Standard or high dose chemoradiotherapy, with or without the protease inhibitor nelfinavir, in patients with locally advanced pancreatic cancer: The phase 1/randomised phase 2 SCALOP-2 trial.

BACKGROUND: The multi-centre two-stage SCALOP-2 trial (ISRCTN50083238) assessed whether dose escalation of consolidative chemoradiotherapy (CRT) or concurrent sensitization using the protease inhibitor nelfinavir improve outcomes in locally advanced pancreatic cancer (LAPC) following four cycles of gemcitabine/nab-paclitaxel. METHODS: In stage 1, the maximum tolerated dose (MTD) of nelfinavir concurrent with standard-dose CRT (50.4 Gy in 28 fractions) was identified from a cohort of 27 patients. In stage 2, 159 patients were enrolled in an open-label randomized controlled comparison of standard versus high dose (60 Gy in 30 fractions) CRT, with or without nelfinavir at MTD. Primary outcomes following dose escalation and nelfinavir use were respectively overall survival (OS) and progression free survival (PFS). Secondary endpoints included health-related quality of life (HRQoL). RESULTS: High dose CRT did not improve OS (16.9 (60 % confidence interval, CI 16.2-17.7) vs. 15.6 (60 %CI 14.3-18.2) months; adjusted hazard ratio, HR 1.13 (60 %CI 0.91-1.40; p = 0.68)). Similarly, median PFS was not improved by nelfinavir (10.0 (60 %CI 9.9-10.2) vs. 11.1 (60 %CI 10.3-12.8) months; adjusted HR 1.71 (60 %CI 1.38-2.12; p = 0.98)). Local progression at 12 months was numerically lower with high-dose CRT than with standard dose CRT (n = 11/46 (23.9 %) vs. n = 15/45 (33.3 %)). Neither nelfinavir nor radiotherapy dose escalation impacted on treatment compliance or grade 3/4 adverse event rate. There were no sustained differences in HRQoL scores between treatment groups over 28 weeks post-treatment. CONCLUSIONS: Dose-escalated CRT may improve local tumour control and is well tolerated when used as consolidative treatment in LAPC but does not impact OS. Nelfinavir use does not improve PFS.

Review of Emerging Pharmacotherapy for the Treatment of Coronavirus Disease 2019.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into an emergent global pandemic. Coronavirus disease 2019 (COVID-19) can manifest on a spectrum of illness from mild disease to severe respiratory failure requiring intensive care unit admission. As the incidence continues to rise at a rapid pace, critical care teams are faced with challenging treatment decisions. There is currently no widely accepted standard of care in the pharmacologic management of patients with COVID-19. Urgent identification of potential treatment strategies is a priority. Therapies include novel agents available in clinical trials or through compassionate use, and other drugs, repurposed antiviral and immunomodulating therapies. Many have demonstrated in vitro or in vivo potential against other viruses that are similar to SARS-CoV-2. Critically ill patients with COVID-19 have additional considerations related to adjustments for organ impairment and renal replacement therapies, complex lists of concurrent medications, limitations with drug administration and compatibility, and unique toxicities that should be evaluated when utilizing these therapies. The purpose of this review is to summarize practical considerations for pharmacotherapy in patients with COVID-19, with the intent of serving as a resource for health care providers at the forefront of clinical care during this pandemic.

Phase I trial of concurrent stereotactic body radiotherapy and nelfinavir for locally advanced borderline or unresectable pancreatic adenocarcinoma.

INTRODUCTION: The HIV protease inhibitor nelfinavir (NFV) displays notable radiosensitizing effects. There have been no studies evaluating combined stereotactic body radiotherapy (SBRT) and NFV for borderline/unresectable pancreatic cancer. The primary objective of this phase I trial (NCT01068327) was to determine the maximum tolerated SBRT/NFV dose, and secondarily evaluate outcomes. METHODS: Following initial imaging, pathologic confirmation, and staging laparoscopy, subjects initially received three 3-week cycles of gemcitabine/leucovorin/fluorouracil; patients without radiologic progression received 5-fraction SBRT/NFV. Dose escalation was as follows: (1) 25 Gy/625 mg BID ×3wks; (2) 25 Gy/1250 mg BID ×3wks; (3) 30 Gy/1250 mg BID ×3wks; (4) 35 Gy/1250 mg BID ×3wks; (5) 35 Gy/1250 mg BID ×5wks; and (6) 40 Gy/1250 mg BID ×5wks. Pancreaticoduodenectomy was performed thereafter if resectable; if not, gemcitabine/leucovorin/fluorouracil was administered. RESULTS: Forty-six patients enrolled (10/2008-5/2013); 39 received protocol-directed therapy. Sixteen (41%) experienced any grade ≥2 event during and 1 month after SBRT. Four grade 3 and both grade 4 events occurred in a single patient at the initial dose level. 40 Gy/1250 mg BID ×5wks was the maximum tolerated dose. Five patients had late gastrointestinal bleeding (n = 2 superior mesenteric artery pseudo-aneurysm, n = 1 disease progression, n = 1 lower GI tract, n = 1 unknown location). The median overall survival was 14.4 months. Six (15%) patients recurred locally; median local failure-free survival was not reached. The median distant failure-free survival was 11 months, and median all failure-free survival was 10 months. CONCLUSIONS: Concurrent SBRT (40 Gy)/NFV (1250 mg BID) for locally advanced pancreatic cancer is feasible and safe, although careful attention to treatment planning parameters is recommended to reduce the incidence of late gastrointestinal bleeding.

Study protocol: a multi-centre randomised study of induction chemotherapy followed by capecitabine ± nelfinavir with high- or standard-dose radiotherapy for locally advanced pancreatic cancer (SCALOP-2).

BACKGROUND: Induction chemotherapy followed by chemoradiation is a treatment option for patients with locally advanced pancreatic cancer (LAPC). However, overall survival is comparable to chemotherapy alone and local progression occurs in nearly half of all patients, suggesting chemoradiation strategies should be optimised. SCALOP-2 is a randomised phase II trial testing the role of radiotherapy dose escalation and/or the addition of the radiosensitiser nelfinavir, following induction chemotherapy of gemcitabine and nab-paclitaxel (GEMABX). A safety run-in phase (stage 1) established the nelfinavir dose to administer with chemoradiation in the randomised phase (stage 2). METHODS: Patients with locally advanced, inoperable, non-metastatic pancreatic adenocarcinoma receive three cycles of induction GEMABX chemotherapy prior to radiological assessment. Those with stable/responding disease are eligible for further trial treatment. In Stage 1, participants received one further cycle of GEMABX followed by capecitabine-chemoradiation with escalating doses of nelfinavir in a rolling-six design. Stage 2 aims to register 262 and randomise 170 patients with responding/stable disease to one of five arms: capecitabine with high- (arms C + D) or standard-dose (arms A + B) radiotherapy with (arms A + C) or without (arms B + D) nelfinavir, or three more cycles of GEMABX (arm E). Participants allocated to the chemoradiation arms receive another cycle of GEMABX before chemoradiation begins. Co-primary outcomes are 12-month overall survival (radiotherapy dose-escalation question) and progression-free survival (nelfinavir question). Secondary outcomes include toxicity, quality of life, disease response rate, resection rate, treatment compliance, and CA19-9 response. SCALOP-2 incorporates a detailed radiotherapy quality assurance programme. DISCUSSION: SCALOP-2 aims to optimise chemoradiation in LAPC and incorporates a modern induction regimen. TRIAL REGISTRATION: Eudract No: 2013-004968-56; ClinicalTrials.gov : NCT02024009.

A spray dried Nelfinavir Mesylate particles for enhanced oral bioavailability: Systematic formulation optimization and in-vivo performance.

The current endeavor was aimed to fabricate spray dried Nelfinavir Mesylate particles (SDNPs) that upon reconstitution with body fluids releases amorphous Nelfinavir Mesylate with enhanced oral bioavailability. For this purpose, feed mixture was prepared containing solubilized NFM, solid substrate and solvent system. The NFM was solubilized in a mixture of Maisine 35-1 (200 mg), Tween80 (500 mg) and Transcutol HP (300 mg). Three different solid substrates with high specific surface area were used: Neusilin® UFL2, (magnesium aluminometasilicate), Aerosil 200® (colloidal silica) and Syloid 244 FP® (porous silicon dioxide). Central composite design-response surface methodology (CCD-RSM) with three-factor (two numeric and one categorical) at three-level was used to select the appropriate solid substrate and to develop optimized SDNPs. The solid characterization by scanning electron microscopy, differential scanning calorimetry and powder X-ray diffraction studies indicated the absence of crystalline NFM in the formulations. The drug distribution analysis using raman spectroscopy suggested uniform distribution of amorphous NFM in optimized SDNPs-1 formulation. The transmission electron microscopy revealed the spherical structure of reconstituted SDNPs that releases amorphous NFM with globules size less than 110 nm. The solid substrate had significant and positive effect in drug dissolution; the mean dissolution time of NFM loaded in SDNPs was considerably improved. The bioavailability study resulted in enhanced magnitude of Cmax and AUC for SDNPs. The tissue distribution studies exhibited significantly higher brain and lymph nodes distribution as compared to putative form. Overall, the results pointed towards the overwhelming response of the SDNPs to be used for HIV treatment.

Metformin combined with nelfinavir induces SIRT3/mROS-dependent autophagy in human cervical cancer cells and xenograft in nude mice.

The molecular mechanisms underlying the antineoplastic properties of metformin combined with nelfinavir remain elusive. To explore this question, transmission electron microscopy (TEM) was used to observe the combinatorial effect of inducing autophagosome formation in human cervical cancer cells. Western blotting respectively assayed protein expression of LC3I, LC3II, Beclin-1, Autophagy-related protein 7 (Atg7), Autophagy-related protein 3 (Atg3), NAD-dependent deacetylase sirtuin-3 (SIRT3) and major histocompatibility complex class I chain-related gene A (MICA). Lactate dehydrogenase (LDH) cytotoxicity assay evaluated natural killer (NK) cell cytotoxicity in the presence of metformin and nelfinavir in combination or each drug alone. Using tumor xenografts in a nude mouse model, antitumor efficacy of the drug combination was assessed. We found that the drug combination could induce autophagosome formation in human cervical cancer cells. The biomarker proteins of autophagy, including Beclin-1, Atg7 and Atg3, decreased, but the ratios of LC3I/II increased. We also found that this drug combination sensitizes human cervical cancer cells to NK cell-mediated lysis by increasing the protein of SIRT3 and MICA. Moreover, this drug combination markedly induced autophagy of SiHa xenografts in nude mice. Therefore, it can be concluded that metformin, in combination with nelfinavir, can induce SIRT3/mROS-dependent autophagy and sensitize NK cell-mediated lysis in human cervical cancer cells and cervical cancer cell xenografts in nude mice. Thus, our findings have revealed the detailed molecular mechanisms underlying the antitumor effects of metformin in combination with nelfinavir in cervical cancer.

Potentiation of the leishmanicidal activity of nelfinavir in combination with miltefosine or amphotericin B.

The present work assesses the effect in vitro of combining the antiretroviral drug nelfinavir (NFV), a drug used against HIV but also a strong in vitro inhibitor of the growth of Leishmania promastigotes and amastigotes, with amphotericin B or miltefosine on different strains of Leishmania infantum. The isobolograms revealed a synergistic effect for both combinations, with a fractional inhibitory concentration index (∑FIC) <0.5. The ∑FIC values obtained with reference strain MCAN/ES/98/LLM-724 were 0.25 ± 0.1 (95% CI: 0.178-0.322) for the combination NFV+AMB and 0.48 ± 0.2 (95% CI: 0.377-0.573) for the combination NFV+MTF. The effect of NFV on visceral leishmaniasis induced by L. infantum in BALB/c mice was also examined, and the results confirmed a leishmanicidal effect when administered alone, with approximately 60% (P<0.05) reductions in the liver and spleen parasite burdens. This is the first time this has been reported in an in vivo model. A significant reduction in the liver (77%; P<0.01) and spleen (76%; P<0.01) parasite burdens was also observed for NFV+MTF compared with those obtained when these drugs were used alone. This indicates that such combinations may be useful treatment options in patients with visceral leishmaniasis who are also infected with HIV.

Stomach Dose-Volume Predicts Acute Gastrointestinal Toxicity in Chemoradiotherapy for Locally Advanced Pancreatic Cancer.

AIMS: Gastrointestinal toxicity impedes dose escalation in chemoradiotherapy for hepatobiliary malignancies. Toxicity risk depends on clinical and radiotherapy metrics. We aimed to identify predictive factors using data from two prospective phase II clinical trials of locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: Ninety-one patients with available data from the ARCII (59.4 Gy in 33 fractions with gemcitabine, cisplatin and nelfinavir, n = 23) and SCALOP (50.4 Gy in 28 fractions with capecitabine or gemcitabine, n = 74) trials were studied. The independent variables analysed comprised age, sex, performance status, baseline symptoms, tumour size, weight loss, chemotherapy regimen and dose-volume histogram of stomach and duodenum in 5 Gy bins. The outcome measures used were Common Terminology Criteria of Adverse Events (CTCAE) grade and risk of CTCAE grade ≥2 acute upper gastrointestinal toxicity (anorexia, pain, nausea and/or vomiting). The risk of CTCAE grade ≥2 events was modelled using multivariable logistic regression and prediction of severity grade using ordinal regression. RESULTS: CTCAE grade ≥2 symptoms occurred in 38 patients (42%). On univariate analysis, stomach V35-45Gy was predictive of risk (odds ratio 1.035, 95% confidence interval 1.007-1.063) and grade (1.023, 1.003-1.044) of toxicity. The area under the curve was 0.632 (0.516-0.747) with toxicity risk 33/66 (50%) above and 5/25 (20%) below the optimal discriminatory threshold (7.1 cm3). Using a threshold of 30 cm3, risk was 13/20 (65%) versus 25/71 (35%). The optimal multivariable logistic regression model incorporated patient sex, chemotherapy regimen and stomach V35-45Gy. Receiving gemcitabine rather than capecitabine (odds ratio 3.965, 95% confidence interval 1.274-12.342) and weight loss during induction chemotherapy (1.216, 1.043-1.419) were significant predictors for the SCALOP cohort, whereas age predicted toxicity risk in ARCII only (1.344, 1.015-1.780). Duodenum dose-volume did not predict toxicity risk or severity in any cohort. CONCLUSIONS: In chemoradiotherapy for LAPC the volume of stomach irradiated to a moderately high dose (35-45 Gy) predicts the incidence and severity of acute toxicity. Other predictive factors can include age, sex, recent weight loss and concomitant chemotherapy agents.

Combining metformin and nelfinavir exhibits synergistic effects against the growth of human cervical cancer cells and xenograft in nude mice.

Human cervical cancer is the fourth most common carcinoma in women worldwide. However, the emergence of drug resistance calls for continuously developing new anticancer drugs and combination chemotherapy regimens. The present study aimed to investigate the anti-cervical cancer effects of metformin, a first-line therapeutic drug for type 2 diabetes mellitus, and nelfinavir, an HIV protease inhibitor, when used alone or in combination. We found that both metformin and nelfinavir, when used alone, were moderately effective in inhibiting proliferation, inducing apoptosis and suppressing migration and invasion of human cervical cell lines HeLa, SiHa and CaSki. When used in combination, these two drugs acted synergistically to inhibit the growth of human cervical cancer cells in vitro and cervical cancer cell xenograft in vivo in nude mice, and suppress cervical cancer cell migration and invasion. The protein expression of phosphoinositide 3-kinase catalytic subunit PI3K(p110α), which can promote tumor growth, was remarkably downregulated, while the tumor suppressor proteins p53 and p21 were substantially upregulated following the combinational treatment in vitro and in vivo. These results suggest that clinical use of metformin and nelfinavir in combination is expected to have synergistic antitumor efficacy and significant potential for the treatment of human cervical cancer.

In-utero exposure to nelfinavir-ethyl methyl sulfone.

Ethyl methyl sulfone contained in nelfinavir between 2007 and 2008 accidentally exposed embryos and fetuses to a powerful mutagen. We report data for 101 HIV-uninfected children exposed in utero included in the French prospective national cohort. The incidence of malformation was similar to that in the cohort as a whole with different drug exposures; no children had developed cancer after 9 years of follow-up.