Lefitolimod in Combination with Ipilimumab in Patients with Advanced Solid Tumors: A Phase I Trial.

Introduction: TLR9 agonists are immunomodulators that have been of interest for combined use with cancer immunotherapy. TLR9 agonists, such as lefitolimod (MGN1703), significantly increased Th1 response in preclinical models and have demonstrated efficacy in early clinical trials. This trial assessed the safety and preliminary efficacy of the combination of lefitolimod and ipilimumab in patients with advanced solid tumors.

Use of Immunoglobulin Replacement Therapy in Clinical Practice: A Review.

Immunoglobulins (Igs) are produced by B lymphocytes and play a key role in humoral immunity. Igs are classified into five isotypes (IgG, IgA, IgM, IgE, and IgD). Their primary function is to recognize and bind to foreign antigens.

A phase I trial of the pan-ERBB inhibitor neratinib combined with the MEK inhibitor trametinib in patients with advanced cancer with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation or KRAS mutation.

Purpose: Aberrant alterations of ERBB receptor tyrosine kinases lead to tumorigenesis. Single agent therapy targeting EGFR or HER2 has shown clinical successes, but drug resistance often develops due to aberrant or compensatory mechanisms. Herein, we sought to determine the feasibility and safety of neratinib and trametinib in patients with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation and KRAS mutation.

Corticosteroid-Refractory Myositis After Dual BRAF and MEK Inhibition in a Patient with BRAF V600E-Mutant Metastatic Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma is a rare malignancy, which is rich in actionable alterations. Genomic aberrations in the mitogen-activated protein kinase (MAPK) pathway are common, and exon 15 p.V600E mutations are present in 5-7% of biliary tract cancers (BTC).

A Phase I Dose-Escalation Study to Evaluate the Safety and Tolerability of Evofosfamide in Combination with Ipilimumab in Advanced Solid Malignancies.

Purpose: As hypoxia can mediate resistance to immunotherapy, we investigated the safety, tolerability, and efficacy of combining evofosfamide, a prodrug that alleviates hypoxia, with ipilimumab, an immune checkpoint inhibitor, in immunologically "cold" cancers, which are intrinsically insensitive to immunotherapy, as well as in "hot/warm" metastatic cancers that are, atypical of such cancers, resistant to immunotherapy.

Patients And Methods: In a phase I, 3+3 dose-escalation trial (NCT03098160), evofosfamide (400-640 mg/m) and ipilimumab (3 mg/kg) were administered in four 3-week cycles. The former was administered on days 1 and 8 of cycles 1-2, while the latter was administered on day 8 of cycles 1-4.

Circadian disruption by shifting the light-dark cycle negatively affects bone health in mice.

The past decade, it has become evident that circadian rhythms within metabolically active tissues are very important for physical health. However, although shift work has also been associated with an increased risk of fractures, circadian rhythmicity has not yet been extensively studied in bone. Here, we investigated which genes are rhythmically expressed in bone, and whether circadian disruption by shifts in light-dark cycle affects bone turnover and structure in mice.

Histopathologic changes inside the lateral femoral cutaneous nerve obtained from patients with persistent symptoms of meralgia paresthetica.

Background: In patients with persistent symptoms of meralgia paresthetica, a neurectomy of the lateral femoral cutaneous nerve (LFCN) can be performed to alleviate pain symptoms. The neurectomy procedure can be performed either as a primary procedure or after failure of a previously performed neurolysis or decompression of the LFNC (secondary neurectomy). The goal of the present study was to quantify the histopathologic changes inside the LFCN obtained from patients with persistent symptoms of meralgia paresthetica, and specifically to compare to what extend these changes are present after primary versus secondary neurectomy.

Phase I study of nab-paclitaxel, gemcitabine, and bevacizumab in patients with advanced cancers.

Background: We performed a phase I modified 3 + 3 dose escalation study to evaluate the safety and activity of bevacizumab plus gemcitabine and nab-paclitaxel in patients with advanced solid tumours.

Methods: Patients were given fixed dose gemcitabine plus increasing doses of nab-paclitaxel and bevacizumab. Toxicity, response, and association with VEGF polymorphism was analysed.

Phase I study of the combination of crizotinib (as a MET inhibitor) and dasatinib (as a c-SRC inhibitor) in patients with advanced cancer.

Background Both MET and c-SRC are important mediators of cancer progression and there is cross talk between the two molecules. Preclinical studies have demonstrated combination of MET and c-SRC inhibitors is effective in multiple cancer types. Methods We analyzed the safety and efficacy of administering a c-SRC inhibitor (dasatinib) in combination with a MET inhibitor (crizotinib) in a two-arm concurrent phase I study.

Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies.

Background: Imatinib mesylate can induce rapid tumor regression, increase tumor antigen presentation, and inhibit tumor immunosuppressive mechanisms. CTLA-4 blockade and imatinib synergize in mouse models to reduce tumor volume via intratumoral accumulation of CD8+ T cells. We hypothesized that imatinib combined with ipilimumab would be tolerable and may synergize in patients with advanced cancer.

Dose-finding study of hepatic arterial infusion of irinotecan-based treatment in patients with advanced cancers metastatic to the liver.

Background: Liver metastases are associated with a poor prognosis. We investigated the use of hepatic arterial infusion (HAI) of irinotecan combination therapy in patients with liver metastases.

Patients And Methods: Patients with histologically confirmed advanced cancer with liver metastases that was refractory to standard therapy were eligible.

Phase I combination of pazopanib and everolimus in PIK3CA mutation positive/PTEN loss patients with advanced solid tumors refractory to standard therapy.

Purpose: Combining agents that block both the VEGF and PI3K/AKT/mTOR pathways may be synergistic. We explored a novel dosing schedule to assess safety, toxicity and activity in patients with advanced solid tumors.

Patients And Methods: Patients with refractory solid tumors were enrolled in a modified 3 + 3 Phase I dose escalation study to determine dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of a combination of everolimus (mTOR inhibitor) and pazopanib (tyrosine kinase inhibitor with anti-VEGF activity).

Dose-finding study of hepatic arterial infusion of oxaliplatin-based treatment in patients with advanced solid tumors metastatic to the liver.

Background: Liver metastases in patients with cancer are associated with poor survival. We hypothesized that hepatic arterial infusion (HAI) of oxaliplatin combination therapy would have antitumor activity in these patients.

Patients And Methods: Patients with advanced cancer and predominant liver metastases were treated on a phase I study of HAI oxaliplatin in combination with systemic bevacizumab, with or without HAI or systemic fluorouracil and/or leucovorin and/or cetuximab.

Intraperitoneal and intravenous chemotherapy in peritoneal carcinomatosis.

Background/aims: We conducted a phase I trial of IP oxaliplatin and paclitaxel with IV paclitaxel and bevacizumab in patients with peritoneal carcinomatosis.

Methodology: Patients received IV bevacizumab (2.5mg/kg) over 1 hour (day 1), then IV paclitaxel (110 mg/m2) 24-hr-infusion (day 1) and IP oxaliplatin (25-40 mg/m2) (day 2), and IP paclitaxel (30-60 mg/m2) (day 8 from cycle 2 onwards).

Exploratory study of hepatic arterial infusion oxaliplatin with systemic 5-fluorouracil/bevacizumab in patients with refractory solid tumor and extensive liver metastases.

Purpose: This pilot clinical trial explored the feasibility, safety, and efficacy of regional hepatic therapy combined with systemic anticancer agents in patients with refractory solid tumors and extensive unresectable liver involvement, including those with compromised hepatic function.

Patients And Methods: Six patients with colorectal (N = 3), ovarian (N = 2), and hepatocellular carcinoma (N = 1) received intra-arterial hepatic oxaliplatin followed by intravenous 5-fluorouracil, leucovorin, and bevacizumab every 2 weeks until disease progression. All had extensive liver metastases; four had elevated baseline serum total bilirubin.

Amphotericin B lipid complex as prophylaxis of invasive fungal infections in patients with acute myelogenous leukemia and myelodysplastic syndrome undergoing induction chemotherapy.

Background: The optimal antifungal prophylactic regimen for patients with acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (MDS) undergoing induction chemotherapy has yet to be identified. A prospective historical control study evaluated the efficacy and safety of amphotericin B lipid complex (ABLC) in this patient population.

Methods: Newly diagnosed patients with AML or high-risk MDS who were undergoing induction chemotherapy received prophylactic ABLC 2.

Intravenous itraconazole for prophylaxis of systemic fungal infections in patients with acute myelogenous leukemia and high-risk myelodysplastic syndrome undergoing induction chemotherapy.

Background: Systemic fungal infections remain the leading cause of mortality in patients with newly diagnosed acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS). The objective of the current study was to determine whether intravenous itraconazole (i.v.

Intravenous corticosteroids to reduce gemtuzumab ozogamicin infusion reactions.

Objective: To assess whether the addition of a brief course of intravenous corticosteroids reduces the incidence of infusion-related adverse events associated with gemtuzumab ozogamicin (GO) administration.

Methods: One hundred forty-three sequential patients received GO-based therapy for refractory myeloid leukemias: 110 patients received the standard regimen of acetaminophen 650 mg orally with diphenhydramine 50 mg intravenously and 33 patients received the same premedications with methylprednisolone sodium succinate 50 mg intravenous piggyback (IVPB) prior to infusion and repeated 1 hour into the infusion.

Results: Of 110 patients who received GO with standard premedications alone, 32 (29%) had grade 2 or above infusion-related adverse events.