Scientific diligence for oncology drugs: a pharmacology, translational medicine and clinical perspective.

Increasingly, new drug development by major pharmaceutical companies relies on in-licensing of innovative therapies. Often there are limited data accompanying these novel entities. By focusing on scientific principles and generating key preclinical and clinical data, discovery companies can improve their valuations. From the lens of a large pharmaceutical company, we highlight key scientific aspects that are assessed to mitigate risk in valuations and deal terms. Our focus is on clinical development aspects for oncology drugs by stage of development. However, these lessons apply equally to other therapeutic areas.

Dose selection of siltuximab for multicentric Castleman's disease.

PURPOSE: Siltuximab is a monoclonal antibody that binds to interleukin (IL)-6 with high affinity and specificity; C-reactive protein (CRP) is an acute-phase protein induced by IL-6. CRP suppression is an indirect measurement of IL-6 activity. Here, modeling and simulation of the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between siltuximab and CRP were used to support dose selection for multicentric Castleman's disease (CD). METHODS: PK/PD modeling was applied to explore the relationship between siltuximab PK and CRP suppression following intravenous siltuximab infusion in 47 patients with B cell non-Hodgkin's lymphoma (n = 17), multiple myeloma (n = 13), or CD (n = 17). Siltuximab was administered as 2.8, 5.5, or 11 mg/kg q2wks, 11 mg/kg q3wks, or 5.5 mg/kg weekly. Simulations of studied or hypothetical siltuximab dosage regimens (15 mg/kg q4wks) were also performed to evaluate maintenance of CRP suppression below the cutoff value of 1 mg/L. RESULTS: A two-compartment PK model and an inhibitory indirect response PD model adequately described the serum siltuximab and CRP concentration-time profiles simultaneously. PD parameter estimates were physiologically plausible. For all disease types, simulations showed that 11 mg/kg q3wks or 15 mg/kg q4wks would reduce serum CRP to below 1 mg/L after the second dose and throughout the treatment period. CONCLUSIONS: PK/PD modeling was used to select doses for further development of siltuximab in multicentric CD. The dosing recommendation was also supported by the observed efficacy dose-response relationship. CRP suppression in the subsequent randomized multicentric CD study was in agreement with the modeling predictions.

Carlumab, an anti-C-C chemokine ligand 2 monoclonal antibody, in combination with four chemotherapy regimens for the treatment of patients with solid tumors: an open-label, multicenter phase 1b study.

C-C chemokine ligand 2 (CCL2) stimulates tumor growth, metastasis, and angiogenesis. Carlumab, a human IgG1κ anti-CCL2 mAb, has shown antitumor activity in preclinical and clinical trials. We conducted a first-in-human phase 1b study of carlumab with one of four chemotherapy regimens (docetaxel, gemcitabine, paclitaxel + carboplatin, and pegylated liposomal doxorubicin HCl [PLD]). Patients had advanced solid tumors for which ≥1 of these regimens was considered standard of care or for whom no other treatment options existed. Dose-limiting toxicities included one grade 4 febrile neutropenia (docetaxel arm) and one grade 3 neutropenia (gemcitabine arm). Combination treatment with carlumab had no clinically relevant pharmacokinetic effect on docetaxel (n = 15), gemcitabine (n = 12), paclitaxel or carboplatin (n = 12), or PLD (n = 14). Total serum CCL2 concentrations increased post-treatment with carlumab alone, consistent with carlumab-CCL2 binding, and continued increase in the presence of all chemotherapy regimens. Free CCL2 declined immediately post-treatment with carlumab but increased with further chemotherapy administrations in all arms, suggesting that carlumab could sequester CCL2 for only a short time. Neither antibodies against carlumab nor consistent changes in circulating tumor cells (CTCs) or circulating endothelial cells (CECs) enumeration were observed. Three of 19 evaluable patients showed a 30 % decrease from baseline urinary cross-linked N-telopeptide of type I collagen (uNTx). One partial response and 18 (38 %) stable disease responses were observed. The most common drug-related grade ≥3 adverse events were docetaxel arm-neutropenia (6/15) and febrile neutropenia (4/15); gemcitabine arm-neutropenia (2/12); paclitaxel + carboplatin arm-neutropenia, thrombocytopenia (4/12 each), and anemia (2/12); and PLD arm-anemia (3/14) and stomatitis (2/14). Carlumab could be safely administered at 10 or 15 mg/kg in combination with standard-of-care chemotherapy and was well-tolerated, although no long-term suppression of serum CCL2 or significant tumor responses were observed.

A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma.

We compared the safety and efficacy of siltuximab (S), an anti-interleukin-6 chimeric monoclonal antibody, plus bortezomib (B) with placebo (plc) + B in patients with relapsed/refractory multiple myeloma in a randomized phase 2 study. Siltuximab was given by 6 mg/kg IV every 2 weeks. On progression, B was discontinued and high-dose dexamethasone could be added to S/plc. Response and progression-free survival (PFS) were analyzed pre-dexamethasone by European Group for Blood and Marrow Transplantation (EBMT) criteria. For the 281 randomized patients, median PFS for S + B and plc + B was 8.0 and 7.6 months (HR 0.869, P = 0.345), overall response rate was 55 versus 47% (P = 0.213), complete response rate was 11 versus 7%, and median overall survival (OS) was 30.8 versus 36.8 months (HR 1.353, P = 0.103). Sustained suppression of C-reactive protein, a marker reflective of inhibition of interleukin-6 activity, was seen with S + B. Siltuximab did not affect B pharmacokinetics. Siltuximab/placebo discontinuation (75 versus 66%), grade ≥3 neutropenia (49 versus 29%), thrombocytopenia (48 versus 34%), and all-grade infections (62 versus 49%) occurred more frequently with S + B. The addition of siltuximab to bortezomib did not appear to improve PFS or OS despite a numerical increase in response rate in patients with relapsed or refractory multiple myeloma.

Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6. No randomised trials have been done to establish the best treatment for the disease. We assessed the safety and efficacy of siltuximab-a chimeric monoclonal antibody against interleukin 6-in HIV-negative patients with multicentric Castleman's disease. METHODS: We did this randomised, double-blind, placebo-controlled study at 38 hospitals in 19 countries worldwide. We enrolled HIV-negative and human herpesvirus-8-seronegative patients with symptomatic multicentric Castleman's disease. Treatment allocation was randomised with a computer-generated list, with block size six, and stratification by baseline corticosteroid use. Patients and investigators were masked to treatment allocation. Patients were randomly assigned (2:1) to siltuximab (11 mg/kg intravenous infusion every 3 weeks) or placebo; all patients also received best supportive care. Patients continued treatment until treatment failure. The primary endpoint was durable tumour and symptomatic response for at least 18 weeks for the intention-to-treat population. Enrolment has been completed. The study is registered with ClinicalTrials.gov, number NCT01024036. FINDINGS: We screened 140 patients, 79 of whom were randomly assigned to siltuximab (n=53) or placebo (n=26). Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1-54·8, p=0·0012). The incidence of grade 3 or more adverse events (25 [47%] vs 14 [54%]) and serious adverse events (12 [23%] vs five [19%]) was similar in each group despite longer median treatment duration with siltuximab than with placebo (375 days [range 1-1031] vs 152 days [23-666]). The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). Three (6%) of 53 patients had serious adverse events judged reasonably related to siltuximab (lower respiratory tract infection, anaphylactic reaction, sepsis). INTERPRETATION: Siltuximab plus best supportive care was superior to best supportive care alone for patients with symptomatic multicentric Castleman's disease and well tolerated with prolonged exposure. Siltuximab is an important new treatment option for this disease. FUNDING: Janssen Research & Development.

A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors.

PURPOSE: This phase I/II study evaluated safety, efficacy, and pharmacokinetics of escalating, multiple doses of siltuximab, a chimeric anti-interleukin (IL)-6 monoclonal antibody derived from a new Chinese hamster ovary (CHO) cell line in patients with advanced/refractory solid tumors. EXPERIMENTAL DESIGN: In the phase I dose-escalation cohorts, 20 patients with advanced/refractory solid tumors received siltuximab 2.8 or 5.5 mg/kg every 2 weeks or 11 or 15 mg/kg every 3 weeks intravenously (i.v.). In the phase I expansion (n = 24) and phase II cohorts (n = 40), patients with Kirsten rat sarcoma-2 (KRAS)-mutant tumors, ovarian, pancreatic, or anti-EGF receptor (EGFR) refractory/resistant non-small cell lung cancer (NSCLC), colorectal, or H&N cancer received 15 mg/kg every 3 weeks. The phase II primary efficacy endpoint was complete response, partial response, or stable disease >6 weeks. RESULTS: Eighty-four patients (35 colorectal, 29 ovarian, 9 pancreatic, and 11 other) received a median of three (range, 1-45) cycles. One dose-limiting toxicity occurred at 5.5 mg/kg. Common grade ≥3 adverse events were hepatic function abnormalities (15%), physical health deterioration (12%), and fatigue (11%). Ten percent of patients had siltuximab-related grade ≥3 adverse events. Neutropenia (4%) was the only possibly related adverse event grade ≥3 reported in >1 patient. Serious adverse events were reported in 42%; most were related to underlying disease. The pharmacokinetic profile of CHO-derived siltuximab appears similar to the previous cell line. No objective responses occurred; 5 of 84 patients had stable disease >6 weeks. Hemoglobin increased ≥1.5 g/dL in 33 of 47 patients. At 11 and 15 mg/kg, completely sustained C-reactive protein suppression was observed. CONCLUSIONS: Siltuximab monotherapy appears to be well tolerated but without clinical activity in solid tumors, including ovarian and KRAS-mutant cancers. The recommended phase II doses were 11 and 15 mg/kg every 3 weeks.

A novel approach to evaluate the pharmacokinetic biocomparability of a monoclonal antibody derived from two different cell lines using simultaneous crossover design.

A parallel study design with a large number of subjects has been a typical path for pharmacokinetic (PK) biocomparability assessment of biotherapeutics with long half-lives and immunogenic propensity, for example, monoclonal antibodies (mAb). A recently published innovative bioanalytical method that can quantify mAb produced from two different cell lines in the same sample opened an avenue to exploring a simultaneous crossover study design for PK biocomparability assessment of biotherapeutics. Siltuximab, a chimeric IgG1 mAb-targeting interleukin-6, was studied as an example. The pharmacokinetic biocomparability of siltuximab derived from mouse myeloma (Sp2/0) cells and Chinese hamster ovary cells was previously assessed and demonstrated in a clinical PK biocomparability study that enrolled more than 140 healthy subjects using a parallel trial design. The biocomparability was successfully shown in six cynomolgus monkeys in a preclinical proof-of-concept study using the new crossover study design supported by the analytical method. The impact of antidrug antibodies on the assessment of biocomparability was minimal. This novel approach opened up a new arena for the evaluation of PK biocomparability of biotherapeutics with unique molecular signatures such as a mAb derived from different cell lines.

Evaluation of the QTc prolongation potential of a monoclonal antibody, siltuximab, in patients with monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or low-volume multiple myeloma.

PURPOSE: A phase 1 study evaluated the QTc prolongation potential of siltuximab, a chimeric, anti-interleukin-6 mAb, in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or low-volume MM. METHODS: Patients with baseline QTcF and QTcB ≤ 500 ms, QRS < 100 ms, PR < 200 ms and no significant cardiac disease received siltuximab 15 mg/kg q3w, the highest dosage used in clinical studies, for 4 cycles. Twelve-lead ECGs obtained at multiple time points pre- and post-infusion at cycles 1 and 4 were evaluated by central cardiology laboratory. No effect on QTc interval was concluded if the upper limit of least square (LS) mean 90 % CI for QTc change from baseline at each time point was <20 ms. RESULTS: An effect on QTc prolongation was ruled out, as the upper bound of 90 % CI was <10 ms at each time point in 27 evaluable patients (13 MGUS, 13 SMM, 1 low-volume MM) with no differences between disease types. Maximum mean QTc increase from baseline occurred 3 h after cycle 1 infusion (QTcF = 3.2 [LS mean 90 % CI -0.01, 6.45] ms; QTcB = 2.7 [-0.69, 6.14] ms). At all other time points, mean QTcF and QTcB increase from baseline was ≤1.5 ms and upper bound 90 % CI was ≤5.1 ms. Twenty patients had mostly low-grade AEs, including nausea, fatigue (20 % each); thrombocytopenia, headache (each 13 %); dyspnea, leukopenia, neutropenia, paresthesia, abnormal hepatic function, URTI (each 10 %). Three MGUS patients achieved 50 % M-protein reduction. There was no association between siltuximab pharmacokinetics and QTc interval. CONCLUSIONS: Siltuximab did not affect the QTc interval. Overall safety was similar to other single-agent siltuximab studies.

A phase 1, randomized study to assess the pharmacokinetic comparability of siltuximab derived from two different cell lines in healthy subjects.

Siltuximab, a monoclonal antibody (mAb) against interleukin (IL-6), is under development by Janssen Research & Development, LLC. During early clinical development, siltuximab was produced in a murine Sp2/0 myeloma cell line. The production cell line was switched to stably transfected Chinese hamster ovary (CHO) cell line for subsequent clinical development. A two-part, parallel-group, phase 1 study was designed to evaluate the safety and pharmacokinetics (PK) of a single IV administration of Sp2/0- and CHO-derived siltuximab in healthy subjects. The results from this study demonstrated PK comparability of siltuximab produced from Sp2/0 and CHO cell lines. The 90% confidence interval of the ratios of geometric means of Cmax and AUC0-84day following 1.4 mg/kg doses was (99.4%, 111.3%) and (98.1%, 109.6%), respectively, both within the pre-specified comparability range of 80-125%. Siltuximab derived from either the Sp2/0 or CHO cell lines was in general well tolerated and was not found to be immunogenic in this study.

Utilizing pharmacokinetics/pharmacodynamics modeling to simultaneously examine free CCL2, total CCL2 and carlumab (CNTO 888) concentration time data.

The chemokine ligand 2 (CCL2) promotes angiogenesis, tumor proliferation, migration, and metastasis. Carlumab is a human IgG1κ monoclonal antibody with high CCL2 binding affinity. Pharmacokinetic/pharmacodynamic data from 21 cancer patients with refractory tumors were analyzed. The PK/PD model characterized the temporal relationships between serum concentrations of carlumab, free CCL2, and the carlumab-CCL2 complex. Dose-dependent increases in total CCL2 concentrations were observed and were consistent with shifting free CCL2. Free CCL2 declined rapidly after the initial carlumab infusion, returned to baseline within 7 days, and increased to levels greater than baseline following subsequent doses. Mean predicted half-lives of carlumab and carlumab-CCL2 complex were approximately 2.4 days and approximately 1 hour for free CCL2. The mean dissociation constant (KD ), 2.4 nM, was substantially higher than predicted by in vitro experiments, and model-based simulation revealed this was the major factor hindering the suppression of free CCL2 at clinically viable doses.

A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease.

PURPOSE: To evaluate the safety and pharmacokinetics of siltuximab, an anti-interleukin-6 chimeric monoclonal antibody (mAb) in patients with B-cell non-Hodgkin lymphoma (NHL), multiple myeloma, or Castleman disease. EXPERIMENTAL DESIGN: In an open-label, dose-finding, 7 cohort, phase I study, patients with NHL, multiple myeloma, or symptomatic Castleman disease received siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every 3 weeks. Response was assessed in all disease types. Clinical benefit response (CBR; composite of hemoglobin, fatigue, anorexia, fever/night sweats, weight, largest lymph node size) was also evaluated in Castleman disease. RESULTS: Sixty-seven patients received a median of 16 siltuximab doses for a median of 8.5 (maximum 60.5) months; 29 were treated 1 year or longer. There was no dose-limiting toxicity, antibodies to siltuximab, or apparent dose-toxicity relationship. The most frequently reported possible drug-related adverse events were thrombocytopenia (25%), hypertriglyceridemia (19%), neutropenia (19%), leukopenia (18%), hypercholesterolemia (15%), and anemia (10%). None of these events led to dose delay/discontinuation except for neutropenia and thrombocytopenia (n = 1 each). No treatment-related deaths occurred. C-reactive protein (CRP) suppression was most pronounced at 12 mg/kg every 3 weeks. Mean terminal-phase half-life of siltuximab ranged 17.73 to 20.64 days. Thirty-two of 37 (86%) patients with Castleman disease improved in 1 or more CBR component; 12 of 36 evaluable Castleman disease patients had radiologic response [complete response (CR), n = 1; partial response (PR), n = 11], including 8 of 19 treated with 12 mg/kg; 2 of 14 (14%) evaluable NHL patients had PR; 2 of 13 (15%) patients with multiple myeloma had CR. CONCLUSION: No dose-related or cumulative toxicity was apparent across all disease indications. A dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease and the sustained CRP suppression. Randomized studies are ongoing in Castleman disease and multiple myeloma.

A first-in-human, first-in-class, phase I study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 in patients with solid tumors.

PURPOSE: The CC-chemokine ligand 2 (CCL2) is highly expressed in various malignancies and promotes carcinogenesis. Blocking CCL2 has preclinical antitumor activity. A phase 1 trial of carlumab (CNTO 888), a human anti-CCL2 IgG1κ mAb, was conducted to evaluate the safety, tolerability, pharmacokinetic-pharmacodynamic profile, and antitumor activity. METHODS: Patients with advanced solid malignancy received escalating doses of carlumab 0.3, 1, 3, 10, or 15 mg/kg by 90-min intravenous infusion on days 1, 28, and every 2 weeks thereafter (dose escalation) or 10 or 15 mg/kg every 2 weeks (dose-expansion). Pharmacodynamic assessments were also performed. RESULTS: Forty-four patients received 206 doses of carlumab. MTD was not established. Carlumab-related adverse events included grade 1-2 fatigue (9 %), nausea (7 %), headache (7 %), vomiting (5 %), and pruritus (5 %). The recommended phase II dose was 15 mg/kg every 2 weeks. Carlumab concentrations declined bi-exponentially with a terminal half-life of 6.6-9.6 days. Free CCL2 was transiently suppressed, while total CCL2 increased dose-dependently >1,000-fold post-treatment. A patient with ovarian cancer and a patient with prostate cancer achieved CA125 and PSA reductions of >50 % and RECIST SD for 10.5 and 5 months, respectively. Two other patients had RECIST SD for 7.2 and 15.7 months. CONCLUSIONS: Carlumab was well tolerated with evidence of transient free CCL2 suppression and preliminary antitumor activity.

Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer.

BACKGROUND: CC-chemokine ligand 2 (CCL2) promotes tumor growth by angiogenesis, macrophage infiltration and tumor invasion, and distant metastasis. Carlumab (CNTO 888) is a human IgG1κ mAb with high affinity and specificity for human CCL2. Preclinical data suggest carlumab may offer clinical benefit to cancer patients. METHODS: In a phase 2, open-label study, patients with metastatic castration-resistant prostate cancer (CRPC) previously treated with docetaxel received a 90-min infusion of 15 mg/kg carlumab q2w. The primary endpoint was response rate: change from baseline in skeletal lesions, extraskeletal lesions, and PSA values. Secondary endpoints included overall response rate (CR + PR) by RECIST, OS, PSA response, safety, pharmacodynamics, pharmacokinetics, immunogenicity. RESULTS: Forty-six patients were treated with 6 median (range 1, 26) doses. One patient had SD >6 months. There were no PSA or RECIST responses. Fourteen (34 %) patients had SD ≥ 3 months. Median OS was 10.2 (95 % CI: 5.2, not estimable) months. Twelve (39 %) patients reported improved pain scores. AEs occurred in 43 (93 %) patients, including 27 (59 %) with grade ≥ 3 AEs. Common grade ≥ 3 AEs were back (11 %) and bone (9 %) pain. Twenty (43 %) patients experienced SAEs, including pneumonia, spinal cord compression, back pain. No patient developed antibodies to carlumab. Steady-state serum concentrations were achieved after 3 repeated doses and were above the 10-µg/mL target concentration. Suppression of free CCL2 serum concentrations was briefly observed following each dose but was not sustained. CONCLUSION: Carlumab was well-tolerated but did not block the CCL2/CCR2 axis or show antitumor activity as a single agent in metastatic CRPC.

A phase 1 study of a chimeric monoclonal antibody against interleukin-6, siltuximab, combined with docetaxel in patients with metastatic castration-resistant prostate cancer.

PURPOSE: Siltuximab is a chimeric, anti-interleukin-6 monoclonal antibody with potential therapeutic benefit in castration-resistant prostate cancer (CRPC) patients. We assessed the safety and tolerability of siltuximab in combination with docetaxel, the pharmacokinetics of docetaxel alone and with siltuximab, and the efficacy and pharmacodynamics of siltuximab plus docetaxel. PATIENTS AND METHODS: In an open-label, dose-escalation, multicenter, phase 1 study, patients with metastatic, progressive CRPC received docetaxel 75 mg/m(2) q3w plus siltuximab 6 mg/kg q2w (n=12), 9 mg/kg q3w (n=12), or 12 mg/kg q3w (n=15). Dose-limiting toxicity (DLT), PSA, and radiologic response according to WHO criteria were evaluated. RESULTS: DLT was reported in 1 of 11 patients receiving 6 mg/kg, 1 of 12 receiving 9 mg/kg, and in 1 of 14 receiving 12 mg/kg. Common Grade ≥ 3 adverse events were neutropenia (73 %), leukopenia (60 %), lymphopenia (30 %), dyspnea (19 %), and fatigue (14 %). Toxicities were not dose dependent. Siltuximab did not affect docetaxel pharmacokinetics. The pharmacokinetic profile for siltuximab in combination was similar to single-agent siltuximab pharmacokinetics. Twenty-three (62 %; 95 % CI 45 %, 78 %) of 37 combination-treated patients achieved a confirmed ≥ 50 % PSA decline. Of 17 patients with measurable disease at baseline, 2 confirmed and 2 unconfirmed radiologic partial responses ranging 190 to 193 days were achieved with 9- and 12-mg/kg siltuximab. C-reactive protein concentrations were suppressed throughout treatment in all patients. CONCLUSION: These results suggest that siltuximab in combination with docetaxel is safe and shows preliminary efficacy in patients with CRPC, although alternative siltuximab schedules may be better tolerated for future studies.

Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours.

AIM: Cediranib is a highly potent inhibitor of vascular endothelial growth factor receptor (VEGFR) signalling. Preclinical and clinical data suggest that inhibition of the VEGFR and epidermal growth factor receptor (EGFR) pathways may be synergistic. Combination treatment with cediranib and gefitinib, an EGFR signalling inhibitor, was evaluated in patients with advanced solid tumours. PATIENTS AND METHODS: Ninety patients received treatment in this four-part, open-label study (NCT00502060). The patients received once-daily oral doses of cediranib (20-45mg) and gefitinib 250mg (part A1; n=16) or 500mg (part B1; n=44). A cohort expansion phase investigated the potential pharmacokinetic interaction of cediranib 30mg with gefitinib 250mg (part A2; n=15) or 500mg (part B2; n=15). The primary objective was to assess the safety and tolerability of cediranib with gefitinib. Secondary assessments included pharmacokinetics, efficacy and pharmacodynamics. RESULTS: Combination treatment was generally well tolerated; the protocol-defined maximum-tolerated dose of cediranib was 30mg/day with gefitinib 250mg/day (part A1) and cediranib 45mg/day was the maximum dose investigated with gefitinib 500mg/day (part B1). The most common adverse events were diarrhoea (84 [93%]), anorexia (63 [70%]) and fatigue (60 [67%]). Cediranib pharmacokinetic parameters were not substantially different when given alone or in combination with gefitinib. Gefitinib pharmacokinetic parameters were similar to those seen previously with gefitinib monotherapy. Efficacy results included eight (9%) confirmed partial responses (6 renal; 1 lung; 1 osteosarcoma) and 38 (42%) patients with stable disease. Pharmacodynamic assessments demonstrated changes in levels of VEGF and soluble VEGFR-2 following treatment. CONCLUSIONS: Combination treatment was generally well tolerated and showed encouraging antitumour activity in patients with advanced solid tumours. These results merit further exploration.

Phase I, dose escalation and pharmacokinetic study of cediranib (RECENTIN), a highly potent and selective VEGFR signaling inhibitor, in Japanese patients with advanced solid tumors.

PURPOSE: To evaluate safety and tolerability of cediranib, a highly potent and selective vascular endothelial growth factor signaling inhibitor, in Japanese patients with advanced solid tumors refractory to standard therapies. METHODS: In part A (n = 16), patients received once-daily oral cediranib (10-45 mg) to identify the maximum tolerated dose (MTD). In part B (n = 24), patients with non-small-cell lung cancer or colorectal cancer received multiple daily doses at the MTD. RESULTS: Cediranib 30 mg/day was considered the MTD since 50% of evaluable patients receiving 45 mg/day experienced dose-limiting toxicities in part A (proteinuria and diarrhea n = 1, proteinuria n = 1, thrombocytopenia n = 1). The most common adverse events were diarrhea (n = 34) and hypertension (n = 32). Pharmacokinetic analysis confirmed cediranib as suitable for once-daily oral dosing. Of 32 evaluable patients, two had partial RECIST responses and 24 had stable disease > or =8 weeks. CONCLUSIONS: Cediranib was generally well tolerated at < or =30 mg/day in these Japanese patients and showed encouraging antitumor activity.

Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: the National Cancer Institute of Canada clinical trials group.

PURPOSE: AZD2171 is a potent inhibitor of vascular endothelial growth factor receptors that showed broad antitumor activity in preclinical models. Doses of up to 45 mg/d of AZD2171 are tolerable when administered alone. This study evaluated escalating doses of AZD2171 in combination with standard chemotherapy in patients with advanced non-small-cell lung cancer. PATIENTS AND METHODS: Eligible patients received carboplatin targeted to an area under the concentration time curve of 6 mg . min/mL and paclitaxel 200 mg/m(2), both on day 1 of a 3-week cycle; daily oral AZD2171 at either 30 mg or 45 mg commenced day 2 of cycle 1. Pharmacokinetics of all drugs were performed, and tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Twenty patients were enrolled. No dose-limiting toxicities were observed during cycle 1 at either dose. Fatigue, diarrhea, anorexia, and granulocytopenia were common; hypertension was manageable with a treatment algorithm designed for this protocol. No clinically significant drug-related bleeding was observed. At 45 mg/d, fatigue and diarrhea were increased, and headache and hoarseness were observed. Paclitaxel clearance decreased during cycle 2, but no other significant pharmacokinetic interactions were observed. After radiology review, confirmed responses were observed in nine patients (response rate, 45%; 95% CI, 23% to 68%); all but one enrolled patient showed evidence of tumor shrinkage, some with cavitation. CONCLUSION: AZD2171 can be combined with standard doses of carboplatin/paclitaxel with encouraging antitumor activity. Toxicity is increased, but predictable and manageable.

Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors.

PURPOSE: AZD2171 is a highly potent oral selective inhibitor of vascular endothelial growth factor (VEGF) signaling. This phase I study was designed to evaluate the safety and tolerability of increasing doses of AZD2171, with additional assessments of pharmacokinetics, pharmacodynamics, and efficacy. PATIENTS AND METHODS: In part A, 36 patients with solid tumors and liver metastases refractory to standard therapies received once-daily oral AZD2171 (0.5 to 60 mg). Doses were escalated in successive cohorts until the maximum-tolerated dose was identified. In part B, patients with (n = 36) or without (n = 11) liver metastases were randomly assigned to receive once-daily AZD2171 (20, 30, or 45 mg). In both parts, treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed. RESULTS: Eighty-three patients received AZD2171, which was generally well tolerated at doses of 45 mg/d or less; the most frequently reported dose-related adverse events were diarrhea, dysphonia, and hypertension. The most common DLT was hypertension (n = 7), which occurred at AZD2171 doses of 20 mg and higher. After a single dose, maximum plasma (peak) drug concentration after single-dose administration (Cmax) was achieved 1 to 8 hours postdosing with an arithmetic mean half-life associated with terminal slope of a semilogarithmic concentration-time curve (t1/2 lamda(z)) of 22 hours. Pharmacodynamic assessments demonstrated time-, dose-, and exposure-related decreases in initial area under the curve, defined over 60 seconds post-contrast arrival in the tissue (iAUC60) using dynamic contrast-enhanced magnetic resonance imaging, as well as dose- and time-dependent reductions in soluble VEGF receptor 2 levels. Preliminary evidence of efficacy included two confirmed partial responses and 22 patients with stable disease; effects on tumor size appeared to be dose related. CONCLUSION: Once-daily oral AZD2171 at doses of 45 mg or less was generally well tolerated and was associated with encouraging antitumor activity in patients with a broad range of advanced solid tumors.

Dihydropyrimidine dehydrogenase and thymidylate synthase polymorphisms and their association with 5-fluorouracil/leucovorin chemotherapy in colorectal cancer.

The causes of interpatient variation in severe toxicity resulting from treatment with weekly 5-fluorouracil (5-FU)/ leucovorin (LV) are poorly understood. This study was undertaken to examine the contribution of commonly occurring polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene to interpatient variability in 5-FU pharmacokinetics and toxicity. Patients with stage III/IV colorectal cancer were treated by bolus intravenous (I.V.) injection with 500 mg/m2 doses of 5-FU and LV once every week. The pharmacokinetics of 5-FU was determined on weeks 1 and 4. Genotyping assays were developed for 8 polymorphisms in the DPYD gene. A well-characterized functional polymorphism in the 5' untranslated region of the thymidylate synthase (TS) gene was also analyzed. A cohort of 22 patients (15 male, 7 female) with a median age of 61 years was evaluated. Although there was no relationship between the area under the plasma concentration time curve (AUC) for the first dose of 5-FU and worst-grade toxicity during the first cycle of therapy, 3 of the 4 patients in whom the AUC on week 4 was more than equal to 5 microgram/h/mL greater than the value for the first dose experienced grade 3/4 toxicity during subsequent treatment. Among the 8 polymorphisms in the DPYD gene, 7 were found to vary in the study population but none were significantly associated with the AUC of 5-FU. There was no relationship between the DPYD and TS genotypes examined and 5-FU toxicity. Extensive polymorphism in the DPYD gene was observed; however, no conclusive correlations existed between the DPYD and TS genotype and 5-FU pharmacokinetics or toxicity. Decreases in 5-FU clearance in certain patients may provide insight into the increased toxicity following repetitive cycles of treatment with weekly I.V. bolus 5-FU. The present study offers useful themes for undertaking larger prospective pharmacogenetic studies in the future.

A phase I trial of daily oral 4'- N -benzoyl-staurosporine in combination with protracted continuous infusion 5-fluorouracil in patients with advanced solid malignancies.

PURPOSE: 4'- N -Benzoyl-staurosporine (PKC412) is an orally available staurosporine derivative that inhibits protein kinase C. The objectives of this phase I trial were to determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLTs), and the pharmacokinetics of PKC412 when co-administered with 5-Fluorouracil (5-FU). EXPERIMENTAL DESIGN: PKC412 was given daily with a 21-day continuous i.v. infusion of 5-FU 200 mg/m2/day, repeated every 4 weeks. The PKC412 dose was escalated by a modified continual reassessment method. The steady-state plasma pharmacokinetics of 5-FU, PKC412, and two of its circulating metabolites were determined during the first cycle of therapy. RESULTS: A total of 33 patients were treated with 70 cycles (median: 2, range: 1-4) of PKC412 at doses ranging from 25 to 225 mg/day. No significant toxicities were encountered with doses up to 150 mg/day. Among nine patients treated with 225 mg/day of PKC412, one experienced grade 3 fatigue and nausea, another developed grade 3 hyperglycemia, and three had grade 2 emesis and stomatitis, leading to early treatment discontinuation. Minor responses consisting of a 40-45% tumor reduction were observed in two patients, one with gall bladder carcinoma and one with breast cancer. Mean values of steady-state pharmacokinetic variables for both PKC412 and 5-FU were comparable to single agent studies. CONCLUSIONS: The recommended phase II dose of PKC412 is 150 mg/day when combined with a continuous infusion of 200 mg/m2/day 5-FU. The dose limiting toxicity was grade 2 emesis and stomatitis and the regimen showed indications of activity. There was no evidence of a pharmacokinetic interaction between the two drugs.