A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors

Purpose

Preclinical data suggest concurrent inhibition of VEGF, mTOR and EGFR pathways may augment antitumor and antiangiogenic effects compared to inhibition of each pathway alone. This study evaluated the maximum tolerated dose/recommended phase II dose and safety and tolerability of bevacizumab, everolimus and panitumumab drug combination.

Methods

Subjects with advanced solid tumors received escalating doses of everolimus and flat dosing of panitumumab at 4.8?mg/kg and bevacizumab at 10?mg/kg every 2?weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity.

Results

Thirty-two subjects were evaluable for toxicity; 31 subjects were evaluable for tumor response. DLTs were observed in cohorts with everolimus at 10 and 5?mg daily and included grade 3 mucositis, skin rash and thrombocytopenia. Therefore, everolimus was dose-reduced to 5?mg three times weekly, which improved the tolerability of the treatment regimen. Common adverse events were skin rash/pruritus (91?%), mucositis/stomatitis (75?%), hypomagnesemia (72?%), hypocalcemia (56?%) and hypokalemia (50?%). There were 3 partial responses; an additional 10 subjects had stable disease ??6?months. Three subjects with ovarian cancer and one with endometrial cancer achieved prolonged disease control ranging from 11 to >40?months.

Conclusions

The recommended phase II dose is everolimus at 5?mg three times weekly plus panitumumab at 4.8?mg/kg and bevacizumab at 10?mg/kg every 2?weeks. This dosing regimen has an acceptable safety and tolerability profile and appears to have moderate the clinical activity in refractory tumors.     

A phase II study of erlotinib in combination with bevacizumab versus chemotherapy plus bevacizumab in the first-line treatment of advanced non-squamous non-small cell lung cancer

Background

Molecularly targeted agents for non-small cell lung cancer (NSCLC) can provide similar efficacy to chemotherapy without chemotherapy-associated toxicities. Combining two agents with different modes of action could further increase the efficacy of these therapies. The TASK study evaluated the efficacy and safety of the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with the anti-angiogenic agent bevacizumab as first-line therapy in unselected, advanced non-squamous NSCLC patients.

Methods

Patients were recruited from December 2007 to September 2008. Planned sample size was 200 patients, a total of 124 patients were randomized. Patients were randomized using a minimization algorithm 1:1 to receive bevacizumab (iv 15 mg/kg day 1 of each 21-day cycle) plus chemotherapy (gemcitabine/cisplatin or carboplatin/paclitaxel standard doses, 4–6 cycles) (BC arm) or bevacizumab plus erlotinib (p.o. 150 mg/day; BE arm) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). If the hazard ratio (HR) of PFS for BE relative to BC was above 1.25 at the pre-planned interim analysis in favor of BC, the study would be re-evaluated. Secondary endpoints included overall survival, response rate and safety.

Results

All randomized patients (n = 63 BE; n = 61 BC) were evaluated for the efficacy analyses. At the updated interim analysis, median PFS was 18.4 weeks (95% confidence interval [CI] 17.0–25.1) versus 25.0 weeks (95% CI 20.6–[not reached]) for BE versus BC, respectively (HR for death or disease progression, BE relative to BC, 2.05, p = 0.0183). The incidence of death was 19% for BE treatment compared with 11.5% for BC treatment. The HR for PFS at the updated interim analysis was above 1.25, therefore patients on the BE arm were permitted to change arms or switch to another drug and the study was terminated. Adverse events reported were as expected.

Conclusions

The TASK study did not show a benefit in terms of PFS for the combination of erlotinib with bevacizumab in unselected first-line advanced non-squamous NSCLC compared with chemotherapy plus bevacizumab.     

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 study of bevacizumab, everolimus, and panobinostat (LBH-589) in advanced solid tumors

Purpose

To define the maximum tolerated dose, clinical toxicities, and pharmacodynamics of bevacizumab, everolimus, and panobinostat (LBH-589) when administered in combination to patients with advanced solid tumor malignancies.

Experiment design

Subjects received 10?mg of panobinostat three times weekly, 5 or 10?mg everolimus daily, and bevacizumab at 10?mg/kg every 2?weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Protein acetylation was assessed in peripheral blood mononuclear cells (PBMC) both at baseline and on treatment.

Results

Twelve subjects were evaluable for toxicity and nine subjects for response. DLTs in cohort 1 included grade 2 esophagitis and grade 3 oral mucositis; DLTs in cohort -1 were grade 2 ventricular arrhythmia and grade 2 intolerable skin rash. Common adverse events were diarrhea (50?%), headache (33?%), mucositis/stomatitis (25?%), hyperlipidemia (25?%), and thrombocytopenia (25?%). There was 1 partial response; an additional 2 subjects had stable disease as best response. No consistent changes in protein acetylation in PBMC were observed in samples available from eight patients on treatment compared with baseline.

Conclusions

Bevacizumab, everolimus, and panobinostat in combination at the lowest proposed doses did not have an acceptable safety and tolerability profile and did not consistently inhibit HDAC activity; therefore, we do not recommend further evaluation.     

A phase I study of sirolimus and bevacizumab in patients with advanced malignancies

Background

We performed a single institution, phase I study of sirolimus and bevacizumab, in order to determine the dose limiting toxicity (DLT) and recommended phase II doses.

Patients and methods

Eligible patients had previously treated advanced malignancies and were enrolled in three cohorts. Sirolimus 90 mg PO weekly (45 mg on days 1 and 2) was combined with bevacizumab 7.5 mg/kg (cohort #1) or bevacizumab 15 mg/kg (cohort #2) IV q3weeks. Sirolimus 4 mg PO daily was combined with bevacizumab 15 mg/kg IV q3weeks (cohort #3).

Results

Twenty-eight patients enrolled. The most common tumour types were colorectal (21%), head/neck (14%), and renal cell (11%). No DLTs were observed in cohorts #1 (4 patients) and #2 (12 patients), while two DLTs (grade 3 confusion and grade 3 fatigue) were observed in the first six patients in cohort #3 (12 patients). The most common grade 3 toxicities were fatigue (18%), hypertension (14%) and anorexia (11%). There were no responses, but one patient has had stable disease for 78 weeks.

Conclusions

The combination of sirolimus and bevacizumab at full doses is tolerable in the majority of patients. The availability and cost of sirolimus compared with other mTOR inhibitors make this an attractive agent to combine with bevacizumab.     

A phase I study of capecitabine in combination with vinorelbine in advanced breast cancer

A phase I study was conducted in order to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the combination of vinorelbine and capecitabine in patients affected with metastatic breast cancer. Eighteen patients with histologically confirmed advanced breast cancer, who had failed =1 prior chemotherapy regimen, were enrolled. The median age was 56 years (range, 39-70 years). All but 1 had previously received a combination of anthracyclines and taxanes; performance status (Eastern Cooperative Oncology Group) was 0/1 or 2 in 13 and 5 patients, respectively. Vinorelbine was administered at a fixed dosage of 25 mg/m2 on days 1 and 8 every 3 weeks. Capecitabine was administered orally, at an escalated dose ranging from 1400 mg/m2 to 2250 mg/m2 for 14 consecutive days starting on day 1 of the cycle, divided into 2 daily doses delivered half an hour after eating at 12-hour intervals. Three patients were treated at each dose level: if 1 patient developed a DLT, an additional 3 patients were treated at the same dose level. If 2 additional patients experienced DLT, no further escalation was allowed and the previous dose level was declared MTD. Dose-limiting toxicity was reached at 2250 mg/m2 of capecitabine with 3 out of 3 patients experiencing grade 4 neutropenia plus grade 3 diarrhea and grade 3 oral mucositis in 1 patient). Thus, MTD was defined at 2000 mg/m2 capecitabine. Other observed grade 2 side effects were: 1 patient with neutropenia, 1 with hand-foot syndrome, 2 with mucositis, 1 with cutaneous rash, and 1 with thrombocytopenia. With regard to response rate, we observed 1 complete response (5.5%), 6 partial responses (33%), and 4 disease stabilizations (22%). The median time to progression was 12 weeks and the median survival 41 weeks. The MTD of capecitabine in combination with vinorelbine at 25 mg/m2 dosage on days 1 and 8 of a 3-week schedule is 2000 mg/m2/day for 14 consecutive days. Moreover, this regimen showed interesting activity with 61% overall disease control (complete plus partial response plus disease stabilization) in patients pretreated with anthracyclines and taxanes warranting further investigations in a large, multicenter phase II study.     

A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma.

PURPOSE: To determine the maximum tolerated dose (MTD) of erlotinib when administered concurrently with twice weekly gemcitabine and radiation therapy (RT) for locally advanced pancreatic cancer, assess the safety and toxicity profile of this combination and secondarily evaluate response, time to tumor progression and overall survival. METHODS: Patients with untreated locally advanced pancreas cancer were treated with daily erlotinib in combination with gemcitabine 40 mg/m(2)/30 min twice weekly and RT delivered at 180 cGy/day in 28 fractions over 5.5 weeks for a total of 5040 cGy. Erlotinib was dose escalated in successive cohorts (100 mg, 125 mg). When the MTD was determined, the cohort was expanded to better define toxicity and preliminarily efficacy. All patients were surgically staged. After chemoradiation, patients received maintenance weekly gemcitabine 1000 mg/m(2) on days 1 and 8 of a 21 day cycle and daily erlotinib for four cycles. RESULTS: Three patients were treated at dose level 1 (erlotinib 100 mg) without limiting toxicity. Two of six patients at dose level 2 (erlotinib 125 mg) had dose-limiting toxicities, neutropenia and thrombocytopenia, causing dose delay and elevated liver enzymes. The MTD for erlotinib in combination with twice weekly gemcitabine-based chemoradiation was 100 mg/day. Eleven additional patients were treated at dose level 1. All twenty patients were assessable for toxicity. Seventeen patients were assessable for response. The partial response rate was 35% and 53% had stable disease. The median survival for all patients was 18.7 months. CONCLUSION: In combination with fixed dose gemcitabine at 40 mg/m(2) twice weekly and radiation at 180 cGy/day, the MTD of erlotinib was found to be 100 mg/day. This is a relatively well tolerated, biologically active combination in a poor prognostic cancer.     

The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer: results of a phase I study with pharmacokinetics

PurposeTo investigate the safety and pharmacokinetics (PK) of combined treatment with letrozole and the oral mTOR inhibitor RAD001 in patients with metastatic breast cancer stable or progressing after ⩾4 months on letrozole alone.MethodsEighteen patients received letrozole (2.5 mg/day) and RAD001 at 5 mg/day (cohort 1) or 10 mg/day (cohort 2). In the absence of DLT in cohort 1, cohort 2 was expanded to 12 patients to obtain additional safety and PK data.ResultsMost common adverse events were stomatitis (50.0% of patients), fatigue (44.4%), anorexia and/or decreased appetite (44.4%), diarrhoea (38.9%), headache (33.3%) and rash (33.3%). There was 1 DLT, a grade 3 thrombocytopaenia in cohort 2. No clinically relevant PK interaction was detected. Seven patients received the combination therapy for >6 months. One patient had a complete response, and one had a 28% reduction in liver metastases, both in cohort 2.ConclusionDaily therapy with RAD001 plus letrozole is promising: the results suggest anti-tumour activity with no PK interactions. The overall safety profile of the combination is consistent with that expected for RAD001 monotherapy. A daily dose of RAD001 10 mg is recommended for further trials.     

A phase II study of bevacizumab plus erlotinib for gemcitabine-refractory metastatic pancreatic cancer

Purpose

No standard of care exists for patients with metastatic pancreatic cancer following progression on first-line chemotherapy. Based on potential for additive or synergistic activity by concurrent inhibition of VEGF and EGFR, we conducted a phase II study evaluating the combination of bevacizumab plus erlotinib in this patient population.

Methods

Patients with metastatic pancreatic adenocarcinoma, ECOG performance status 0–1, and previous exposure to 1–3 systemic therapies (at least one gemcitabine-based) were eligible. Treatment consisted of bevacizumab 15 mg/kg every 21 days plus erlotinib 150 mg daily.

Results

Thirty-six patients were enrolled, including eight who had previously received VEGF-targeted therapy and nine prior erlotinib. Median number of treatment cycles was 2 (range, 1–7). Common toxicities included rash (72%), diarrhea (25%), venous thromboembolic events (15%), and hypertension (11%). One patient demonstrated partial response and seven others stable disease for >2 cycles. CA19-9 decline ≥25% was observed in 4/26 patients with baseline levels >2x ULN. Estimated median time to progression was 40 days (95% CI, 35–41 days) and median survival 102 days (95% CI, 74–117 days), with a 6-month survival rate of 22%. Baseline concentration of circulating endothelial cells (CD45^?/CD34⁺/CD31⁺) was inversely associated with overall survival.

Conclusions

The combination of bevacizumab and erlotinib is safe but relatively ineffective in patients with gemcitabine-refractory metastatic pancreatic cancer. Future studies should focus on refining subsets of patients in this challenging population likely to benefit from treatment beyond first-line.     

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.     

The combination of a chemotherapy doublet (gemcitabine and capecitabine) with a biological doublet (bevacizumab and erlotinib) in patients with advanced pancreatic adenocarcinoma. The results of a phase I/II study

BackgroundPreclinical data support the combined inhibition of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways in the treatment of pancreatic cancer. Following a dose finding phase I study the efficacy and toxicity of a four-drug regimen utilising the cytotoxic doublet of gemcitabine and capecitabine (GemCap), with the biological doublet of erlotinib and bevacizumab were further assessed in patients with advanced pancreatic cancer.Patients and methodsIn a phase II expansion cohort, patients with chemonaive locally advanced or metastatic pancreatic cancer received gemcitabine (1000 mg/m² D1, 8, 15), capecitabine (1400 mg/m² D1–21), erlotinib (100 mg daily) and bevacizumab (5 mg/kg D1, 15) every 28 days. The primary endpoint was radiological response rate by response evaluation criteria in solid tumours (RECIST). Computed tomography (CT) assessment was performed every 8 weeks. Consolidation radiotherapy was considered in locally advanced patients following six cycles of treatment.ResultsIn total 44 patients (phases I & II) were recruited. The median cycles delivered were 6 (range 1–16). Confirmed radiological responses were seen in 23% (95% confidence interval (CI): 11–38%) of patients. The median progression-free and overall survival for the entire cohort was 8.4 and 12.6 months, respectively. In patients with metastatic disease the median overall survival was 10.1 months. Common grade 3/4 toxicities were; neutropenia 52%, lethargy 32%, diarrhoea 18% and hand-foot syndrome 18%.ConclusionThe combination of gemcitabine, capecitabine, erlotinib and bevacizumab was feasible with a manageable toxicity profile and demonstrated encouraging efficacy data in a good performance status population.     

Phase I study of sorafenib in combination with everolimus (RAD001) in patients with advanced neuroendocrine tumors

Purpose

Sorafenib and everolimus are both active against neuroendocrine tumors (NET). Because of potential synergy between VEGF pathway and mTOR inhibitors, we performed a phase I study to evaluate the safety and feasibility of combining sorafenib and everolimus in patients with advanced NET.

Methods

Patients were treated with everolimus 10 mg daily in combination with sorafenib (dose level 1: 200 mg twice daily; dose level 2: 200 mg per morning, 400 mg per evening) using standard phase I dose escalation design. Dose-limiting toxicity (DLT) was defined within the first cycle (28 days) of therapy. Treatment was continued until tumor progression, unacceptable toxicity, or withdrawal of consent. Twelve additional patients were treated at the maximum tolerated dose (MTD) level to further characterize safety and a preliminary assessment of activity.

Results

One patient in Cohort 1 experienced DLT (grade 3 skin rash); the cohort was expanded to 6 patients with no further DLTs. All 3 patients in Cohort 2 experienced DLT, consisting of thrombocytopenia, hand–foot skin reaction, and rash/allergic reaction. Sorafenib 200 mg twice daily in combination with everolimus 10 mg daily was established as the MTD. Independently reviewed best objective responses revealed that 62 % of patients had some degree of tumor shrinkage. By RECIST, we observed partial response in 1 patient, stable disease in 13 patients, and progressive disease in 3 patients.

Conclusion

Sorafenib 200 mg twice daily with everolimus 10 mg daily represents the MTD of this combination in patients with advanced NET. While the combination is active, toxicity concerns may preclude more widespread use.     

Phase I study of cetuximab, erlotinib, and bevacizumab in patients with advanced solid tumors

Background  Complex interrelationships exist between the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) receptor pathways. EGFR activation elicits cell proliferation and increased VEGF expression. To maximally inhibit EGFR and then downstream VEGF activity, this phase I study was initiated to determine the maximum tolerated dose (MTD) of erlotinib with fixed-dose cetuximab, and then combine with bevacizumab in patients with advanced malignancies. Patients and methods  Patients with advanced malignancies likely to express EGFR were treated with a full dose of cetuximab intravenous weekly, combined with various doses of oral erlotinib daily (Part 1). Once the MTD was determined in Part 1, escalating doses of bevacizumab were administered intravenously biweekly (Part 2). Results  Forty patients were enrolled and received 155 courses over four dose levels. In Part 1, dose-limiting grade 3 rash occurred in two patients administered with erlotinib at 100 mg daily, and the MTD of erlotinib for this combination was 50 mg daily with standard-dose cetuximab (11 patients treated). Other adverse events included rash, diarrhea, fatigue, and hypomagnesemia. In Part 2, bevacizumab at 10 mg/kg intravenous every 2 weeks was safely added, with additional nondose-limiting headache, proteinuria, and hypertension. There was one partial response in a patient with renal cell carcinoma. Durable stable disease was observed in five patients for 6–11 months. Conclusions  The MTD for Part 1 was 50 mg daily of erlotinib combined with standard cetuximab. Bevacizumab at 10 mg/kg biweekly can be safely administered with the MTD for erlotinib and cetuximab combination. Presented in part at the 42nd Annual Meeting of American Society of Clinical Oncology, Atlanta, Georgia, June 2–6, 2006, and at the 18th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Prague, Czech Republic, November 7–10, 2006. Chia-Chi Lin and Emiliano Calvo contributed equally to this study.     

A phase 1 study of OSI-930 in combination with erlotinib in patients with advanced solid tumours

AimTo determine the maximum tolerated dose (MTD) of OSI-930 that can be combined with erlotinib, and establish recommended phase 2 doses when both agents are administered daily in patients with advanced solid tumours.Patients and methodsEligible patients with advanced solid tumours were enrolled into this standard “three + three” dose escalation study. Study treatment commenced on day 1 with OSI-930, and erlotinib was introduced on day 8. PK profiles of OSI-930, erlotinib and its active metabolite, OSI-420, were determined. Changes in sVEGFR2 as a pharmacodynamic biomarker of OSI-930 activity were assessed.ResultsTwenty one patients were enrolled to 1 of 3 cohorts: 200 mg OSI-930 BID + 100 mg erlotinib QD; 200 mg OSI-930 BID + 150 mg erlotinib QD; 300 mg OSI-930 BID + 150 mg erlotinib QD. The most common adverse events were anorexia (85%), diarrhoea (75%), rash (70%) and lethargy (65%). The MTD was not reached but the onset of cumulative toxicity necessitating dose modification after the 28-d DLT assessment period was common at the highest dose level. A PK interaction was identified with co-administration of both agents resulting in a two-fold increase in OSI-930 exposure. Pharmacodynamic activity was observed with a decline in sVEGFR levels detected in all patients. Ten patients had disease stabilization (median duration 119 d).Conclusions200 mg OSI-930 BID + 150 mg erlotinib QD were the recommended doses for further evaluation of this combination.     

Biomarker-based phase I dose-escalation, pharmacokinetic, and pharmacodynamic study of oral apricoxib in combination with erlotinib in advanced nonsmall cell lung cancer

BACKGROUND:

Apricoxib, a novel once‐daily selective cyclooxygenase‐2 inhibitor, was investigated in combination with erlotinib for recurrent stage IIIB/IV nonsmall cell lung cancer to determine the maximum tolerated dose, dose‐limiting toxicity, and recommended phase II dose (RP2D) based on changes in urinary prostaglandin E₂ metabolite (PGE‐M).

METHODS:

Patients received escalating doses of apricoxib (100, 200, and 400 mg/day) in combination with erlotinib 150 mg/day until disease progression or unacceptable toxicity. Urinary PGE‐M was used to assess biologic activity and inform the optimal biologic dose.

RESULTS:

Twenty patients were treated (3 at 100 mg; 3 at 200 mg; 14 at 400 mg apricoxib) with a median of 4 cycles (range, 2‐14 cycles); 8 patients (40%) received prior EGFR‐directed therapies. No dose‐limiting toxicity was observed. Study drug‐related adverse events (AEs) included diarrhea, rash, dry skin, anemia, fatigue, and increased serum creatinine; 4 patients had grade ≥3 drug‐related AEs (diarrhea, perforated duodenal ulcer, hypophosphatemia, and deep vein thrombosis). The RP2D was 400 mg/day based on safety, biologic activity based on decreases in urinary PGE‐M, and pharmacokinetics. One patient had a partial response, and 11 had stable disease. Stable disease was observed in patients who had received prior EGFR inhibitor therapy but was greater in patients not previously treated with an EGFR inhibitor. Seventeen patients had elevated urinary PGE‐M at baseline, and 14 (70%) had a decrease from baseline, which was associated with disease control.

CONCLUSIONS:

Apricoxib plus erlotinib was well tolerated and yielded a 60% disease control rate. A phase II trial is currently investigating 400 mg/day apricoxib plus 150 mg/day erlotinib in patients selected based on change in urinary PGE‐M. Cancer 2011. © 2010 American Cancer Society.     

A phase II study of erlotinib in gemcitabine refractory advanced pancreatic cancer

BackgroundErlotinib induced skin toxicity has been associated with clinical benefit in several tumour types. This phase II study evaluated the efficacy of erlotinib, dose escalated to rash, in patients with advanced pancreatic cancer previously treated with gemcitabine.MethodsErlotinib was given at an initial dose of 150 mg/day, and the dose was escalated by 50 mg every 2 weeks (to a maximum of 300 mg/day) until >grade 1 rash or other dose limiting toxicities occurred. Erlotinib pharmacokinetics were performed, and baseline tumour tissue was collected for mutational analysis and epidermal growth factor receptor (EGFR) expression. The primary end-point was the disease control rate (objective response and stable disease >8 weeks).ResultsFifty-one patients were accrued, and 49 received treatment. Dose-escalation to 200–300 mg of erlotinib was possible in 9/49 (18%) patients. The most common ⩾grade 3 adverse events included fatigue (6%), rash (4%) and diarrhoea (4%). Thirty-seven patients were evaluable for response, and the best response was stable disease in 12 patients (32% (95% confidence interval (CI) 17–47%)). Disease control was observed in nine patients (24% (95% CI: 10–38%)). Median survival was 3.8 months, and 6 month overall survival rate was 32% (95% CI 19–47%). Mutational analysis and EGFR expression were performed on 29 patients, with 93% having KRAS mutations, none having EGFR mutations, and 86% expressing EGFR. Neither KRAS mutational status nor EGFR expression was associated with survival.ConclusionsErlotinib dose escalated to rash was well tolerated but not associated with significant efficacy in non-selected patients with advanced pancreatic cancer.     

A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer

BACKGROUND:

Inhibition of mammalian target of rapamycin with everolimus may improve the efficacy of taxanes. Everolimus and docetaxel are both metabolized by CYP3A4, which could result in a pharmacokinetic (PK) interaction.

METHODS:

Fifteen patients with metastatic breast cancer were treated with docetaxel (doses of 40‐75 mg/m² intravenously on day 1 of a 21‐day cycle) in combination with everolimus (doses ranging from 20 to 50 mg orally on days 1 and 8 of a 21‐day cycle) in a phase 1 trial using the continuous reassessment method to determine maximum tolerated dose. The first 2 patients developed a dose‐limiting toxicity (neutropenic infection), prompting a mandatory dose reduction and PK evaluation of both everolimus and docetaxel for patients enrolled in subsequent dosing cohorts.

RESULTS:

Fifteen patients were treated. Dose‐limiting toxicity included grade 3 mucositis (n = 1), prolonged grade 4 neutropenia (n = 1), and grade 3 infection/febrile neutropenia (n = 3). Day 8 of everolimus was commonly held for neutropenia despite a dose reduction in docetaxel to 40 mg/m². Eleven patients underwent complete PK evaluation for everolimus, and 9 patients underwent complete PK evaluation for both everolimus and docetaxel. Widely variable changes in clearance were seen for both drugs, and the study was terminated because of lack of efficacy and concerns regarding toxicity seen with the combination.

CONCLUSIONS:

Weekly everolimus in combination with docetaxel every 3 weeks was associated with excessive neutropenia and variable clearance of both drugs, making combination therapy unpredictable, even at low doses of both drugs. Cancer 2012. © 2011 American Cancer Society.     

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

Introduction  

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).