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Purpose:The purpose of this study was to evaluate the rational combination of TORC1/2 inhibitor TAK-228 and Aurora A kinase inhibitor alisertib in preclinical models of triple-negative breast cancer (TNBC) and to conduct a phase I dose escalation trial in patients with advanced solid tumors.Experimental Design:TNBC cell lines and patient-derived xenograft (PDX) models were treated with alisertib, TAK-228, or the combination and evaluated for changes in proliferation, cell cycle, mTOR pathway modulation, and terminal cellular fate, including apoptosis and senescence. A phase I clinical trial was conducted in patients with advanced solid tumors treated with escalating doses of alisertib and TAK-228 using a 3+3 design to determine the maximum tolerated dose (MTD).Results:The combination of TAK-228 and alisertib resulted in decreased proliferation and cell-cycle arrest in TNBC cell lines. Treatment of TNBC PDX models resulted in significant tumor growth inhibition and increased apoptosis with the combination. In the phase I dose escalation study, 18 patients with refractory solid tumors were enrolled. The MTD was alisertib 30 mg b.i.d. days 1 to 7 of a 21-day cycle and TAK-228 2 mg daily, continuous dosing. The most common treatment-related adverse events were neutropenia, fatigue, nausea, rash, mucositis, and alopecia.Conclusions:The addition of TAK-228 to alisertib potentiates the antitumor activity of alisertib in vivo, resulting in increased cell death and apoptosis. The combination is tolerable in patients with advanced solid tumors and should be evaluated further in expansion cohorts with additional pharmacodynamic assessment.

Pharmacodynamic effects of alisertib and TAK-228 in patient tissue samples

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PDF file, 70KB, Platelet P-AKT Inhibition.

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PDF file, 54KB, Mutational Status for Arm 1.

Purpose: The objectives of the study were to evaluate the maximum tolerated dose (MTD), safety, pharmacodynamics, pharmacokinetics, and antitumor activity of PX-866 in patients with incurable cancers.Experimental Design: This was a phase I, open-label, dose-escalation study. Drug was administered orally once per day either on an intermittent (arm 1; days 1–5 and 8–12 of a 28-day cycle) or continuous (arm 2; days 1–28 of a 28-day cycle) schedule. Additional patients were treated at the arm 2 MTD in a food effects substudy.Results: Eighty-four patients were treated in the arm 1 (n = 51), arm 2 (n = 20), and food effects (n = 13) cohorts. The most frequent study drug–related adverse events were gastrointestinal disorders (69.0%), with diarrhea being the most common (48.8%). The MTD was 12 and 8 mg for arm 1 and 2, respectively. The dose-limiting toxicities (DLT) consisted of grade III diarrhea (n = 3) and grade III elevated aspartate aminotransferase (AST; n = 1). The pharmacokinetics profile was dose proportional, with no evidence of drug accumulation. PX-866–associated inhibition of platelet pAKTSER473 was observed at the arm 2 MTD. The best response per Response Evaluation Criteria in Solid Tumors (RECIST) was stable disease in 22% of evaluable patients in arm 1, 53% in arm 2, and 11% in the food effects cohort. Eight patients were on study for 4 or more months.Conclusions: This first-in-human study shows that PX-866, an irreversible small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), was well tolerated and was associated with prolonged stable disease, particularly when using a continuous dosing schedule. Clin Cancer Res; 18(15); 4173–82. ©2012 AACR.

This phase I study evaluates the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary anticancer activity of enavatuzumab, a humanized IgG1 antibody to the TWEAK receptor, in patients with advanced solid malignancies. Patients received escalating doses of enavatuzumab given intravenously over 60 minutes every 2 weeks. Blood was obtained for PK and biomarker assessment. Three patients were enrolled per dose level in a standard 3+3 design with response assessment by RECIST version 1.0, every 8 weeks. Thirty patients were enrolled at 6 dose levels ranging from 0.1 to 1.5 mg/kg. Dose-limiting toxicities included grade 4 (G4) lipase, G3 bilirubin, and G4 amylase elevations. There was no apparent correlation of liver or pancreatic enzyme elevation with drug exposure or the presence of liver metastases. Enavatuzumab exhibited a two-compartment linear PK model. Estimated systemic clearance was 23 to 33 mL/h with an elimination half-life of 7 to 18 days. The predicted target efficacious peak and trough concentrations occurred at 1.0 mg/kg following the second dose. There were no objective responses; 4 patients had stable disease. The MTD of enavatuzumab is 1.0 mg/kg i.v. every 2 weeks. Higher doses were not tolerated due to hepatopancreatic lab abnormalities. Further evaluation of the mechanisms of the liver and pancreatic enzyme toxicities is needed before embarking on further single-agent or combination strategies. Mol Cancer Ther; 17(1); 215–21. ©2017 AACR.

Purpose: The objectives of the study were to evaluate the maximum tolerated dose (MTD), safety, pharmacodynamics, pharmacokinetics, and antitumor activity of PX-866 in patients with incurable cancers. Experimental Design: This was a phase I, open-label, dose-escalation study. Drug was administered orally once per day either on an intermittent (arm 1; days 1–5 and 8–12 of a 28-day cycle) or continuous (arm 2; days 1–28 of a 28-day cycle) schedule. Additional patients were treated at the arm 2 MTD in a food effects substudy. Results: Eighty-four patients were treated in the arm 1 (n = 51), arm 2 (n = 20), and food effects (n = 13) cohorts. The most frequent study drug–related adverse events were gastrointestinal disorders (69.0%), with diarrhea being the most common (48.8%). The MTD was 12 and 8 mg for arm 1 and 2, respectively. The dose-limiting toxicities (DLT) consisted of grade III diarrhea (n = 3) and grade III elevated aspartate aminotransferase (AST; n = 1). The pharmacokinetics profile was dose proportional, with no evidence of drug accumulation. PX-866–associated inhibition of platelet pAKTSER473 was observed at the arm 2 MTD. The best response per Response Evaluation Criteria in Solid Tumors (RECIST) was stable disease in 22% of evaluable patients in arm 1, 53% in arm 2, and 11% in the food effects cohort. Eight patients were on study for 4 or more months. Conclusions: This first-in-human study shows that PX-866, an irreversible small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), was well tolerated and was associated with prolonged stable disease, particularly when using a continuous dosing schedule. Clin Cancer Res; 18(15); 4173–82. ©2012 AACR.

Background: MLN0128 is an oral inhibitor of mTOR kinase and mTORC1/2 signaling. Alisertib is an oral inhibitor of Aurora A kinase. Senescence and upregulation of genes in the PI3K/AKT/mTor pathway have been observed in triple-negative breast cancer (TNBC) patient-derived xenograft models treated with alisertib, with greater tumor growth inhibition demonstrated in combination with MLN0128 as compared to each agent alone. An investigator-initiated trial was developed to evaluate the combination of MLN0128 and alisertib in patients with advanced solid tumors, followed by an expansion cohort in metastatic TNBC and other selected cancers. The goals of this ongoing study are to evaluate safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of the combination. Results of dose escalation are presented here. Methods: Patients with advanced solid tumors refractory to standard therapy were treated orally at escalating doses with the combination of MLN0128 daily on a continuous schedule and alisertib twice daily (BID) on days 1-7 of a 21-day cycle. Dose escalation was conducted according to a standard 3+3 design. Key eligibility criteria included HgbA1c Citation Format: S. Lindsey Davis, Elaine T. Lam, Bradley R. Corr, Cindy L. O'Bryant, Ashley Glode, Nichole Adler, Todd M. Pitts, John J. Tentler, Anna Capasso, Kyrie Dailey, Natalie J. Serkova, Colin D. Weekes, Daniel L. Gustafson, Christopher H. Lieu, Wells A. Messersmith, Stephen Leong, S. Gail Eckhardt, Jennifer R. Diamond. A phase Ib study of the combination of MLN0128 (dual TORC1/2 inhibitor) and MLN8237 (Aurora A inhibitor, alisertib) in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A083.

This phase I study was designed to determine the maximum tolerated dose (MTD) and toxicity profile of the combination of gefitinib, capecitabine, and celecoxib in patients with advanced solid tumors. Patients were treated with escalating doses of gefitinib once daily, capecitabine twice daily (14 of 28 days), and celecoxib twice daily. Plasma samples for biomarkers were obtained at baseline and weekly for the first 2 cycles. Pharmacokinetic variables were correlated with toxicity and presence of biological effect. Tumor biopsies from 5 patients were analyzed for changes in tumor metabolic activity by nuclear magnetic resonance spectroscopy. [18F]fluorodeoxyglucose positron emission tomography was done as a correlate in 6 patients at the MTD. Thirty-nine patients received 168 cycles of therapy. The dose-limiting toxicities observed included nausea, dehydration and nausea, diarrhea, and stomatitis. The MTD was 250 mg/d gefitinib (days 1-14) and 2,000 mg/m2/d capecitabine divided twice daily (days 8-21) every 28 days. Celecoxib was eliminated due to concerns of increased risk for cardiovascular toxicity, although no patients in this study had cardiac events. One patient with cholangiocarcinoma had a confirmed partial response. Fourteen of 39 (36%) patients maintained prolonged stable disease for a median of 4 months (range, 3-24 months). [18F]fluorodeoxyglucose positron emission tomography scan and metabolomic analyses revealed differences in metabolic response to gefitinib versus capecitabine. The combination of gefitinib and capecitabine is well tolerated and appears to have activity against certain advanced solid tumors, providing a rationale for further evaluation in advanced solid malignancies. [Mol Cancer Ther 2008;7(12):3685–94]

Purpose: PI-88 is a mixture of highly sulfated oligosaccharides that inhibits heparanase, an extracellular matrix endoglycosidase, and the binding of angiogenic growth factors to heparan sulfate. This agent showed potent inhibition of placental blood vessel angiogenesis as well as growth inhibition in multiple xenograft models, thus forming the basis for this study. Experimental Design: This study evaluated the toxicity and pharmacokinetics of PI-88 (80-315 mg) when administered s.c. daily for 4 consecutive days bimonthly (part 1) or weekly (part 2). Results: Forty-two patients [median age, 53 years (range, 19-78 years); median performance status, 1] with a range of advanced solid tumors received a total of 232 courses. The maximum tolerated dose was 250 mg/d. Dose-limiting toxicity consisted of thrombocytopenia and pulmonary embolism. Other toxicity was generally mild and included prolongation of the activated partial thromboplastin time and injection site echymosis. The pharmacokinetics were linear with dose. Intrapatient variability was low and interpatient variability was moderate. Both AUC and Cmax correlated with the percent increase in activated partial thromboplastin time, showing that this pharmacodynamic end point can be used as a surrogate for drug exposure. No association between PI-88 administration and vascular endothelial growth factor or basic fibroblast growth factor levels was observed. One patient with melanoma had a partial response, which was maintained for >50 months, and 9 patients had stable disease for ≥6 months. Conclusion: The recommended dose of PI-88 administered for 4 consecutive days bimonthly or weekly is 250 mg/d. PI-88 was generally well tolerated. Evidence of efficacy in melanoma supports further evaluation of PI-88 in phase II trials.

Purpose: Exisulind (sulindac sulfone, FGN-1, Aptosyn) is a sulindac metabolite that induces apoptosis via inhibition of cyclic GMP-phosphodiesterase. This agent demonstrated tumor growth inhibition in rodent models of colon, breast, prostate, and lung carcinogenesis. In an orthotopic model of human non–small-cell lung cancer, the combination of exisulind and docetaxel prolonged survival in athymic nude rats, forming the basis of this phase I combination study. Experimental Design: This study evaluated the toxicity and pharmacokinetics of combining exisulind (150–250 mg) given orally twice daily and docetaxel (30–36 mg/m2) administered intravenously on days 1, 8, and 15 of a 4-week cycle. Results: Twenty patients with a range of advanced solid tumors (median age, 59 years; age range, 35–77 years; median performance status, 1) received a total of 70 courses. Observed adverse events were mild to moderate, and there was no dose-limiting toxicity at any level. Grade 3 gastrointestinal toxicities were present in 10 of the 70 cycles (10%) and included nausea, vomiting, dyspepsia, and elevated alkaline phosphatase. Neutropenia was present in four cycles in patients treated with a docetaxel dose of 36 mg/m2. Pharmacokinetic analysis did not demonstrate a clear effect of exisulind on docetaxel pharmacokinetics and vice versa. Relationships were evident between the plasma concentration of exisulind and the development of grade 2 or greater toxicities. One third of patients maintained stable disease for 3 to 12 cycles, but no objective responses were observed. Conclusions: The combination of docetaxel (36 mg/m2, weekly) and exisulind (500 mg/d) was reasonably well tolerated, and it is undergoing phase II testing in patients with non–small-cell lung cancer.

Background: TWEAK receptor (TweakR, TNFRSF12A, CD266) is a member of the TNF receptor superfamily and is expressed on a range of solid tumors. Enavatuzumab is a humanized IgG1 antibody to TweakR that exhibits anti-tumor activity in preclinical models through two mechanisms: direct signaling through TweakR and antibody-dependent cellular cytotoxicity. Methods: This phase I, multicenter study was designed to determine the maximum tolerated dose (MTD) and to evaluate the safety and pharmacokinetic (PK) profiles of enavatuzumab, given intravenously over 60 minutes on days 1 and 15 of each 28-day cycle. Pts with advanced solid tumors; ECOG ≤1; adequate hematologic, renal, and hepatic function; no brain metastasis; no history of cirrhosis or pancreatitis; no recent history of acute cholecystitis; and not on immunosuppressive drugs were enrolled. Cohorts of 3–6 pts were treated at escalating dose levels of enavatuzumab ranging from 0.1 mg/kg to 1.5 mg/kg. Dose limiting toxicity (DLT) was defined as grade (G) 3 AST or ALT lasting >14 days or associated with clinical hepatitis and/or bilirubin ≥G2; G3 amylase or lipase lasting >14 days; ≥G3 bilirubin; any G4 AST, ALT, amylase, or lipase; acute pancreatitis; ≥G3 hematologic and non-hematologic toxicities; G4 cytokine release syndrome (CRS) or G3 CRS despite premedication. MTD was defined as the highest dose level with 0/3 or ≤1 of 6 pts experiencing a first-cycle DLT. PK sampling was performed on cycle 1 day 1 (C1D1), C1D2, C1D8, Day 15 of all cycles, C1D16, C2D1, and C3D1. Response was assessed by RECIST every 8 weeks. Results: Thirty pts [12 male, 18 female; median age 64.5 (range 36–82)] were enrolled at 6 dose levels: 0.1, 0.3, 0.5, 0.7, 1.0, and 1.5 mg/kg. Tumor types included colorectal (15); pancreas (4); ovarian (4); and tongue, cervical, prostate, endometrial, breast, hepatocellular, and thyroid (1 each). Sixteen pts had liver metastases. DLTs included G4 lipase and G3 bilirubin in 1 of 6 pts at the 1.0 mg/kg level and G4 lipase and G4 amylase in 1 pt at the 1.5 mg/kg level. Grade 3/4 toxicities in ≥5% of subjects included fatigue, pneumonia, hyponatremia, hypoxia, dyspnea, and elevated AST, ALT, GGT, lipase, and amylase. There was no apparent correlation of liver or pancreatic enzyme elevation with tumor type or presence of liver metastases. Of the disease evaluable pts, 11 had disease progression as their best response and 2 had stable disease (2 and 4 month duration). Enavatuzumab followed a two-compartment linear PK model. The estimated clearance was 23–33 mL/hr and elimination half-life was 7–18 days. The mean Cmax after the first dose was 2.0 mcg/mL and 28.1 mcg/mL for the 0.1 mg/kg and 1.0 mg/kg cohorts, respectively. Mean Css was reached following the second dose and was within the target efficacious peak and trough levels for the 1.0 mg/kg cohort. Conclusions: The MTD for this first-in-class drug was reached at 1.0 mg/kg. Six of 7 pts at 1.0 mg/kg and 1 of 1 pts at 1.5 mg/kg had ≥G3 liver and/or pancreatic enzyme elevations; therefore higher doses are not being tested. The mechanisms of liver and pancreatic enzyme toxicity are currently being investigated and preclinical studies are ongoing to assess potential combination strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C18.

Background: Belinostat (B) is a low molecular weight, synthetic hydroxamic acid derivative that inhibits class I and II histone deacetylases. Bortezomib (Bz) is a potent, selective inhibitor of the 26S proteasome. In preclinical studies, synergistic antiproliferative and pro-apoptotic effects were observed with the combination, providing the rationale for this study. Methods: This phase 1 study is designed to determine the maximum tolerated dose (MTD) and to evaluate the safety and pharmacokinetic (PK) behavior of the combination of B and Bz. Each 21-day treatment cycle consists of B (600–1000 mg/m2) IV daily over 30 minutes on days 1–5 and Bz (0.7–1.5 mg/m2) IVP over 3–5 seconds on days 1, 4, 8, and 11 (days 2, 5, 8 and 11, cycle 1 only). Results: To date, 26 patients have been enrolled (median age 59 [range 27–72]; median PS 1 [range 0–1]). Twenty-two patients were evaluable for toxicity and received a total of 58 treatment cycles (median 2 [range 1–6]). Four patients, 2 at dose level (DL) 3 (B: 600 mg/m2)/Bz: 1.3 mg/m2) and 2 at DL 5 (B: 1000 mg/m2)/Bz: 1.5 mg/m2) experienced a dose limiting toxicity (DLT). At DL 3, the DLTs were grade (gr) 3 dehydration and gr 4 thrombocytopenia. The exact relationship of the gr 3 dehydration and study combination is unclear as the patient had uncontrolled constipation and decreased oral intake as a result of a change in pain medications on cycle 1 day 1. This cohort was expanded to 9 pts to further determine tolerability of the study combination. No other DLTs were identified and dose escalation continued. At DL 5, DLTs included gr 4 thrombocytopenia and gr 4 fatigue. Most adverse events (AEs) have been mild to moderate. Gr 1–2 AEs (number of cycles) include anorexia (8), acute infusion reaction (5), fatigue (14), nausea (19), neutropenia (1), pain (12), phlebitis (6), thrombocyctopenia (11), and vomiting (12). Gr 3 AEs (occurring after course 1) include anorexia, dehydration, fatigue, nausea, vomiting, hypoalbuminemia, and elevation of alkaline phosphatase. Analysis of B PK demonstrates no statistical differences in the parameters between days 1 (B only) and 2 (B + Bz) for AUC, Cmax, clearance, or t1/2. Likewise, increasing Bz doses have no effect on B PK, whereas doses of B from 600 to 1000 mg/m2 result in dose-proportional increases in drug exposure. Four patients have maintained stable disease for 4–6 cycles of therapy. Conclusions: Belinostat and bortezomib is a reasonable combination with a tolerable toxicity profile and no evidence of pharmacological interactions. Accrual is ongoing at the MTD, DL 4 (B: 1000 mg/m2)/Bz: 1.3 mg/m2). Additional biological assessments are planned in an expanded cohort of patients. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B238.