386 were reported. The most common adverse events were diarrhea and hypomagnesemia (n = 3 each). One patient developed grade 2 hypertension and one had grade 1 subconjunctival eye hemorrhage. No neutralizing antibodies to AMG 386 were detected. There were no pharmacokinetic interactions between AMG 386 and F, C/P, or D. One patient receiving AMG 386 plus C/P for bladder cancer refractory to gemcitabine/cisplatin had a complete response at week 8. The remaining best tumor responses were partial response (n = 3, one from each cohort), stable disease > or =8 weeks (n = 13), and progressive disease (n = 1). CONCLUSIONS: Weekly administration of AMG 386 in combination with three common chemotherapy regimens was well tolerated in patients with advanced solid tumors. No pharmacokinetic interactions between AMG 386 and any of the tested chemotherapy regimens were noted. Promising antitumor activity was observed with all three treatment combinations.