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A phase Ib dose-escalation and expansion study of the oral MEK inhibitor pimasertib and PI3K/MTOR inhibitor voxtalisib in patients with advanced solid tumours.
Schram, AM, Gandhi, L, Mita, MM, Damstrup, L, Campana, F, Hidalgo, M, Grande, E, Hyman, DM, Heist, RS
British journal of cancer. 2018;(12):1471-1476
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Abstract
BACKGROUND This phase Ib study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of pimasertib (MSC1936369B), a MEK1/2 inhibitor, in combination with voxtalisib (SAR245409), a pan-PI3K and mTORC1/mTORC2 inhibitor, in patients with advanced solid tumours. METHODS This study included a dose escalation and expansion in patients with select tumour types and alterations in the MAPK or PI3K pathways. A 3 + 3 design was used to determine MTD. Patients were evaluated for adverse events and tumour response. RESULTS 146 patients were treated, including 63 in dose escalation and 83 in expansion. The MTD was pimasertib 90 mg and voxtalisib 70 mg daily. Based on the safety profile, the recommended phase 2 dose (RP2D) was pimasertib 60 mg and voxtalisib 70 mg. The most frequent treatment-emergent adverse events (TEAEs) were diarrhoea (75%), fatigue (57%), and nausea (50%). Responses included a complete response in one patient (1%), partial response in five (5%), and stable disease in 51 (46%). At the RP2D, 74 patients required dose interruption (73%), 20 required dose reduction (20%), and 26 discontinued treatment due to TEAEs (26%). CONCLUSIONS The combination of pimasertib and voxtalisib showed poor long-term tolerability and limited anti-tumour activity in patients with advanced solid tumours.
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A Multi-Arm Phase I Study of the PI3K/mTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer.
Wainberg, ZA, Alsina, M, Soares, HP, Braña, I, Britten, CD, Del Conte, G, Ezeh, P, Houk, B, Kern, KA, Leong, S, et al
Targeted oncology. 2017;(6):775-785
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Abstract
BACKGROUND This phase I, four-arm, open-label study (NCT01347866) evaluated the PI3K/mTOR inhibitors PF-04691502 (arms A, B) and gedatolisib (PF-05212384; arms C, D) in combination with the MEK inhibitor PD-0325901 (arm A, D) or irinotecan (arm B, C) in patients with advanced solid tumors. OBJECTIVES Primary endpoint was dose-limiting toxicity with each combination. Secondary endpoints included safety, pharmacokinetics and preliminary antitumor activity. PATIENTS AND METHODS Dose escalation followed a 3 + 3 design in arm C and a zone-based design in arm D. RESULTS The PF-04691502 combination arms were closed prematurely due to low tolerability, and the maximum tolerated doses (MTDs) were not determined for either arm. The MTD for the combination of gedatolisib with irinotecan 180 mg/m2 was estimated to be 110 mg weekly and for the combination with PD-0325901 was not reached at the highest dose evaluated (gedatolisib 154 mg weekly). Plasma concentrations of gedatolisib were generally similar across dose groups in arm C (with irinotecan) and arm D (with PD-0325901). Frequent dose delays or dose reductions were required for both combinations, potentially preventing sustained therapeutic drug concentrations. Gedatolisib plus irinotecan produced a response rate of ~5% and clinical benefit in 16% of patients with advanced colorectal cancer (progression-free survival, 2.8 months). Preliminary evidence of clinical activity was observed with gedatolisib plus PD-0325901 in patients with ovarian cancer (three partial responses, n = 5) or endometrial cancer (one partial response, n = 1) and KRAS mutations. CONCLUSIONS Further evaluations of gedatolisib are warranted in patients with advanced solid malignancies.
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Phase I trial of MEK 1/2 inhibitor pimasertib combined with mTOR inhibitor temsirolimus in patients with advanced solid tumors.
Mita, M, Fu, S, Piha-Paul, SA, Janku, F, Mita, A, Natale, R, Guo, W, Zhao, C, Kurzrock, R, Naing, A
Investigational new drugs. 2017;(5):616-626
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Background Dual inhibition of activated MAPK and mTOR signaling pathways may enhance the antitumor efficacy of the MEK 1/2 inhibitor pimasertib and the mTOR inhibitor temsirolimus given in combination. Methods In this phase I study, patients with refractory advanced solid tumors (NCT01378377) received once-weekly temsirolimus plus once-daily oral pimasertib in 21-day cycles in a modified 3 + 3 dose-escalation design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of pimasertib in combination with temsirolimus, safety and pharmacokinetics (PK) were investigated. Results Of 33 patients evaluated, all experienced ≥1 treatment-emergent adverse event (TEAE) and 31 had treatment-related TEAEs, most frequently stomatitis and thrombocytopenia. TEAEs were reversible. No deaths were attributed to treatment. Nine patients had dose-limiting toxicities (stomatitis, thrombocytopenia, serum creatinine phosphokinase increase, visual impairment) and the MTD was determined as 45 mg/day pimasertib plus 25 mg/week temsirolimus. However, due to overlapping toxicities no further investigations were performed and the RP2D was not defined. PK profiles of both agents were not adversely affected. Seventeen patients (17/26 patients) had a best response of stable disease; five had stable disease lasting >12 weeks. Conclusions The RP2D was not defined and the pimasertib plus temsirolimus combination investigated did not warrant further study.
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A phase I trial of everolimus in combination with 5-FU/LV, mFOLFOX6 and mFOLFOX6 plus panitumumab in patients with refractory solid tumors.
McRee, AJ, Davies, JM, Sanoff, HG, Goldberg, RM, Bernard, S, Dees, EC, Keller, K, Ivanova, A, O'Neil, BH
Cancer chemotherapy and pharmacology. 2014;(1):117-23
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PURPOSE This phase I study investigated the safety, dose-limiting toxicity, and efficacy in three cohorts all treated with the mTOR inhibitor everolimus that was delivered (1) in combination with 5-fluorouracil with leucovorin (5-FU/LV), (2) with mFOLFOX6 (5-FU/LV + oxaliplatin), and (3) with mFOLFOX6 + panitumumab in patients with refractory solid tumors. METHODS Patients were accrued using a 3-patient cohort design consisting of two sub-trials in which the maximum tolerated combination (MTC) and dose-limiting toxicity (DLT) of everolimus and 5-FU/LV was established in Sub-trial A and of everolimus in combination with mFOLFOX6 and mFOLFOX6 plus panitumumab in Sub-trial B. RESULTS Thirty-six patients were evaluable for toxicity, 21 on Sub-trial A and 15 on Sub-trial B. In Sub-trial A, DLT was observed in 1/6 patients enrolled on dose level 1A and 2/3 patients in level 6A. In Sub-trial B, 2/3 patients experienced DLT on level 1B and subsequent patients were enrolled on level 1B-1 without DLT. Three of six patients in cohort 2B-1 experienced grade 3 mucositis, and further study of the combination of everolimus, mFOLFOX6 and panitumumab was aborted. Among the 24 patients enrolled with refractory metastatic colorectal cancer, the median time on treatment was 2.7 months with 45 % of patients remaining on treatment with stable disease for at least 3 months. CONCLUSIONS While a regimen of everolimus in addition to 5-FU/LV and mFOLFOX6 appears safe and tolerable, the further addition of panitumumab resulted in an unacceptable level of toxicity that cannot be recommended for further study. Further investigation is warranted to better elucidate the role which mTOR inhibitors play in patients with refractory solid tumors, with a specific focus on mCRC as a potential for the combination of this targeted and cytotoxic therapy in future studies.
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Phase I study of sorafenib in combination with everolimus (RAD001) in patients with advanced neuroendocrine tumors.
Chan, JA, Mayer, RJ, Jackson, N, Malinowski, P, Regan, E, Kulke, MH
Cancer chemotherapy and pharmacology. 2013;(5):1241-6
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PURPOSE Sorafenib and everolimus are both active against neuroendocrine tumors (NET). Because of potential synergy between VEGF pathway and mTOR inhibitors, we performed a phase I study to evaluate the safety and feasibility of combining sorafenib and everolimus in patients with advanced NET. METHODS Patients were treated with everolimus 10 mg daily in combination with sorafenib (dose level 1: 200 mg twice daily; dose level 2: 200 mg per morning, 400 mg per evening) using standard phase I dose escalation design. Dose-limiting toxicity (DLT) was defined within the first cycle (28 days) of therapy. Treatment was continued until tumor progression, unacceptable toxicity, or withdrawal of consent. Twelve additional patients were treated at the maximum tolerated dose (MTD) level to further characterize safety and a preliminary assessment of activity. RESULTS One patient in Cohort 1 experienced DLT (grade 3 skin rash); the cohort was expanded to 6 patients with no further DLTs. All 3 patients in Cohort 2 experienced DLT, consisting of thrombocytopenia, hand-foot skin reaction, and rash/allergic reaction. Sorafenib 200 mg twice daily in combination with everolimus 10 mg daily was established as the MTD. Independently reviewed best objective responses revealed that 62 % of patients had some degree of tumor shrinkage. By RECIST, we observed partial response in 1 patient, stable disease in 13 patients, and progressive disease in 3 patients. CONCLUSION Sorafenib 200 mg twice daily with everolimus 10 mg daily represents the MTD of this combination in patients with advanced NET. While the combination is active, toxicity concerns may preclude more widespread use.
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Phase I study of the combination of temsirolimus and pazopanib in advanced solid tumors.
Semrad, TJ, Eddings, C, Dutia, MP, Christensen, S, Lara, PN
Anti-cancer drugs. 2013;(6):636-40
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Inhibition of either vascular endothelial growth factor receptor or mammalian target of rapamycin (mTOR) signaling improves outcomes in patients with several advanced solid tumors. We conducted a phase I trial of temsirolimus with pazopanib to investigate the feasibility of simultaneous 'vertical inhibition' of vascular endothelial growth factor receptor and mTOR pathways. Patients with advanced solid tumors, no previous pazopanib or mTOR inhibitor, good performance status, and acceptable end-organ function were eligible. In a typical 3+3 escalation design starting at temsirolimus 15 mg by an intravenous infusion weekly and pazopanib 400 mg orally daily, we defined dose-limiting toxicity (DLT) as attributable grade 3 or higher nonhematologic adverse events in the first 28-day cycle and the maximum tolerable dose as the maximum dose level at which less than two patients experienced DLT. At the initial dose level, two patients had four DLTs (anorexia, fatigue, hyponatremia, and hypophosphatemia). After reduction to temsirolimus 10 mg intravenous infusion weekly and pazopanib 200 mg orally daily, one of three patients had DLT (fatigue) and the first patient in the subsequent expansion had dose-limiting hypophosphatemia. Attributable grade 3 or higher adverse events in more than one patient included leukopenia, neutropenia, fatigue, and hypophosphatemia. Tumor reduction not fulfilling the RECIST criteria for partial response was the best response in four of seven evaluable patients. The combination of temsirolimus and pazopanib was not feasible at clinically meaningful doses in this population because of constitutional and electrolyte disturbances.
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Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation.
Gomez-Martin, C, Bustamante, J, Castroagudin, JF, Salcedo, M, Garralda, E, Testillano, M, Herrero, I, Matilla, A, Sangro, B
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2012;(1):45-52
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There is currently no consensus on the most suitable treatment for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation. This open, multicenter, retrospective, uncontrolled cohort study was designed to evaluate the safety and preliminary efficacy of the combined use of a mammalian target of rapamycin (mTOR) inhibitor and sorafenib in this setting. In 31 patients who suffered from HCC recurrence after liver transplantation, the immunosuppressive therapy was changed to mTOR inhibitors, and systemic treatment with sorafenib was initiated. This combination was maintained until symptomatic tumor progression, death, hepatic decompensation, or unacceptable toxicity occurred. Primary treatment efficacy was determined by overall survival and progression-free survival, and secondary efficacy was determined by the overall response rate. Toxicity parameters associated with the use of sorafenib and mTOR inhibitors were also analyzed. The overall response rate according to the Response Evaluation Criteria in Solid Tumors was 3.8% (1/26), and there was sustained stabilization of the disease in 13 additional cases (50.0%). The median overall survival was 19.3 months [95% confidence interval (CI) = 13.4-25.1 months], and the median time to progression was 6.77 months (95% CI = 2.3-11.1 months). Only 2 grade 3/4 cases of hyperglycemia and 1 case of grade 3/4 mucositis were reported, and they were possibly related to mTOR inhibitors. The most common severe adverse event probably related to sorafenib was diarrhea (12.9%). In conclusion, the coadministration of sorafenib and an mTOR inhibitor could be effective despite notable toxicity in patients with post-liver transplant HCC recurrence not suitable for radical therapy. The toxicity and efficacy need to be further evaluated in randomized controlled studies for this combination to be considered a valid option.
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Preemptive use of Mammalian target of rapamycin inhibitors in living donor transplantation.
Vodenik, B, Rovira, J, Diekmann, F, Revuelta, I, Oppenheimer, F, Campistol, JM
Transplantation proceedings. 2011;(7):2568-73
Abstract
UNLABELLED Sirolimus (SRL) has demonstrated beneficial impacts on the development of chronic allograft dysfunction (CAD). In living donor transplantation, strategies mostly seek to prevent graft dysfunction and respond to a decline in renal function. The present study focused on proactive, preemptive SRL administration for patients with repeated renal transplantations and those engrafted with an extended criteria donor organ. MATERIAL AND METHODS This retrospective, monocenter study describes 7 renal transplant recipients with stable graft function receiving SRL within the first year posttransplantation and 3 recipients of second transplantations who started SRL treatment before obtaining their repeat grafts. RESULTS A proactive use of SRL revealed stable renal function parameters at 1 year after SRL introduction: Creatinine 1.33 ± 0.21 mg/dL; Modification of Diet in Renal Disease (MDRD) equation glomerular filtration rate, 57 ± 19 mL/min; PU 452 ± 338 mg/24 hours. Cell counts, hemoglobin concentrations, as well as triglyceride and total cholesterol levels did not differ over the 1-year follow-up. SRL administration before retransplantation provided good graft survival and renal function with a creatinine of 1.2 ± .32 mg/dL, MDRD of 60 ± 28 mg/dL, and PU 502 ± 432 mg/24 hour. Cell counts, hemoglobin concentrations, as well as triglyceride and total cholesterol levels did not differ over 1-year follow-up. CONCLUSION Preemptive SRL-induction before signs of graft deterioration or chronic injury may be a useful approach to prevent CAD.
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[Third-line therapy for metastasized renal cell carcinoma: a randomized, multicenter non-blinded phase III study to compare safety and effectiveness of TF1258 versus sorafenib in patients with metastasized renal cell carcinoma following failure of antiangiogenic (VEGF targeted and mTOR inhibition) therapy (GOLD-AN 31/11 of the Working Group Urological Oncology)].
Rexer, H
Der Urologe. Ausg. A. 2011;(10):1319-21
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A phase I dose-escalation study to evaluate safety and tolerability of sorafenib combined with sirolimus in patients with advanced solid cancer.
Desar, IM, Timmer-Bonte, JN, Burger, DM, van der Graaf, WT, van Herpen, CM
British journal of cancer. 2010;(11):1637-43
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BACKGROUND The combination of sorafenib (vascular endothelial growth factor receptor 2 inhibitor) and sirolimus (mammalian target of rapamycin inhibitor) might work synergistically. METHODS A phase I dose-escalation study with sorafenib twice a day (b.i.d.) and sirolimus once daily (q.d.) was performed to determine the recommended dose of the combination in patients with solid tumours. Secondary objectives were to determine the safety profile and maximum tolerated dose (MTD), and to evaluate the pharmacokinetics (PK) of the combination. RESULTS Dose-limiting toxicities were transaminitis and cutaneous toxicity. The most frequently reported adverse events were elevated transaminases, hypophosphatemia, fatigue, anorexia, diarrhoea, nausea, rash and palmar-plantar erythrodysaesthesia. Sirolimus did not change the PK of sorafenib; in contrast, sorafenib reduced the AUC(0-96) and C(max) of sirolimus. No objective responses were observed; eight patients showed stable disease for a median of 16.3 weeks (range 8-24). The MTD of the combination was sorafenib 200 mg b.i.d. with sirolimus 1 mg q.d. CONCLUSION The combination of sorafenib and sirolimus showed enhanced toxicity, which could not be explained by the PK of both drugs. The relative low doses at the MTD, in combination with the PK results, do not warrant further development of this combination.