The National Cancer Institute-supported adult cooperative oncology
research groups (now officially Network groups) have a long-standing history of
participating in international collaborations throughout the world. Most
frequently, the U.S. based cooperative groups work reciprocally with the
Canadian national adult cancer clinical trial group, NCIC CTG (previously the
National Cancer Institute of Canada Clinical Trials Group). Thus, Canada is the
largest contributor to cooperative groups based in the U.S., and vice versa.
Although international collaborations have many benefits, they are most
frequently utilized to enhance patient accrual to large phase III trials
originating in the U.S. or Canada. Within the cooperative group setting,
adequate attention has not been given to the study of cancers that are unique to
countries outside the U.S. and Canada, such as those frequently associated with
infections in Latin America, Asia and Africa. Global collaborations are limited
by a number of barriers, some of which are unique to the countries involved,
while others are related to financial support and to U.S. policies that restrict
drug distribution outside the U.S. This manuscript serves to detail the
cooperative group experience in international research and describe how
international collaboration in cancer clinical trials is a promising and
important area that requires greater consideration in the future.
To characterize the pharmacokinetics of temsirolimus and its major metabolite, sirolimus, in patients receiving enzyme-inducing antiepileptic drugs (EIAED) compared with patients receiving non-EIAEDs. An additional objective was to determine whether concentrations of temsirolimus or sirolimus were achieved in brain tumor tissue.
Patients with recurrent malignant gliomas not receiving EIAEDs initially received temsirolimus weekly at a dose of 250 mg i.v. The dose was subsequently reduced to 170 mg due to intolerable side effects. For patients taking EIAEDs, the starting dose of temsirolimus was 250 mg with standard dose escalation until the maximal tolerated dose was established. Ten whole blood samples were obtained over a period of 24 h after administration of temsirolimus for pharmacokinetic assessments. Patients eligible for cytoreductive surgery received temsirolimus before tumor resection. Whole blood and tumor tissue were obtained for analysis.
Significant differences in the pharmacokinetic variables for temsirolimus and sirolimus were observed between the two patient groups at a comparable dose level of 250 mg. For patients receiving EIAEDs, the systemic exposure to temsirolimus was lower by 1.5-fold. Likewise, peak concentrations and exposure to sirolimus were lower by 2-fold. Measurable concentrations of temsirolimus and sirolimus were observed in brain tumor specimens. The average tissue to whole blood ratio for temsirolimus was 1.43 and 0.84 for sirolimus.
Drugs that induce cytochrome P450 3A4, such as EIAEDs, significantly affect the pharmacokinetics of temsirolimus and its active metabolite, sirolimus. Total exposure to temsirolimus and sirolimus was lower in the EIAED group at the maximum tolerated dose of 250 mg compared with the non-EIAED group at the maximum tolerated dose of 170 mg. However, brain tumor tissue concentrations of temsirolimus and sirolimus were relatively comparable in both groups of patients at their respective dose levels. Correlative analyses of the tissue for the inhibition of the key regulators (p70S6 kinase and 4E-binding protein 1) of mammalian target of rapamycin are necessary to define the therapeutic significance of the altered exposure to temsirolimus.
This Phase I trial aimed to determine the maximum-tolerated-dose of erlotinib administered with two standard chemoradiotherapy regimens for non-small cell lung cancer.
Unresectable stage III non-small cell lung cancer patients were enrolled in this 2-arm dose-escalation study. Erlotinib, given only during chemoradiotherapy, was escalated from 50 to 150 mg/d in 3 to 6 patient cohorts. Arm A: erlotinib with cisplatin (50 mg/m2 IV days 1, 8, 29, 36), etoposide (50 mg/m2 IV days 1–5, 29–33) and chest radiotherapy (66 Gy, 2 Gy/d) followed by docetaxel (75 mg/m2 IV Q21 d) for 3 cycles. Arm B: induction carboplatin (AUC 6) and paclitaxel (200 mg/m2) for two 21-d cycles then radiotherapy with erlotinib, carboplatin (AUC = 2/wk) and paclitaxel (50 mg/m2/wk).
Seventeen patients were treated in each arm. Patient characteristics: performance status 0 to 24 patients, 1 to 10 patients, median age 63 years, adenocarcinoma 21% and female 14 patients. Dose-escalation of erlotinib to 150 mg/d was possible on both chemoradiotherapy regimens. Grade 3/4 leukopenia and neutropenia were predominant toxicities in both arms. Grade 3 chemoradiotherapy toxicities in arm A were esophagitis (3 patients), vomiting (1), ototoxicity (1), diarrhea (2), dehydration (3), pneumonitis (1); and arm B was esophagitis (6). Seven patients (21%) developed rash (all grade 1/2). Median survival times for patients on Arm A and B were 10.2 and 13.7 months, respectively. Three-year overall survival in patients with and without rash were 53% and 10%, respectively (log-rank P = 0.0807). Epidermal growth factor receptor IHC or FISH positive patients showed no significant overall survival difference.
Addition of standard-dose erlotinib to chemoradiotherapy is feasible without evident increase in toxicities. However, the survival data are disappointing in this unselected patient population and does not support further investigation of this approach.
Non-small cell lung cancer; Chemoradiotherapy; Multimodality therapy; Erlotinib; Epidermal-growth factor inhibitor
This study sought to determine the efficacy and safety profile of lapatinib in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN).
This phase II multi-institutional study enrolled patients with recurrent/metastatic SCCHN into 2 cohorts: those without (arm A) and those with (arm B) prior exposure to an epidermal growth factor receptor (EGFR) inhibitor. All subjects were treated with lapatinib 1500 mg daily. Primary endpoints were response rate (arm A) and progression-free survival (arm B). The biologic effects of lapatinib on tumor growth and survival pathways were assessed in paired tumor biopsies obtained before and after therapy.
Forty-five patients were enrolled, 27 in arm A and 18 in arm B. Diarrhea was the most frequent toxicity occurring in 49% of patients. Seven patients experienced related grade 3 toxicity (3 fatigue, 2 hyponatremia, 1 vomiting, 1 diarrhea). In an intent-to-treat analysis, no complete or partial responses were observed and stable disease was the best response observed in 41% of arm A (median duration 50 days, range 34 – 159) and 17% of arm B subjects (median 163 days, range 135 – 195). Median PFS was 52 days in both arms. Median OS was 288 (95% CI, 62–374) and 155 (95% CI, 75–242) days for arms A and B, respectively. Correlative analyses revealed an absence of EGFR inhibition in tumor tissue.
Lapatinib as a single agent in recurrent/metastatic SCCHN, although well tolerated, appears to be inactive in either EGFR inhibitor naive or refractory subjects.
Inhibition of epidermal growth factor receptor (EGFR) and the mechanistic target of rapamycin (mTOR) may have synergistic antitumor effects in high-grade glioma patients.
We conducted a phase I/II study of the EGFR inhibitor erlotinib (150 mg/day) and the mTOR inhibitor temsirolimus. Patients initially received temsirolimus 50 mg weekly, and the dose adjusted based on toxicities. In the phase II component, the primary endpoint was 6-month progression-free survival (PFS6) among glioblastoma patients.
Twenty-two patients enrolled in phase I, 47 in phase II. Twelve phase I patients treated at the maximum tolerated dosage were included in the phase II cohort for analysis. The maximum tolerated dosage was 15 mg temsirolimus weekly with erlotinib 150 mg daily. Dose-limiting toxicities were rash and mucositis. Among 42 evaluable glioblastoma patients, 12 (29%) achieved stable disease, but there were no responses, and PFS6 was 13%. Among 16 anaplastic glioma patients, 1 (6%) achieved complete response, 1 (6%) partial response, and 2 (12.5%) stable disease, with PFS6 of 8%. Tumor levels of both drugs were low, and posttreatment tissue in 3 patients showed no reduction in the mTOR target phosphorylated (phospho-)S6S235/236 but possible compensatory increase in phospho-AktS473. Presence of EGFR variant III, phospho-EGFR, and EGFR amplification did not correlate with survival, but patients with elevated phospho–extracellular signal-regulated kinase or reduced phosphatase and tensin homolog protein expression had decreased progression-free survival at 4 months.
Because of increased toxicity, the maximum tolerated dosage of temsirolimus in combination with erlotinib proved lower than expected. Insufficient tumor drug levels and redundant signaling pathways may partly explain the minimal antitumor activity noted.
anaplastic glioma; clinical trial; epidermal growth factor; erlotinib; glioblastoma; temsirolimus
Developments in genomics, including next-generation sequencing technologies, are expected to enable a more personalized approach to clinical care, with improved risk stratification and treatment selection. In oncology, personalized medicine is particularly advanced and increasingly used to identify oncogenic variants in tumor tissue that predict responsiveness to specific drugs. Yet, the translational research needed to validate these technologies will be conducted in patients with late-stage cancer and is expected to produce results of variable clinical significance and incidentally identify genetic risks. To explore the experiential context in which much of personalized cancer care will be developed and evaluated, we conducted a qualitative interview study alongside a pilot feasibility study of targeted DNA sequencing of metastatic tumor biopsies in adult patients with advanced solid malignancies. We recruited 29/73 patients and 14/17 physicians; transcripts from semi-structured interviews were analyzed for thematic patterns using an interpretive descriptive approach. Patient hopes of benefit from research participation were enhanced by the promise of novel and targeted treatment but challenged by non-findings or by limited access to relevant trials. Family obligations informed a willingness to receive genetic information, which was perceived as burdensome given disease stage or as inconsequential given faced challenges. Physicians were optimistic about long-term potential but conservative about immediate benefits and mindful of elevated patient expectations; consent and counseling processes were expected to mitigate challenges from incidental findings. These findings suggest the need for information and decision tools to support physicians in communicating realistic prospects of benefit, and for cautious approaches to the generation of incidental genetic information.
personalized medicine; cancer care; qualitative research; clinical trials; genetic testing; clinical sequencing
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.
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.
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.
phase I; sorafenib; temsirolimus; metastatic melanoma; BRAF
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.
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.
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.
Temozolomide; Gefitinib; Malignant gliomas; Enzyme-inducing anti-epileptic drugs
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.
anaplastic glioma; glioblastoma; malignant glioma; sorafenib; temsirolimus
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.
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.
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.
Erlotinib; Squamous cell carcinoma of the head and neck; OSI-774; Phase I
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.
meningioma; erlotinib; gefitinib; epidermal growth factor receptor inhibitor
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.
Multiple myeloma; mTOR; temsirolimus; pharmacokinetics
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.
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.
Melanoma; Adjuvant; Interferon; Retinopathy
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.
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.
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.
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.
UCN-01; Irinotecan; Phase I; Cell cycle; G2/M checkpoint
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.
Irinotecan; UCN-01; Chk1; Metastatic triple negative breast cancer; TP53; p53
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.
metastatic melanoma; ipilimumab; vemurafenib; antitumor
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.
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.
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.
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).
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.
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.
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.
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.
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.
Epidermal growth factor receptor; head and neck cancer; gefitinib; paclitaxel; radiation
This phase I study was conducted to determine the maximum tolerated dose (MTD) of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) in patients with advanced colorectal cancer (CRC). Bevacizumab was later included as standard of care at the MTD.
Patients and Methods
Patients received FOLFOX4 with escalating doses of erlotinib: dose level (DL) 1, 50 mg; DL 2, 100 mg; and DL 3, 150 mg once daily continuously. Bevacizumab 5 mg/kg days 1 and 15 was added at the MTD upon Food and Drug Administration approval. Correlative studies included pharmacokinetics, pharmacodynamics was assessed in paired skin biopsies, and fluorodeoxyglucose positron emission tomography scans.
Fifteen patients received 60 cycles (120 FOLFOX treatments). Two dose-limiting toxicities (DLTs) were seen at DL 3: intolerable grade 2 rash (Common Terminology Criteria for Adverse Events version 2) lasting > 1 week, and grade 4 neutropenia. Dose level 2 was expanded to 6 more patients, this time adding bevacizumab, and 1 DLT of grade 3 mucositis occurred. As expected, the primary toxicities were cytopenias, diarrhea, rash, and fatigue. There were 2 occurrences of pneumatosis. One patient experienced an unrelated grade 4 myocardial infarction before starting chemotherapy. No pharmacokinetic drug interactions were observed. The Response Evaluation Criteria in Solid Tumors response rate was 11 of 14 (78%), median progression-free survival was 9.5 months, and median overall survival was 30 months. Three patients are currently alive > 3 years, with 1 having no evidence of disease.
The MTD of erlotinib with FOLFOX4 with or without bevacizumab is 100 mg daily. The regimen appeared to increase toxicity but showed activity in patients with CRC.
Epidermal growth factor receptor; Pharmacokinetics; Tyrosine kinase
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.
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.
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.
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.
cyclin-dependent kinase inhibitor; protein kinase C; phase I; combination chemotherapy; UCN-01; prednisone
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.
erlotinib; glioblastoma; glioma; meningioma; pharmacokinetics
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.
erlotinib; glioblastoma; glioma; meningioma; pharmacokinetics
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.
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.
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.
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.