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Razelle Kurzrock,
Nash Gabrail,
Chandtip Chandhasin,
Stacy Moulder,
Carrie Smith,
Andrew Brenner, Kamalesh Sankhala,
Alain Mita,
Kelly Elian,
Danielle Bouchard,
John Sarantopoulos
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ABSTRACT: GRN1005 is a novel peptide-drug conjugate composed of paclitaxel covalently linked to a peptide, angiopep-2, that targets the low-density lipoprotein receptor-related protein 1. This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and efficacy of GRN1005 in patients with advanced solid tumors. Patients in sequential cohorts (one patient per cohort until grade 2 toxicity, then 3 + 3 design) received intravenous GRN1005 at escalating doses between 30 and 700 mg/m(2) once in every 21 days. In the maximum tolerated dose (MTD) expansion group, patients were required to have brain metastases. Fifty-six patients received GRN1005, including 41 with brain metastases (median number of prior therapies = 4). MTD was 650 mg/m(2); the main dose-limiting toxicity was myelosuppression. Sixteen of 20 patients dosed at the MTD had brain metastases. Pharmacokinetics was dose linear and the mean terminal-phase elimination half-life was 3.6 hours. No evidence of accumulation was observed after repeat dosing. No anti-GRN1005 antibodies were detected. Five of the 20 patients (25%) dosed at 650 mg/m(2) (MTD), three of whom had previous taxane therapy, achieved an overall partial response (breast, n = 2; non-small cell lung cancer, n = 2; and ovarian cancer, n = 1); responses in all five patients were also accompanied by shrinkage of brain lesions (-17% to -50%). In addition, six patients (11%; doses 30-700 mg/m(2)) experienced stable disease that lasted 4 months or more. GRN1005 was well tolerated and showed activity in heavily pretreated patients with advanced solid tumors, including those who had brain metastases and/or failed prior taxane therapy.
Molecular Cancer Therapeutics 12/2011; 11(2):308-16. · 5.23 Impact Factor
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ABSTRACT: The mammalian target of rapamycin (mTOR) is a protein kinase that functions as a key regulator of cell growth, proliferation and differentiation, cell-cycle progression, angiogenesis, protein degradation, and apoptosis. Following activation by a number of oncogenic signals such as growth factors, energy and nutrients, mTOR stimulates several downstream effectors including the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4 E binding protein-1 (4 EBP-1), as well as a complex network of regulatory loops. Activation of the mTOR pathway plays a critical role in the development of many tumor types, including renal cell and breast carcinomas, neuroendocrine tumors, and sarcomas. Bone and soft tissue sarcomas are rare, heterogeneous tumors that are curable by local treatments if diagnosed at early stages; however advanced or metastatic sarcomas are rarely curable and very few drugs are efficacious in this setting. Several disruptions in phosphatidylinositol-3 kinase (PI3K)-Akt-mTOR signaling are associated with malignant transformation or progression in various sarcoma sub-types. The PI3K-Akt-mTOR pathway is therefore an exciting target for therapy of sarcomas, and its blockade represents an opportunity to improve outcomes in this poor-prognosis disease. Early studies with mTOR inhibitors have demonstrated promising antitumor activity in patients with metastatic sarcoma who have failed standard treatments. This article discusses the mTOR signaling pathway and summarizes the clinical experience with mTOR inhibitors in patients with advanced or metastatic sarcoma.
Targeted Oncology 03/2011; 6(1):29-39. · 3.61 Impact Factor
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Anthony W Tolcher,
Christopher J Sweeney,
Kyri Papadopoulos,
Amita Patnaik,
Elena G Chiorean,
Alain C Mita, Kamalesh Sankhala,
Eric Furfine,
Jochem Gokemeijer,
Lisa Iacono,
Cheryl Eaton,
Bruce A Silver,
Monica Mita
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ABSTRACT: To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of CT-322 (BMS-844203), a VEGFR-2 inhibitor and the first human fibronectin domain-based targeted biologic (Adnectin) to enter clinical studies.
Patients with advanced solid malignancies were treated with escalating doses of CT-322 intravenously (i.v.) weekly (qw), or biweekly (q2w). Plasma samples were assayed for CT-322 concentrations, plasma VEGF-A concentrations, and antidrug antibodies.
Thirty-nine patients completed 105 cycles of 0.1 to 3.0 mg/kg CT-322 i.v. either qw or q2w. The most common treatment-emergent grade 1/2 toxicities were fatigue, nausea, proteinuria, vomiting, anorexia, and hypertension. Grade 3/4 toxicities were rare. Reversible proteinuria, retinal artery, and vein thrombosis, left ventricular dysfunction, and reversible posterior leukoencephalopathy syndrome were dose limiting at 3.0 mg/kg. The MTD was 2 mg/kg qw or q2w. CT-322 plasma concentrations increased dose proportionally. Plasma VEGF-A levels increased with dose and plateaued at 2 mg/kg qw. Anti-CT-322 antibodies developed without effects on pharmacokinetics, VEGF-A levels, or safety. Minor decreases in tumor measurements occurred in 4 of 34 evaluable patients and 24 patients had stable disease.
CT-322 can be safely administered at 2 mg/kg i.v. qw or q2w and exhibits promising antitumor activity in patients with advanced solid tumors. The absence of severe toxicities at the MTD, demonstration of plasma drug concentrations active in preclinical models, and clinical pharmacodynamic evidence of VEGFR-2 inhibition warrant further development of CT-322 and suggest strong potential for Adnectin-based targeted biologics.
Clinical Cancer Research 01/2011; 17(2):363-71. · 7.74 Impact Factor
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Alain C Mita,
Chris H Takimoto,
Monica Mita,
Anthony Tolcher, Kamalesh Sankhala,
John Sarantopoulos,
Manuel Valdivieso,
Leslie Wood,
Erik Rasmussen,
Yu-Nien Sun,
Z Don Zhong,
Michael B Bass,
NgocDiep Le,
Patricia LoRusso
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ABSTRACT: To evaluate the safety, pharmacokinetics, and antitumor activity of AMG 386, an investigational selective angiopoietin 1/2-neutralizing peptibody, in combination with FOLFOX-4 (F), carboplatin/paclitaxel (C/P), or docetaxel (D), in adult patients with advanced solid tumors.
Three cohorts of patients (F, n = 6; C/P, n = 8; D, n = 12) received one full cycle of chemotherapy alone during the pretreatment phase, followed by administration of AMG 386 10 mg/kg i.v. weekly in combination with chemotherapy until disease progression or intolerance. Safety and tolerability, tumor response, pharmacokinetic profiles, and biomarkers were assessed.
Twenty-six patients were enrolled; 22 received treatment with AMG 386. No dose-limiting toxicities or grade 3 or 4 adverse events related to AMG 386 were reported. The most common adverse events were diarrhea and hypomagnesemia (n = 3 each). One patient developed grade 2 hypertension and one had grade 1 subconjunctival eye hemorrhage. No neutralizing antibodies to AMG 386 were detected. There were no pharmacokinetic interactions between AMG 386 and F, C/P, or D. One patient receiving AMG 386 plus C/P for bladder cancer refractory to gemcitabine/cisplatin had a complete response at week 8. The remaining best tumor responses were partial response (n = 3, one from each cohort), stable disease > or =8 weeks (n = 13), and progressive disease (n = 1).
Weekly administration of AMG 386 in combination with three common chemotherapy regimens was well tolerated in patients with advanced solid tumors. No pharmacokinetic interactions between AMG 386 and any of the tested chemotherapy regimens were noted. Promising antitumor activity was observed with all three treatment combinations.
Clinical Cancer Research 06/2010; 16(11):3044-56. · 7.74 Impact Factor
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ABSTRACT: Sarcomas are a group of heterogeneous tumors that arise from mesenchymal tissue and account for approximately 1% of all adult solid malignancies diagnosed, although its incidence approaches 20% in pediatric cancers. Characterization of molecular abnormalities in patients with sarcomas, in particular the up-regulation of the receptor tyrosine kinase and the PI3K-AKT-mTOR pathway, loss or deletions of retinoblastoma (Rb) and p53 gene, increased VEGF expression and angiogenesis, dysregulation of apoptosis through Bcl-2 overexpression, along with oncogene mutations and activations, such as c-KIT in Gastrointestinal stromal tumors (GISTs), makes treatment with novel biological therapies a promising option. This review focuses on the molecular heterogeneity of soft tissue and bone sarcomas, novel biological therapies currently in clinical trials to target the various molecular pathways, and the potential biological agents in pre-clinical and early clinical development.
Current drug targets 10/2009; 10(10):937-49. · 3.93 Impact Factor
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ABSTRACT: Sarcomas are a group of heterogeneous tumors that arise from mesenchymal tissue and account for approximately 1% of all adult solid malignancies diagnosed, although its incidence approaches 20% in pediatric cancers. Characterization of molecular abnormalities in patients with sarcomas, in particular the up-regulation of the receptor tyrosine kinase and the PI3K-AKT-mTOR pathway, loss or deletions of retinoblastoma (Rb) and p53 gene, increased VEGF expression and angiogenesis, dysregulation of apoptosis through Bcl-2 overexpression, along with oncogene mutations and activations, such as c-KIT in Gastrointestinal stromal tumors (GISTs), makes treatment with novel biological therapies a promising option. This review focuses on the molecular heterogeneity of soft tissue and bone sarcomas, novel biological therapies currently in clinical trials to target the various molecular pathways, and the potential biological agents in preclinical and early clinical development.
Current Drug Targets 09/2009; 10(10):937-949. · 3.55 Impact Factor
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ABSTRACT: Despite significant advances in the treatment of hematological malignancies over the last decade, morbidity and mortality from these disorders remain high. New discoveries in the pathogenesis of these malignancies have led to better understanding of these diseases and new thinking in drug development. mTOR is a downstream effector of the PI3K/Akt (protein kinase B) signaling pathway that mediates cell survival and proliferation and is known to be deregulated in many cancers. Preclinical activity of mTOR inhibitors has been very promising in various hematological malignancies. Rapamycin analogs with relatively favorable pharmaceutical properties, including temsirolimus (CCI-779), everolimus (RAD001) and deforolimus (AP23573), are under clinical evaluations in patients with hematologic malignancies. They have shown encouraging results thus far and a favorable toxicity profile. Their utility, mainly as cytostatic agents, needs to be further explored in combination with pre-existing chemotherapeutic agents for various hematological malignancies.
Expert Review of Hematology 08/2009; 2(4):399-414. · 1.16 Impact Factor
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ABSTRACT: Mammalian target of rapamycin (mTOR) has emerged as an important target for cancer therapy. Rapamycin has a distinct, well-documented toxicity profile and most of the toxicity data has been reported in patients with organ transplantation. Newer mTOR inhibitors have slightly different pharmacokinetic properties, yet they present toxicity profiles similar to rapamycin. Most of these toxicities are mild to moderate in severity and can be managed clinically by dose modification and supportive measures. Mucositis and pneumonitis are the most commonly reported toxicities, but they rarely lead to treatment discontinuation. Pathogenesis of pneumonitis is uncertain, but various hypotheses have been suggested, including cell-mediated immune response to the drug.
Targeted Oncology 05/2009; 4(2):135-42. · 3.61 Impact Factor
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ABSTRACT: The mammalian target of rapamycin (mTOR) is an intracellular protein with a key role in cellular protein synthesis and energy balance that influences many aspects of cell growth and proliferation, including differentiation, cell-cycle progression, angiogenesis, protein degradation and apoptosis. mTOR can be activated by numerous oncogenic signals, such as growth factor activation through the EGF, IGF and VEGF receptors, mutation and silencing of the PTEN tumor suppressor gene, activating mutations in the PI3K catalytic subunit, Akt amplification and the Ras-Raf-MEK pathway. Once activated, the cellular functions of mTOR are achieved through its downstream targets, 4E-BP1 and p70S6K1. The mTOR pathway can be further regulated through a negative feedback loop, which may lead to resistance to specific inhibitors of mTOR. This review will outline the mTOR signaling pathway, which is often activated in cancers and account for tumor proliferation and growth, highlight the rationale in targeting mTOR with a focus on the preclinical and clinical development of one of these inhibitors, deforolimus (AP23573, MK-8669), and discuss potential benefit and barriers to these agents being introduced in the clinic.
Future Oncology 05/2009; 5(3):291-303. · 3.16 Impact Factor
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Leukemia & lymphoma 02/2009; 50(2):297-9. · 2.40 Impact Factor
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ABSTRACT: mTOR was determined to be a promising anticancer target and several drug inhibitors of mTOR are currently in clinical development. Rapamycin (RAP) was the first mTOR inhibitor discovered. However, RAP has poor aqueous solubility and chemical stability and therefore its utilization at doses susceptible to produce an effect as an anticancer agent is limited. This represented the main rationale for developing new RAP analogs. The RAP analogs currently in clinical development as anticancer agents include temsirolimus (CCI-779), everolimus (RAD-001), and deforolimus (AP23573). These agents have demonstrated antiproliferative activity against a diverse range of malignancies in preclinical studies, and clinical evaluations have been very encouraging thus far. Deforolimus (AP23573), a non-RAP prodrug, has been tested in Phase I and II clinical trials and shows promising results in several tumor types including sarcoma. A Phase III study in patients with sarcoma is currently ongoing. The preclinical and clinical studies with deforolimus will be presented.
Expert Opinion on Investigational Drugs 01/2009; 17(12):1947-54. · 5.27 Impact Factor
