A phase 1 study of veliparib (ABT-888) plus weekly carboplatin and paclitaxel in advanced solid malignancies, with an expansion cohort in triple negative breast cancer (TNBC) (ETCTN 8620).

BACKGROUND: Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly paclitaxel is associated with improved overall survival. We aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib with weekly carboplatin and paclitaxel as well as safety, pharmacokinetics, and preliminary clinical activity in triple negative breast cancer (TNBC). METHODS: Patients with locally advanced/metastatic solid tumors and adequate organ function were eligible. A standard 3 + 3 dose-escalation design was followed by a TNBC expansion cohort. Veliparib doses ranging from 50 to 200 mg orally bid were tested with carboplatin (AUC 2) and paclitaxel (80 mg/m2) given weekly in a 21-day cycle. Adverse events (AE) were evaluated by CTCAE v4.0, and objective response rate (ORR) was determined by RECIST 1.1. RESULTS: Thirty patients were enrolled, of whom 22 had TNBC. Two dose-limiting toxicities were observed. The RP2D was determined to be 150 mg PO bid veliparib with weekly carboplatin and paclitaxel 2 weeks on, 1 week off, based on hematologic toxicity requiring dose reduction in the first 5 cycles of treatment. The most common grade 3/4 AEs included neutropenia, anemia, and thrombocytopenia. PK parameters of veliparib were comparable to single-agent veliparib. In 23 patients with evaluable disease, the ORR was 65%. In 19 patients with TNBC with evaluable disease, the ORR was 63%. CONCLUSION: Veliparib can be safely combined with weekly paclitaxel and carboplatin, and this triplet combination has promising clinical activity.

A phase I, multicenter, open-label, first-in-human, dose-escalation study of the oral smoothened inhibitor Sonidegib (LDE225) in patients with advanced solid tumors.

PURPOSE: This phase I trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog signaling, in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma and basal cell carcinoma (BCC), at doses ranging from 100 to 3,000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose pharmacokinetics run-in period. Dose escalations were guided by a Bayesian logistic regression model. Safety, tolerability, efficacy, pharmacokinetics, and biomarkers in skin and tumor biopsies were assessed. RESULTS: The MTDs of sonidegib were 800 mg daily and 250 mg twice daily. The main DLT of reversible grade 3/4 elevated serum creatine kinase (18% of patients) was observed at doses ≥ the MTD in an exposure-dependent manner. Common grade 1/2 adverse events included muscle spasm, myalgia, gastrointestinal toxicities, increased liver enzymes, fatigue, dysgeusia, and alopecia. Sonidegib exposure increased dose proportionally up to 400 mg daily, and displayed nonlinear pharmacokinetics at higher doses. Sonidegib exhibited exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed in patients with medulloblastoma and BCC were associated with evidence of hedgehog pathway activation. CONCLUSIONS: Sonidegib has an acceptable safety profile in patients with advanced solid tumors and exhibits antitumor activity in advanced BCC and relapsed medulloblastoma, both of which are strongly associated with activated hedgehog pathway, as determined by gene expression.

Outcomes with FOLFIRINOX for borderline resectable and locally unresectable pancreatic cancer.

BACKGROUND: Trials examining FOLFIRINOX in metastatic pancreatic cancer demonstrate higher response rates compared to gemcitabine-based regimens. There is currently limited experience with neoadjuvant FOLFIRINOX in pancreatic cancer. METHODS: Retrospective review of outcomes of patients with borderline resectable or locally unresectable pancreatic cancer who were recommended to undergo neoadjuvant treatment with FOLFIRINOX. RESULTS: FOLFIRINOX was recommended for 25 patients with pancreatic cancer, 13 (52%) unresectable and 12 (48%) borderline resectable. Four patients (16%) refused treatment or were lost to follow-up. Twenty-one patients (84%) were treated with a median of 4.7 cycles. Six patients (29%) required dose reductions secondary to toxicity. Two patients (9%) were unable to tolerate treatment and three patients (14%) had disease progression on treatment. Seven patients (33%) underwent surgical resection following treatment with FOLFIRINOX alone, 2 (10%) of which were initially unresectable. Two patients underwent resection following FOLFIRINOX + stereotactic body radiation therapy (SBRT). The R0 resection rate for patients treated with FOLFIRINOX ± SBRT was 33% (55% borderline resectable, 10% unresectable). A total of five patients (24%) demonstrated a significant pathologic response. CONCLUSIONS: FOLFIRINOX is a biologically active regimen in borderline resectable and locally unresectable pancreatic cancer with encouraging R0 resection and pathologic response rates.

Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients.

S-CKD602 is a PEGylated liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. The objective of this study was to characterize the bidirectional pharmacokinetic-pharmacodynamic (PK-PD) interaction between S-CKD602 and monocytes. Plasma concentrations of encapsulated CKD-602 and monocytes counts from 45 patients with solid tumors were collected following intravenous administration of S-CKD602 in the phase I study. The PK-PD models were developed and fit simultaneously to the PK-PD data, using NONMEM(®). The monocytopenia after administration of S-CKD602 was described by direct toxicity to monocytes in a mechanism-based model, and by direct toxicity to progenitor cells in bone marrow in a myelosuppression-based model. The nonlinear PK disposition of S-CKD602 was described by linear degradation and irreversible binding to monocytes in the mechanism-based model, and Michaelis-Menten kinetics in the myelosuppression-based model. The mechanism-based PK-PD model characterized the nonlinear PK disposition, and the bidirectional PK-PD interaction between S-CKD602 and monocytes.

Population pharmacokinetics of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced malignancies.

S-CKD602 is a pegylated long-circulating liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. A population pharmacokinetic (PK) model for encapsulated and released CKD-602 following administration of S-CKD602 was developed to assess factors that may influence S-CKD602 PK. Plasma samples from 45 patients with solid tumors were collected in a phase 1 study. S-CKD602 was administered as a 1-hour intravenous infusion with doses ranging from 0.1 to 2.5 mg/m(2) . Plasma concentrations of encapsulated and released CKD-602 were used to develop a population PK model using NONMEM. PK of encapsulated CKD-602 was described by a 1-compartment model with nonlinear clearance, and PK of released CKD-602 was described by a 2-compartment model with linear clearance for all patients. Covariate analysis revealed that tumor in the liver was a significant covariate for clearance of encapsulated CKD-602 and that age significantly influenced the release rate of CKD-602 from S-CKD602. Maximum elimination rate in patients with liver tumor is 1.5-fold higher compared with patients without liver tumor. Release rate of CKD-602 from S-CKD602 in patients less than 60 years old was 2.7-fold higher compared with patients 60 years old or older. These observations have potential implications in the optimal dosing of liposomal agents.

Phase II study of irinotecan and cetuximab given every 2 weeks as second-line therapy for advanced colorectal cancer.

BACKGROUND: Irinotecan and weekly cetuximab (I+C) is a standard second-line regimen for metastatic colorectal cancer (mCRC). This study investigated the safety and efficacy of every 2 weeks I+C in patients with mCRC. PATIENTS AND METHODS: Patients with mCRC refractory to first-line fluoropyrimidine/oxaliplatin regimens and not previously treated with I+C were eligible. Response rate (RR) was the primary endpoint. Cetuximab 500 mg/m(2) and irinotecan 180 mg/m(2) were administered intravenously (I.V.) on day 1 every 2 weeks. RESULTS: Patient characteristics (n = 31): male (n = 17), median age 62; Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1 (n = 30), and PS = 2 (n = 1). Median number of cycles = 3 (range, 1-22). I+C doses were modified in 18 and 12 patients, respectively. Grade 3/4 adverse events: acneiform rash (n = 6); neutropenia (n = 6); and diarrhea (n = 5); there was one grade 5 respiratory failure, possibly related to therapy. Two patients had a partial response, 11 had stable disease, and 18 had progressive disease resulting in an overall RR of 6% and disease control rate of 41.9%. Median overall survival (OS) was 9.3 months (95% CI, 5.1-15), and time to progression (TTP) was 2.4 months (95% CI, 1.3-4.6). K-ras and BRAF mutations were detected in 39% and 9%, respectively, of the patients tested. There was a trend toward longer TTP among patients with wild-type K-ras and BRAF (2.6 vs. 1.7 months; P = 0.16), and OS was significantly longer in those patients (14.1 vs. 5.5 months; P = 0.04). CONCLUSIONS: The RR and TTP were lower than expected and may reflect the reduced dose intensity due to toxicities. While the OS was consistent with previous publications, the efficacy of this combination was not demonstrated.

Phase I and pharmacokinetic study of dasatinib and cetuximab in patients with advanced solid malignancies.

BACKGROUND: Combined inhibition of epidermal growth factor receptor (EGFR) and Src family kinases (SFK) may lead to improved therapeutic effects. We evaluated the combination of dasatinib, an inhibitor of SFK and other kinases, and cetuximab, an anti-EGFR monoclonal antibody. PATIENTS AND METHODS: Patients with advanced solid malignancies received cetuximab intravenously on a standard weekly schedule and dasatinib orally, once daily at 3 dose levels: (1) 100 mg, (2) 150 mg, (3) 200 mg. Pharmacokinetic and pharmacodynamic studies of dasatinib were performed prior to starting cetuximab and following 14 days of treatment. RESULTS: Twenty-five patients (3 dose level 1; 19 dose level 2; 3 dose level 3) were initially treated. Three patients developed dose-limiting toxicities: 1 at dose level 2 (headache) and 2 at dose level 3 (headache, nausea). Grade 3-4 toxicities in more than 2 patients included: dyspnea (4), vomiting (4), nausea (3), hypersensitivity reactions (3), headache (3) and anemia (3). Twenty-one patients developed headache (8 grade 1; 10 grade 2), which occurred after the loading of cetuximab and lasted 1-3 days. Six additional patients were treated with dasatinib starting 3 days after the loading dose of cetuximab; none developed headache after dasatinib. Dasatinib pharmacokinetics and a transient decrease in SFK PY416 levels in peripheral blood mononuclear cells were not altered by cetuximab. Patients with higher plasma TGF-alpha levels had worse progression-free survival. CONCLUSIONS: Dasatinib 150 mg once daily plus weekly cetuximab is recommended for phase II studies. Early-onset headache was ameliorated by starting dasatinib after cetuximab.

A phase I and pharmacokinetic study of oral 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in the treatment of advanced-stage solid cancers: a California Cancer Consortium Study.

BACKGROUND: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavailability of 3-AP in patients with advanced-stage solid tumors. METHODS: Twenty patients received one dose of intravenous and subsequent cycles of oral 3-AP following a 3 + 3 patient dose escalation. Intravenous 3-AP was administered to every patient at a fixed dose of 100 mg over a 2-h infusion 1 week prior to the first oral cycle. Oral 3-AP was administered every 12 h for 5 consecutive doses on days 1-3, days 8-10, and days 15-17 of every 28-day cycle. 3-AP was started at 50 mg with a planned dose escalation to 100, 150, and 200 mg. Dose-limiting toxicities (DLT) and bioavailability were evaluated. RESULTS: Twenty patients were enrolled. For dose level 1 (50 mg), the second of three treated patients had a DLT of grade 3 hypertension. In the dose level 1 expansion cohort, three patients had no DLTs. No further DLTs were encountered during escalation until the 200-mg dose was reached. At the 200 mg 3-AP dose level, two treated patients had DLTs of grade 3 hypoxia. One additional DLT of grade 4 febrile neutropenia was subsequently observed at the de-escalated 150 mg dose. One DLT in 6 evaluable patients established the MTD as 150 mg per dose on this dosing schedule. Responses in the form of stable disease occurred in 5 (25%) of 20 patients. The oral bioavailability of 3-AP was 67 ± 29% and was consistent with the finding that the MTD by the oral route was 33% higher than by the intravenous route. CONCLUSIONS: Oral 3-AP is well tolerated and has an MTD similar to its intravenous form after accounting for the oral bioavailability. Oral 3-AP is associated with a modest clinical benefit rate of 25% in our treated patient population with advanced solid tumors.

Bidirectional pharmacodynamic interaction between pegylated liposomal CKD-602 (S-CKD602) and monocytes in patients with refractory solid tumors.

BACKGROUND: STEALTH(®) liposomal CKD-602 (S-CKD602), a camptothecin analog, is eliminated by the reticuloendothelial system (RES), which consists of cells, including monocytes. We evaluated the relationship between monocyte and absolute neutrophil counts (ANCs) in the blood and pharmacokinetic disposition of S-CKD602 and nonliposomal CKD-602 (NL-CKD602) in patients. METHODS: As part of a phase I study of S-CKD602 and phase I and II studies of NL-CKD602, the percent decreases in ANC and monocytes at their nadir were calculated. After S-CKD602, the amount of CKD-602 recovered in urine was measured. RESULTS: For S-CKD602 in patients <60 years, the percent decrease in ANC and monocytes were 43 ± 31 and 58 ± 26%, respectively (P = 0.001). For S-CKD602 in patients ≥60, the percent decrease in ANC and monocytes were 41 ± 31 and 45 ± 36%, respectively (P = 0.50). For NL-CKD602 (n = 42), the percent decrease in ANC and monocytes were similar (P > 0.05). For S-CKD602, the relationship between the percent decrease in monocytes and CKD-602 recovered in urine was stronger in patients <60 (R(2) = 0.82), compared with patients ≥60 (R(2) = 0.30). CONCLUSIONS: Monocytes are more sensitive to S-CKD602, compared with neutrophils, and the increased sensitivity is related to the liposomal formulation, not CKD-602. These results suggest that monocytes engulf S-CKD602, which causes the release of CKD-602 from the liposome and toxicity to the monocytes, and that the effects are more prominent in patients <60.

Phase I and pharmacokinetic study of pegylated liposomal CKD-602 in patients with advanced malignancies.

PURPOSE: S-CKD602 is a pegylated liposomal formulation of CKD602, a semisynthetic camptothecin analogue. Pegylated (STEALTH) liposomes can achieve extended drug exposure in plasma and tumor. Based on promising preclinical data, the first phase I study of S-CKD602 was done in patients with refractory solid tumors. EXPERIMENTAL DESIGN: S-CKD602 was administered i.v. every 3 weeks. Modified Fibonacci escalation was used (three to six patients/cohort), and dose levels ranged from 0.1 to 2.5 mg/m2. Serial plasma samples were obtained over 2 weeks and total (lactone+hydroxyl acid) concentrations of encapsulated, released, and sum total (encapsulated+released) CKD602 measured by liquid chromatography-tandem mass spectrometry. RESULTS: Forty-five patients (21 males) were treated. Median age, 62 years (range, 33-79 years) and Eastern Cooperative Oncology Group status, 0 to 1 (43 patients) and 2 (2 patients). Dose-limiting toxicities of grade 3 mucositis occurred in one of six patients at 0.3 mg/m2, grade 3 and 4 bone marrow suppression in two of three patients at 2.5 mg/m2, and grade 3 febrile neutropenia and anemia in one of six patients at 2.1 mg/m2. The maximum tolerated dose was 2.1 mg/m2. Partial responses occurred in two patients with refractory ovarian cancer (1.7 and 2.1 mg/m2). High interpatient variability occurred in the pharmacokinetic disposition of encapsulated and released CKD602. CONCLUSIONS: S-CKD602 represents a promising new liposomal camptothecin analogue with manageable toxicity and promising antitumor activity. Phase II studies of S-CKD602 at 2.1 mg/m2 i.v. once every 3 weeks are planned. Prolonged plasma exposure over 1 to 2 weeks is consistent with STEALTH liposomes and provides extended exposure compared with single doses of nonliposomal camptothecins.

A phase I study of 17-allylamino-17-demethoxygeldanamycin combined with paclitaxel in patients with advanced solid malignancies.

BACKGROUND: 17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits heat shock protein 90, promotes degradation of oncoproteins, and exhibits synergy with paclitaxel in vitro. We conducted a phase I study in patients with advanced malignancies to determine the recommended phase II dose of the combination of 17-AAG and paclitaxel. METHODS: Patients with advanced solid malignancies that were refractory to proven therapy or without any standard treatment were included. 17-AAG (80-225 mg/m2) was given on days 1, 4, 8, 11, 15, and 18 of each 4-week cycle to sequential cohorts of patients. Paclitaxel (80-100 mg/m2) was administered on days 1, 8, and 15. Pharmacokinetic studies were conducted during cycle 1. RESULTS: Twenty-five patients were accrued to five dose levels. The median number of cycles was 2. Chest pain (grade 3), myalgia (grade 3), and fatigue (grade 3) were dose-limiting toxicities at dose level 4 (225 mg/m2 17-AAG and 80 mg/m2 paclitaxel). None of the six patients treated at dose level 3 with 17-AAG (175 mg/m2) and paclitaxel (80 mg/m2) experienced dose-limiting toxicity. Disease stabilization was noted in six patients, but there were no partial or complete responses. The ratio of paclitaxel area under the concentration to time curve when given alone versus in combination with 17-AAG was 0.97 +/- 0.20. The ratio of end-of-infusion concentration of 17-AAG (alone versus in combination with paclitaxel) was 1.14 +/- 0.51. CONCLUSIONS: The recommended phase II dose of twice-weekly 17-AAG (175 mg/m2) and weekly paclitaxel (80 mg/m2/wk) was tolerated well. There was no evidence of drug-drug pharmacokinetic interactions.

Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies.

PURPOSE: The primary objective of this study was to determine the recommended phase II doses of the novel histone deacetylase inhibitor vorinostat when administered in combination with carboplatin and paclitaxel. EXPERIMENTAL DESIGN: Patients (N = 28) with advanced solid malignancies were treated with vorinostat, administered orally once daily for 2 weeks or twice daily for 1 week, every 3 weeks. Carboplatin and paclitaxel were administered i.v. once every 3 weeks. Doses of vorinostat and paclitaxel were escalated in sequential cohorts of three patients. The pharmacokinetics of vorinostat, its metabolites, and paclitaxel were characterized. RESULTS: Vorinostat was administered safely up to 400 mg qd or 300 mg bd with carboplatin and paclitaxel. Two of 12 patients at the 400 mg qd schedule experienced dose-limiting toxicities of grade 3 emesis and grade 4 neutropenia with fever. Non-dose-limiting toxicity included nausea, diarrhea, fatigue, neuropathy, thrombocytopenia, and anemia. Of 25 patients evaluable for response, partial responses occurred in 11 (10 non-small cell lung cancer and 1 head and neck cancer) and stable disease occurred in 7. Vorinostat pharmacokinetics were linear over the dose range studied. Vorinostat area under the concentration versus time curve and half-life increased when vorinostat was coadministered with carboplatin and paclitaxel, but vorinostat did not alter paclitaxel pharmacokinetics. CONCLUSIONS: Both schedules of vorinostat (400 mg oral qd x 14 days or 300 mg bd x 7 days) were tolerated well in combination with carboplatin (area under the concentration versus time curve = 6 mg/mL x min) and paclitaxel (200 mg/m(2)). Encouraging anticancer activity was noted in patients with previously untreated non-small cell lung cancer.

Phase I and pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with refractory advanced cancers.

PURPOSE: The primary objective was to establish the dose-limiting toxicity (DLT) and recommended phase II dose of 17-(allylamino)-17-demethoxygeldanamycin (17AAG) given twice a week. EXPERIMENTAL DESIGN: Escalating doses of 17AAG were given i.v. to cohorts of three to six patients. Dose levels for schedule A (twice weekly x 3 weeks, every 4 weeks) were 100, 125, 150, 175, and 200 mg/m(2) and for schedule B (twice weekly x 2 weeks, every 3 weeks) were 150, 200, and 250 mg/m(2). Peripheral blood mononuclear cells (PBMC) were collected for assessment of heat shock protein (HSP) 90 and HSP90 client proteins. RESULTS: Forty-four patients were enrolled, 32 on schedule A and 12 on schedule B. On schedule A at 200 mg/m(2), DLTs were seen in two of six patients (one grade 3 thrombocytopenia and one grade 3 abdominal pain). On schedule B, both patients treated at 250 mg/m(2) developed DLT (grade 3 headache with nausea/vomiting). Grade 3/4 toxicities seen in >5% of patients were reversible elevations of liver enzymes (47%), nausea (9%), vomiting (9%), and headache (5%). No objective tumor responses were observed. The only consistent change in PBMC proteins monitored was a 0.8- to 30-fold increase in HSP70 concentrations, but these were not dose dependent. The increase in PBMC HSP70 persisted throughout the entire cycle of treatment but returned to baseline between last 17AAG dose of cycle 1 and first 17AAG dose of cycle 2. CONCLUSIONS: The recommended phase II doses of 17AAG are 175 to 200 mg/m(2) when given twice a week and consistently cause elevations in PBMC HSP70.

Final results of a placebo-controlled study of filgrastim in small-cell lung cancer: exploration of risk factors for febrile neutropenia.

BACKGROUND: A phase III study of filgrastim as an adjunct to combination chemotherapy in previously untreated patients with limited- or extensive-stage small-cell lung cancer was conducted. This final analysis explores baseline factors that might predict febrile neutropenia and also reports the results of 463 open-label filgrastim cycles that were delivered after patients' initial episode of the primary endpoint, ie, febrile neutropenia. PATIENTS AND METHODS: A total of 244 patients were randomized to receive placebo or filgrastim in