Phase I study of pazopanib in combination with weekly paclitaxel in patients with advanced solid tumors

Purpose.

To evaluate the maximum tolerated regimen (MTR), dose-limiting toxicities, and pharmacokinetics of pazopanib, an oral small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, in combination with paclitaxel.

Patients and Methods.

Pazopanib was given daily with weekly paclitaxel on days 1, 8, and 15 every 28 days. Dose levels of pazopanib (mg/day)/paclitaxel (mg/m²) were 400/15, 800/15, 800/50, and 800/80. An expanded cohort was enrolled at the MTR. Plasma samples were collected to evaluate the effect of pazopanib, an inhibitor of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP3A4 and CYP2C8 substrate.

Results.

Of 26 enrolled patients, 17 were treated at the MTR of 800 mg pazopanib and 80 mg/m² paclitaxel. Dose-limiting toxicities included a grade 3 abscess and grade 2 hyperbilirubinemia. Other toxicities included elevated liver transaminases and diarrhea. Six patients (23%) had partial responses and 15 patients (58%) had stable disease. Administration of 800 mg pazopanib resulted in a 14% lower paclitaxel clearance and a 31% higher paclitaxel maximal concentration than with administration of paclitaxel alone at 15, 50, and 80 mg/m². At the MTR, coadministration of 800 mg pazopanib and 80 mg/m² paclitaxel resulted in a 26% higher geometric mean paclitaxel area under the curve.

Conclusion.

Pazopanib, at a dose of 800 mg daily, can be safely combined with a therapeutic dose of paclitaxel at 80 mg/m² when administered on days 1, 8, and 15, every 28 days. The observed greater plasma concentrations of paclitaxel given concurrently with pazopanib suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2C8.     

Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer

BACKGROUND:

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are rational targets for therapy in hepatocellular cancer (HCC).

METHODS:

Patients with histologically proven HCC and not amenable to curative or liver directed therapy were included in this 2‐stage phase 2 trial. Eligibility included an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and Child's Pugh score of A or B, and 1 prior systemic therapy. Patients received erlotinib 150 mg daily and bevacizumab 10 mg/kg on days 1 and 15 every 28 days. Objective tumor response was the primary end point.

RESULTS:

Twenty‐seven patients with advanced HCC (median age, 60 years) were enrolled in this multi‐institutional study. The proportion of patients with Child's A classification was 74%. One patient had a confirmed partial response and 11 (48%) achieved stable disease. Median time to disease progression was 3.0 months (95% confidence interval [CI], 1.8‐7.1). Median survival time was 9.5 months (95% CI, 7.1‐17.1). Grade 3 toxicities included rash, hypertension, fatigue, and diarrhea.

CONCLUSIONS:

In this trial, erlotinib combined with bevacizumab had minimal activity in patients with advanced HCC based on objective response and progression‐free survival. The role of targeting EGFR and VEGF in HCC needs further evaluation in molecularly selected patients. Cancer 2012. © 2011 American Cancer Society.     

Phase I and pharmacokinetic study of vatalanib plus capecitabine in patients with advanced cancer

Angiogenesis inhibition is now a proven therapeutic strategy in treatment of several solid tumors. Vatalanib is a potent inhibitor of all known vascular endothelial growth factor receptor (VEGFR) tyrosine kinases. In view of the effectiveness of angiogenesis inhibitor therapy when combined with chemotherapy and the established role of capecitabine in treatment of colorectal and breast cancer, we undertook a phase I clinical trial of the combination of capecitabine and vatalanib with the goal of developing a combination oral regimen. The study objectives were to determine the maximally tolerated dose of vatalanib that could be safely administered daily with capecitabine given orally for 14 out of 21 days to patients with advanced cancer; to characterize the safety, tolerability, and pharmacokinetic profile of vatalanib given in combination with capecitabine; and to describe any pharmacokinetic interactions between the drugs. The study had an initial dose escalation phase followed by a dose expansion phase. During the dose escalation phase, cohorts of at least three patients each were treated with capecitabine and escalating doses of vatalanib until the maximally tolerated dose of vatalanib was determined. Vatalanib given continuously at a dose of 1,250 mg/day could be safely combined with capecitabine at a dose of 2,000 mg/m²/day given for 14 of 21 days. Dose-limiting toxicities of the combination included fatigue, hypertension, dizziness, and proteinuria. Vatalanib did not alter the pharmacokinetics of 5-FU, the active metabolite of capecitabine. Vatalanib and capecitabine can be safely combined without unexpected toxicities or significant pharmacokinetic interactions.     

Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma

BACKGROUND: Epidermal growth factor receptor (EGFR) and ligand expression is frequently seen in hepatocellular carcinoma (HCC). A phase 2 study was performed with cetuximab, a chimeric monoclonal antibody that binds specifically to EGFR, in patients with advanced HCC. METHODS: Eligibility criteria included unresectable or metastatic measurable HCC, an Eastern Cooperative Oncology Group performance status 相似文献   

Phase I study of olaratumab in Japanese patients with advanced solid tumors

Olaratumab (IMC‐3G3) is a fully human IgG1 monoclonal antibody that selectively binds the external domain of human platelet‐derived growth factor receptor‐α with high affinity and blocks ligand binding. This was a single‐center, dose‐escalation, phase I trial of olaratumab in Japanese patients with advanced/refractory solid malignancies. Three to six patients were enrolled into each of three cohorts: Patients received i.v. olaratumab: 10 mg/kg on days 1 and 8 every 3 weeks (cohort 1); 20 mg/kg every 2 weeks (cohort 2); and 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3). Doses were escalated from cohort 1 through cohort 3. The primary objective was to establish the safety and pharmacokinetic profile of olaratumab. Sixteen patients were treated across three cohorts. There were no dose‐limiting toxicities, so the maximum tolerated dose was not reached. The most common olaratumab‐related treatment‐emergent adverse events (TEAEs) were proteinuria (25.0%) and elevated aspartate transaminase (12.5%). One patient (cohort 2) had two olaratumab‐related Grade 3 TEAEs (increased aspartate aminotransferase and tumor hemorrhage); otherwise, olaratumab‐related TEAEs were Grade 1/2. Seven patients (43.8%) had a best response of stable disease. Based on the pharmacokinetic concentration profile of olaratumab, the trough concentrations following single and multiple doses at 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3) and multiple doses at 20 mg/kg every 2 weeks (cohort 2) were above the 155 μg/mL target. Thus, these two doses could represent an acceptable schedule for future trials in Japanese patients. Olaratumab had an acceptable safety profile and was well tolerated.     

Treatment of advanced renal cell carcinoma with the combination bevacizumab/erlotinib/imatinib: a phase I/II trial

PURPOSE: The aim of this study was to evaluate the efficacy and toxicity of imatinib, a platelet-derived growth factor-beta receptor antagonist, when added to the combination bevacizumab/erlotinib in the treatment of patients with advanced clear cell renal carcinoma. PATIENTS AND METHODS: Ninety-four patients with metastatic clear cell renal carcinoma were treated with bevacizumab 10 mg/kg intravenously every 2 weeks, erlotinib 150 mg orally daily, and imatinib 400 mg orally daily. Patients were reevaluated after 8 weeks of treatment; patients with objective response or stable disease (SD) continued to receive treatment until they experienced tumor progression. RESULTS: Fifteen of 88 evaluable patients (17%; 95% confidence interval, 10%-26%) had partial responses, whereas an additional 54 patients (61%) had SD. The median progression-free and overall survival for all patients was 8.9 months and 17.2 months, respectively. The addition of imatinib markedly increased toxicity compared with the bevacizumab/erlotinib regimen; the most common grade 3/4 toxicities were diarrhea, rash, and fatigue. CONCLUSION: Bevacizumab/erlotinib/imatinib was unacceptably toxic in this group of patients. Inhibition of the PDGF receptor (PDGFR) with imatinib did not appear to improve efficacy compared retrospectively with the results of treatment with bevacizumab/erlotinib. The importance of PDGFR inhibition in the treatment of advanced clear cell renal carcinoma remains unclear. Further development of this particular combination is not planned or recommended.     

Phase II randomised discontinuation trial of cabozantinib in patients with advanced solid tumours

BackgroundCabozantinib is an inhibitor of tyrosine kinases, including MET, vascular endothelial growth factor receptor, AXL and RET. This multi-cohort phase II randomised discontinuation trial explored anticancer activity of cabozantinib in nine tumour types.Patients and methodsCabozantinib was administered (100 mg, once daily) to patients with advanced, recurrent or metastatic cancers. Those with stable disease at week 12 were randomised 1:1 to cabozantinib or placebo. Primary end-points were objective response rate (ORR) at week 12 and progression-free survival (PFS) in the randomised phase.ResultsA total of 526 patients were enrolled. The highest ORR was observed in ovarian cancer (OC) (21.7%); the largest PFS benefit was observed in castration-resistant prostate cancer (CRPC) (median 5.5 versus 1.4 months for placebo; hazard ratio 0.14, 95% confidence interval: 0.04, 0.52). Disease control rates were >40% for CRPC, OC, melanoma, metastatic breast cancer (MBC), hepatocellular carcinoma (HCC) and non–small cell lung cancer. Median duration of response ranged from 3.3 (MBC) to 11.2 months (OC). Encouraging efficacy results and symptomatic improvements prompted early suspension of the randomised stage and conversion to open-label non-randomised expansion cohorts. Dose reductions to manage adverse events (AEs) occurred in 48.7% of patients. The most frequent grade III–IV AEs were fatigue (12.4%), diarrhoea (10.5%), hypertension (10.5%) and palmar-plantar erythrodysesthesia syndrome (8.7%).ConclusionsClinical antitumour activity of cabozantinib was observed in a subset of tumour types: CRPC and OC were evaluated further in expansion cohorts. Phase III programs were initiated in CRPC and HCC. Interpretation of efficacy outcomes was limited by early termination of the randomised portion of the trial.Trial registration numberNCT00940225.     

Safety and pharmacokinetic study of RPI.4610 (ANGIOZYME), an anti-VEGFR-1 ribozyme, in combination with carboplatin and paclitaxel in patients with advanced solid tumors

Purpose RPI.4610 (ANGIOZYME) is a chemically stabilized ribozyme targeting vascular endothelial growth factor receptor 1. The purpose of this study was to evaluate the safety and pharmacokinetics of RPI.4610 in combination with carboplatin and paclitaxel in patients with advanced solid tumors.Methods The study used a sequential treatment design evaluating a single dose level for all three drugs: paclitaxel 175 mg m^–2 and carboplatin AUC=6 on day 1 of a 21-day cycle, and RPI.4610 100 mg m^–2 day^–1 beginning on day 8 and continuing daily thereafter. Pharmacokinetic samples were drawn on day 1 of courses 1 (chemotherapy alone) and 2 (chemotherapy+RPI.4610), and on day 8 of course 1 (RPI.4610 alone). Ratios were generated by comparing the pharmacokinetic parameters for the combination of carboplatin with paclitaxel when administered alone or together with RPI.4610.Results Twelve patients were enrolled in this trial and received two to six courses of treatment each. The most common grade 3–4 toxicities were neutropenia (three patients), thrombocytopenia (three patients), pain (three patients), anemia (two patients) and fatigue (two patients). The ratio of the mean maximum plasma concentration (Cmax) for carboplatin when administered with paclitaxel alone versus when administered with paclitaxel and RPI.4610 was 1.07 (90% confidence interval, 0.77–1.37). Similarly, the ratio of the mean AUC_0-last for carboplatin was 1.04 (0.73–1.35). For paclitaxel the ratio of the mean Cmax when administered with carboplatin alone versus with carboplatin and RPI.4610 was 1.17 (1.03–1.31), and the ratio of the mean AUC_0–last was 1.17 (1.04–1.30). Objective tumor responses were observed and included one patient with a complete response (bladder cancer) and one patient with a partial response (esophageal cancer).Conclusions These results indicate that RPI.4610, carboplatin, and paclitaxel can be administered safely in combination without substantial pharmacokinetic interactions.     

Bevacizumab plus erlotinib in Chinese patients with untreated,EGFR-mutated,advanced NSCLC (ARTEMIS-CTONG1509): A multicenter phase 3 study

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Phase I dose escalation study of telatinib (BAY 57-9352) in patients with advanced solid tumours

Telatinib (BAY 57-9352) is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor receptor β tyrosine kinases. In this multicentre phase I dose escalation study, 71 patients with refractory solid tumours were enroled into 14 days on/7 days off (noncontinuous dosing) or continuous dosing groups to receive telatinib two times daily (BID). Hypertension (23%) and diarrhoea (7%) were the most frequent study drug-related adverse events of CTC grade 3. The maximum-tolerated dose was not reached up to a dose of 1500 mg BID continuous dosing. Telatinib was rapidly absorbed with median t_max of 3 hours or less. Geometric mean C_max and AUC₀₋₁₂ increased in a less than dose-proportional manner and plateaued in the 900–1500 mg BID dose range. Two renal cell carcinoma patients reached a partial response. Tumour blood flow measured by contrast-enhanced magnetic resonance imaging and sVEGFR-2 plasma levels decreased with increasing AUC₀₋₁₂ of telatinib. Telatinib is safe and well tolerated up to a dose of 1500 mg BID continuous dosing. Based on pharmacokinetic and pharmacodynamic criteria, 900 mg telatinib BID continuously administered was selected as the recommended phase II dose.     

EGFR mutation frequency and effectiveness of erlotinib: A prospective observational study in Danish patients with non-small cell lung cancer

Objectives

In 2008, we initiated a prospective study to explore the frequency and predictive value of epidermal growth factor receptor (EGFR) mutations in an unselected population of Danish patients with non-small cell lung cancer offered treatment with erlotinib, mainly in second-line.

Materials and methods

Four hundred and eighty eight patients with advanced NSCLC were included. The mutation status was assessed using the cobas^® EGFR Mutation Test. Erlotinib was administrated (150 mg/d) until disease progression or unacceptable toxicities occurred. The primary endpoint was progression-free survival. Secondary endpoints were overall survival and response.

Results

Biopsies were retrieved from 467 patients, and mutation results obtained for 462. We identified 57 (12%) patients with EGFR mutations: 33 exon 19 deletions, 13 exon 21 mutations, 5 exon 18 mutations, 3 exon 20 insertions, 1 exon 20 point mutation (S768I), and two complex mutations. Seven percent of the patients were never smokers. The differences in median progression-free survival and overall survival between the mutated group and the wild-type group were 8.0 vs. 2.5 months, p < 0.001 and 12.1 vs. 3.9 months, p < 0.001. Performance status (0–1 vs. 2–3) and line of treatment (1st vs. 2nd and 3rd) had no influence on outcome in EGFR-mutated patients.

Conclusion

We found a higher frequency of EGFR mutations than expected in a cohort with less than 10% never smokers. The outcome after treatment with erlotinib was much better in patients with EGFR mutations than in patients with wild-type EGFR and was independent of performance status and treatment line in EGFR-mutated patients.     

Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies

Background:

We assessed the maximum tolerated regimen (MTR) and dose-limiting toxicities of pazopanib and lapatinib in combination with weekly paclitaxel, and the effect of pazopanib and lapatinib on paclitaxel pharmacokinetics.

Methods:

Patients received intravenous paclitaxel on days 1, 8, and 15 of a 28-day cycle concurrently with daily pazopanib and lapatinib. Dose levels of paclitaxel (mg m⁻²)/pazopanib(mg)/lapatinib(mg) were 50/400/1000, 50/800/1000, 80/800/1000, and 80/400/1000. At the MTR, additional patients were enrolled to further evaluate tolerability, and the potential effects of pazopanib and lapatinib, inhibitors of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP2C8 and CYP3A4 substrate.

Results:

Twenty-six patients were enrolled. Dose-limiting toxicities at the MTR (80/400/1000) included grade 4 thrombosis and grade 3 aspartate aminotransferase elevation. Other toxicities included diarrhoea, neutropenia, fatigue, and liver enzyme elevations. Coadministration of pazopanib 400 mg and lapatinib 1000 mg increased paclitaxel maximum plasma concentration (38%) and area under the curve (37%) relative to paclitaxel alone. One patient with a salivary gland tumour had a partial response; three patients had stable disease (⩾6 months).

Conclusions:

Pazopanib 400 mg per day and lapatinib 1000 mg per day can be combined with paclitaxel 80 mg m⁻² in 28-day cycles. Coadministration of pazopanib and lapatinib, weak inhibitors of CYP2C8 and CYP3A4, had an inhibitory effect on paclitaxel clearance.     

Phase I ficlatuzumab monotherapy or with erlotinib for refractory advanced solid tumours and multiple myeloma

Background:

Ficlatuzumab, a humanised hepatocyte growth factor (HGF) IgG1κ inhibitory monoclonal antibody, was evaluated for recommended phase II dose (RP2D), safety, pharmacokinetics (PKs), antidrug antibody (ADA), pharmacodynamics (PDs) and antitumour activity as monotherapy or combined with erlotinib.

Methods:

Patients with solid tumours received ficlatuzumab 2, 5, 10 or 20 mg kg^–1 intravenously every 2 weeks (q2w). Additional patients were treated at the RP2D erlotinib.

Results:

Forty-one patients enrolled at doses ⩽20 mg kg^–1. Common adverse events (AEs) included peripheral oedema, fatigue and nausea. Three patients experienced grade ⩾3 treatment-related hyperkalaemia/hypokalaemia, diarrhoea or fatigue. Best overall response (44%) was stable disease (SD); median duration was 5.5 months (0.4–18.7 months). One patient has been on therapy with SD for >4 years. Pharmacokinetics of ficlatuzumab showed low clearance (0.17–0.26 ml h^–1 kg^–1), a half-life of 6.8–9.4 days and dose-proportional exposure. Ficlatuzumab/erlotinib had no impact on the PK of either agent. No ADAs were detected. Ficlatuzumab increased serum HGF levels.

Conclusions:

Recommended phase II dose is 20 mg kg^–1 q2w for ficlatuzumab monotherapy or with erlotinib. Preliminary antitumour activity and manageable AEs were observed. Pharmacokinetics were dose-proportional and consistent with other IgG therapeutics. Ficlatuzumab was not immunogenic, and serum HGF was a potential PD marker.     

A phase 1b,open-label study of trebananib plus bevacizumab or motesanib in patients with solid tumours

Background

To examine the angiopoietin pathway inhibitor trebananib IV plus the anti-VEGF agents bevacizumab or motesanib in advanced solid tumours.

Methods

In this open-label phase 1b study, patients received IV trebananib 3 mg kg⁻¹ QW plus bevacizumab 15 mg kg⁻¹ Q3W (cohort 1) or motesanib orally 75 mg (cohort 2); or trebananib 10 mg kg⁻¹ plus bevacizumab 15 mg kg⁻¹ (cohort 3) or motesanib 125 mg (cohort 4). If <33% of patients had dose-limiting toxicities (DLTs), dose escalation occurred. Endpoints were treatment–related adverse events (AEs) incidence and pharmacokinetics (primary); anti-trebananib antibodies, biomarkers, and tumour response (secondary).

Results

Thirty-six patients received ≥1 dose of trebananib (cohorts 1, 2, 3, 4; n = 6, 8, 19, 3). DLT of G3 intestinal perforation and G3 tumor haemorrhage occurred in cohorts 2 and 3, respectively (both n = 1). Across both trebananib plus bevacizumab cohorts, the most common AEs included fatigue (n = 8), diarrhoea (n =4), constipation (n = 3), nausea (n = 3), and epistaxis (n = 3). Three patients across those cohorts had grade ≥3 AEs. Across the trebananib plus motesanib cohorts, the most common AEs included hypertension (n = 4), diarrhoea (n = 4), nausea (n = 3), fatigue (n = 3), vomiting (n = 2), and decreased appetite (n = 2). Two patients had grade ≥3 AEs. Trebananib did not markedly affect motesanib pharmacokinetics. Across the trebananib plus bevacizumab cohorts, two patients had a partial response; 11 patients had stable disease lasting >6 months. Across the trebananib plus motesanib cohorts, one patient had a partial response; five patients had stable disease lasting >6 months.

Conclusion

Trebananib IV 3 mg kg⁻¹ or 10 mg kg⁻¹ plus bevacizumab or motesanib in advanced solid tumours may be associated with less severe toxicities relative to those emerging when combining two anti-VEGF agents.     

Phase I targeted combination trial of sorafenib and erlotinib in patients with advanced solid tumors.

PURPOSE: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, the combination of these drugs is of considerable interest in solid malignancies. This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities. EXPERIMENTAL DESIGN: Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed. RESULTS: Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100%) followed by diarrhea (15 patients; 88%), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response. CONCLUSIONS: Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies.     

Efficacy and safety of erlotinib in patients with locally advanced or metastatic breast cancer

Purpose To evaluate the efficacy and safety of erlotinib in advanced breast cancer. Experimental design Multicenter, phase II study of erlotinib (150 mg orally daily). Cohort 1: progression after anthracyclines, taxanes, and capecitabine (n = 47). Cohort 2: progression after >1 chemotherapy for advanced-stage disease (n = 22). Primary endpoint was response rate (World Health Organization criteria). Secondary endpoints were safety, time to progression, and survival. Results One patient in each cohort (n = 2, 3.0%) had a partial response. Response duration was 17 weeks for the Cohort 1 patient and 32 weeks for the Cohort 2 patient. Median time to progression was 43 days for Cohort 1 (range 1–204) and 43 days for Cohort 2 (range 25–419). Common adverse events were diarrhea, rash, dry skin, asthenia, nausea, anorexia. Conclusion Erlotinib had minimal activity in unselected previously treated women with advanced breast cancer. Predictive factors are needed to identify breast cancer patients who may derive benefit from erlotinib treatment.