Phase I and pharmacokinetic study of dasatinib and cetuximab in patients with advanced solid malignancies.
ABSTRACT: Combined inhibition of epidermal growth factor receptor (EGFR) and Src family kinases (SFK) may lead to improved therapeutic effects. We evaluated the combination of dasatinib, an inhibitor of SFK and other kinases, and cetuximab, an anti-EGFR monoclonal antibody.Patients with advanced solid malignancies received cetuximab intravenously on a standard weekly schedule and dasatinib orally, once daily at 3 dose levels: (1) 100 mg, (2) 150 mg, (3) 200 mg. Pharmacokinetic and pharmacodynamic studies of dasatinib were performed prior to starting cetuximab and following 14 days of treatment.Twenty-five patients (3 dose level 1; 19 dose level 2; 3 dose level 3) were initially treated. Three patients developed dose-limiting toxicities: 1 at dose level 2 (headache) and 2 at dose level 3 (headache, nausea). Grade 3-4 toxicities in more than 2 patients included: dyspnea (4), vomiting (4), nausea (3), hypersensitivity reactions (3), headache (3) and anemia (3). Twenty-one patients developed headache (8 grade 1; 10 grade 2), which occurred after the loading of cetuximab and lasted 1-3 days. Six additional patients were treated with dasatinib starting 3 days after the loading dose of cetuximab; none developed headache after dasatinib. Dasatinib pharmacokinetics and a transient decrease in SFK PY416 levels in peripheral blood mononuclear cells were not altered by cetuximab. Patients with higher plasma TGF-alpha levels had worse progression-free survival.Dasatinib 150 mg once daily plus weekly cetuximab is recommended for phase II studies. Early-onset headache was ameliorated by starting dasatinib after cetuximab.
Project description:Src family kinases (SFKs) are hyperactivated in acute myeloid leukemia (AML). SFKs impede the retinoic acid receptor, and SFK inhibitors enhance all-trans retinoic acid (ATRA)-mediated cellular differentiation in AML cell lines and primary blasts. To translate these findings into the clinic, we undertook a phase-I dose-escalation study of the combination of the SFK inhibitor dasatinib and ATRA in patients with high-risk myeloid neoplasms. Nine subjects were enrolled: six received 70?mg dasatinib plus 45?mg/m2 ATRA daily, and three received 100?mg dasatinib plus 45?mg/m2 ATRA daily for 28 days. Headache and QTc prolongations were the only two grade 3 adverse events observed. No significant clinical responses were observed. We conclude that the combination of 70?mg dasatinib and 45?mg/m2 ATRA daily is safe with acceptable toxicity. Our results provide the safety profile for further investigations into the clinical efficacy of this combination therapy in myeloid malignancies.
Project description:OBJECTIVE:Src family kinase (SFK) activation circumvents epidermal growth factor receptor (EGFR) targeting in head and neck squamous cell carcinoma (HNSCC); dual SFK-EGFR targeting could overcome cetuximab resistance. PATIENTS AND METHODS:We conducted a Simon two-stage, phase II trial of the SFK inhibitor, dasatinib, and cetuximab in biomarker-unselected patients with cetuximab-resistant, recurrent/metastatic HNSCC. Pre- and post-treatment serum levels of interleukin-6 (IL6) were measured by ELISA. HNSCC cell lines were assessed for viability and effects of IL6 modulation following dasatinib-cetuximab treatment. RESULTS:In the first stage, 13 patients were evaluable for response: 7 had progressive and 6 had stable disease (SD). Enrollment was halted for futility, and biomarker analysis initiated. Low serum IL6 levels were associated with SD (raw p=0.028, adjusted p=0.14) and improved overall survival (p=0.010). The IL6 classifier was validated in a separate trial of the same combination, but was unable to segregate survival risk in a clinical trial of cetuximab and bevacizumab suggesting serum IL6 may be specific for the dasatinib-cetuximab combination. Enhanced in vitro HNSCC cell death was observed with dasatinib-cetuximab versus single agent treatment; addition of IL6-containing media abrogated this effect. CONCLUSION:Clinical benefit and overall survival from the dasatinib-cetuximab combination were improved among patients with low serum IL6. Preclinical studies support IL6 as a modifier of dasatinib-cetuximab response. In the setting of clinical cetuximab resistance, serum IL6 is a candidate predictive marker specific for combined dasatinib-cetuximab. The trial was modified and redesigned as a biomarker-enriched Phase II study enrolling patients with undetectable IL6.
Project description:PURPOSE Dasatinib is an orally available tyrosine kinase inhibitor with low nanomolar activity against SRC family kinases, BCR-ABL, c-KIT, EPHA2, and the PDGF-? receptor. Dasatinib was found to have selective activity in several tumor models in the Pediatric Preclinical Testing Program. PATIENTS AND METHODS A phase I study of dasatinib in pediatric patients with refractory solid tumors or imatinib-refractory, Philadelphia chromosome-positive leukemia was performed. Dose levels of 50, 65, 85, and 110 mg/m²/dose, administered orally twice daily for 28 days, with courses repeated without interruption, were studied. Pharmacokinetic studies were performed with the initial dose.A total of 39 patients (solid tumors, n = 28; chronic myeloid leukemia [CML], n = 9; acute lymphoblastic leukemia, n = 2) were enrolled. No dose-limiting toxicities (DLTs) were observed at the 50, 65, and 85 mg/m² dose levels. At 110 mg/m², two of six patients experienced DLT including grade 2 diarrhea and headache. In children with leukemia, grade 4 hypokalemia (50 mg/m²), grade 3 diarrhea (85 mg/m²), and grade 2 creatinine elevation (50 mg/m²) were observed. DLT in later courses included pleural effusions, hemangiomatosis, and GI hemorrhage. There were three complete cytogenetic responses, three partial cytogenetic responses, and two partial/minimal cytogenetic responses observed in evaluable patients with CML. CONCLUSION Overall, drug disposition and tolerability of dasatinib were similar to those observed in adult patients.
Project description:BACKGROUND:We studied the combination of pemetrexed, a multi-targeted antifolate, and cetuximab, an mAb against the epidermal growth factor receptor, with radiotherapy in poor prognosis head and neck cancer. PATIENTS AND METHODS:Patients received pemetrexed on days 1, 22, and 43 on a dose-escalation scheme with starting level (0) 350 mg/m(2) (level -1, 200 mg/m(2); level +1, 500 mg/m(2)) with concurrent radiotherapy (2 Gy/day) and cetuximab in two separate cohorts, not previously irradiated (A) and previously irradiated (B), who received 70 and 60-66 Gy, respectively. Genetic polymorphisms of thymidylate synthase and methylenetetrahydrofolate reductase were evaluated. RESULTS:Thirty-two patients were enrolled. The maximum tolerated dose of pemetrexed was 500 mg/m(2) in cohort A and 350 mg/m(2) in cohort B. Prophylactic antibiotics were required. In cohort A, two dose-limiting toxicities (DLTs) occurred (febrile neutropenia), one each at levels 0 and +1. In cohort B, two DLTs occurred at level +1 (febrile neutropenia; death from perforated duodenal ulcer and sepsis). Grade 3 mucositis was common. No association of gene polymorphisms with toxicity or efficacy was evident. CONCLUSION:The addition of pemetrexed 500 mg/m(2) to cetuximab and radiotherapy is recommended for further study in not previously irradiated patients.
Project description:The FOLFOXIRI regimen (irinotecan, oxaliplatin, fluorouracil [5-FU] and folinic acid [FA]) increased the response rate and overall survival compared to FOLFIRI in patients with metastatic colorectal cancer (mCRC). Adding cetuximab to FOLFOX or FOLFIRI increased efficacy in patients with k-ras wild type mCRC. We explored the dose limiting toxicity and feasibility of the combination cetuximab, irinotecan, oxaliplatin, 5-FU and FA in mCRC patients.In a dose-escalation study patients with previously untreated mCRC and a WHO performance status 0-1 received cetuximab (500 mg/m2, 2 h), followed by irinotecan (95, 125, and 165 mg/m2 in the dose levels [DL] 1, 2, and 3 respectively), followed by oxaliplatin (85 mg/m2, 2 h) which was given parallel to FA (400 mg/m2, 2 h) and followed by 5-FU (3200 mg/m2, 46 h) in an outpatient setting every two weeks. The primary endpoints were the maximum tolerable dose and the safety. The trial was approved by the local ethics committee.From 2007 to 2008, twenty patients were treated in this trial. In the first dose level (irinotecan 95 mg/m2) one patient developed neutropenia grade 4. One patient experienced diarrhoea grade 3 as DLT in dose level 2 (irinotecan 125 mg/m2). In dose level 3 (irinotecan 165 mg/m2), three patients experienced a DLT (diarrhoea grade 3 and two patients with neutropenia grade 4). Thus, the recommended dose for a phase II trial is 125 mg/m2 irinotecan in combination with oxaliplatin, 5-FU/FA and cetuximab. Most common grade ?3 toxicities were neutropenia (40%), diarrhoea (25%) and acne-like rash (15%). No therapy associated death occurred.The confirmed overall response rate in all cohorts was 75% (95%-CI 51-91%). The best response was reached after a median of 3.0 (95%-CI 2.2 to 3.7) months. Median progression free survival (PFS) is 16 (95%-CI 12.6-19.4) months, overall survival (OS) 33 (95%-CI 26.2-39.8) months.The combination of cetuximab and FOLFOXIRIis feasible and has an acceptable toxicity profile in patients with a good performance status. The observed clinical activity with a confirmed response rate of 75% is promising and further evaluated in the ongoing CELIM2.http://www.clinicaltrials.gov: NCT00422773.
Project description:BACKGROUND:The combination of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab overcomes intrinsic and acquired resistance in both EGFR-sensitive and EGFR-resistant preclinical models of colorectal cancer (CRC). METHODS:Utilizing a standard 3+3 design, a phase I study was designed to determine safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) of the regorafenib plus cetuximab combination among patients with advanced cancer including CRC. Comprehensive genomic profiling was performed on the exceptional responder. RESULTS:Among the 27 patients enrolled the median age was 54 years. None of 19 patients treated at dose level 1 (cetuximab i.v. 200 mg/m2 followed by 150 mg/m2 weekly + regorafenib 80 mg daily) experienced a DLT, and 2 of 5 patients treated at dose level 2 (cetuximab i.v. 200 mg/m2 followed by 150 mg/m2 weekly + regorafenib 120 mg daily) experienced a DLT (grade 3 thrombocytopenia [n = 1] and grade 3 intra-abdominal bleed [n = 1]). Most common adverse events were grade 1 or 2 rash (20 patients). Of 24 evaluable patients, 11 (46%) patients had clinical benefit (stable disease > 6 cycles or partial response [PR]) (CRC n = 8, one patient each with head and neck cancer, carcinoma of unknown primary, and glioblastoma). A CRC patient, who progressed on anti-EGFR and regorafenib, achieved a PR (46% decrease per RECIST v1.1) lasting 15 months. Genomic profiling of an exceptional responder with response for over 27 cycles revealed hypermutated genotype with microsatellite instability (MSI). CONCLUSION:Regorafenib 80 mg daily plus cetuximab 200 mg/m2 loading dose, followed by 150 mg/m2 every week is the MTD/recommended phase II dose. The combination demonstrated early signals of activity in wild-type CRC, including 1 exceptional responder with MSI high. TRIAL REGISTRATION:clinicaltrials.gov NCT02095054FUNDING. The University of Texas MD Anderson Cancer Center is supported by the NIH Cancer Center Support Grant CA016672. This work was supported in part by the Cancer Prevention Research Institute of Texas grant RP110584 and National Center for Advancing Translational Sciences grant UL1 TR000371 (Center for Clinical and Translational Sciences).
Project description:To determine the optimal dose of the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab that can be safely administered in combination with a standard daily dose of erlotinib in patients with advanced solid malignancies.Patients with advanced solid malignancies who had failed standard chemotherapies received escalating doses of cetuximab without a loading dose (100, 200, 250 mg/m(2) i.v. weekly) in combination with a fixed dose of erlotinib (150 mg daily orally) until disease progression or unacceptable toxicity.Twenty-two patients were treated, including 14 patients (64%) with non-small cell lung cancer. Twenty patients received combination treatment at the highest dose level for a median of 5.5 weeks (range, 1-31 weeks). One dose-limiting toxicity was observed: grade 3 skin rash. Overall, the most common adverse events (any grade, grade 3/4) were consistent with the safety profiles of the individual drugs: acneform rash (100%, 9%), diarrhea (77%, 5%), and hypomagnesemia (59%, 12%). Seven of 18 evaluable patients (38.9%) had stable disease lasting for a median of 16.6 weeks (range, 6.1-25.1 weeks).Dual EGFR inhibition with cetuximab and erlotinib is feasible; the observed toxicities were manageable and consistent with the safety profiles of the individual drugs. The recommended doses for phase II studies are 250 mg/m(2) i.v. weekly for cetuximab and 150 mg daily orally for erlotinib.
Project description:The safety, tolerability, and pharmacokinetic (PK) interactions of MK-0646 in combination with cetuximab and irinotecan were investigated in Japanese patients with advanced colorectal cancer.Twenty patients were treated in the following study arms in combination with cetuximab and irinotecan: A [MK-0646 (10 mg/kg) weekly starting on Day 22], B [MK-0646 (15 mg/kg) on Day 8, followed by 7.5 mg/kg every 2 weeks], or C [MK-0646 (10 mg/kg) on Day 1 and weekly starting on Day 22]. Dose limiting toxicities (DLTs) were evaluated during a prespecified 4-week period in arms A and B. Full PK sampling was performed to evaluate the PK interactions.One of the 6 evaluable patients in arm A developed a DLT (grade 3 hyperglycemia); no DLTs occurred in the 6 patients in arm B. Common treatment-related adverse events included leukopenia, neutropenia, dermatitis acneiform, paronychia, nausea, stomatitis, diarrhea, and decreased appetite. The co-administration of cetuximab and irinotecan with MK-0646 increased the MK-0646 AUC0-168h by 25 %, with MK-0646 accumulation from the previous dose contributing to the observed increase. The co-administration of MK-0646 with cetuximab and irinotecan did not affect the PK of cetuximab and irinotecan, but reduced the C max (from 16.8 to 13.0 ng/mL) and the AUC0-24h (by 13 %) of SN-38, the active metabolite of irinotecan.The triple combination of MK-0646, cetuximab, and irinotecan was well tolerated in Japanese patients with advanced colorectal cancer. These results indicate a minimal potential for PK interactions between MK-0646 and cetuximab and between MK-0646 and irinotecan/SN-38.
Project description:To determine the activity and tolerability of 100-mg once-daily (QD) dasatinib in patients with metastatic castration-resistance prostate cancer (CRPC). Dasatinib, an oral Src family kinase inhibitor, has demonstrated both preclinical and clinical activity with twice-daily dosing in patients with metastatic CRPC.Chemotherapy-naive men with metastatic CRPC and increasing prostate-specific antigen levels were treated with dasatinib 100 mg QD. The primary measurement was a composite lack of disease progression, according to the Prostate Cancer Working Group 2 criteria, determined every 12 weeks during the study. The other analyses included changes in the prostate-specific antigen level, bone lesions, soft tissue disease, and bone turnover markers (urine N-telopeptide and bone alkaline phosphatase).The present trial was designed before the publication of the recent Prostate Cancer Working Group 2 criteria; however, the analyses are presented to conform to the updated guidelines. A total of 48 patients received dasatinib. A lack of disease progression was observed in 21 patients (44%) at week 12 and in 8 (17%) at week 24. Urine N-telopeptide was reduced by ?40% from baseline in 22 (51%) of 43 patients, and bone alkaline phosphatase was decreased in 26 (59%) of 44 patients. Dasatinib was well-tolerated, with only 6 patients (13%) with drug-related grade 3-4 adverse events and 3 (6%) with grade 3 adverse events. The most common treatment-related adverse events (?20%) were fatigue, nausea, diarrhea, headache, and anorexia.Dasatinib 100 mg QD has a favorable safety profile and maintains a similar degree of activity as the previously reported twice-daily dosing schedules. These data support additional study of dasatinib 100 mg QD for metastatic CRPC.