Adkins, D., J. Ley, P. Neupane, F. Worden, A. G. Sacco, K. Palka, J. E. Grilley-Olson, R. Maggiore, N. N. Salama, K. Trinkaus, et al., "Palbociclib and cetuximab in platinum-resistant and in cetuximab-resistant human papillomavirus-unrelated head and neck cancer: a multicentre, multigroup, phase 2 trial.", The Lancet. Oncology, vol. 20, issue 9, pp. 1295-1305, 2019. Abstract

BACKGROUND: Most head and neck squamous-cell carcinomas (HNSCCs) are driven by p16 inactivation and cyclin D1 overexpression that results in hyperactivation of cyclin-dependent kinase 4 and 6 (CDK4/6), rather than by the human papillomavirus (HPV). Deregulated cyclin D1 expression also causes resistance to EGFR inhibitors. We previously reported that palbociclib (a selective CDK4/6 inhibitor) given with cetuximab (an EGFR inhibitor) was safe. The aim of this study was to establish the proportion of patients achieving an objective response with palbociclib and cetuximab in recurrent or metastatic HNSCC.

METHODS: We did a multicentre, multigroup, phase 2 trial to evaluate the activity of palbociclib and cetuximab in platinum-resistant (group 1) and cetuximab-resistant (group 2) HPV-unrelated HNSCC. The study was done across eight university sites in the USA. Eligibility required measurable disease (according to Response Evaluation Criteria in Solid Tumors, version 1·1 [RECIST 1·1]), Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, age of 18 years or older, and disease progression on platinum but cetuximab-naive (group 1) or disease progression on cetuximab (group 2). All patients received palbociclib orally (125 mg/day, on days 1-21) and intravenous cetuximab (400 mg/m on cycle one, day 1, then 250 mg/m once per week) in 28-day cycles. The primary endpoint was objective response (complete responses and partial responses per RECIST 1·1). Analyses were done per protocol. This trial was registered with, NCT02101034, and is ongoing, but both groups are closed to accrual.

FINDINGS: Between Oct 19, 2015, and Nov 7, 2018, 62 patients were enrolled onto the trial: 30 patients were enrolled in group 1 and 32 in group 2. Median follow-up was 5·4 months (IQR 4·4-12·1) for group 1 and 5·5 months (4·3-8·3) for group 2. In group 1, of 28 evaluable patients, an objective response was achieved by 11 (39%; 95% CI 22-59). In group 2, of 27 evaluable patients, an objective response was achieved by five (19%; 6-38) in group 2. The most common grade 3-4 palbociclib-related adverse event was neutropenia (in 21 [34%] of 62 patients). No treatment-related deaths occurred.

INTERPRETATION: In patients with platinum-resistant or cetuximab-resistant HPV-unrelated HNSCC, palbociclib and cetuximab results in promising activity outcomes. Further studies of CDK4/6 inhibitors are warranted in HPV-unrelated HNSCC.

FUNDING: Pfizer.

Scoville, B. A., J. H. Segal, N. N. Salama, M. Heung, B. E. Bleske, R. F. Eyler, and B. A. Mueller, "Single dose oral ranolazine pharmacokinetics in patients receiving maintenance hemodialysis.", Renal failure, vol. 41, issue 1, pp. 118-125, 2019. Abstract

PURPOSE: Ranolazine is a novel anti-angina treatment approved in the United States for chronic stable angina. Ranolazine pharmacokinetics have not been studied previously in patients who receive maintenance hemodialysis. This study describes the pharmacokinetics of ranolazine and three major metabolites (CVT-2738, CVT-2512, CVT-2514) in patients receiving thrice weekly hemodialysis.

METHODS: Eight participants receiving maintenance hemodialysis completed this prospective, open-label study (study identifier NCT01435174 at Three participants received a single tablet of ranolazine 500 mg (followed by an interim analysis), and five received 2 tablets of ranolazine 500 mg. Blood samples were collected over 65 h to determine the pharmacokinetic characteristics during and between hemodialysis sessions. Non-compartmental analysis was used to determine the individual pharmacokinetic parameters.

RESULTS: Ranolazine off-hemodialysis elimination phase half-lives were 3.6 and 3.9 h for 500 mg and 1000 mg doses, respectively. The time to maximum concentration ranged from 2 to 18 hours and the average maximum concentration was 0.65 ± 0.27 mcg/mL and 1.18 ± 0.48 mcg/mL for ranolazine 500 mg and 1000 mg dose, respectively. The mean hemodialysis percent reduction ratio for the ranolazine 500 mg dose was 52.3 ± 8.1% and for the ranolazine 1000 mg dose was 69.2 ± 37.6%.

CONCLUSIONS: Data on ranolazine dosing in patients receiving maintenance hemodialysis is almost non-existent. Given the extent of pharmacokinetic variability observed with the 500 mg and 1000 mg oral doses of ranolazine, neither can be recommended as a starting dose in patients receiving maintenance hemodialysis. Guided by the information gained form this study about the extent of hemodialytic drug clearance, further multi-dose clinical trials of ranolazine are needed to optimize therapeutic outcomes in this patient population.

Adkins, D., P. Mehan, J. Ley, M. J. Siegel, B. A. Siegel, F. Dehdashti, X. Jiang, N. N. Salama, K. Trinkaus, and P. Oppelt, "Pazopanib plus cetuximab in recurrent or metastatic head and neck squamous cell carcinoma: an open-label, phase 1b and expansion study.", The Lancet. Oncology, vol. 19, issue 8, pp. 1082-1093, 2018 Aug. Abstractlancet_oncology_2018.pdf

BACKGROUND: Angiogenesis is a hallmark of head and neck squamous cell carcinoma (HNSCC), and a mechanism of resistance to EGFR inhibition. We investigated the safety and potential activity of pazopanib, an angiogenesis inhibitor, plus cetuximab, an EGFR inhibitor, in patients with recurrent or metastatic HNSCC.

METHODS: We did an open-label, single-centre, dose-escalation phase 1b trial using a standard 3 + 3 design, followed by an expansion cohort phase. Eligible participants were patients with histologically or cytologically confirmed recurrent or metastatic HNSCC, aged at least 18 years, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and an Eastern Cooperative Oncology Group performance status of 0-1. During dose escalation, pazopanib oral suspension was administered daily in 8-week cycles at doses of 200 mg/day, 400 mg/day, 600 mg/day, or 800 mg/day, with cetuximab given intravenously once per week (400 mg/m first dose and 250 mg/m in consecutive cycles). The primary endpoint was to determine the maximum tolerated dose or recommended phase 2 dose of pazopanib in combination with cetuximab. Analyses were done per protocol. This trial is registered with, number NCT01716416, and it is ongoing but closed to accrual.

FINDINGS: Between June 5, 2013, and April 4, 2017, we enrolled 22 patients into the phase 1b, dose-escalation phase of the trial. A maximum tolerated dose of pazopanib in combination with cetuximab was not reached. Single dose-limiting toxic events (all grade 3) during dose escalation occurred with pazopanib 400 mg/day (neutropenia with infection), 600 mg/day (proteinuria), and 800 mg/day (fatigue). The established recommended phase 2 dose for the combination was 800 mg/day of pazopanib during cycles of 8 weeks each, plus cetuximab 400 mg/m on day 1 of cycle 1, then cetuximab 250 mg/m weekly. A further nine patients were enrolled into the expansion cohort and treated with the established recommended phase 2 dose. The most common (grade 3-4) adverse events for all patients were hypertension (ten [32%] of 31), lymphocyte count decrease (seven [23%]), and dysphagia (seven [23%]). There were no treatment-related deaths. 11 (35%; 95% CI 19·2-54·6) of 31 patients achieved an overall response, as assessed by the investigator; two (6%) had a complete response and nine (29%) a partial response. Tumour responses were also observed in six (55%) of 11 patients with platinum-naive and cetuximab-naive disease, three (25%) of 12 patients with cetuximab-resistant disease, and five (28%) of 18 patients with platinum-resistant disease.

INTERPRETATION: Pazopanib oral suspension at a dose of 800 mg/day was feasible to administer in combination with standard weekly cetuximab for patients with recurrent or metastatic HNSCC. Encouraging preliminary antitumour activity was observed with this combination therapy and warrants further validation in randomised trials.

FUNDING: GlaxoSmithKline and Novartis.

de la Puente, P., N. Fettig, M. J. Luderer, A. Jin, S. Shah, B. Muz, V. Kapoor, S. M. Goddu, N. N. Salama, C. Tsien, et al., "Injectable Hydrogels for Localized Chemotherapy and Radiotherapy in Brain Tumors.", Journal of pharmaceutical sciences, vol. 107, pp. 922-933, 2017 Nov 21, 2018. Abstractj_pharm_sci-_2018.pdf

Overall survival of patients with newly diagnosed glioblastoma (GBM) remains dismal at 16 months with state-of-the-art treatment that includes surgical resection, radiation, and chemotherapy. GBM tumors are highly heterogeneous, and mechanisms for overcoming tumor resistance have not yet fully been elucidated. An injectable chitosan hydrogel capable of releasing chemotherapy (temozolomide [TMZ]) while retaining radioactive isotopes agents (iodine, [131I]) was used as a vehicle for localized radiation and chemotherapy, within the surgical cavity. Release from hydrogels loaded with TMZ or 131I was characterized in vitro and in vivo and their efficacy on tumor progression and survival on GBM tumors was also measured. The in vitro release of 131I was negligible over 42 days, whereas the TMZ was completely released over the first 48 h. 131I was completely retained in the tumor bed with negligible distribution in other tissues and that when delivered locally, the chemotherapy accumulated in the tumor at 10-fold higher concentrations than when delivered systemically. We found that the tumors were significantly decreased, and survival was improved in both treatment groups compared to the control group. Novel injectable chemo-radio-hydrogel implants may potentially improve the local control and overall outcome of aggressive, poor prognosis brain tumors.

de la Puente, P., M. J. Luderer, C. Federico, A. Jin, R. C. Gilson, C. Egbulefu, K. Alhallak, S. Shah, B. Muz, J. Sun, et al., "Enhancing proteasome-inhibitory activity and specificity of bortezomib by CD38 targeted nanoparticles in multiple myeloma.", Journal of controlled release : official journal of the Controlled Release Society, vol. 270, pp. 158-176, 2017 Nov 28, 2018. Abstractj_of_controlled_release_2018.pdf

The establishment of more effective treatments that can circumvent chemoresistance in Multiple Myeloma (MM) is a priority. Although bortezomib (BTZ) is one of the most potent proteasome inhibitors available, still possesses limitations related to dose limiting side effects. Several strategies have been developed to improve the delivery of chemotherapies to MM by targeting different moieties expressed on MM cells to nanoparticle delivery systems (NPs), which have failed mainly due to their heterogeneous expression on these cells. Our goal was to test CD38 targeted chitosan NPs as novel targeting moiety for MM to improve the potency and efficacy of BTZ in MM cells and reduce the side effects in healthy tissue. We have showed preferential BTZ release in tumor-microenvironment, specific binding to MM cells, and an improved drug cellular uptake through BTZ diffusion from the surface and endocytosed NPs, which translated in enhanced proteasome inhibition and robust cytotoxic effect on MM cells when BTZ was administered through anti-CD38 chitosan NPs. Furthermore, the anti-CD38 chitosan NPs specifically delivered therapeutic agents to MM cells improving therapeutic efficacy and reducing side effects in vivo. The anti-CD38 chitosan NPs showed low toxicity profile allowing enhancement of proteasome-inhibitory activity and specificity of BTZ by endocytosis-mediated uptake of CD38 representing a promising therapy in MM.

Bilger, R., R. Chereson, and N. N. Salama, "Should Torsion Balance Technique Continue to be Taught to Pharmacy Students?", American journal of pharmaceutical education, vol. 81, issue 5, pp. 85, 2017 Jun. Abstractam_j_of_pharmaceutical_education_2017.pdf

Objective. To determine the types of balances used in compounding pharmacies: torsion or digital. Methods. A survey was mailed to the pharmacist-in-charge at 698 pharmacies, representing 47% of the pharmacies in Missouri as of July 2013. The pharmacies were randomly selected and stratified by region into eight regions to ensure a representative sample. Information was gathered regarding the type and use of balances and pharmacists' perspectives on the need to teach torsion balance technique to pharmacy students. Results. The response rate for the survey was 53.3%. Out of the total responses received, those pharmacies having a torsion balance, digital balance or both were 46.8%, 27.4% and 11.8%, respectively. About 68.3% of respondents compound prescriptions. The study showed that 52% of compounding pharmacies use torsion balances in their practice. Of those with a balance in their pharmacy, 65.6% favored continuation of torsion balance instruction. Conclusions. Digital balances have become increasingly popular and have replaced torsion balances in some pharmacies, especially those that compound a significant number of prescriptions. The results of this study indicate that torsion balances remain integral to compounding practice. Therefore, students should continue being taught torsion balance technique at the college.

Muz, B., H. D. Kusdono, F. Azab, P. de la Puente, C. Federico, M. Fiala, R. Vij, N. N. Salama, and A. K. Azab, "Tariquidar sensitizes multiple myeloma cells to proteasome inhibitors via reduction of hypoxia-induced P-gp-mediated drug resistance.", Leukemia & lymphoma, vol. 58, issue 12, pp. 2916-2925, 2017 Dec. Abstractleukemia_and_lymphoma_2017.pdf

Multiple myeloma (MM) presents a poor prognosis and high lethality of patients due to development of drug resistance. P-glycoprotein (P-gp), a drug-efflux transporter, is upregulated in MM patients post-chemotherapy and is involved in the development of drug resistance since many anti-myeloma drugs (including proteasome inhibitors) are P-gp substrates. Hypoxia develops in the bone marrow niche during MM progression and has long been linked to chemoresistance. Additionally, hypoxia-inducible transcription factor (HIF-1α) was demonstrated to directly regulate P-gp expression. We found that in MM patients P-gp expression positively correlated with the hypoxic marker, HIF-1α. Hypoxia increased P-gp protein expression and its efflux capabilities in MM cells in vitro using flow cytometry. We reported herein that hypoxia-mediated resistance to carfilzomib and bortezomib in MM cells is due to P-gp activity and was reversed by tariquidar, a P-gp inhibitor. These results suggest combining proteasome inhibitors with P-gp inhibition for future clinical studies.

de la Puente, P., N. Quan, R. S. Hoo, B. Muz, R. C. Gilson, M. Luderer, J. King, S. Achilefu, N. N. Salama, R. Vij, et al., "Newly established myeloma-derived stromal cell line MSP-1 supports multiple myeloma proliferation, migration, and adhesion and induces drug resistance more than normal-derived stroma.", Haematologica, vol. 101, issue 7, pp. e307-11, 2016 Jul. salama-_haematologica_2016.pdf
de la Puente, P., B. Muz, A. Jin, F. Azab, M. Luderer, N. N. Salama, and A. K. Azab, "MEK inhibitor, TAK-733 reduces proliferation, affects cell cycle and apoptosis, and synergizes with other targeted therapies in multiple myeloma.", Blood cancer journal, vol. 6, pp. e399, 2016 Feb 26. salama-_blood_cancer_j_2016.pdf
Abraham, J., N. N. Salama, and A. K. Azab, "The role of P-glycoprotein in drug resistance in multiple myeloma", Leukemia & Lymphoma, vol. 56, issue 1, pp. 26-33, 2015. salama-2015.pdf