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1.  Phase I study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma 
Purpose
This phase I clinical trial was conducted to determine the safety, efficacy, and molecular effects of sorafenib with temsirolimus in patients with advanced melanoma.
Patients and Methods
Patients with stage IV or unresectable or recurrent stage III melanoma and ECOG performance status of 0 to 1 were eligible. Sorafenib was given orally once or twice daily and temsirolimus was given intravenously weekly, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per RECIST criteria. Consenting patients with accessible tumors underwent optional tumor biopsies prior to treatment and after the second infusion of temsirolimus. Tumor biopsies were analyzed for activating mutations in BRAF and NRAS, and for expression of P-ERK and P-S6 proteins.
Results
A total of 25 patients were accrued to the study. The MTD doses were sorafenib 400 mg qAM / 200 mg qPM daily and temsirolimus 25 mg IV weekly. Dose-limiting toxicities included thrombocytopenia, hand-foot syndrome (HFS), serum transaminase elevation and hypertriglyceridemia. There were no complete (CR) or partial (PR) responses with the combination; 10 patients achieved stabilization of disease as their best response. The median progression-free survival (PFS) was 2.1 months. Matching pre-treatment and day 15 tumor biopsies demonstrated marked inhibition of P-S6 with treatment in 3 of 4 evaluable patients, but minimal inhibition of P-ERK.
Conclusions
Combination therapy with sorafenib and temsirolimus resulted in significant toxicity at higher dose levels, failed to achieve any clinical responses in genetically unselected patient population, and did not inhibit P-ERK.
doi:10.1158/1078-0432.CCR-11-2436
PMCID: PMC3906678  PMID: 22223528
phase I; sorafenib; temsirolimus; metastatic melanoma; BRAF
2.  Phase-1 trial of gefitinib and temozolomide in patients with malignant glioma: a North American brain tumor consortium study 
Cancer chemotherapy and pharmacology  2007;61(6):10.1007/s00280-007-0556-y.
Purpose
This is a phase-I study of gefitinib in combination with temozolomide in patients with gliomas. The goal of the study was to define the maximum tolerated dose (MTD) and to characterize the pharmacokinetics of gefitinib when combined with temozolomide.
Patients and methods
Patients were stratified according to co-administration of enzyme-inducing anti-epileptic drugs (EIAEDs). There were 26 evaluable patients enrolled (16 on EIAEDs, 10 not on EIAEDs). All but seven patients had Glioblastoma Multiforme (GBM), and only six cases had a Karnosfsky Performance Status (KPS) of less than 80; median age was 51 years. All had received prior radiotherapy and 14 patients had no prior chemotherapy. The starting dose of temozolomide was 150 mg/m2/day for 5 days every 28 days and could be escalated to a maximum dose of 200 mg/m2/day in subsequent cycles. The starting dose of gefitinib was 500 mg/day given by mouth on a continuous basis. Dose-limiting toxicity was assessed in cycle one only.
Results
For patients on EIAEDs, the MTD of gefitinib was 1,000 mg/day in combination with temozolomide. Dose-limiting toxicity (DLT) was due to diarrhea, nausea and vomiting. For patients not on EIAEDs, the MTD was 250 mg/day in combination with temozolomide. The DLT was due to increases in liver transaminases. Rash was not a significant toxicity at these dose levels. The peak concentration and AUC0–24hr at the 500 mg dose level was 1.8 and 2.5-fold lower, respectively, in the EIAED group compared to the non-EIAED group; trough levels of gefitinib increased in both groups consistent with the reported terminal half-life ranging from 27 to 51 h.
Conclusion
The recommended phase-2 dose of gefitinib when used in combination with temozolomide is 1,000 and 250 mg/day, respectively, for patients on or not on EIAEDs.
doi:10.1007/s00280-007-0556-y
PMCID: PMC3873156  PMID: 17694310
Temozolomide; Gefitinib; Malignant gliomas; Enzyme-inducing anti-epileptic drugs
3.  Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02 
Neuro-Oncology  2012;14(12):1511-1518.
The activity of single-agent targeted molecular therapies in glioblastoma has been limited to date. The North American Brain Tumor Consortium examined the safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, and platelet-derived growth factor receptor–β, and temsirolimus (CCI-779), an inhibitor of mammalian target of rapamycin. This was a phase I/II study. The phase I component used a standard 3 × 3 dose escalation scheme to determine the safety and tolerability of this combination therapy. The phase II component used a 2-stage design; the primary endpoint was 6-month progression-free survival (PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the dose-limiting toxicity. Eighteen patients were treated in the phase II component. At interim analysis, the study was terminated and did not proceed to the second stage. No patients remained progression free at 6 months. Median PFS was 8 weeks. The toxicity of this combination therapy resulted in a maximum tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 2 combined agents.
doi:10.1093/neuonc/nos264
PMCID: PMC3499017  PMID: 23099651
anaplastic glioma; glioblastoma; malignant glioma; sorafenib; temsirolimus
4.  Phase I and pharmacokinetic study of erlotinib (OSI-774) in combination with docetaxel in squamous cell carcinoma of the head and neck (SSCHN) 
Cancer chemotherapy and pharmacology  2010;67(3):10.1007/s00280-010-1332-y.
Purpose
This phase I study determined the maximal-tolerated dose, dose-limiting toxicities, pharmacokinetics, and recommended dose of erlotinib with docetaxel.
Patients and methods
Twenty-eight patients with head and neck cancer were enrolled. Patients were orally given erlotinib (50 mg) daily plus 35 mg/m2 of docetaxel intravenously weekly × 3 every 4 weeks. Dose escalation of erlotinib was in 50-mg increments until toxicity. Pharmacokinetics were studied with LC–MS/MS, standard, and population pharmacokinetic methods.
Results
Ninety-five courses were successfully given (median 3, range 1–6). The most frequent side effects were diarrhea, fatigue, skin rash, anemia, and hypoalbuminemia. Dose de-escalation for both erlotinib and docetaxel was due to skin rash, neutropenia and/or severe infection with docetaxel to 25 mg/m2 and erlotinib to starting dose of 50 mg and re-escalation of docetaxel to 35 mg/m2. Responses were observed in 4/26 evaluable patients (100 mg erlotinib). In 24 patients, the mean Cmax and AUC erlotinib values increased with dose and following cumulative dosing (days 7 and 8 vs. day1, p < 0.05). The CL/F (~7 L/h), V/F (~140 L), and t1/2 (~20 h) for erlotinib were similar to the reported. The mean AUC ratio of metabolite OSI-420 to erlotinib following repetitive dosing at 100 mg (+ or − docetaxel) showed a ~50% increase (p < 0.02), possibly suggesting self-enzyme induction. Population pharmacokinetic studies showed no significant covariate affecting erlotinib pharmacokinetics.
Conclusions
The combination of erlotinib and docetaxel was associated with significant toxicity, which limited the amount of administered erlotinib. Dosing for phase II trials was docetaxel 35 mg/m2 and erlotinib 50 mg. The reason for excessive toxicity is not clear, but not due to change in pharmacokinetics.
doi:10.1007/s00280-010-1332-y
PMCID: PMC3828747  PMID: 20490801
Erlotinib; Squamous cell carcinoma of the head and neck; OSI-774; Phase I
5.  Phase II Trials of Erlotinib or Gefitinib in Patients with Recurrent Meningioma 
Journal of neuro-oncology  2009;96(2):211-217.
There are no established treatments for recurrent meningioma when surgical and radiation options are exhausted. The epidermal growth factor receptor (EGFR) is often over-expressed in meningiomas and may promote tumor growth. In open label, single arm phase II studies of the EGFR inhibitors gefitinib (NABTC 00-01) and erlotinib (NABTC 01-03) for recurrent malignant gliomas, we included exploratory subsets of recurrent meningioma patients. We have pooled the data and report the results here. Patients with recurrent histologically confirmed meningiomas with no more than 2 previous chemotherapy regimens were treated with gefitinib 500 mg/day or erlotinib 150 mg/day until tumor progression or unacceptable toxicity. Twenty-five eligible patients were enrolled with median age 57 years (range 29–81) and median Karnofsky performance status (KPS) score 90 (range 60–100). Sixteen patients (64%) received gefitinib and 9 (36%) erlotinib. Eight patients (32%) had benign tumors, 9 (36%) atypical, and 8 (32%) malignant. For benign tumors, the 6-month progression-free survival (PFS6) was 25%, 12-month PFS (PFS12) 13%, 6-month overall survival (OS6) 63%, and 12-month OS (OS12) 50%. For atypical and malignant tumors, PFS6 was 29%, PFS12 18%, OS6 71%, and OS12 65%. The PFS and OS were not significantly different by histology. There were no objective imaging responses, but 8 patients (32%) maintained stable disease. Although treatment was well-tolerated, neither gefitinib nor erlotinib appear to have significant activity against recurrent meningioma. The role of EGFR inhibitors in meningiomas is unclear. Evaluation of multi-targeted inhibitors and EGFR inhibitors in combination with other targeted molecular agents may be warranted.
doi:10.1007/s11060-009-9948-7
PMCID: PMC3786190  PMID: 19562255
meningioma; erlotinib; gefitinib; epidermal growth factor receptor inhibitor
6.  Phase II Trial of Temsirolimus in Patients with Relapsed or Refractory Multiple Myeloma 
Leukemia research  2009;33(11):1475-1480.
In a phase II trial, 16 patients with relapsed refractory multiple myeloma received temsirolimus 25 mg IV weekly until progression. One partial response and 5 minor responses were observed for a total response rate of 38%. The median time to progression was 138 days. Grade 3–4 toxicity included fatigue (n=3), neutropenia (n=2), thrombocytopenia (n=2), interstitial pneumonitis (n=1), stomatitis (n=1) and diarrhea (n=1). Clinical activity was associated with a higher area under the curve (AUC) and maximal reduction in phosphorylated p70S6K and 4EBP1 in peripheral blood mononuclear cells. At the dose and schedule used, temsirolimus had low single agent activity. Investigation of alternate dosing schedules and use in combinations is indicated.
doi:10.1016/j.leukres.2009.01.039
PMCID: PMC3771631  PMID: 19261329
Multiple myeloma; mTOR; temsirolimus; pharmacokinetics
7.  Management of Metabolic Effects Associated With Anticancer Agents Targeting the PI3K-Akt-mTOR Pathway 
Journal of Clinical Oncology  2012;30(23):2919-2928.
Agents inhibiting the phosphoinositide 3–kinase–Akt–mammalian target of rapamycin (PAM) pathway are currently in various stages of clinical development in oncology, ranging from some in early-phase evaluations to others that have already received regulatory approval for treatment in advanced cancers. The administration of PAM pathway inhibitors has been associated with metabolic toxicities of hyperlipidemia and hyperglycemia. The PAM Task Force of the National Cancer Institute Investigational Drug Steering Committee convened an interdisciplinary expert panel to review the pathophysiology of hyperlipidemia and hyperglycemia induced by PAM pathway inhibitors, summarize the incidence of these metabolic toxicities induced by such agents in the current literature, advise on clinical trial screening and monitoring criteria, and provide management guidance and therapeutic goals on occurrence of these toxicities. The overarching aim of this consensus report is to raise awareness of these metabolic adverse events to enable their early recognition, regular monitoring, and timely intervention in clinical trials. Hyperglycemia and hyperlipidemia are generally not acutely toxic and most often reversible with therapeutic intervention. Dose modifications or discontinuation of PAM pathway inhibitors should only be considered in situations of severe events or if progressive metabolic derangement persists after therapeutic interventions have been attempted for a sufficient duration. Specialty consultation should be sought to aid clinical trial planning and the management of these metabolic adverse events.
doi:10.1200/JCO.2011.39.7356
PMCID: PMC3410405  PMID: 22778315
8.  Retinopathy Associated with Adjuvant High-Dose Interferon-α2b in a Patient with Resected Melanoma: A Case Report and Review of the Literature 
The Oncologist  2012;17(3):384-387.
A case of interferon-associated retinopathy in a patient with cutaneous malignant melanoma is presented.
Interferon is the only accepted adjuvant treatment for patients with melanoma; hence, oncologists should be aware of the possibility of retinal abnormalities resulting from its use. Interferon-associated retinopathy in patients being treated for resected melanoma is a rare phenomenon with a proposed immunological basis. Patients are usually asymptomatic or have mild visual impairments, with cotton wool infarcts and hemorrhages. These symptoms and signs usually resolve with the discontinuation of interferon, but in a few severe presentations the visual impairments and retinal changes can be irreversible.
doi:10.1634/theoncologist.2011-0324
PMCID: PMC3316924  PMID: 22334452
Melanoma; Adjuvant; Interferon; Retinopathy
9.  Phase I and pharmacokinetic study of UCN-01 in combination with irinotecan in patients with solid tumors 
Purpose
7-Hydroxystaurosporine (UCN-01) is a protein kinase inhibitor that inhibits several serine–threonine kinases including PKC and PDK1. Due to the preclinical synergistic effects seen with topoisomerase I inhibitors and non-overlapping toxicity, UCN-01 and irinotecan were combined in a dose-finding study designed to determine the maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics (PK) of UCN-01 and irinotecan.
Methods
Patients with incurable solid malignancies received UCN-01 intravenously (IV) as a 3-h infusion on day 1 and irinotecan IV over 90 min on days 1 and 8 of a 21-day cycle. Doses of UCN-01 for subsequent cycles were half the starting dose. Dose level 1 (DL1) consisted of UCN-01 and irinotecan doses of 50 and 60 mg/m2, respectively. Blood samples were collected in cycle 1 for UCN-01, irinotecan, and irinotecan metabolites.
Results
A total of 16 patients were enrolled on the trial at UCN-01/Irinotecan doses of 50/60 mg/m2 (DL1; n = 1), 70/60 mg/m2 (DL2; n = 6), 90/60 mg/m2 (DL3; n = 4), and 70/90 mg/m2 (DL4; n = 5). Two dose-limiting toxicities were observed each in DL3 and DL4 (2 grade 3 hypophosphatemia, 1 grade 4 hyperglycemia and grade 3 hypophosphatemia, 1 grade 4 febrile neutropenia). Fatigue, diarrhea, nausea, and anorexia were the most prevalent toxicities. No objective responses were documented, and four patients had stable disease for at least ten cycles. The long half-life (292.0 ± 135.7 h), low clearance (0.045 ± 0.038 1/h), and volume of distribution (14.3 ± 5.9 l) observed for UCN-01 are consistent with prior UCN-01 data. There was a significant decrease in Cmax of APC, AUC of APC and SN-38, and AUC ratio of SN-38:irinotecan when comparing days 1 and 8 PK.
Conclusions
APC and SN-38 exposure decreased when administered in combination with UCN-01. The MTD of the combination based on protocol criteria was defined as 70 mg/m2 of UCN-01 on day 1 and 60 mg/m2 of irinotecan on days 1 and 8 in a 21-day cycle.
doi:10.1007/s00280-007-0485-9
PMCID: PMC3557498  PMID: 17429623
UCN-01; Irinotecan; Phase I; Cell cycle; G2/M checkpoint
10.  A phase II study of UCN-01 in combination with irinotecan in patients with metastatic triple negative breast cancer 
Mutations in TP53 lead to a defective G1 checkpoint and the dependence on checkpoint kinase 1 (Chk1) for G2 or S phase arrest in response to DNA damage. In preclinical studies, Chk1 inhibition resulted in enhanced cytotoxicity of several chemotherapeutic agents. The high frequency of TP53 mutations in triple negative breast cancer (TNBC: negative for estrogen receptor, progesterone receptor, and HER2) make Chk1 an attractive therapeutic target. UCN-01, a non-selective Chk1 inhibitor, combined with irinotecan demonstrated activity in advanced TNBC in our Phase I study. The goal of this trial was to further evaluate this treatment in women with TNBC. Patients with metastatic TNBC previously treated with anthracyclines and taxanes received irinotecan (100–125 mg/m2 IV days 1, 8, 15, 22) and UCN-01 (70 mg/m2 IV day 2, 35 mg/m2 day 23 and subsequent doses) every 42-day cycle. Peripheral blood mononuclear cells (PBMC) and tumor specimens were collected. Twenty five patients were enrolled. The overall response (complete response (CR) + partial response (PR)) rate was 4 %. The clinical benefit rate (CR + PR + stable disease ≥6 months) was 12 %. Since UCN-01 inhibits PDK1, phosphorylated ribosomal protein S6 (pS6) in PBMC was assessed. Although reduced 24 h post UCN-01, pS6 levels rose to baseline by day 8, indicating loss of UCN-01 bioavailability. Immunostains of γH2AX and pChk1S296 on serial tumor biopsies from four patients demonstrated an induction of DNA damage and Chk1 activation following irinotecan. However, Chk1 inhibition by UCN-01 was not observed in all tumors. Most tumors were basal-like (69 %), and carried mutations in TP53 (53 %). Median overall survival in patients with TP53 mutant tumors was poor compared to wild type (5.5 vs. 20.3 months, p = 0.004). This regimen had limited activity in TNBC. Inconsistent Chk1 inhibition was likely due to the pharmacokinetics of UCN-01. TP53 mutations were associated with a poor prognosis in metastatic TNBC.
doi:10.1007/s10549-012-2378-9
PMCID: PMC3539064  PMID: 23242585
Irinotecan; UCN-01; Chk1; Metastatic triple negative breast cancer; TP53; p53
11.  Targeted agents for the treatment of metastatic melanoma 
OncoTargets and therapy  2012;5:31-46.
In the last year, the armamentarium of melanoma therapeutics has radically changed. Recent discoveries in melanoma biology and immunology have led to novel therapeutics targeting known oncogenes and immunotherapeutic antibodies. Phase III clinical trials of these agents have reported measurable and meaningful benefits to patients with metastatic disease. In this article, we review recent findings and discuss their significance in melanoma therapy. As our understanding of melanoma biology grows, this initial therapeutic success may be enhanced through the use of molecular markers to select patients, and new targeted immunotherapies in sequential or combination drug regimens.
doi:10.2147/OTT.S21259
PMCID: PMC3299555  PMID: 22419879
metastatic melanoma; ipilimumab; vemurafenib; antitumor
12.  Phase II Study of Temsirolimus in Women With Recurrent or Metastatic Endometrial Cancer: A Trial of the NCIC Clinical Trials Group 
Journal of Clinical Oncology  2011;29(24):3278-3285.
Purpose
Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene, and loss of function mutations are common and appear to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN causes deregulated phosphatidylinositol-3 kinase/serine-threonine kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle progression. Temsirolimus, an ester derivative of rapamycin that inhibits mTOR, was evaluated in this setting.
Patients and Methods
Sequential phase II studies evaluated single-agent activity of temsirolimus in women with recurrent or metastatic chemotherapy-naive or chemotherapy-treated endometrial cancer. Temsirolimus 25 mg intravenously was administered weekly in 4-week cycles.
Results
In the chemotherapy-naive group, 33 patients received a median of four cycles (range, one to 23 cycles). Of the 29 patients evaluable for response, four (14%) had an independently confirmed partial response and 20 (69%) had stable disease as best response, with a median duration of 5.1 months (range, 3.7 to 18.4 months) and 9.7 months (range, 2.1 to 14.6 months). Only five patients (18%) had progressive disease. In the chemotherapy-treated group, 27 patients received a median of three cycles (range, one to six cycles). Of the 25 patients evaluable for response, one (4%) had an independently confirmed partial response, and 12 patients (48%) had stable disease, with a median duration of 4.3 months (range, 3.6 to 4.9 months) and 3.7 months (range, 2.4 to 23.2 months). PTEN loss (immunohistochemistry and mutational analysis) and molecular markers of PI3K/Akt/mTOR pathway did not correlate with the clinical outcome.
Conclusion
mTOR inhibition with temsirolimus has encouraging single-agent activity in endometrial cancer which is higher in chemotherapy-naive patients than in chemotherapy-treated patients and is independent of PTEN status. The difference in activity according to prior therapy should be factored into future clinical trial designs.
doi:10.1200/JCO.2010.34.1578
PMCID: PMC3158598  PMID: 21788564
13.  Temsirolimus Has Activity in Non–Mantle Cell Non-Hodgkin's Lymphoma Subtypes: The University of Chicago Phase II Consortium 
Journal of Clinical Oncology  2010;28(31):4740-4746.
Purpose
Despite high initial remission rates, most lymphomas relapse and require further therapy. The mammalian target of rapamycin (mTOR) pathway is a validated target in mantle cell lymphoma, but has not been extensively evaluated in other lymphomas.
Patients and Methods
We performed a phase II trial of single-agent temsirolimus 25-mg weekly in patients with relapsed aggressive and indolent lymphomas. The primary objective was overall and complete response rate. Patients were stratified by histology: group A (diffuse large B-cell lymphoma, transformed follicular lymphoma), group B (follicular lymphoma), and group C (chronic lymphocytic leukemia/small lymphocytic lymphoma, and other indolent lymphomas).
Results
Eighty-nine patients were treated, with outcome strongly dependent on histology. Group A had an overall and complete response rate of 28.1% and 12.5%, respectively, and median progression-free survival (PFS) of 2.6 months and median overall survival (OS) of 7.2 months. Group B had overall and complete response rates of 53.8% and 25.6%, respectively, and median PFS of 12.7 months; median OS has not yet been reached. Group C had a partial response rate of 11% with no complete responders. Toxicity was mainly mild and/or reversible myelosuppression and mucositis; however, four patients developed pneumonitis.
Conclusions
Single-agent temsirolimus has significant activity in both diffuse large B-cell lymphoma and follicular lymphoma, although the durability of responses and PFS are longer for patients with follicular lymphoma. This is the first report of substantial activity of temsirolimus in lymphomas other than mantle cell lymphoma, and supports further evaluation of mTOR as a target in these diseases.
doi:10.1200/JCO.2010.29.2813
PMCID: PMC3020703  PMID: 20837940
14.  Molecular and Clinical Responses in a Pilot Study of Gefitinib with Paclitaxel and Radiation in Locally Advanced Head and Neck Cancer 
Purpose
Epidermal growth factor receptor (EGFR) overexpression in head and neck squamous cell carcinoma (HNSCC) stimulates tumor cell proliferation, inhibits apoptosis, and increases chemotherapy and radiation resistance. We examined the toxicity, safety and the effects on EGFR signaling in tumor biopsies from patients with locally advanced HNSCC treated with the EGFR signaling inhibitor gefitinib (GEF) combined with weekly intravenous paclitaxel (PAC) and radiation therapy (RT).
Methods and Materials
A pilot phase I dose-escalation study. Eligibility included stage III-IVB HNSCC, age ≥18 years, no prior RT or chemotherapy, adequate organ function and informed consent. Endpoints included determination of maximum tolerated dose (MTD) and analysis of treatment effect on EGFR signaling, tumor cell proliferation and apoptosis in biopsies.
Results
Ten patients were treated. The MTD of this combination was GEF 250 mg/d with PAC 36 mg/m2 I.V. weekly × 6 with concurrent RT. Grade 3/4 toxicities included prolonged (>8 weeks) stomatitis (7 patients), infection (1), and interstitial pneumonitis (1). There were five complete responses (CR) and two partial responses (PR). Of 7 patients undergoing serial biopsies, only one demonstrated a reduction in phosphorylated-EGFR, decreased downstream signaling and reduced cellular proliferation after initiating GEF.
Conclusions
GEF inhibition of EGFR was observed in only one of seven tumors studied. The addition of GEF to PAC and RT did not appear to improve the response of locally advanced HNSCC compared to our prior experience with PAC and RT alone. This treatment appeared to delay recovery from stomatitis.
doi:10.1016/j.ijrobp.2009.05.037
PMCID: PMC2868084  PMID: 19879702
Epidermal growth factor receptor; head and neck cancer; gefitinib; paclitaxel; radiation
15.  Phase I Trial of Oxaliplatin, Infusional 5-Fluorouracil, and Leucovorin (FOLFOX4) With Erlotinib and Bevacizumab in Colorectal Cancer 
Clinical colorectal cancer  2010;9(5):297-304.
Rationale
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.
Results
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.
Conclusion
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.
doi:10.3816/CCC.2010.n.043
PMCID: PMC3033228  PMID: 21208844
Epidermal growth factor receptor; Pharmacokinetics; Tyrosine kinase
16.  A Phase I Trial of UCN-01 and Prednisone in Patients With Refractory Solid Tumors and Lymphomas 
Purpose
UCN-01 potently inhibits protein kinase C, phosphatidylinositide-dependent kinase-1, and checkpoint kinase 1, which are involved in regulating cell cycle progression. We designed a phase I study to determine the maximum tolerated dose (MTD) of UCN-01 with prednisone in patients with advanced malignancies.
Methods
UCN-01 was administered as a continuous intravenous infusion over 72 h in cycle 1 and 36 h in subsequent cycles. Prednisone was given orally at 60 mg/m2/day for 5 consecutive days within each 28-day cycle. Standard dose escalation was employed, and MTD was defined as the dose at which no more than one of six patients experienced a dose-limiting toxicity (DLT). Plasma pharmacokinetics of UCN-01 were assessed.
Results
Fifteen patients received a total of 55 courses of treatment. The MTD and the recommended phase II dose of UCN-01 in this combination is 72 mg/m2 total dose over 72 h for cycle 1 followed by 36 mg/m2/cycle over 36 h. All patients experienced hyperglycemia but responded to insulin treatment. Hypophosphatemia was a DLT in two patients. There were no cumulative toxicities. No objective responses were observed, but five patients had stable disease, including two patients with lymphoid malignancies who had prolonged disease stabilizations. UCN-01 has a long terminal half-life and low clearance; there was wide inter-patient variability in peak concentrations.
Conclusion
UCN-01 can be safely administered in combination with prednisone without unacceptable toxicity. The prolonged stable disease in two patients with lymphoid malignancies is proof of principle for the evaluation of cyclin-dependent kinase inhibitors in oncology.
doi:10.1007/s00280-009-1154-y
PMCID: PMC2854012  PMID: 19894051
cyclin-dependent kinase inhibitor; protein kinase C; phase I; combination chemotherapy; UCN-01; prednisone
17.  A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy† 
Neuro-Oncology  2009;12(1):95-103.
Patients with (a) recurrent malignant glioma (MG): glioblastoma (GBM) or recurrent anaplastic glioma (AG), and (b) nonprogressive (NP) GBM following radiation therapy (RT) were eligible. Primary objective for recurrent MG was progression-free survival at 6 months (PFS-6) and overall survival at 12 months for NP GBM post-RT. Secondary objectives for recurrent MGs were response, survival, assessment of toxicity, and pharmacokinetics (PKs). Treatment with enzyme-inducing antiepileptic drugs was not allowed. Patients received 150 mg/day erlotinib. Patients requiring surgery were treated 7 days prior to tumor removal for PK analysis and effects of erlotinib on epidermal growth factor receptor (EGFR) and intracellular signaling pathways. Ninety-six patients were evaluable (53 recurrent MG and 43 NP GBM); 5 patients were not evaluable for response. PFS-6 in recurrent GBM was 3% with a median PFS of 2 months; PFS-6 in recurrent AG was 27% with a median PFS of 2 months. Twelve-month survival was 57% in NP GBMs post-RT. Primary toxicity was dermatologic. The tissue-to-plasma ratio normalized to nanograms per gram dry weight for erlotinib and OSI-420 ranged from 25% to 44% and 30% to 59%, respectively, for pretreated surgical patients. No effect on EGFR or intratumoral signaling was seen. Patients with NP GBM post-RT who developed rash in cycle 1 had improved survival (P < .001). Single-agent activity of erlotinib is minimal for recurrent MGs and marginally beneficial following RT for NP GBM patients. Development of rash in cycle 1 correlates with survival in patients with NP GBM after RT.
doi:10.1093/neuonc/nop015
PMCID: PMC2940554  PMID: 20150372
erlotinib; glioblastoma; glioma; meningioma; pharmacokinetics
18.  A phase I trial of erlotinib in patients with nonprogressive glioblastoma multiforme postradiation therapy, and recurrent malignant gliomas and meningiomas† 
Neuro-Oncology  2009;12(1):87-94.
The objective of this phase I study was to determine the maximal tolerated dose (MTD) of erlotinib in patients with recurrent malignant gliomas (MGs) or recurrent meningiomas on enzyme-inducing antiepileptic drugs (EIAEDs). Dose escalation was by a standard 3 × 3 design. The initial starting dose of erlotinib was 150 mg daily. If no dose-limiting toxicity (DLT) was observed, then dose escalation occurs as follows: 200 mg/day, 275 mg/day, and then increased in 125 mg increments until the MTD was reached. The MTD was defined as the dose where ≤1 of 6 patients experienced a DLT and the dose above had 2 or more DLTs. The MTD was 650 mg/day; the observed DLTs were grade 3 rash in 2 patients at 775 mg/day. Pharmacokinetic analysis showed a significant influence of EIAEDs on the metabolism of erlotinib when compared with our phase II data published separately. Primary toxicities were rash and diarrhea. The MTD of erlotinib in patients receiving EIAEDs is substantially higher than the standard dose of 150 mg. This has important implications for further development of this drug in the treatment of MG as well as the optimal management of patients with other malignancies such as NSCLC who are on enzyme-inducing drugs.
doi:10.1093/neuonc/nop017
PMCID: PMC2940559  PMID: 20150371
erlotinib; glioblastoma; glioma; meningioma; pharmacokinetics
19.  A Multi-institutional Phase II study of the efficacy and tolerability of Lapatinib in patients with advanced hepatocellular carcinomas 
Background
Hepatocellular carcinoma (HCC) is on the rise worldwide. HCC responds poorly to chemotherapy. Lapatinib is an inhibitor of EGFR and HER2/NEU both implicated in hepatocarcinogenesis. This trial was designed to determine the safety and efficacy of lapatinib in HCC.
Methods
A Fleming phase II design with a single stage of 25 patients with a 90% power to exclude a true response rate of < 10% and detect a true response rate of ≥30% was utilized. The dose of lapatinib was 1,500 mg/d administered orally in 28-day cycles. Tumor and blood specimens were analyzed for expression of HER2/NEU/CEP17 and status of downstream signal pathway proteins.
Results
Twenty-six patients with HCC enrolled on this study. 19% had one prior therapy. Most common toxicities were diarrhea (73%), nausea (54%) and rash (42%). No objective responses were observed. Ten (40%) patients had stable disease (SD) as their best response including 6 (23%) with SD lasting > 120 days. Median progression-free-survival was 1.9 months and median overall survival 12.6 months. Patients who developed a rash had a borderline statistically significant longer survival. Tissue and blood specimens were available on >90% of patients. No somatic mutations in EGFR (exons 18–21) were found. In contrast to our previous findings, we did not find evidence of HER2/NEU somatic mutations. PTEN, P-AKT and P70S6K expression did not correlate with survival.
Conclusions
Lapatinib is well-tolerated but appears to benefit only a subgroup of patients for whom predictive molecular or clinical characteristics are not yet fully defined.
doi:10.1158/1078-0432.CCR-09-0465
PMCID: PMC2774354  PMID: 19737952
20.  A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies 
Cancer Chemotherapy and Pharmacology  2010;67(6):1225-1237.
Purpose
UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors.
Experimental design
Patients received irinotecan (75–125 mg/m2 IV on days 1, 8, 15, 22) and UCN-01 (50–90 mg/m2 IV on day 2 and 25–45 mg/m2 on day 23 and subsequent doses) every 42 days. Blood for pharmacokinetics of UCN-01 and irinotecan, and blood, normal rectal mucosa, and tumor biopsies for pharmacodynamic studies were obtained.
Results
Twenty-five patients enrolled to 5 dose levels. The MTD was irinotecan 125 mg/m2 on days 1, 8, 15, 22 and UCN-01 70 mg/m2 on day 2 and 35 mg/m2 on day 23. DLTs included grade 3 diarrhea/dehydration and dyspnea. UCN-01 had a prolonged half-life and a low clearance rate. There was a significant reduction in SN-38 Cmax and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives. Phosphorylated ribosomal protein S6 was reduced in blood, normal rectal mucosa, and tumor biopsies at 24 h post-UCN-01. Two partial responses were observed in women with ER, PgR, and HER2-negative breast cancers (TBNC). Both tumors were defective for p53. Twelve patients had stable disease (mean duration 18 weeks, range 7–30 weeks).
Conclusion
UCN-01 and irinotecan demonstrated acceptable toxicity and target inhibition. Anti-tumor activity was observed and a study of this combination in women with TNBC is underway.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-010-1410-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s00280-010-1410-1
PMCID: PMC3102212  PMID: 20694727
Phase 1; Irinotecan; UCN-01; Chk1; Ribosomal protein S6
21.  Fluorescence in situ hybridization gene amplification analysis of EGFR and HER2 in patients with malignant salivary gland tumors treated with lapatinib 
Head & neck  2009;31(8):1006-1012.
Aim
Gene amplification status of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER2) were analyzed and correlated with clinical outcome in patients with progressive malignant salivary glands tumors (MSGT) treated with the dual EGFR/Her2 tyrosine kinase inhibitor lapatinib
Methods
Fluorescence in situ hybridization (FISH) analysis for both EGFR and HER2 gene amplification was performed successfully in the archival tumor specimens of 20 patients with adenoid cystic carcinomas (ACC) and 17 patients with non-ACC, all treated with lapatinib.
Results
For ACC, no EGFR or HER2 amplifications were detected. For non-ACC, no EGFR gene amplifications were detected but 3 patients (18%) were HER2 amplified and all had stained 3+ for both EGFR and HER2 by immunohistochemistry (IHC) in their archival specimens. Two of these patients had time-to-progression (TTP) durations of 8.3 months and 18.4 months respectively. Interestingly, patients with low and high HER2/chromosome-specific centromeric enumeration probe (CEP) 17 ratio had a prolonged TTP than those with moderate ratios for both ACC and non-ACC subtypes.
Conclusions
HER2 to CEP17 FISH ratio may predict which patients with MSGT have an increased likelihood to benefit from lapatinib. The finding of HER2:CEP17 ratio as a predictive marker of efficacy to lapatinib warrants further investigation.
doi:10.1002/hed.21052
PMCID: PMC2711990  PMID: 19309723
MSGT; lapatinib; EGFR and HER2 gene amplification; FISH
22.  A Phase II Study of Erlotinib and Bevacizumab in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck 
The lancet oncology  2009;10(3):247-257.
Background
The epidermal growth factor receptor (EGFR) is a validated target in squamous cell carcinoma of the head and neck but in patients with recurrent or metastatic disease, EGFR targeting agents have displayed modest efficacy. Vascular endothelial growth factor (VEGF) mediated angiogenesis has been implicated as a mechanism of resistance to anti-EGFR therapy. This study combined an EGFR inhibitor, erlotinib, with an anti-VEGF antibody, bevacizumab.
Methods
This multi-institutional phase I/II study enrolled patients with recurrent or metastatic squamous cell carcinoma of the head and neck to receive erlotinib (150 mg daily) and bevacizumab in escalating dose cohorts. The primary objectives in the phase I and II portions, respectively, were to determine the maximum tolerated dose and dose-limiting toxicity of bevacizumab when administered with erlotinib and to determine the objective response rate and time to disease progression. Pre-treatment serum and tissues were collected and analyzed by Enzyme-Linked ImmunoSorbent Assay and immunofluorescence quantitative laser analysis, respectively. This study was registered with ClinicalTrials.gov, number NCT00055913.
Findings
The phase I portion enrolled 10 subjects in three successive cohorts without dose-limiting toxicity observed. An additional 46 subjects were enrolled at the phase II dose (bevacizumab 15 mg/kg every 3 weeks). The most common toxicities of any grade were rash and diarrhea (41 and 16 of 48 subjects, respectively). Three patients experienced serious bleeding events. The observed response rate was 15% with 4 complete responses (CR) allowing rejection of the null hypothesis. The median overall and progression-free survival (PFS) durations were 7.1 (95% Confidence Interval: 5.7 to 9.0) and 4.1 (95% Confidence Interval: 2.8 to 4.4) months, respectively. Higher ratios of phosphorylated over total VEGF receptor-2 and EGFR in pre-treatment biopsies were associated with CR (0.7043 vs. 0.3857, p=0.036 and 0.949 vs. 0.332, p=0.036, respectively) and tumor shrinkage (p=0.007 and p=0.008, respectively) in a subset of 11 subjects with available tissue.
Interpretation
The combination of erlotinib and bevacizumab is well tolerated in recurrent or metastatic squamous cell carcinoma of the head and neck. Some patients appear to derive a sustained benefit and complete responses were associated with expression of putative targets in pre-treatment tumor tissue.
doi:10.1016/S1470-2045(09)70002-6
PMCID: PMC2768532  PMID: 19201650
23.  A phase I study of gefitinib, capecitabine, and celecoxib in patients with advanced solid tumors 
Molecular cancer therapeutics  2008;7(12):3685.
This phase I study was designed to determine the maximum tolerated dose (MTD) and toxicity profile of the combination of gefitinib, capecitabine, and celecoxib in patients with advanced solid tumors. Patients were treated with escalating doses of gefitinib once daily, capecitabine twice daily (14 of 28 days), and celecoxib twice daily. Plasma samples for biomarkers were obtained at baseline and weekly for the first 2 cycles. Pharmacokinetic variables were correlated with toxicity and presence of biological effect. Tumor biopsies from 5 patients were analyzed for changes in tumor metabolic activity by nuclear magnetic resonance spectroscopy. [18F]fluororodeoxyglucose positron emission tomography was done as a correlate in 6 patients at the MTD. Thirty-nine patients received 168 cycles of therapy. The dose-limiting toxicities observed included nausea, dehydration and nausea, diarrhea, and stomatitis. The MTD was 250 mg/d gefitinib (days 1–14) and 2,000 mg/m2/d capecitabine divided twice daily (days 8–21) every 28 days. Celecoxib was eliminated due to concerns of increased risk for cardiovascular toxicity, although no patients in this study had cardiac events. One patient with cholangiocarcinoma had a confirmed partial response. Fourteen of 39 (36%) patients maintained prolonged stable disease for a median of 4 months (range, 3–24 months). [18F]fluorodeoxyglulucose positron emission tomography scan and metabolomic analyses revealed differences in metabolic response to gefitinib versus capecitabine. The combination of gefitinib and capecitabine is well tolerated and appears to have activity against certain advanced solid tumors, providing a rationale for further evaluation in advanced solid malignancies.
doi:10.1158/1535-7163.MCT-08-0436
PMCID: PMC2813692  PMID: 19074845
24.  A Phase II Trial of Erlotinib in Combination with Bevacizumab in Patients with Metastatic Breast Cancer 
Purpose
To evaluate the efficacy and toxicity of erlotinib plus bevacizumab in patients with metastatic breast cancer (MBC), targeting the epidermal growth factor receptor (EGFR/HER1) and the vascular endothelial growth factor (VEGF) pathway.
Experimental Design
Thirty-eight patients with MBC were enrolled and treated at two institutions with erlotinib, a small molecule EGFR tyrosine kinase inhibitor (150 mg orally daily) plus bevacizumab, an anti-VEGF antibody (15 mg/kg intravenously every 3 weeks). Patients had 1-2 prior chemotherapy regimens for metastatic disease. The primary end point was response rate by RECIST criteria using a Simon 2-stage design. Secondary end points included toxicity, time to progression (TTP), response duration, and stabilization of disease ≥ 26 weeks. Correlative studies were performed on tumor tissue, including EGFR expression and mutation analysis.
Results
One patient achieved a partial response for 52+ months. Fifteen patients had stable disease at first evaluation at 9 weeks; 4 of these patients had stable disease beyond 26 weeks. Median TTP was 11 weeks (95% confidence interval [CI] 8-18 weeks). Diarrhea of any grade was observed in 84% of patients (grade 3 in 3%); 76% experienced grade 1 or 2 skin rash, and 18% developed hypertension (grade 3 in 11%). The level of EGFR expression was not predictive of response to therapy.
Conclusions
The combination of erlotinib and bevacizumab was well tolerated, but had limited activity in unselected patients with previously treated MBC. Biomarkers are needed to identify those MBC patients likely to respond to anti-EGFR/HER1 plus anti-VEGF therapy.
doi:10.1158/1078-0432.CCR-08-0141
PMCID: PMC2748748  PMID: 19047117
25.  A Perspective on Challenges and Issues in Biomarker Development and Drug and Biomarker Codevelopment 
A workshop sponsored by the National Cancer Institute and the US Food and Drug Administration addressed past lessons learned and ongoing challenges faced in biomarker development and drug and biomarker codevelopment. Participants agreed that critical decision points in the product life cycle depend on the level of understanding of the biology of the target and its interaction with the drug, the preanalytical and analytical factors affecting biomarker assay performance, and the clinical disease process. The more known about the biology and the greater the strength of association between an analytical signal and clinical result, the more efficient and less risky the development process will be. Rapid entry into clinical practice will only be achieved by using a rigorous scientific approach, including careful specimen collection and standardized and quality-controlled data collection. Early interaction with appropriate regulatory bodies will ensure studies are appropriately designed and biomarker test performance is well characterized.
doi:10.1093/jnci/djp334
PMCID: PMC2773185  PMID: 19855077

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