Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced non-small cell lung cancer (NSCLC). Based on preclinical models, we hypothesized pharmacodynamic separation, achieved by intermittent delivery of EGFR TKIs intercalated with chemotherapy, as a reasonable strategy to deliver combination therapy.
A Phase I dose-escalating trial employing two scheduling strategies (arm A and arm B) was conducted in advanced solid tumor patients to determine the feasibility of intermittent erlotinib and docetaxel. Phase II efficacy evaluation was conducted in an expanded cohort of previously treated advanced NSCLC patients using arm B scheduling. Docetaxel was given every 21 days (70–75 mg/m2 intravenously) in both arms. In arm A, erlotinib was administered on Days 2, 9, and 16 (600–1000 mg); in arm B, erlotinib was delivered on Days 2 through 16 (150 – 300 mg). Patients without progression or unacceptable toxicity after 6 cycles continued erlotinib alone.
Eighty-one patients were enrolled in this study (17 arm A; 25 arm B; 39 at phase II dose). Phase I patients had advanced solid tumors and 22 with NSCLC (10 and 12 patients for arms A and B, respectively). Treatment was well-tolerated for both arms, with dose-limiting toxicities including: grade 3 infection and febrile neutropenia in arm A (maximum tolerated dose [MTD] of erlotinib 600 mg/docetaxel 70 mg/m2); grade 4 rash, febrile neutropenia, grade 3 mucositis, and grade 3 diarrhea in arm B (MTD of erlotinib 200 mg/docetaxel 70 mg/m2). The MTD for arm B was chosen for phase II evaluation given the feasibility of administration, number of responses (1 complete response, 3 partial responses), and achievement of pharmacodynamic separation. The response rate for patients treated at the phase II dose was 28.2% and disease control rate was 64.1%. Median progression-free and overall survival was 4.1 and 18.2 months, respectively. Common grade ≥ 3 toxicities were neutropenia (36%) and diarrhea (18%).
Pharmacodynamic separation utilizing intercalated schedules of erlotinib delivered on an intermittent basis together with docetaxel chemotherapy is feasible and tolerable. Further studies employing this approach together with interrogation of relevant molecular pathways are ongoing.
erlotinib; docetaxel; pharmacodynamic separation; non-small cell lung cancer; phase II
The primary objective of this phase I dose-escalation study was to identify the maximum tolerated dose (MTD) of sunitinib plus pemetrexed in patients with advanced cancer.
Using a 3 + 3 dose-escalation design, patients received oral sunitinib qd by continuous daily dosing (CDD schedule; 37.5 or 50 mg) or 2 weeks on/1 week off treatment schedule (Schedule 2/1; 50 mg). Pemetrexed (300–500 mg/m2 IV) was administered q3w. At the proposed recommended phase 2 dose (RP2D), additional patients with non-small cell lung cancer (NSCLC) were enrolled.
Thirty-five patients were enrolled on the CDD schedule and seven on Schedule 2/1. MTDs were sunitinib 37.5 mg/day (CDD/RP2D) or 50 mg/day (Schedule 2/1) with pemetrexed 500 mg/m2. Dose-limiting toxicities included grade (G) 5 cerebral hemorrhage, G3 febrile neutropenia, and G3 anorexia. Common G3/4 drug-related non-hematologic adverse events (AEs) at the CDD MTD included fatigue, anorexia, and hand–foot syndrome. G3/4 hematologic AEs included lymphopenia, neutropenia, and thrombocytopenia. No significant drug–drug interactions were identified. Five (24%) NSCLC patients had partial responses.
In patients with advanced solid malignancies, the MTD of sunitinib plus 500 mg/m2 pemetrexed was 37.5 mg/day (CDD schedule) or 50 mg/day (Schedule 2/1). The CDD schedule MTD was tolerable and demonstrated promising clinical benefit in NSCLC.
Antiangiogenic; Pemetrexed; Phase I; Solid tumors; Sunitinib; Tyrosine kinase inhibitor; Lung cancer
Combination of S-1, an oral fluorouracil derivative, plus docetaxel against non-small cell lung cancer (NSCLC) showed promising efficacy but clinically problematic emesis. A phase I/II study utilising a new schedule for this combination was conducted.
A biweekly regimen of docetaxel on day 1 with oral S-1 on days 1–7 was administered to previously treated NSCLC patients. Doses of docetaxel/S-1 were escalated to 30/80, 35/80, and 40/80 mg m−2, respectively, and its efficacy was investigated at the recommended dose below maximum tolerated dose (MTD).
In phase I study employing 13 patients, dose-limiting toxicities were febrile neutropenia and treatment delay, with the respective MTDs for docetaxel 40 mg m−2/S-1 80 mg m−2. In the phase II study, 34 patients were treated with docetaxel 35 mg m−2/S-1 80 mg m−2 for a median cycle of 6. The response and disease control rates were 34.3% (95% confidence interval (CI), 18.6–50.0%) and 62.9% (95% CI, 46.8–72.9%), respectively. Median progression-free survival was 150.5 days. Haematologic grade 4 toxicities were observed in neutropenia (11.8%) and thrombocytopenia (2.9%). Regarding non-haematologic toxicities, including emesis, there were no grade 3/4 side effects.
Combination of 1-week administration of S-1 with biweekly docetaxel is safe and active for NSCLC.
non-small cell lung cancer; docetaxel; S-1; phase I study; phase II study
Everolimus is a novel inhibitor of the mammalian target of rapamycin (mTOR) pathway, which is aberrantly activated in non-small cell lung cancer (NSCLC). We conducted a phase I and pharmacokinetic study of everolimus and docetaxel for recurrent NSCLC.
Patients with advanced stage NSCLC and progression following prior platinum-based chemotherapy were eligible. Sequential cohorts were treated with escalating doses of docetaxel (day 1) and everolimus (PO daily, days 1–19), every 3 weeks. Pharmacokinetic (PK) sampling of everolimus and docetaxel were done in cycle 1. The primary endpoint was determination of the recommended phase II doses (RP2D) of the combination.
Twenty-four patients were enrolled. Median age, 62 yrs; Females, 11; number of prior regimens, 1(n=13), 2 (n=6), ≥3 (n=5) ECOG PS 0(n=6), 1(n=17). The dose-limiting toxicities (DLT) were fever with grade 3/4 neutropenia, grade 3 fatigue and grade 3 mucositis. None of the 7 patients treated at the RP2D (docetaxel 60 mg/m2 and everolimus 5 mg daily) experienced DLT. Everolimus area under the concentration time curve (AUC) was not different with 60 or 75 mg/m2 docetaxel. Mean ±SD AUC-based accumulation factors (R) for everolimus on days 8 and 15 were 1.16 ± 0.37 and 1.42 ± 0.42, respectively. Docetaxel day 1 half-life was 9.4 ± 3.4 hours. Among 21 patients evaluable, 1 had a partial response, and 10 had disease stabilization.
The RP2D of docetaxel and everolimus for combination therapy are 60 mg/m2 and 5 mg PO daily, respectively. Promising anti-cancer activity has been noted.
Everolimus; docetaxel; phase I; pharmacokinetics; non-small cell lung cancer
Cigarette smoking induces CYP1A1/1A2 and is hypothesized to alter erlotinib pharmacokinetics. This study aimed to determine the maximum tolerated dose (MTD) of erlotinib in advanced non–small-cell lung cancer (NSCLC) patients who smoke and compare the pharmacokinetics of erlotinib at the MTD in current smokers with 150 mg.
Patients and Methods
Cohorts of NSCLC patients currently smoking ≥ 10 cigarettes per day for ≥ 1 year received escalating doses of erlotinib for 14 days until dose-limiting toxicity (DLT). A separate cohort of patients was then randomly assigned to erlotinib at either MTD or 150 mg daily with pharmacokinetics assessed at day 14. Erlotinib was continued until progression or intolerable toxicity.
Four dose levels were evaluated in 22 patients: 200, 250, 300, and 350 mg. DLT was observed in one of six patients at 300 mg (rash) and two of five patients at 350 mg (acneiform dermatitis and fatigue/decreased Eastern Cooperative Oncology Group performance status). Thirty-five patients were randomly assigned to 150 mg or 300 mg. Common adverse events (all grades) were: skin toxicity (150 mg, 29%; 300 mg, 67%), diarrhea (150 mg, 18%; 300 mg, 50%), and fatigue (150 mg, 12%; 300 mg, 17%). Erlotinib exposure was dose-proportional within dose range tested. Median steady-state trough erlotinib plasma concentrations were 0.375 and 1.22 μg/mL for 150 mg and 300 mg, respectively.
The MTD of erlotinib in NSCLC patients who smoke was 300 mg. Steady-state trough plasma concentrations and incidence of rash and diarrhea in smokers at 300 mg were similar to those in former or never smokers receiving 150 mg in previous studies. The potential benefit of higher erlotinib doses in current smokers warrants further evaluation.
This phase I study was conducted to determine the maximum tolerated dose (MTD) of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) in patients with advanced colorectal cancer (CRC). Bevacizumab was later included as standard of care at the MTD.
Patients and Methods
Patients received FOLFOX4 with escalating doses of erlotinib: dose level (DL) 1, 50 mg; DL 2, 100 mg; and DL 3, 150 mg once daily continuously. Bevacizumab 5 mg/kg days 1 and 15 was added at the MTD upon Food and Drug Administration approval. Correlative studies included pharmacokinetics, pharmacodynamics was assessed in paired skin biopsies, and fluorodeoxyglucose positron emission tomography scans.
Fifteen patients received 60 cycles (120 FOLFOX treatments). Two dose-limiting toxicities (DLTs) were seen at DL 3: intolerable grade 2 rash (Common Terminology Criteria for Adverse Events version 2) lasting > 1 week, and grade 4 neutropenia. Dose level 2 was expanded to 6 more patients, this time adding bevacizumab, and 1 DLT of grade 3 mucositis occurred. As expected, the primary toxicities were cytopenias, diarrhea, rash, and fatigue. There were 2 occurrences of pneumatosis. One patient experienced an unrelated grade 4 myocardial infarction before starting chemotherapy. No pharmacokinetic drug interactions were observed. The Response Evaluation Criteria in Solid Tumors response rate was 11 of 14 (78%), median progression-free survival was 9.5 months, and median overall survival was 30 months. Three patients are currently alive > 3 years, with 1 having no evidence of disease.
The MTD of erlotinib with FOLFOX4 with or without bevacizumab is 100 mg daily. The regimen appeared to increase toxicity but showed activity in patients with CRC.
Epidermal growth factor receptor; Pharmacokinetics; Tyrosine kinase
GTI-2040, an antisense oligonucleotide, targets the ribonucleotide reductase R2 subunit, critical for DNA synthesis. This study determined the recommended phase 2 dose (RP2D) of docetaxel plus GTI-2040, toxicity, and response rate in advanced NSCLC.
Patients and Methods
Advanced solid tumor patients, preferably with platinum-treated NSCLC, performance status 0–2, no symptomatic CNS metastases, adequate organ and bone marrow function, and ≤ 1 prior chemotherapy regimen were treated with escalating doses of GTI-2040 given by 14-day continuous intravenous infusion plus docetaxel every 21 days.
29 patients were treated, (24 NSCLC, 3 hormone-refractory prostate cancer, 1 head and neck and 1 small cell lung cancer). GTI-2040 5 mg/kg as CVI for 14 days plus docetaxel 75 mg/m2 IV q21days was determined as the RP2D. Dose-limiting toxicity was not seen. Two patients at RP2D developed grade 4/5 febrile neutropenia. One PSA response was seen in Phase I, but no objective tumor responses in NSCLC patients. Median time to progression was 3.4 months, 3.2 months in NSCLC patients treated at RP2D.
Activity of the combination at RP2D, GTI-2040 5 mg/kg/day × 14 days by CVI plus docetaxel 75 mg/m2 does not appear superior to docetaxel alone in previously treated NSCLC.
antisense oligonucleotide; lung cancer; second-line; docetaxel; GTI-2040; ribonucleotide reductase; R2 subunit
High-dose ketoconazole and docetaxel have shown activity as single agents against castration-resistant prostate cancer (CRPC). The goal of this phase I study was to determine the maximum tolerated doses, side effects, and pharmacokinetic interaction of coadministered docetaxel and ketoconazole.
Patients with metastatic CRPC received weekly docetaxel for 3 of every 4 weeks, plus daily ketoconazole. Pharmacokinetic studies were performed on day 1 (docetaxel alone) and day 16 (after ketoconazole).
The study enrolled 42 patients at 9 different dose levels. The combination regimens investigated included docetaxel weekly for three weeks out of four escalating from 5 to 43 mg/m2, with starting doses of ketoconazole of 600, 800, or 1200 mg/day. Declines in prostate-specific antigen of ≥ 50% were seen in 62% of patients. Of 25 patients with soft tissue disease, 7 (28%) had partial response. Median overall survival was 22.8 months, and was significantly greater in docetaxel-naïve patients than in patients pretreated with docetaxel (36.8 vs. 10.3 months; P = 0.0001). The most frequently observed adverse events were anemia, edema, fatigue, diarrhea, nausea, sensory neuropathy, and elevated liver function tests. The fractional change in docetaxel clearance correlated significantly with ketoconazole exposure (P < 0.01). Concomitant ketoconazole increased docetaxel exposure 2.6-fold with 1200 mg/day, 1.6-fold with 800 mg/day, and 1.3- to 1.5-fold with 600 mg/day.
Results suggest that the combination of weekly docetaxel and ketoconazole has significant antitumor activity in CRPC with manageable toxicities. The extremely long survival in the docetaxel-naïve cohort (36.8 months) warrants additional larger trials of docetaxel with ketoconazole or possibly CYP17A1 inhibitors such as abiraterone.
castration-resistant prostate cancer; docetaxel; ketoconazole; drug-drug interaction; CYP3A4
PF299804 is a potent, orally available, irreversible inhibitor of tyrosine kinase human epidermal growth factor receptors (HER) 1 (EGFR), HER2, and HER4. This first-in-human study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF299804 in patients with advanced solid malignancies.
PF299804 was administered once daily continuously (schedule A), and intermittently (schedule B). Dose escalation proceeded until intolerable toxicities occurred. Skin biopsies were taken pre-dose and after 14 days of treatment, to establish a pharmacokinetic/pharmacodynamic relationship. Tumor response was measured once every 2 cycles. Efficacy was correlated with tumor genotypes in non-small cell lung cancer (NSCLC) patients.
121 patients were included (111 in schedule A, 10 in schedule B). The maximum tolerated dose (MTD) was 45 mg/day. Dose-limiting toxicities included stomatitis and skin toxicities. Most adverse events were mild and comprised skin toxicities, fatigue, and gastrointestinal side-effects including diarrhea, nausea, and vomiting. Pharmacokinetic analyses revealed dose-dependent increases in PF299804 exposure associated with target inhibition in skin biopsy samples. Fifty-seven patients with non-small cell lung cancer (NSCLC) were treated in this study. Four patients, all previously treated with gefitinib or erlotinib (2 with exon 19 deletions, 1 with exon 20 insertion, 1 mutational status unknown), had a partial response to PF299804.
The MTD of PF299804 is 45 mg/day. Both continuous and intermittent treatment schedules were well tolerated, and encouraging signs of antitumor activity were observed in gefitinib/erlotinib treated NSCLC patients.
Phase I clinical trial; Non-small cell lung cancer; epidermal growth factor receptor; mutation; kinase inhibitor
S-1 is a novel oral fluorouracil prodrug that plays a role in non-small cell lung cancer (NSCLC). Docetaxel (DTX) is one of the standard agents for relapsed NSCLC. We performed a phase I study of DTX plus S-1 combination therapy as second-line treatment for NSCLC to determine the maximum tolerated dose (MTD) and recommended dose (RD). Patients with recurrent NSCLC, aged 20–74 years with an Eastern Cooperative Oncology Group performance status of 0–1 and measurable lesions, were enrolled. The treatment consisted of four dose levels. The patients received DTX (40–60 mg/m2 intravenously on day 1) and S-1 (65–80 mg/m2 orally, daily on days 1–14) for each 21-day cycle. Three to six patients were treated at each dose level with the two drugs, with MTD defined as the dose level at which dose-limiting toxicity (DLT) occurred in 33% of the patients. A total of 17 patients were enrolled. At dose level 4 (DTX, 60 mg/m2; S-1, 80 mg/m2) 3 of 5 patients experienced DLT and this level was regarded as the MTD. Therefore, dose level 3 (DTX, 60 mg/m2; S-1, 65 mg/m2) was selected as the RD for subsequent studies. The DLTs were neutropenia (grade 4) and mucositis (grade 3). The response rate was 5.9% (1 of 17 patients achieved a partial response) and 14 of 17 patients achieved stable disease. This combination regimen showed a tolerable and manageable profile in recurrent NSCLC and therefore warrants further evaluation.
docetaxel; S-1; phase I
The purpose of this study was to investigate the safety, tolerability, and pharmacokinetics of motesanib when combined with docetaxel or paclitaxel in patients with metastatic breast cancer. In this open-label, dose-finding, phase 1b study, patients received motesanib 50 or 125-mg orally once daily (QD), beginning day 3 of cycle 1 of chemotherapy, continuously in combination with either paclitaxel 90 mg/m2 on days 1, 8, and 15 every 28-day cycle (Arm A) or docetaxel 100 mg/m2 on day 1 every 21-day cycle (Arm B). Dose escalation to motesanib 125 mg QD occurred if the incidence of dose-limiting toxicities (DLTs, primary endpoint) was ≤33 %. If the maximum tolerated dose (MTD) of motesanib was established in Arm B, additional patients could receive motesanib at the MTD plus docetaxel 75 mg/m2. Forty-six patients were enrolled and 45 received ≥1 dose of motesanib. The incidence of DLTs was <33 % in all cohorts; thus, motesanib 125 mg QD was established as the MTD. Seven patients (16 %) had grade 3 motesanib-related adverse events including cholecystitis (2 patients) and hypertension (2 patients). Pharmacokinetic parameters of motesanib were similar to those reported in previous studies. The objective response rate was 56 % among patients with measurable disease at baseline who received motesanib in combination with taxane-based chemotherapy. The addition of motesanib to either paclitaxel or docetaxel was generally tolerable up to the 125-mg QD dose of motesanib. The objective response rate of 56 % suggests a potential benefit of motesanib in combination with taxane-based chemotherapy.
Motesanib; Breast cancer; Angiogenesis; VEGF; Chemotherapy
The aim of the study was to determine the maximum tolerated dose (MTD) for the combination of high-dose epirubicin and vinorelbine in chemotherapy-naive patients with inoperable non-small-cell lung cancer (NSCLC). Twenty-one patients with stage IIIB and IV NSCLC were treated in a single-centre study with escalating doses of epirubicin and vinorelbine given on an outpatient basis. The first dose level comprised epirubicin 100 mg m-2 on day 1 and vinorelbine 20 mg m-2 (days 1 and 8) given intravenously every 3 weeks. Escalating doses for epirubicin and vinorelbine were respectively 120 (day 1) and 20 (days 1 and 8), 120 (day 1) and 25 (days 1 and 8) and 135 (day 1) and 25 (days 1 and 8) mg m-2. Inclusion criteria were age < or = 75 years, ECOG performance score < or = 2 and normal renal, hepatic and bone marrow functions. Dose-limiting toxicities were thrombocytopenia grade II and neutropenia grade III on day 8, febrile neutropenia, and neutropenia lasting > 7 days. No dose-limiting toxicity (DLT) was observed at the first dose level; at the 135/25 mg m-2 dose level three out of six patients had a DLT which was considered as unacceptable. The only non-haematological toxicity reaching grade III was nausea/vomiting. One patient showed cardiac toxicity. No neurotoxicity and no treatment-related deaths were seen. The maximum tolerated dose of epirubicin and vinorelbine is 135 mg m-2 (day 1) and 25 mg m-2 (days 1 and 8) respectively, causing mainly haematological toxicity. The recommended dose of epirubicin and vinorelbine for phase II studies is found to be 120 mg m-2 and 20 mg m-2 respectively.
Although docetaxel monotherapy has shown clinical benefits for previously treated patients with advanced non-small cell lung cancer (NSCLC), the efficacy of salvage docetaxel chemotherapy for elderly patients or patients with poor performance status (PS) is controversial. Therefore, we conducted a phase II trial to evaluate the safety and efficacy of weekly low-dose docetaxel monotherapy in these patients. Forty NSCLC patients, who had been previously treated with one or more chemotherapy regimens, received docetaxel at a dose of 25 mg/m2 weekly on days 1, 8, and 15 of a 28-day cycle. All patients were ≥65 yr or had a PS of grade 2 in the cases of <65 yr. Weekly low-dose docetaxel was well-tolerated. Grade 3/4 non-hematologic toxicities were rare; fatigue in 3 patients (8%), anorexia in 3 patients (8%) and stomatitis in 2 patients (5%). Grade 3/4 neutropenia was noted in only one patient (3%). By intent-to-treat analysis, nine patients (23%) had partial responses and eleven patients (28%) demonstrated stable disease. The median progression-free survival and overall survival were 9.9 weeks and 37.7 weeks, respectively. Weekly low-dose docetaxel therapy provides a reasonable alternative for NSCLC salvage treatment in pretreated elderly patients or in patients with a reduced PS.
Weekly Docetaxel; Carcinoma, Non-small-Cell Lung; Aged; Second-Line Therapy
Docetaxel alone has been confirmed to be beneficial to patients with advanced previously treated non-small cell lung cancer (NSCLC). However, the duration and survival time is short. The study of two-agent combination regimens has important clinical significance. We conducted this randomized controlled phase II trial to comparatively evaluate the efficacy and side effects of capecitabine combined with docetaxel in previously treated patients with NSCLC. Patients with previously treated NSCLC who failed first-line chemotherapy were randomized into two groups; one received capecitabine combined with docetaxel (XT group) and the other received docetaxel alone (T group). Patients in the XT group received chemotherapy as follows: capecitabine 625 mg/m2, p.o. bid, days 5-18; and docetaxel 30 mg/m2, days 1 and 8, while patients in the T group received docetaxel 35 mg/m2 on days 1 and 8. The primary endpoint was time to progression (TTP), and secondary endpoints were overall survival (OS), response rate (RR) and disease control rate (DCR). Forty-eight patients were recruited (23 in the XT group and 25 in the T group). TTP, median survival time (MST) and 1-year OS rate in the XT group and the T group were 7 months, 12 months, 47.6% and 3 months, 12 months, 39.6%, respectively. The TTP in the XT group was significantly longer compared to that in the T group (χ2=4.763, p=0.029). The RR and DCR in the XT group and T group were 13.0% (3/23), 78.3% (18/23) and 12.0% (3/25), 76% (19/25), respectively. The difference was not significant (p>0.05). The major side effects observed in the two groups were neutropenia, fatigue and nausea, and toxicities were mild to modest. No severe cases of hand-foot syndrome were observed in the XT group. In conclusion, compared with docetaxel alone, capecitabine combined with docetaxel for patients with previously treated NSCLC achieved a significantly longer TTP and this regimen was well tolerated. The relatively high median TTP, 1-year OS rate and DCR encourage further evaluation of this regimen in a randomized phase III trial.
non-small cell lung cancer; chemotherapy; second-line therapy; capecitabine; docetaxel
We conducted a phase I study of dasatinib, an oral SRC-family tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in advanced and recurrent epithelial ovarian cancer.
The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included defining toxicity, response rate (RR), pharmacokinetics and pharmacodynamics. Using a “3+3” design, cohorts of 3–6 patients received paclitaxel (175 mg/m2) and carboplatin (AUC 6) every three weeks with escalating doses of dasatinib (100, 120, 150 mg daily), followed by an 8 patient expansion cohort.
Twenty patients were enrolled between 06/07 and 12/09. The median age was 61 years (42–82) with a median of 2 prior regimens (0–6), and 71% had platinum-sensitive disease. There were 3–6 patients in each cohort, and 8 in the expansion cohort. Pharmacokinetics were observed over the first 2 cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia). Other toxicities in all cycles included neutropenia (95% grade 3–4; 91% in the 150 mg dosing cohort), thrombocytopenia (35% grade 3–4), and fatigue (10% grade 3). The RR was 40% (3 complete responses, (15%); 5 partial responses, (25%)),10 (50%) had stable disease, and 2 were not evaluable. The PFS6-month actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively.
Due to the high incidence of myelosuppression with subsequent cycles the recommended phase II dose of dasatinib is 150 mg daily in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity.
dasatinib; chemotherapy; ovarian cancer
A Phase I study to define toxicity and recommend a Phase II dose of the HSP90 inhibitor alvespimycin (17-DMAG; 17-dimethylaminoethylamino-17-demethoxygeldanamycin). Secondary endpoints included evaluation of pharmacokinetic profile, tumor response and definition of a biologically effective dose (BED).
Patients and Methods
Patients with advanced solid cancers were treated with weekly, intravenous (IV) 17-DMAG. An accelerated titration dose escalation design was used. The maximum tolerated dose (MTD) was the highest dose at which ≤ 1/6 patients experienced dose limiting toxicity (DLT). Dose de-escalation from the MTD was planned with mandatory, sequential tumor biopsies to determine a BED. Pharmacokinetic and pharmacodynamic assays were validated prior to patient accrual.
Twenty five patients received 17-DMAG (range 2.5 to 106 mg/m2). At 106mg/m2 of 17-DMAG 2/4 patients experienced DLT, including one treatment related death. No DLT occurred at 80mg/m2. Common adverse events were gastrointestinal, liver function changes and ocular. AUC and Cmax increased proportionally with 17-DMAG doses ≤ 80mg/m2. In peripheral blood mononuclear cells significant (p <0.05) HSP72 induction was detected (≥ 20mg/m2) and sustained for 96 hours (≥ 40mg/m2). Plasma HSP72 levels were greatest in the two patients who experienced DLT. At 80mg/m2 client protein (CDK4, LCK) depletion was detected and tumor samples from 3/5 patients confirmed HSP90 inhibition. Clinical activity included complete response (castration refractory prostate cancer, CRPC 124 weeks), partial response (melanoma, 159 weeks) and stable disease (chondrosarcoma, CRPC and renal cancer for 28, 59 and 76 weeks respectively).
The recommended Phase II dose of 17-DMAG is 80mg/m2 weekly, IV.
Published data suggests that docetaxel combined with 5-fluorouracil (5-FU) may have synergistic activity in treating advanced gastric cancer. We performed a phase I study of docetaxel and 5-FU to determine the maximum tolerated dose (MTD), the recommended dose for phase II studies, and the safety of this combination.
Eligible patients had recurrent and/or metastatic advanced gastric cancer with normal cardiac, renal and hepatic function. Traditional phase I methodology was employed in assessing dose-limiting toxicity (DLT) and MTD. On day 1 every 3 weeks, docetaxel 75 mg/m2 (fixed dose) was infused over 1-h, followed immediately by 5-FU as a 5-day continuous infusion.
Dose escalation schema was as follows: dose level (DL) 1 (5-FU 250 mg/m2/day), 2 (500), 3 (750), and 4 (1000). Three patients were enrolled on DL1, without DLT. On DL2, 1 DLT (grade 3 stomatitis) was developed in first 3 patients, and this cohort was expanded to 6 patients. Three patients had been enrolled on DL3. Because two out of 3 patients had DLTs, the MTD was reached at DL3.
The recommended phase II dose of this combination is 75 mg/m2 docetaxel on day 1 immediately followed by a 5-day continuous infusion of 5-FU 500 mg/m2/day.
This investigator-initiated study explores the safety, maximum tolerated dose (MTD), clinical response, and pharmacokinetics (PK) of hydroxychloroquine (HCQ) with and without erlotinib in patients with advanced non-small cell lung cancer (NSCLC).
Patients with prior clinical benefit from an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor were randomized to HCQ or HCQ plus erlotinib in a 3+3 dose escalation schema.
Twenty-seven patients were treated, 8 with HCQ (arm A) and 19 with HCQ plus erlotinib (arm B). EGFR mutations were detected in 74% of patients and 85% had received ≥2 prior therapies. Arm A had no dose-limiting toxicities (DLTs), but the MTD was not reached as this arm closed early to increase overall study accrual. In arm B, 1 patient each experienced grade 3 rash, nail changes, skin changes, nausea, dehydration, and neutropenia, 1 had grade 4 anemia, and 1 developed fatal pneumonitis, all considered unrelated to HCQ. There were no DLTs, therefore the highest tested dose for HCQ with erlotinib 150mg was 1000mg daily. One patient had a partial response (PR) to erlotinib/HCQ, for an overall response rate of 5% (95% CI, 1–25). This patient had an EGFR mutation and remained on therapy for 20 months. Administration of HCQ did not alter the PK of erlotinib.
HCQ with or without erlotinib was safe and well-tolerated. The recommended phase 2 dose of HCQ was 1000mg when given in combination with erlotinib 150mg.
This phase ii clinical trial examined the activity of a metronomic dosing schedule of docetaxel and capecitabine chemotherapy in patients with advanced breast cancer. Patients also received daily oral celecoxib in an effort to improve outcome measures and to ameliorate some of the common side effects of chemotherapy.
Patients received docetaxel at a starting dose of 15 mg/m2 weekly, oral capecitabine 1250 mg/m2 once daily, and oral celecoxib 200 mg twice daily. The primary endpoint was clinical benefit: percentage of patients experiencing either an objective response or stable disease (sd) for more than 6 months. In the absence of significant neutropenia, the dose of docetaxel was escalated after 4 and 8 weeks of treatment. Therapy was given until disease progression or development of unacceptable toxicity. The level of thymidine phosphorylase expression in peripheral white blood cells of patients was measured before and during treatment to determine the effect on this capecitabine-activating enzyme.
Of 47 patients enrolled, 38 (81%) completed treatment to a disease endpoint. No complete responses were achieved, but 13 of the 38 patients (34%) experienced a partial response, and another 3 patients (8%) experienced sd for more than 6 months. The clinical benefit rate was therefore 42% (95% confidence interval: 27% to 57%). The median time to disease progression for all evaluable patients was 3.6 months (range: 0.9–21.7 months). The most common nonhematologic toxicities were diarrhea, plantar– palmar erythrodysesthesia, fatigue, mucositis, and vomiting. Most patients (89%) received combination chemotherapy until disease progression.
The present study demonstrates that metronomic docetaxel–capecitabine chemotherapy with daily celecoxib can produce significant anticancer activity, with predictable toxicity. Efficacy fell short of expectations, with outcome measures being similar to those obtained when the study agents are given in conventional dosing. Furthermore, there is mounting evidence to indicate that a low dose of taxanes fails to induce thymidine phosphorylase expression, an effect believed to be important in achieving therapeutic synergism when taxanes are given concurrently with capecitabine.
Metastatic breast cancer; metronomic chemotherapy; docetaxel; capecitabine
This phase I study assessed the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of SJG-136, a sequence-specific DNA cross-linking agent, in patients with advanced cancer.
In Schedule A, seven patients received escalating doses of SJG-136 (6, 12, 24, and 48 µg/m2) daily for 5 of 21 days. Blood samples were collected for PK analysis on Days 1 and 5 of Cycle 1. In Schedule B, SJG-136 was given daily for 3 of 21 days (N=17; doses 20, 25, 30, and 35 µg/m2). Blood samples were collected on Days 1 and 3 of Cycles 1 and 2 for PK and PD analysis. Patients in Schedule B received dexamethasone and early diuretic care.
Schedule A: dose-limiting toxicities included Grade 3 edema, dyspnea, fatigue, and delayed liver toxicity (Grade 3/4). PK analysis revealed dose-dependent increases in AUC and Cmax. Substantial changes in volume of distribution at steady-state (Vss) occurred after repeated dosing in some patients prior to the onset of edema. Schedule B: the same toxicities were manageable with steroid premedication and diuretic support. No significant myelosuppression occurred on either schedule. DNA interstrand cross-links correlated with systemic exposure of SJG-136 following the second dose in Cycle 1 and were still detectable immediately before Cycle 2.
The MTD of SJG-136 in this study was 30 µg/m2 administered on a daily × 3 basis with no myelosuppression effects. Coupled with supportive management, SJG-136 is now advancing to a Phase II trial in ovarian cancer.
SJG-136; clinical trial; cancer; Phase I; pharmacokinetics; pharmacodynamics
To improve local control for inoperable non-small cell lung cancer (NSCLC), a phase I dose escalation study for locally advanced and medically inoperable patients was devised to escalate tumor dose while limiting the dose to organs at risk including the esophagus, spinal cord, and residual lung. Helical tomotherapy provided image-guided IMRT, delivered in a 5-week hypofractionated schedule to minimize the effect of accelerated repopulation.
Forty-six patients judged not to be surgical candidates with Stage I-IV NSCLC were treated. Concurrent chemotherapy was not allowed. Radiotherapy was delivered via helical tomotherapy and limited to the primary site and clinically proven or suspicious nodal regions without elective nodal irradiation. Patients were placed in 1 of 5 dose bins, all treated for 25 fractions, with dose per fraction ranging from 2.28 to 3.22 Gy. The bin doses of 57 to 80.5 Gy result in 2 Gy/fraction normalized tissue dose (NTD) equivalents of 60 to 100 Gy. In each bin, the starting dose was determined by the relative normalized tissue mean dose modeled to cause < 20% Grade 2 pneumonitis. Dose constraints included spinal cord maximum NTD of 50 Gy, esophageal maximum NTD < 64 Gy to ≤ 0.5 cc volume, and esophageal effective volume of 30%.
No grade 3 RTOG acute pneumonitis (NCI-CTC v.3) or esophageal toxicities (CTCAE v.3.0 and RTOG) were observed at median follow-up of 8.1 months. Pneumonitis rates were 70% grade 1 and 13% grade 2. Multivariate analysis identified lung NTDmean (p=0.012) and administration of adjuvant chemotherapy following radiotherapy (p=0.015) to be independent risk factors for grade 2 pneumonitis. Only 7 patients (15%) required narcotic analgesics (RTOG grade 2 toxicity) for esophagitis, with only 2.3% average weight loss during treatment. Best in-field gross response rates were 17% complete response, 43% partial response, 26% stable disease, and 6.5% in-field thoracic progression. The out-of-field thoracic failure rate was 13%, and distal failure rate was 28%. The median survival was 18 months with 2-year overall survival of 46.8% ± 9.7% for this cohort, 50% of whom were stage IIIB and 30% stage IIIA.
Dose escalation can be safely achieved in NSCLC with lower than expected rates of pneumonitis and esophagitis using hypofractionated image-guided IMRT. The maximum tolerated dose has yet to be reached.
Hypofractionation; Dose Escalation; Tomotherapy; Image Guided Radiotherapy; IMRT
To study a commonly used Astragalus-based herbal formula previously found effective in non-small cell lung cancer (NSCLC) on the pharmacokinetics of docetaxel in patients with NSCLC.
Patients with advanced NSCLC who progressed after prior platinum-containing chemotherapy were accrued and received docetaxel at 35 mg/m2 for 3 weeks followed by 1 week of rest. At 4 days prior to the second dosing, Jinfukang was given orally. Pharmacokinetic studies of initial-dose docetaxel (in the absence of Jinfukang) and the third dose (in the presence of Jinfukang) were compared.
Of the 24 patients enrolled, 21 started Jinfukang and docetaxel. Jinfukang had no significant impact on the pharmacokinetics of docetaxel. Median time to progression or withdrawal from treatment was 7 weeks. Twelve patients were removed from study for progression of disease; nine patients withdrew.
Jinfukang did not alter the pharmacokinetics of docetaxel nor appear to affect survival in this study.
Lung cancer; Chemotherapy; Docetaxel; Botanicals; Astragalus
Exisulind is an apoptotic agent with preclinical activity in non-small cell lung cancer (NSCLC). Vinorelbine is safe and effective in older patients with advanced NSCLC. We assessed these agents together as palliative treatment for older patients with advanced NSCLC.
Chemotherapy-naïve patients ≥ 70 years old with stage IIIB-IV NSCLC and a performance status (PS) ≤ 2 were eligible. Primary endpoints were the maximum tolerated dose (MTD, phase I) and time-to-progression (TTP, phase II) of oral exisulind with 25 mg/m2/week of intravenous (IV) vinorelbine on a 28-day cycle. Patients with clinical benefit after six cycles of this combination received exisulind alone.
Fourteen phase I patients (median PS 1; median age 78 years) were enrolled. Dose-limiting toxicities included grade 3 constipation (one patient), grade 3 febrile neutropenia (one patient) and grade 3 diarrhea (one patient). The MTD of oral exisulind with 25 mg/m2/week of IV vinorelbine was 125 mg twice daily. Thirty phase II patients (median PS 1; median age 78 years) were enrolled. Grade ≥ 3 neutropenia occurred in 14/30 patients. Two patients experienced neutropenic fever. There were no complete responses, one partial response and 12 patients with stable disease as their best response. The objective response rate was 4.0% (95% CI: 0.1–20.4%). Phase II median TTP was 4.7 months (95% CI: 3.1 – 9.3 months) and median OS was 9.6 months (95% CI: 6.6 – 19.1 months).
This combination is safe, appears to have activity in the elderly with advanced NSCLC and a PS ≤ 2, and warrants further investigation.
Elderly; exisulind; sulindac sulfone; non-small cell lung cancer; vinorelbine; phase I; phase II
To evaluate the anticancer activity of erlotinib in patients with previously treated, advanced non-small cell lung cancer (NSCLC) whose dose is increased to that associated with a maximal level of tolerable skin toxicity (i.e., target rash (TR)); to characterise the pharmacokinetics (PK) and pharmacodynamics (PD) of higher doses of erlotinib.
Patients initially received erlotinib 150 mg per day. The dose was successively increased in each patient to that associated with a TR. Anticancer activity was evaluated. Plasma, skin, and hair were sampled for PK and PD studies.
Erlotinib dose escalation to 200–475 mg per day was feasible in 38 (90%) of 42 patients. Twenty-four (57%) patients developed a TR, but 19 (79%) did so at 150 mg per day. Five (12%) patients, all of whom developed a TR, had a partial response. Median progression-free survival (PFS) was 2.3 months (95% CI: 1.61, 4.14); median PFS was 3.5 months and 1.9 months, respectively, for patients who did and did not experience a TR (hazard ratio, 0.51; P=0.051). Neither rash severity nor response correlated with erlotinib exposure.
Intrapatient dose escalation of erlotinib does not appreciably increase the propensity to experience a maximal level of tolerable skin toxicity, or appear to increase the anticancer activity of erlotinib in NSCLC.
erlotinib; non-small cell lung cancer; EGFR; skin rash
BIBF 1120 is an oral, potent, tyrosine kinase inhibitor that simultaneously targets vascular endothelial growth factor receptors 1–3, platelet-derived growth factor receptors α and β, and fibroblast growth factor receptors 1–3, as well as FLT3 and Src. Currently, the molecule is in phase III development for second-line non-small cell lung cancer and first-line ovarian cancer patients.
This phase I dose-escalation study assessed the safety and maximum tolerated dose of continuous daily treatment with BIBF 1120 plus standard-dose docetaxel (75 mg m−2, every 3 weeks) and prednisone (5 mg BID) in patients with metastatic, chemo-naive, hormone-refractory prostate cancer (HRPC). Secondary objectives were characterisation of BIBF 1120 and docetaxel pharmacokinetics (PK), and preliminary antitumour activity.
Patients received BIBF 1120 100 mg BID (n=3), 150 mg BID (n=3), 200 mg BID (n=3), and 250 mg BID (n=12). The most frequent drug-related adverse events were diarrhoea (71.4%), asthenia (61.9%), nausea (28.6%), vomiting (28.6%), and alopecia (23.8%). The maximum tolerated dose was 250 mg BID of BIBF 1120. Overall, reversible grade 3/4 liver enzyme elevations occurred in six of twelve patients at this dose level. Among 19 assessable patients, 13 (68.4%) showed a ⩾50% reduction in prostate serum antigen levels from baseline and among 6 evaluable patients with measurable lesions 1 patient experienced a partial response by Response Evaluation Criteria In Solid Tumours criteria. Pharmacokinetic analysis showed no interactions between BIBF 1120 and docetaxel/prednisone.
Based on the overall safety profile, 200 mg BID was the recommended dose for the combination of BIBF 1120 with the standard dose of 75 mg m−2 of docetaxel and prednisone that might be further investigated in HRPC patients. This combination was well tolerated, with preliminary signs of efficacy and no indication of PK interaction between BIBF 1120 and docetaxel.
phase I; multi-kinase inhibitor; prostate cancer