Advanced Solid Tumor Malignancies Research Articles

Increase in blood pressure with sorafenib exposure: Renal cell carcinoma (RCC) versus other solid tumors.

e15564 Background: Tyrosine kinase inhibitors (TKIs) such as sorafenib are widely used in the treatment of solid tumor malignancies. Incident hypertension with angiogenesis inhibitors has been well-documented in the RCC where incident hypertension on treatment is associated with improved clinical outcome. Little has been reported about increases in (BP) with TKIs in other solid tumor malignancies. Methods: We performed a retrospective cohort study examining changes in BP with sorafenib among the 101 patients treated at the University of Pennsylvania on a randomized discontinuation trial examining sorafenib in patients with advanced solid tumor malignancies. Solid tumor diagnoses were established on the basis of tumor histology. Treatment of patients on study with sorafenib was initiated at 400 mg BID. Patients were treated for at least 12 weeks and were evaluated at least every three weeks in the clinic. BP was recorded at each visit. Sorafenib exposure was recorded by patients in a pill diary. The primary endpoint for this study was a maximal change in BP defined as the difference between baseline BP and highest subsequent recorded systolic and diastolic BPs on treatment. Results: 72% of RCC patients developed an increase in systolic BP (SBP) of at least 20 mmHg as compared to 32% of non-RCC patients. The mean increase in SBP on study for RCC patients was 30 mmHg versus 19 mmHg in non-mRCC patients. RCC patients in the top quartile of increased SBP showed a mean increase of 54 mmHg as compared to 35 mmHg for non-mRCC patients. A chi-squared test of proportions and t-tests were used to compare rates and means, respectively. Each of the aforementioned differences were found to be statistically significant with p-values <0.003. These relationships also held true for diastolic BP. There was no difference in SBP between groups in terms of age or sorafenib exposure. Differences in BP were not related to differences in glomerular filtration rate. Conclusions: In these sorafenib-treated patients, the proportion of patients with increased BP and the mean amplitude of change in BP both were significantly greater in the RCC population than in the non-RCC group.

A phase I first-in-human study of REGN910 (SAR307746), a fully human and selective angiopoietin-2 (Ang2) monoclonal antibody (MAb), in patients with advanced solid tumor malignancies.

2517 Background: REGN910 is a selective, fully human Ang2 MAb that potently blocks signaling through the Tie2 receptor regulating tumor angiogenesis and growth. In multiple mouse xenograft models of human solid tumors, REGN910 inhibits tumor growth. Methods: This first-in-human phase I study (3+3 design) explored the safety, recommended phase II dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of REGN910 as a single agent. REGN910 was given IV at escalating doses. At RP2D, expansion cohorts were initiated to confirm safety and assess anti-tumor activity in about 20 patients (pts). Results: 37 pts [17M/20F; median age 57 (range 22-82); ECOG PS 0(9)/1(28)] were enrolled. Twenty-three (23) pts were enrolled in the dose escalation cohorts. No DLTs were reported, and a MTD was not reached. Most common G1/2 treatment-related adverse events (TRAEs) were fatigue 7(19%), peripheral edema 6(17%), diarrhea 5(14%), abdominal distension 4(11%), and decreased appetite 4(11%). There were no ≥ Grade 3 TRAEs. A confirmed sustained PR (16 wks) was observed in 1 pt with adrenocortical cancer treated at 1 mg/kg. SD (range 6.9-46.8 wks) was reported for 17 of 32 (53%) pts evaluable for efficacy. Fourteen pts received treatment >16 wks. One pt with thyroid cancer had SD for 46 wks, and 1 pt with hepatocellular cancer had SD for 16 wks with ≥50% decline in alpha-fetoprotein. Across all dose levels, REGN910 pharmacokinetics appeared linear and dose-proportional. The PK profile was characterized by an initial distribution and a single mono-exponential elimination phase. Total circulating serum Ang2 levels appeared saturated following treatment in all cohorts, indicating systemic target engagement at all doses tested. Conclusions: Administration of REGN910 in patients with advanced cancer is well tolerated, with generally mild and moderate TRAEs. Dose escalation is completed, and enrollment to the expansion cohorts continues. The safety profile supports combination with chemotherapy and/or other anti-angiogenic agents. Clinical trial information: NCT01271972.

A phase Ib study of combined angiogenesis blockade with REGN910 (SAR307746), a selective monoclonal antibody (MAb) against angiopoietin-2 (Ang2) and ziv-aflibercept in patients with advanced solid tumor malignancies.

TPS2618 Background: REGN910 is a selective, fully human Angiopoietin-2 (ANG-2) MAb, which potently blocks signaling through the Tie2 receptor. Ziv-aflibercept (ZAFL) is a recombinant human fusion protein that acts as a decoy receptor for vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PlGF), thereby preventing the interaction of these ligands with their receptors. In several mouse xenograft models, combination of the 2 anti-angiogenic compounds, REGN910 and ZAFL, demonstrated significantly enhanced tumor growth inhibition relative to either agent alone, suggesting that dual angiogenic blockade is worth exploring in cancer patients. Methods: This phase 1b study employs a standard 3+3 dose escalation design exploring 5 different combination treatment dose levels of REGN910 and ZAFL. Once the recommended phase 2 dose (RD) of the combination treatment is determined, additional patients will be enrolled in a safety expansion cohort, for a planned total enrollment of up to 40 patients. The primary study objectives are to evaluate the safety and determine the RD of the 2 drugs in combination when both are administered IV every 2 weeks in patients with advanced solid tumors. Secondary endpoints include characterization of the PK and potential immunogenicity of REGN910 and ZAFL when given in combination, evaluation of correlative PD biomarkers related to REGN910 and ZAFL, and identification of antitumor activity. Enrollment to cohorts 1 and 2 has been completed without DLT. Enrollment to cohort 3 opened in December 2012. Updated enrollment status will be presented. Reference: ClinicalTrials.gov Identifier: NCT01688960. Clinical trial information: NCT01688960.

Abstract LB-86: Preliminary results from an ongoing phase I trial of RRx-001, a tumor selective cytotoxic agent.

Abstract Background and objectives: RRx-001, is the first member of a new class of anticancer compounds that binds to hemoglobin and drives heme and iron-catalyzed redox reactions under hypoxic conditions thereby enhancing oxidative and nitrosative stress in cancer cells through glutathione depletion and the generation of high local concentrations of nitric oxide. The objectives of this Phase 1 dose-escalation trial were to investigate safety, dose-limiting toxicities (DLTs), pharmacodynamics and pharmacokinetics (PK) of RRx-001. Methodology: Eligible patients had advanced solid tumor malignancies; ECOG PS 0-2; adequate bone marrow function. In a 3+3 escalation design, RRx-001 was administered intravenously (IV) for up to 6 hours weekly for 8 weeks to patients with advanced cancer in successive dose-escalating cohorts. PK samples were collected. Tumor response (CT, PET-CT, biopsy) was determined every 4 or 8 weeks. Preliminary Data: 19 pts have been dosed over 5 successive cohorts (10, 16.7, 24.6, 33 and 55 mg/m2). Tumor types included pancreas (3), colorectal (9), head and neck (2), melanoma (1), cholangiocarcinoma (1), uterine (1), lung (1) and HCC (1). RRx-001 has been extremely well tolerated with no DLTs or treatment-associated SAEs observed. The only drug-related adverse event (AEs) across all cohorts was acute and transient injection-site vasodilation and pain on infusion, moderate in severity and generally managed with lengthening of the infusion time, using peripheral venous access and prior administration of corticosteroids. No RRx-001-induced systemic toxicities have been observed to date. 14 patients were evaluable for response, 1 with partial response (parotid tumor). Eight patients had stable disease (3 pancreas, 3 with colorectal cancer, 1 uterine, 1 HCC). Two of these pts (salivary and CRC) have remained stable for 6 and 10 months, respectively, and another 2 pts (uterine and HCC) are continuing stably on trial for >3 months. The pt. with CRC who progressed after 10 months on trial responded to previously failed chemotherapy as evidenced by marked decrease in CEA (511 to 311) and re-stabilization of disease for >3 months. Two patients with pancreatic and CRC had an increase in tumor size with extensive central necrosis suggestive of pseudoprogression. Conclusions: In the ongoing nearly completed Phase 1 trial, RRx-001, an anticancer agent with a novel structure and mechanism of action, is well tolerated with infusion-site pain the only observed AE. Toxicities normally associated with anticancer agents were absent. Single agent activity with a high response rate (64-79%) among patients with advanced, refractory cancer was observed including a renewed response to a previously failed chemotherapy regimen. Phase 2 planning in colorectal cancer and HCC is underway. Citation Format: Tony Reid, Jeffrey R. Infante, Asit Paul, Howard A. Burris, Bryan Oronsky, Curtis Scribner, Susan Knox, Janet Stephens, John Santini, Jan Scicinski. Preliminary results from an ongoing phase I trial of RRx-001, a tumor selective cytotoxic agent. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-86. doi:10.1158/1538-7445.AM2013-LB-86

Increase in blood pressure with sorafenib exposure in renal cell carcinoma versus other solid tumors.

384 Background: Tyrosine kinase inhibitors (TKIs) such as sorafenib are widely used in the treatment of solid tumor malignancies. Incident hypertension with angiogenesis inhibitors has been well-documented in the population of patients with renal cell carcinoma (RCC) where incident hypertension on treatment is associated with improved clinical outcome. Little has been reported about increases in blood pressure with TKIs in other solid tumor malignancies. Methods: We performed a retrospective cohort study examining changes in blood pressure with sorafenib among the 101 patients treated at the University of Pennsylvania on a randomized discontinuation trial examining sorafenib in patients with advanced solid tumor malignancies. Solid tumor diagnoses were established on the basis of tumor histology. Treatment of patients on study with sorafenib was initiated at 400 mg BID. Patients were treated for at least 12 weeks and were evaluated at least every three weeks in the clinic. Blood pressure was recorded at each visit. Sorafenib exposure was recorded by patients in a pill diary. The primary endpoint for this study was a maximal change in blood pressure defined as the difference between baseline blood pressure and highest subsequent recorded systolic and diastolic blood pressures on treatment. Results: 72% of RCC patients developed an increase in systolic blood pressure (SBP) of at least 20 mmHg as compared to 32% of non-RCC patients. The mean increase in SBP on study for RCC patients was 30 mmHg versus 19 mmHg in non-mRCC patients. RCC patients in the top quartile of increased SBP showed a mean increase of 54 mmHg as compared to 35 mmHg for non-mRCC patients. A chi-squared test of proportions and t-tests were used to compare rates and means, respectively. Each of the aforementioned differences were found to be statistically significant with p-values <0.003. These relationships also held true for diastolic blood pressure. There was no difference in SBP between groups in terms of age or sorafenib exposure. Conclusions: In these patients treated with sorafenib the proportion of patients with increased blood pressure and the mean amplitude of change in blood pressure both were significantly greater in the RCC population than in the non-RCC group.

First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies

Patients with advanced solid malignancies were enrolled to an open-label, single-arm, dose-escalation study, in which CRLX101 was administered intravenously over 60 min among two dosing schedules, initially weekly at 6, 12, and 18 mg/m(2) and later bi-weekly at 12, 15, and 18 mg/m(2). The maximum tolerated dose (MTD) was determined at 15 mg/m(2) bi-weekly, and an expansion phase 2a study was completed. Patient samples were obtained for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Response was evaluated per RECIST criteria v1.0 every 8 weeks. Sixty-two patients (31 male; median age 63 years, range 39-79) received treatment. Bi-weekly dosing was generally well tolerated with myelosuppression being the dose-limiting toxicity. Among all phase 1/2a patients receiving the MTD (n = 44), most common grade 3/4 adverse events were neutropenia and fatigue. Evidence of systemic plasma exposure to both the polymer-conjugated and unconjugated CPT was observed in all treated patients. Mean elimination unconjugated CPT Tmax values ranged from 17.7 to 24.5 h, and maximum plasma concentrations and areas under the curve were generally proportional to dose for both polymer-conjugated and unconjugated CPT. Best overall response was stable disease in 28 patients (64 %) treated at the MTD and 16 (73 %) of a subset of NSCLC patients. Median progression-free survival (PFS) for patients treated at the MTD was 3.7 months and for the subset of NSCLC patients was 4.4 months. These combined phase 1/2a data demonstrate encouraging safety, pharmacokinetic, and efficacy results. Multinational phase 2 clinical development of CRLX101 across multiple tumor types is ongoing.

Activity observed in a phase I dose escalation trial of the hypoxia-activated, NO prodrug, RRx001.

241 Background: RRx-001, the first member of a new class of anticancer compounds sourced from the defense industry, is a hypoxia-selective, nitrite reductase-activated prodrug of nitric oxide (NO). The active metabolites selectively enhance oxidative and nitrosative stress in cancer cells through glutathione depletion, ROS formation, and the generation of high local concentrations of NO. The objectives of this Phase 1 dose-escalation trial were to investigate safety, dose-limiting toxicities (DLTs), pharmacodynamics and pharmacokinetics (PK) of RRx-001. Methods: Eligible patients had advanced solid tumor malignancies; ECOG PS 0-2; adequate bone marrow function. In a 3+3 escalation design, RRx-001 was administered intravenously (IV) over 2-3 hours once weekly for 8 weeks to patients with advanced cancer in successive dose-escalating cohorts. PK was collected on days 1 and 50, and tumor blood flow, assessed by CEUS or DCE/DWI-MRI, was performed on days 1 and 8. Tumor response was determined every 8 weeks. Results: To date 12 patients have been dosed across 3 successive cohorts (10, 16.7, and 24.6 mg/m2). Tumor types included pancreas (3), colorectal (5), head and neck (2), melanoma (1), and cholangiocarcinoma (1). No DLTs or treatment-associated SAEs were observed. Transient infusion site pain was reported in 10/12 patients, grade 1 (9/10) or grade 2 (1/10), generally managed by lengthening the infusion duration and using peripheral venous access. No relevant treatment-related changes in laboratory values were observed. Seven patients were evaluable for response, with 1 partial response (parotid tumor). Three patients had stable disease ≥ 2 months (2 pancreas, 1 colorectal with treatment duration 10+ months, exceeding the response to his previous chemo regimen). One pancreas patient with an increase in tumor size due to treatment-related central necrosis was diagnosed with pseudoprogression and remained on study for 4 months. Conclusions: RRx-001, an anticancer agent with a novel structure and mechanism of action, is well tolerated with mild infusion-site pain. PK and PD data will be presented. Escalation is ongoing, but preliminary evidence of anti-tumor activity is promising. Clinical trial information: NCT01359982.

A phase I study of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies

Docetaxel is a taxane anticancer drug used in a wide variety of solid tumors. Liposomes are versatile drug carriers that may increase drug solubility, serve as sustained release systems, provide protection from drug degradation and toxicities, and help overcome multidrug resistance. This phase I study was conducted to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and clinical response of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies. LE-DT was administered using a standard 3 + 3 dose escalation schema with dose levels of 50, 65, 85, 110, and 132 mg/m(2) IV on a 3-week cycle. Toxicities were assessed using the NCI-CTCAE version 3.0, and response was assessed using RECIST criteria (version 1.0). PK samples were drawn during cycle 1 and analyzed using a non-compartmental analysis. Twenty-four patients were treated for 1-30 cycles (median = 4). No DLTs were experienced through dose levels of 50, 65, 85, and 110 mg/m(2). Two out of two patients experienced grade 4 neutropenia at the 132 mg/m(2) dose level. When an additional three patients were treated at the expanded 110 mg/m(2) dose level, two experienced grade 4 neutropenia. The 85 mg/m(2) dose level was reassessed with an expanded group of three additional patients, and only one of three patients experienced grade 4 neutropenia. The protocol was amended to allow G-CSF during cycle 1, and an additional three patients were treated at 110 mg/m(2) with no DLTs experienced. No patient experienced significant neuropathy, even patients treated for 19, 20, and 30 cycles. PK followed a two-compartment elimination pattern; there was no correlation between PK and toxicity. Two patients with thyroid and neuroendocrine cancer had partial responses (PR, 8%), and one patient with non-small-cell lung cancer had an unconfirmed PR. Eight patients (33%) had stable disease lasting more than 3 months, for a clinical benefit rate of 41%. LE-DT was well tolerated with expected toxicities of neutropenia, anemia, and fatigue, but without neuropathy or edema. Clinical benefit (SD + PR) was observed in 41% of the patients. The recommended phase II dose of LE-DT is 85 mg/m(2) without G-CSF or 110 mg/m(2) with G-CSF.

588 A First-in-patient Phase I Study of the Novel Gamma Secretase Inhibitor PF-03084014 in Patients with Advanced Solid Tumor Malignancies

588 A First-in-patient Phase I Study of the Novel Gamma Secretase Inhibitor PF-03084014 in Patients with Advanced Solid Tumor Malignancies

Phase I trial of sunitinib and gemcitabine in patients with advanced solid tumors

Combining cytotoxic agents with bevacizumab has yielded significant benefits in a number of solid tumors. Combining small-molecule kinase inhibitors of VEGFR with chemotherapy has yet to demonstrate clinical benefit. The dose, schedule and agents used may be critical to the development of this combinatorial therapy. We performed a phase I trial of sunitinib and gemcitabine in patients with advanced solid tumor malignancies based on strong preclinical rationale. Two different MTDs were determined. The schedule of gemcitabine 800 mg/m(2) on days 1, 8, 15 and sunitinib 25 mg daily was considered to be a MTD. However, omission of day 15 gemcitabine was common, and thus, a second MTD of gemcitabine of 675 mg/m(2) on days 1 and 8 with sunitinib 25 mg daily was determined to be the recommended phase II dose. Grade 4 neutropenia and thrombocytopenia occurred in 33 and 6 %, respectively. Grade 3/4 non-hematological toxicities were uncommon. Four of 33 patients had a partial response. Another 11 patients had stable disease ranging from 3 to 36 months. Thus, the recommended phase II dose of this combination is gemcitabine 675 mg/m(2) on days 1 and 8 on an every 21-day schedule along with sunitinib 25 mg continuous daily. This combination is well-tolerated and has significant clinical activity.

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.

Population pharmacokinetic/pharmacodynamic modeling of drug-induced adverse effects of a novel homocamptothecin analog, elomotecan (BN80927), in a Phase I dose finding study in patients with advanced solid tumors

To characterize the pharmacokinetic profile of elomotecan, a novel homocamptothecin analog, evaluate the dose-limiting toxicities, and establish the relationship between exposure and toxicity in the first Phase I study in patients with advanced malignant solid tumors. Preliminary antitumor efficacy results are also provided. Elomotecan was administered as a 30-min intravenous infusion at doses ranging from 1.5 to 75mg once every 3weeks to 56 patients with advanced solid tumors. Plasma concentration data and adverse effects were modeled using the population approach. Elomotecan showed linear pharmacokinetics, and clearance was decreased with age. The model predicts a 47 and 61% reduction in CL for patients aged 60 and 80years, respectively, when compared with younger patients (30years). Neutropenia represented the dose-limiting toxicity. The maximum tolerated dose and the recommended dose (RD) were 75 and 60mg, respectively. Elomotecan elicited a 20, 5, 2, and 2% severe (grade 4) neutropenia, asthenia, nausea, and vomiting at the RD, respectively. Of the subjects in the RD cohort, 41.7% had a stable disease mean duration of 123.6±43.4days. The pharmacokinetic parameters and the toxicity pattern of elomotecan suggest that this novel homocamptothecin analog should be further explored in the clinical setting using a dose of 60mg administered as a 30-min intravenous infusion, once every 3weeks.

A phase I and pharmacokinetic study of multiple schedules of ganetespib (STA-9090), a heat shock protein 90 inhibitor, in combination with docetaxel for subjects with advanced solid tumor malignancies.

3094 Background: Ganetespib is a next-generation Hsp90 inhibitor unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has superior activity to these agents in preclinical studies. Ganetespib is well tolerated with promising antitumor activity. Based on synergy between ganetespib (G) and docetaxel (D), a phase I study evaluating preclinical dosing models was performed. Methods: Patients (pts) with advanced solid tumor malignancies and ECOG performance status (PS) 0-2 were eligible. Sequential cohorts of pts were treated (3+3 design) with increasing doses of D (day 1) and G (days 1, 8) (A) Q 21 days. Following MTD determination, safety and exploratory cohorts of D day 1 with G days 1, 15 (B); or G days 1, 4, 15 (C) were completed. PK sampling was performed during schedule A. The primary endpoint was determination of optimal doses and schedule of the two agents for combination therapy. Results: Twenty-seven patients were enrolled in schedules A (n=12), B (n=8), and C (n=7). Median age-64 (44-75); 11-M, 16-F; ECOG PS: 0 (n=5), 1 (n=21), 2 (n=1). Most pts had NSCLC (n=9), others were head/neck (n=4), and SCLC (n=3). The defined MTD was level 2 (D-75 mg/m2, G-150 mg/m2), as 2 of 4 pts at level 3 (D-75 mg/m2, G-200 mg/m2) had DLTs (febrile neutropenia and one g4 neutropenia of > 7 days), requiring expansion of level 2. The median number of cycles received is 2 (1-11), with 3 pts in schedule C still on study. Among 22 pts evaluable for response, 1 had a PR (head/neck), 12 had SD following 6 weeks evaluation, 10 pts for 12 weeks and 6 pts for 18 weeks. Common AEs included neutropenia, diarrhea, anemia, fatigue, nausea, and febrile neutropenia. Prophylactic filgrastim/pegfilgrastim was not used at any time. PK data indicates similar G exposure alone compared to G administered prior to D. No accumulation was observed following once-weekly dosing, consistent with studies of G alone. Conclusions: The combination is well tolerated at the recommended doses of D 75 mg/m2 and G 150 mg/m2. Promising anti-cancer activity was noted, and a randomized phase 2b/3 study with D day 1 and G days 1, 15 regimen is ongoing in advanced NSCLC (NCT01348126).

A validated HPLC assay for the determination of R-(−)-gossypol in human plasma and its application in clinical pharmacokinetic studies

R-(-)-gossypol acetic acid (AT-101), a natural BH3 mimetic, is investigated in a Phase I/II clinical trial for the treatment of advanced solid tumor malignancies. Gossypol undergoes rapid degradation in solution phase, which causes major technical difficulty for its quantitation in plasma. We developed and validated a sensitive HPLC assay for pharmacokinetic evaluation of gossypol. Acetonitrile deproteinization method was chosen for sample preparation and Schiff's base derivative, R-(-)-gossypol-diamino-propanol (GDP), was used as internal standard. Chromatographic separation of gossypol in plasma was performed using a Zorbax Eclipse XDB column C(18) at 30 °C. The mobile phase consists of 10 mmol/L KH(2)PO(4) (pH 3.0) and acetonitrile (20:80) at 1.0 mL/min flow rate. Linearity ranged over 56-3585 ng/mL (R(2)=0.9997±0.0003, n=4), and the limit of detection was 28 ng/mL. The intra- and inter-assay precision was less than 13.7% and the bias ranged from -7.4 to 7.0%. The method was successfully applied to characterize the pharmacokinetics of AT-101 in a Phase I clinical trial. The validated assay is accurate, and sensitive with minimum loss and rapid analysis time and suitable for quantification of gossypol for pharmacokinetics evaluation.

Phase I Study of Bosutinib, a Src/Abl Tyrosine Kinase Inhibitor, Administered to Patients with Advanced Solid Tumors

Bosutinib, a potent ATP-competitive, quinolinecarbonitrile Src/Abl kinase inhibitor, was tested in this first-in-human phase I trial in patients with advanced solid tumor malignancies. This trial was conducted in 2 parts. In part 1 (dose escalation), increasing oral bosutinib doses were administered using a 3 + 3 design. In part 2 (dose expansion), approximately 30 patients each with refractory colorectal, pancreas, or non-small cell lung cancer were treated at the recommended phase II dose (RP2D). Primary efficacy endpoints for part 2 were median progression-free survival (colorectal and non-small cell lung) and median overall survival (pancreas). In part 1, dose-limiting toxicities of grade 3 diarrhea (two patients) and grade 3 rash occurred with bosutinib 600 mg/day and the maximum tolerated dose identified was 500 mg/day. However, the majority of patients treated with 500 mg/day had grade 2 or greater gastrointestinal toxicity, and 400 mg/day was identified as the RP2D. The most common bosutinib-related adverse events were nausea (60% patients), diarrhea (47%), vomiting (40%), fatigue (38%), and anorexia (36%). Bosutinib had a mean half-life of 19 to 20 hours at the RP2D. A partial response (breast) and unconfirmed complete response (pancreas) were observed; 8 of 112 evaluable patients had stable disease for 22 to 101 weeks. However, the primary efficacy endpoints for part 2 were not met. Bosutinib was generally well tolerated in patients with solid tumors, with the main toxicity being gastrointestinal. The RP2D was 400 mg/day orally. Further study of bosutinib is planned in combination regimens.

Phase I dose-escalating study of ES-285 given as a three-hour intravenous infusion every three weeks in patients with advanced malignant solid tumors

ES-285 (spisulosine) is a novel compound derived from the marine mollusk Spisula polynoma with evidence of preclinical antitumor activity. This phase I clinical trial was designed to identify the maximum tolerated dose (MTD) and the recommended dose for phase II trials (RD), as well as to evaluate the safety profile, pharmacokinetics and preliminary efficacy data of ES-285 in patients with advanced solid tumors. Sixty-one patients at two medical institutions were treated with a 3-h ES-285 intravenous infusion every 3 weeks. Nine dose levels were evaluated. No dose-limiting toxicities (DLTs) were observed during dose escalation from 4 to 128 mg/m(2). Six patients had seven DLTs at the three highest dose levels tested: 256 mg/m(2) (n = 2), 200 mg/m(2) (n = 3) and 160 mg/m(2) (n = 1). Grade 3/4 transaminase increases (n = 3), grade 3/4 central nervous system disorders [confusion (n = 2) and ataxia (n = 1)], and grade 3 pyrexia (n = 1) were the dose-limiting toxicities found with this ES-285 administration schedule. Pharmacokinetic analysis showed ES-285 dose linearity, wide distribution and a long half-life. One non-confirmed partial response was observed in a patient with metastatic melanoma treated with ES-285 128 mg/m(2), and 18 patients showed stable disease at different dose levels, lasting longer than 3 months in six patients. Dose level VIII (200 mg/m(2)) was considered the MTD, and dose level IX (160 mg/m(2)) was defined as the RD. Limited antitumor activity was observed.

Abstract A97: Final phase 1/2a results evaluating the cyclodextrin-containing nanoparticle CRLX101 in patients with advanced solid tumor malignancies.

Abstract Introduction: Topoisomerase-1-inhibiting camptothecin (CPT) and derivatives such as irinotecan (CPT-11) and topotecan demonstrate clinical utility across multiple cancer types. Use of these agents remains limited by insufficient tumor exposure and high systemic toxicity. A novel cyclodextrin-containing polymer conjugate of CPT that self-assembles into nanoparticles, CRLX101 delivers sustained levels of active CPT into cancer cells while substantially reducing systemic exposure. In vitro and in vivo data suggest superior activity of CRLX101 in multiple tumor models. Efforts are made now to demonstrate the safety and efficacy of CRLX101 in human patients with advanced solid tumor malignancies. Experimental Procedures: CRLX101 was administered intravenously over 1 hour every other week (EOW) to patients (pts.) with advanced and multiply pre-treated solid tumor malignancies. In phase 1, 24 pts. received CRLX101 at 5 escalating dose levels. Following identification of a maximum tolerated dose (MTD), a 38 patient phase 2a MTD-expansion cohort was enrolled at 3 clinical sites. Summary of Data: As of a data cut-off of 6/1/11, 62 total pts. (31 F; 31 M) received CRLX101 at doses ranging from 6 mg/m2 to 18 mg/m2 of CPT equivalent per dose. In phase 1, 2 pts. (18 mg/m2) experienced dose limiting toxicity of CTCAE v3.0 grade (G)4 thrombocytopenia with one of these pts. additionally experiencing G4 neutropenia. An MTD/recommended phase 2 dose (RP2D) of CRLX101 was established at 15 mg/m2 EOW. Among 44 phase 1 or 2a pts. receiving the MTD/RP2D, most common grade 3/4 adverse events considered by investigators to be at least possibly related to study drug included neutropenia (9 events observed among 6 pts.) and lymphopenia (3 events observed among 2 pts.). Phase 2a pts. received CRLX101 for periods of time ranging from 1 day to approximately 13 months (mos.) with an average duration of 3.3 mos. Among 36 evaluable phase 2a pts. receiving the MTD, mean plasma Cmax and AUCall were 306 μg./L. and 27.1 mg./L.*hr. (polymer-unconjugated) and 8260 μg./L. and 300 mg./L.*hr. (polymer-conjugated), respectively. Mean urinary clearance of polymer-conjugated and free CPT over the 0–8 hr., 8–24 hr., and 24–48 hr. collection intervals post CRLX101 dosing were 0.0299, 0.0074, and 0.0062 L./hr. (polymer-conjugated) and 0.0888, 0.0898, and 0.1010 L./hr. (free CPT), respectively. Among all phase 2a pts., overall median progression-free survival (mPFS) was 3.7 mos., with mPFS of 4.4 mos. observed among 21 NSCLC pts. (4.8 mos. excluding 6/21 pts. with squamous cell histology). At time of data cut-off, 6 pts. (incl. 3 NSCLC pts.) remain on therapy. Notably, of the 21 NSCLC pts. in phase 2a (with an average of 3 prior regimens of chemotherapy), 66.7% (14/21) achieved stable disease (SD) ≥ 3 mos. and 14.3% (3/21) achieved SD ≥ 6 mos. Conclusions: CRLX101 appears to be extremely well tolerated with an MTD/RP2D of 15 mg/m2 EOW. Pharmacokinetics are linear and suggest prolonged duration of CPT tumor exposure. Similarly, extended periods of stable disease observed across multiple tumor types are encouraging and merit further investigation. Patients are currently being enrolled into a multinational randomized clinical trial in 2nd/3rd line NSCLC and additional studies in renal cell cancer, small-cell lung cancer, ovarian cancer, and gastric cancer are being developed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A97.

A phase I study of 5-azacytidine and erlotinib in advanced solid tumor malignancies

The epidermal growth factor receptor (EGFR) is a validated target in malignancy; however, patients with wild type EGFR obtain little sustained benefit from anti-EGFR monotherapy. Epigenetic therapy to reactivate tumor suppressor genes may enhance the anti-proliferative effect of erlotinib. This phase I study evaluated the combination of erlotinib and 5-azacytidine for safety and maximal tolerated dose (MTD). Thirty patients with advanced solid tumors were treated in a standard 3+3 cohort design. Erlotinib was dosed at 150mg daily, and 5-azacytidine was escalated by increasing the number of daily doses of 75mg/m(2) per cycle. Patients were followed for dose-limiting toxicity (DLT). Efficacy was assessed by RECIST criteria. Common non-hematologic toxicities included rash, diarrhea, nausea, and fatigue; the majority was ≤ Grade 2. DLTs included conjunctivitis in cohort 1 and infusion reaction in cohort 2. No DLTs occurred in cohorts 3, 4, or 5; however, 2 serious neutropenic infections arose in cohort 5 after cycle 1. Cohort 4 was expanded to 6 patients and was the MTD. Partial response (lung, ovarian) and stable disease occurred in 2 and 11 patients, respectively. Median progression-free survival was 2months. Two patients with lung and larynx cancer had prolonged stable disease. The combination of erlotinib and 5-azacytidine was well tolerated with interesting clinical activity in lung, head and neck, and ovarian cancer. The recommended dose for phase II study is erlotinib 150mg daily and 5-azacytidine 75 mg/m(2) daily on days 1-4 and 15-18 of a 28-day cycle.

Effect of trabectedin on the QT interval in patients with advanced solid tumor malignancies

PurposeThe primary objective of this study was to access the potential effects of trabectedin on the QT/QTc interval in patients with locally advanced or metastatic solid tumors.MethodsPatients (n = 75) who had received ≤3 previous lines of chemotherapy and had either relapsed or had progressive disease were enrolled. Patients were administered 3-h intravenous infusions of placebo (saline) on day 1 and trabectedin (1.3 mg/m2) on day 2. Time-matched serial triplicate ECG recordings and pharmacokinetic blood samples were collected over 24 h on both days. Heart rate corrected mean QT intervals and changes from predose baseline in QTc (ΔQTc) were assessed. The difference in ΔQTc between trabectedin and placebo was calculated at each time point (ΔΔQTc).ResultsThe upper limits of the 90% confidence interval for ΔΔQTcF and ΔΔQTcB at all time points were less than the prespecified noninferiority margin of 10 ms (≤6.65 ms). No patient had a QTc > 500 ms or a time-matched increase from baseline in QTc > 60 ms at any time point. Regression analyses indicated ΔΔQTc was poorly correlated with trabectedin concentration. No adverse events suggestive of proarrhythmic potential were reported.ConclusionTrabectedin did not prolong the QTc interval. Safety and pharmacokinetic profiles of trabectedin were similar to that observed in other ovarian and breast cancer studies.

A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer

IntroductionWe previously reported data on the safety, tolerability, and recommended phase II dose of obatoclax mesylate in conjunction with topotecan in patients with advanced solid tumor malignancies. Preliminary efficacy data suggested activity in patients with recurrent small cell lung cancer (SCLC). Based on these data, we performed a phase II study of obatoclax mesylate plus topotecan in patients with relapsed SCLC to assess efficacy. MethodsThis was an open-label, single-arm, phase II extension of obatoclax mesylate plus topotecan in patients with relapsed SCLC. Obatoclax mesylate was given intravenously (IV) at a dose of 14mg/m2 on days 1 and 3 with IV topotecan at 1.25mg/m2 on days 1–5 of an every 3-week cycle. The primary end-point of this study was overall response rate. ResultsNine patients with recurrent SCLC were enrolled into the first stage of the study. Patients received a median of 2 cycles of treatment. All patients were evaluable for the primary end-point of overall response. There were no partial or complete responses. Five patients (56%) had stable disease. The remaining four patients (44%) developed progressive disease. The most common grade 3 or 4 adverse events included thrombocytopenia (22%), anemia (11%), neutropenia (11%), and ataxia (11%). ConclusionObatoclax mesylate added to topotecan does not exceed the historic response rate seen with topotecan alone in patients with relapsed SCLC following the first-line platinum-based therapy.