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1.  Pharmacokinetics and Safety of Bortezomib in Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction: Phase 1 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.
Methods
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/m2 standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m2, respectively, up to a 1.3 mg/m2 maximum. Serial blood samples were collected for 24 hours post-dose 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 (AUC0-tlast) or Cmax compared with patients with normal function. Mean dose-normalized AUC0-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/m2.
doi:10.1158/1078-0432.CCR-11-2873
PMCID: PMC3834726  PMID: 22394984
Bortezomib; hepatic impairment; pharmacokinetics; cytochrome P450 enzymes; metabolism
2.  Phase I Study of Folate Conjugate EC145 (Vintafolide) in Patients With Refractory Solid Tumors 
Journal of Clinical Oncology  2012;30(32):4011-4016.
Purpose
EC145 (vintafolide), a conjugate of folic acid and the vinca alkaloid desacetylvinblastine hydrazide (DAVLBH), is a ligand for the folate receptor (FR), with activity against FR-positive tumor xenografts in vivo. This phase I study determined the maximum-tolerated dose (MTD) of EC145 administered as a bolus intravenous injection or 1-hour infusion in patients with refractory solid tumors.
Patients and Methods
EC145 was administered as a bolus injection or 1-hour infusion on days 1, 3, and 5 and days 15, 17, and 19 of each 28-day cycle with dose escalation in cohorts of three to six patients until the MTD was identified. Plasma pharmacokinetics were determined on days 1 and 3 of the first cycle.
Results
The MTD of EC145 was 2.5 mg when administered as either a bolus injection or 1-hour infusion. Constipation was the dose-limiting toxicity with both routes. Constipation, nausea, fatigue, and vomiting were the most commonly reported adverse events. One partial response to therapy was observed in a patient with metastatic ovarian cancer.
Conclusion
EC145 administered by bolus injection or as a 1-hour infusion at a dose of 2.5 mg on days 1, 3, and 5 and days 15, 17, and 19 of a 28-day cycle has an acceptable safety profile in patients with advanced cancer. On the basis of these findings, phase II studies of EC145 have been initiated in patients with advanced epithelial ovarian cancer and non–small-cell lung cancer.
doi:10.1200/JCO.2011.41.4946
PMCID: PMC4104289  PMID: 23032618
3.  The intersection of immune-directed and molecularly targeted therapy in advanced melanoma: Where we have been, are, and will be 
In three years, four drugs have gained regulatory approval for the treatment of metastatic and unresectable melanoma with at least seven other drugs having recently completed, currently in, or soon to be in phase III clinical testing. This amazing achievement has been made following a remarkable increase of knowledge in molecular biology and immunology that led to the identification of high-valued therapeutic targets and the clinical development of agents that effectively engage and inhibit these targets. The discovery of either effective molecularly targeted therapies or immunotherapies would have led to dramatic improvements to the standard of care treatment of melanoma. However, through parallel efforts that have showcased the efficacy of small molecule BRAF and MEK inhibitors as well as the immune checkpoint inhibitors, namely ipilimumab and the anti-PD1/PDL1 antibodies (lambrolizumab, nivolumab, MPDL3280), an opportunity exists to transform the treatment of melanoma specifically and cancer generally by exploring rational combinations of molecularly targeted therapies, immunotherapies, and molecular targeted therapies with immunotherapies. This overview presents the historical context to this therapeutic revolution, reviews the benefits and limitations of current therapies, and provides a look ahead at where the field is headed.
doi:10.1158/1078-0432.CCR-13-2151
PMCID: PMC4100326  PMID: 24089441
Melanoma; BRAF inhibitor; MEK inhibitor; PI3K; PD1/PDL1; combined molecular targeted and immunotherapy
4.  AZD1480: A Phase I Study of a Novel JAK2 Inhibitor in Solid Tumors 
The Oncologist  2013;18(7):819-820.
Background.
AZD1480 is a novel agent that inhibits Janus-associated kinases 1 and 2 (JAK1 and JAK2). The primary objective of this phase I study was to investigate the safety and tolerability of AZD1480 when administered as monotherapy to patients with solid tumors.
Methods.
Thirty-eight patients with advanced malignancies were treated at doses of 10–70 mg once daily (QD) and 20–45 mg b.i.d. .
Results.
Pharmacokinetic (PK) analysis revealed rapid absorption and elimination with minimal accumulation after repeated QD or b.i.d. dosing. Exposure increased in a dose-dependent manner from 10–50 mg. Maximum plasma concentration (Cmax) was attained ∼1 hour after dose, and t1/2 was ∼5 hours. Pharmacodynamic analysis of circulating granulocytes demonstrated maximum phosphorylated STAT3 (pSTAT3) inhibition 1–2 hours after dose, coincident with Cmax, and greater pSTAT3 inhibition at higher doses. The average pSTAT3 inhibition in granulocytes at the highest dose tested, 70 mg QD, was 56% (standard deviation: ±21%) at steady-state drug levels. Dose-limiting toxicities (DLTs) consisted of pleiotropic neurologic adverse events (AEs), including dizziness, anxiety, ataxia, memory loss, hallucinations, and behavior changes. These AEs were generally reversible with dose reduction or treatment cessation.
Conclusions.
Whether the DLTs were due to inhibition of JAK-1/2 or to off-target effects is unknown. The unusual DLTs and the lack of clinical activity led to discontinuation of development.
doi:10.1634/theoncologist.2013-0198
PMCID: PMC3720635  PMID: 23847256
6.  Theoretical and Practical Application of Traditional and Accelerated Titration Phase I Clinical Trial Designs: The Wayne State University Experience 
Journal of biopharmaceutical statistics  2009;19(3):10.1080/10543400902800460.
The traditional and accelerated titration (AT) designs are two frequently utilized Phase I clinical trial designs. Although each design has theoretical advantages and disadvantages, a summary of the practical application of these theories has not been reported. We report our center's experience in evaluating novel agents using both types of Phase I trial designs over a 13-year period. Results from nine Phase I clinical trials of multiple cytotoxic agents conducted at Wayne State University/Karmanos Cancer Institute in Detroit, MI, and published from 1995–2005 were analyzed for this report. Parameters analyzed included the number of patients, the number of dose levels, the total time to completion of the study, and adverse events. The mean number of patients treated on four Phase I trials using the traditional Phase I trial design was 34 compared to a mean of 23.8 patients treated on five Phase I trials using the AT schema. The mean number of dose levels in patients treated using the traditional Phase I trial design was 8.8 (range 7–11) compared to a mean of 10.6 (range 7–15) dose levels using the AT design. The mean length of study time (25–26 months) was similar in both trial designs. The theoretical advantages and disadvantages of both Phase I trial designs did not readily emerge in their actual application in clinical trials conducted at our institution.
doi:10.1080/10543400902800460
PMCID: PMC3859298  PMID: 19384685
Accelerated design; Phase I clinical trials; Traditional design
7.  Implications of Plasma Protein Binding for Pharmacokinetics and Pharmacodynamics of the γ-Secretase Inhibitor RO4929097 
Purpose
Understanding of plasma protein binding will provide mechanistic insights into drug interactions or unusual pharmacokinetic properties. This study investigated RO4929097 binding in plasma and its implications for the pharmacokinetics and pharmacodynamics of this compound.
Experimental Design
RO4929097 binding to plasma proteins was determined using a validated equilibrium dialysis method. Pharmacokinetics of total and unbound RO4929097 was evaluated in eight patients with breast cancer receiving RO4929097 alone and in combination with the Hedgehog inhibitor GDC-0449. The impact of protein binding on RO4929097 pharmacodynamics was assessed using an in vitro Notch cellular assay.
Results
RO4929097 was extensively bound in human plasma, with the total binding constant of 1.0 × 106 and 1.8 × 104 L/mol for α1-acid glycoprotein (AAG) and albumin, respectively. GDC-0449 competitively inhibited RO4929097 binding to AAG. In patients, RO4929097 fraction unbound (Fu) exhibited large intra- and interindividual variability; GDC-0449 increased RO4929097 Fu by an average of 3.7-fold. Concomitant GDC-0449 significantly decreased total (but not unbound) RO4929097 exposure. RO4929097 Fu was strongly correlated with the total drug exposure. Binding to AAG abrogated RO4929097 in vitro Notch-inhibitory activity.
Conclusions
RO4929097 is highly bound in human plasma with high affinity to AAG. Changes in plasma protein binding caused by concomitant drug (e.g., GDC-0449) or disease states (e.g., ↑AAG level in cancer) can alter total (but not unbound) RO4929097 exposure. Unbound RO4929097 is pharmacologically active. Monitoring of unbound RO4929097 plasma concentration is recommended to avoid misleading conclusions on the basis of the total drug levels.
doi:10.1158/1078-0432.CCR-11-2684
PMCID: PMC3856649  PMID: 22351688
8.  A phase II study of 17-allylamino-17-demethoxygeldanamycin in metastatic or locally advanced, unresectable breast cancer 
Breast cancer research and treatment  2011;131(3):10.1007/s10549-011-1866-7.
Heat shock protein 90 (Hsp90) is an attractive target for breast cancer treatment, as it is required for the proper folding and stabilization of several proteins known to be involved in breast cancer growth and development. These proteins include the epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), progesterone receptor (PR), and src. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is an intravenous Hsp90 inhibitor in development for breast cancer treatment. We conducted a phase II study of 17-AAG 220 mg/m2 on days 1, 4, 8, and 11 every 21 days in patients with metastatic and locally advanced breast cancer. Since we expected the molecular effects of Hsp90 inhibition to extend beyond just ER, PR, and HER2 down regulation and to impact a variety of other cellular proteins, patients were not selected based on ER, PR, or HER2 status. Eleven patients, including 6 patients with triple negative breast cancer, were enrolled and treated. There were no responses and 3 patients had stable disease as their best response. Five patients developed grade 3/4 toxicities, which were primarily hepatic and pulmonary. Based on these results, we do not recommend further study of 17-AAG at this dosing schedule or in unselected breast cancer patients.
doi:10.1007/s10549-011-1866-7
PMCID: PMC3839045  PMID: 22083229
17-AAG; 17-allylamino-17-demethoxygeldanamycin; Breast cancer; Hsp90; Heat shock protein 90
9.  Phase I dose-escalation study of the thioxanthone SR271425 administered intravenously once every 3 weeks in patients with advanced malignancies 
Investigational new drugs  2008;26(4):347-354.
Summary
This study was performed to determine the dose limiting toxicity (DLT), the recommended phase II dose and the pharmacokinetic profile for SR271425, given over 1 h every 3 weeks. The initial starting dose of SR271425 was 17 mg/m2. Patient selection was based on common phase I criteria as well as additional cardiac criteria. Thirty-eight patients were accrued to 16 dose levels from 17 to 1,320 mg/m2. Patient characteristics included 24 males and 14 females ages 35–78 with an Eastern Cooperative Oncology Group performance status of 0 (ten patients), 1 (27) and 2 (1). Tumor types were typical for a phase I study. The maximum administered dose was 1,320 mg/m2 with two DLTs, both QTc grade 3 prolongation. No drug related hematological toxicity was noted. Grade 1 toxicities included rash, flushing, pruritus, weight loss, diarrhea, hypertension and fatigue. Grade 2 toxicities included yellow discoloration of the skin, nausea and vomiting. QTc prolongation and hyperbilirubinemia were the only grade 3 toxicities noted. No confirmed tumor response was observed; however, two patients had prolonged stable disease. Both Cend and area under the plasma concentration– time curve increased in a dose related manner. Plasma drug concentrations declined in a biphasic manner with a mean terminal elimination half-life (t1/2) of 7.1 h (±1.3). There was no change in clearance or volume of distribution over the dose range studied. Due to cardiac toxicity occurring with both the parent compound, SR233377, as well as this analog, this series of agents was abandoned from further clinical development.
doi:10.1007/s10637-008-9135-2
PMCID: PMC3771109  PMID: 18449472
Thioxanthone; SR271425; QTc prolongation
10.  Pharmacokinetics of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Locally Advanced or Metastatic Solid Tumors: the Role of Alpha-1-Acid Glycoprotein Binding 
Purpose
In a phase I trial for patients with refractory solid tumors, hedgehog pathway inhibitor vismodegib (GDC-0449) showed little decline in plasma concentrations over 7 days after a single oral dose and nonlinearity with respect to dose and time after single and multiple dosing. We studied the role of GDC-0449 binding to plasma protein alpha-1-acid glycoprotein (AAG) to better understand these unusual pharmacokinetics.
Experimental Design
Sixty-eight patients received GDC-0449 at 150 (n = 41), 270 (n = 23), or 540 (n = 4) mg/d, with pharmacokinetic (PK) sampling at multiple time points. Total and unbound (dialyzed) GDC-0449 plasma concentrations were assessed by liquid chromatography/tandem mass spectrometry, binding kinetics by surface plasmon resonance–based microsensor, and AAG levels by ELISA.
Results
A linear relationship between total GDC-0449 and AAG plasma concentrations was observed across dose groups (R2 = 0.73). In several patients, GDC-0449 levels varied with fluctuations in AAG levels over time. Steady-state, unbound GDC-0449 levels were less than 1% of total, independent of dose or total plasma concentration. In vitro, GDC-0449 binds AAG strongly and reversibly (KD = 13 μmol/L) and human serum albumin less strongly (KD = 120 μmol/L). Simulations from a derived mechanistic PK model suggest that GDC-0449 pharmacokinetics are mediated by AAG binding, solubility-limited absorption, and slow metabolic elimination.
Conclusions
GDC-0449 levels strongly correlated with AAG levels, showing parallel fluctuations of AAG and total drug over time and consistently low, unbound drug levels, different from previously reported AAG-binding drugs. This PK profile is due to high-affinity, reversible binding to AAG and binding to albumin, in addition to solubility-limited absorption and slow metabolic elimination properties.
doi:10.1158/1078-0432.CCR-10-2736
PMCID: PMC3703823  PMID: 21300760
11.  Sunitinib in combination with paclitaxel plus carboplatin in patients with advanced solid tumors: phase I study results 
Purpose
To evaluate the maximum tolerated dose (MTD), safety, and antitumor activity of sunitinib combined with paclitaxel and carboplatin.
Methods
Successive cohorts of patients with advanced solid tumors received oral sunitinib (25, 37.5, or 50 mg) for 2 consecutive weeks of a 3-week cycle (Schedule 2/1) or as a continuous daily dose for 3-week cycles (CDD schedule) in combination with paclitaxel (175–200 mg/m2) plus carboplatin (AUC 6 mg•min/mL) on day 1 of each of 4 cycles. Dose-limiting toxicities (DLTs) and adverse events (AEs) were evaluated to determine the MTD. Efficacy parameters were analyzed in patients with measurable disease.
Results
Forty-three patients were enrolled (n = 25 Schedule 2/1; n = 18 CDD schedule). Across all doses, 6 DLTs were observed (grade 4 papilledema, grade 5 GI hemorrhage, grade 3 neutropenic infection, grade 4 thrombocytopenia [n = 3]). The MTD for Schedule 2/1 was sunitinib 25 mg plus paclitaxel 175 mg/m2 and carboplatin AUC 6 mg•min/mL. The MTD was not determined for the CDD schedule. Treatment-related AEs included neutropenia (77%), thrombocytopenia (56%), and fatigue (47%). Of 38 evaluable patients, 4 (11%) had partial responses and 12 (32%) had stable disease. PK data indicated an increase in maximum and total plasma exposures to sunitinib and its active metabolite when given with paclitaxel and carboplatin compared with sunitinib monotherapy.
Conclusions
Myelosuppression resulting in prolonged dose delays and frequent interruptions was observed, suggesting that this treatment combination is not feasible in the general cancer population.
doi:10.1007/s00280-010-1536-1
PMCID: PMC3400085  PMID: 21140147
Sunitinib; Phase I; Solid tumor; NSCLC; Antiangiogenesis; Chemotherapy
12.  Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer 
Cancer Chemotherapy and Pharmacology  2012;69(5):1229-1240.
Purpose
Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab and DM1, a microtubule polymerization inhibitor, covalently bound via a stable thioether linker. To characterize the pharmacokinetics (PK) of T-DM1 in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, data from four studies (TDM3569g, TDM4258g, TDM4374g, and TDM4688g) of single-agent T-DM1 administered at 3.6 mg/kg every 3 weeks (q3w) were assessed in aggregate.
Methods
Multiple analytes—T-DM1, total trastuzumab (TT), DM1, and key metabolites—were quantified using enzyme-linked immunosorbent assays or liquid chromatography tandem mass spectrometry. PK parameters of T-DM1, TT, and DM1 exposure were calculated using standard noncompartmental approaches and correlated to efficacy (objective response rate) and safety (platelet counts, hepatic transaminase concentrations). Immunogenicity was evaluated by measuring anti-therapeutic antibodies (ATA) to T-DM1 after repeated dosing using validated bridging antibody electrochemiluminescence or enzyme-linked immunosorbent assays.
Results
PK parameters for T-DM1, TT, and DM1 were consistent across studies at cycle 1 and steady state. T-DM1 PK was not affected by residual trastuzumab from prior therapy or circulating extracellular domain of HER2. No significant correlations were observed between T-DM1 exposure and efficacy, thrombocytopenia, or increased concentrations of transaminases. Across the studies, ATA formation was detected in 4.5% (13/286) of evaluable patients receiving T-DM1 q3w.
Conclusions
The PK profile of single-agent T-DM1 (3.6 mg/kg q3w) is predictable, well characterized, and unaffected by circulating levels of HER2 extracellular domain or residual trastuzumab. T-DM1 exposure does not correlate with clinical responses or key adverse events.
doi:10.1007/s00280-011-1817-3
PMCID: PMC3337408  PMID: 22271209
Trastuzumab emtansine; T-DM1; Breast cancer; HER2; Antibody–drug conjugate; Medicine & Public Health; Pharmacology/Toxicology; Cancer Research; Oncology
13.  Participation and survival of geriatric patients in Phase I clinical trials: the Karmanos Cancer Institute (KCI) experience. 
Journal of geriatric oncology  2011;2(1):18-24.
Background
Geriatric cancer patients (age 65 or older) comprise a majority of cancer cases in the United States, yet they are underrepresented in therapeutic clinical trials. It is therefore important to increase our understanding of their participation, survival outcomes, and recruitment barriers. This study aims to describe the demographics, treatment, toxicity, and overall survival (OS) of all patients ≥ 65 years of age who presented to the Phase I Clinical Trials service at Karmanos Cancer Institute (KCI).
Methods
A retrospective chart review was performed of all referred and seen patients ≥ 65 years of age at Phase I clinical service at KCI between 1995-2005. Data on demographics, co-morbidities, tumor type, reason not enrolled, toxicities and OS were obtained.
Results
A total of 216 patients met the study criteria. The median age was 71 years. 114 (59%) patients were performance status 1. 102 (47%) patients were enrolled and of those 95 (44%) patients were treated. More than half of the patients failed to enroll with predominant reasons being protocol ineligibility (30%), loss to follow up (12%), patient refusal (8%), or unavailability of trial (2%). The median OS duration of treated patients was 8.4 months (95% CI: 6.2-10.5). This was significantly longer than the patients who failed to enroll or did not receive treatment (p < 0.0001).
Conclusion
This study suggests that elderly patients who were treated on a Phase I clinical trial(s) at our institution survived significantly longer than our elderly patients who did not receive treatment.
doi:10.1016/j.jgo.2010.09.004
PMCID: PMC3077761  PMID: 21503272
Elderly; Phase I clinical Trials; Barriers; Survival
14.  SAFETY, EFFICACY, PHARMACOKINETICS AND PHARMACODYNAMICS OF THE COMBINATION OF SORAFENIB AND TANESPIMYCIN 
PURPOSE
Heat shock protein 90 inhibition affects the Raf-kinase signaling pathway and could enhance anti-tumor effects of sorafenib, a Raf-kinase inhibitor. The combination of sorafenib and tanespimycin (17-AAG/17-allyl-amino-geldanamycin; NSC # 330507/KOS-953) was evaluated in a phase I trial with the primary objective of defining a phase II dose
PATIENTS AND METHODS
The dose cohorts consisted of fixed continuous oral dosing of sorafenib 400 mg twice daily, starting 14 days prior to tanespimycin which was administered intravenously, at escalating doses, (starting at 300 mg/m,2 with 50 mg/m2 increments), on days 1, 8 and 15, in a 28-day cycle. Toxicity was assessed weekly; response was evaluated every 2 cycles.
RESULTS
Twenty-seven toxicity-evaluable patients were enrolled and treated at four dose levels. Predominant primary malignancies were: renal cancer (12), melanoma (6) and colorectal cancer (4). Dose-limiting toxicities of grade 4 transaminitis and grade 3 hand-foot syndrome in 1 patient each were observed at 450 mg/m2 of tanespimycin. 114 cycles were administered with a median of four cycles (range 1–17 cycles). Plasma concentrations of sorafenib and metabolites reached steady-state after 7 days. Tanespimycin did not alter sorafenib concentrations. Pharmacodynamics showed a decrease in Hsp90 levels and induction of Hsp70. Clinical efficacy was observed in 9 of 12 renal cancer patients and 4 of 6 melanoma patients
CONCLUSIONS
Recommended phase II doses of this combination are sorafenib 400 mg twice daily and tanespimycin 400 mg/m2 on days 1, 8 and 15 every 28 days. Clinical and pharmacodynamic activity was observed in kidney cancer and melanoma.
doi:10.1158/1078-0432.CCR-10-0503
PMCID: PMC2909581  PMID: 20525756
Heat shock protein inhibitors; sorafenib; 17-AAG; tanespimycin; KOS-953; renal cancer; melanoma; phase I clinical trial

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