Hani M. Babiker

The impact of concomitant medication use on patient eligibility for phase I cancer clinical trials.

Concomitant medication (CM) use may result in Phase I cancer clinical trial ineligibility due to concern for potential CM-investigational drug interactions or alteration of investigational drug absorption. Few studies have examined the impact of CM use on trial eligibility. Methods: We reviewed records of 274 patients on Phase I trials at a single academic institution. Demographics, CM identities and classes, CM discontinuation, reasons, and incidence of CM substitution were recorded. CM-investigational drug cytochrome P450 (CYP) enzyme interactions were documented. Statistical analysis was performed using descriptive statistics. Results: 273 of 274 patients (99.6%, 95% confidence interval [CI] 98.9-100%) took CM, with a median of 8 CM per patient (range 0 - 42). CM discontinuation occurred in 67 cases (25%, 95% CI 19-30%). The most common CM classes discontinued were herbal (17 cases, 25%, 95% CI 16-37%) and proton pump inhibitors (15 cases, 22%, 95% CI 12-32%). CM discontinuation reasons were: protocol prohibition (32 cases, 48%, 95% CI 36-60%); potential CM-investigational drug interaction (25 cases, 37%, 95% CI 26-49%); other (10 cases, 15%, 95% CI 6-23%). A potential CM-investigational drug CYP interaction was noted in 122 cases (45%, 95% CI 39-50%). CM potentially weakly decreased investigational drug metabolism in 52 cases (43%, 95% CI 34-51%), and potentially strongly decreased investigational drug metabolism in 17 cases (14%, 95% CI 8-20%). Investigational drug potentially weakly decreased CM metabolism in 39 cases (32%, 95% CI 24-40%), and potentially strongly decreased CM metabolism in 28 cases (23%, 95% CI 15-30%). CM substitution occurred in 36/67 cases (54%, 95% CI 41-66%) where CM were discontinued to allow for eventual participation in clinical trials. Overall in 2 cases (0.7%, 95% CI 0.1-2.6%), patients were protocol ineligible because CM could not be discontinued or substituted. Conclusions: This study highlights the high prevalence of concomitant medication use among cancer patients enrolled in phase I clinical trials. Most patients did meet trial eligibility criteria with careful substitution and discontinuation of CM. The most common reason for discontinuation of CM was protocol prohibition. The most common medications discontinued were herbal, proton pump inhibitors, selective serotonin reuptake inhibitor anti-depressants, and non-steroidal anti-inflammatory drugs.

Oncolytic virotherapy including Rigvir and standard therapies in malignant melanoma

The treatment of metastatic melanoma has evolved from an era where interferon and chemotherapy were the mainstay of treatments to an era where immunotherapy has become the frontline. Ipilimumab (IgG1 CTLA-4 inhibitor), nivolumab (IgG4 PD-1 inhibitor), pembrolizumab (IgG4 PD-1 inhibitor) and nivolumab combined with ipilimumab have become first-line therapies in patients with metastatic melanoma. In addition, the high prevalence of BRAF mutations in melanoma has led to the discovery and approval of targeted molecules, such as vemurafenib (BRAF kinase inhibitor) and trametinib (MEK inhibitor), as they yielded improved responses and survival in malignant melanoma patients. This is certainly a burgeoning time in immunotherapy drug development, and the aforementioned efforts along with the recent US Food and Drug Administration approval of talimogene laherparepvec (T-VEC), a recombinant oncolytic herpes virus, have paved the way to exploring the role of additional oncolytic viruses, such as the echovirus Rigvir, as new and innovative treatment modalities in patients with melanoma. Herein, we discuss the current standard of care treatment in melanoma with an emphasis on immunotherapy and oncolytic viruses in development.

The effect of PD-L1 testing on the cost-effectiveness and economic impact of immune checkpoint inhibitors for the second-line treatment of NSCLC.

Background Immune checkpoint inhibitors improve outcomes compared with chemotherapy in lung cancer. Tumor PD-L1 receptor expression is being studied as a predictive biomarker. The objective of this study was to assess the cost-effectiveness and economic impact of second-line treatment with nivolumab, pembrolizumab, and atezolizumab with and without the use of PD-L1 testing for patient selection. Design We developed a decision-analytic model to determine the cost-effectiveness of PD-L1 assessment and second-line immunotherapy versus docetaxel. The model used outcomes data from randomized clinical trials (RCTs) and drug acquisition costs from the United States. Thereafter, we used epidemiologic data to estimate the economic impact of the treatment. Results We included four RCTs (2 with nivolumab, 1 with pembrolizumab, and 1 with atezolizumab). The incremental quality-adjusted life year (QALY) for nivolumab was 0.417 among squamous tumors and 0.287 among non-squamous tumors and the incremental cost-effectiveness ratio (ICER) were

Tumor-Treating Fields: A Fourth Modality in Cancer Treatment

155 605 and

The great masquerader of malignancy: chronic intestinal pseudo-obstruction

187 685, respectively. The QALY gain in the base case for atezolizumab was 0.354 and the ICER was

Heart of Lymphoma: Primary Mediastinal Large B-Cell Lymphoma with Endomyocardial Involvement

215 802. Compared with treating all patients, the selection of patients by PD-L1 expression improved incremental QALY by up to 183% and decreased the ICER by up to 65%. Pembrolizumab was studied only in patients whose tumors expressed PD-L1. The QALY gain was 0.346 and the ICER was

PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma

98 421. Patient selection also reduced the budget impact of immunotherapy. Conclusion The use of PD-L1 expression as a biomarker increases cost-effectiveness of immunotherapy but also diminishes the number of potential life-years saved.

Ublituximab for the treatment of CD20 positive B-cell malignancies

Despite major advances in therapy, cancer continues to be a leading cause of mortality. In addition, toxicities of traditional therapies pose a significant challenge to tolerability and adherence. TTFields, a noninvasive anticancer treatment modality, utilizes alternating electric fields at specific frequencies and intensities to selectively disrupt mitosis in cancerous cells. TTFields target proteins crucial to the cell cycle, leading to mitotic arrest and apoptosis. TTFields also facilitate an antitumor immune response. Clinical trials of TTFields have proven safe and efficacious in patients with glioblastoma multiforme (GBM), and are FDA approved for use in newly diagnosed and recurrent GBM. Trials in other localized solid tumors are ongoing. Clin Cancer Res; 24(2); 266–75. ©2017 AACR.

Cardiotoxic effects of chemotherapy: A review of both cytotoxic and molecular targeted oncology therapies and their effect on the cardiovascular system

Paraneoplastic syndromes can precede the initial manifestation and diagnosis of cancer. Paraneoplastic syndromes are a heterogeneous group of disorders caused by mechanisms other than the local presence of tumor cells. These phenomena are mediated by humoral factors secreted by tumor cells or by tumor mediated immune responses. Among paraneoplastic syndromes, chronic intestinal pseudo-obstruction (CIPO) is rare and represents a particularly difficult clinical challenge. Paraneoplastic CIPO is a highly morbid syndrome characterized by impaired gastrointestinal propulsion with symptoms and signs of mechanical bowel obstruction. Clinical outcomes of paraneoplastic CIPO are often deleterious. The current standard of care for the management of CIPO includes supportive treatment with promotility and anti-secretory agents. However, the majority of patients with CIPO eventually require the resection of the non-functioning gut segment. Here, we present a 62-year-old patient with anti-Hu antibody associated paraneoplastic CIPO and underlying small cell lung cancer who underwent treatment with cisplatin and etoposide. Herein, we discuss diagnosis, prognosis, proposed mechanisms, treatment options, and future potential therapeutic strategies of paraneoplastic CIPO.

Hypoxia-activated prodrugs in the treatment of advanced pancreatic adenocarcinoma

Primary mediastinal B-cell lymphoma (PMBCL) is an uncommon aggressive subset of diffuse large B-cell lymphomas. Although PMBCL frequently spreads locally from the thymus into the pleura or pericardium, it rarely invades directly through the heart. Herein, we report a case of a young Mexican female diagnosed with PMBCL with clear infiltration of lymphoma through the cardiac wall and into the right atrium and tricuspid valve leading to tricuspid regurgitation. This was demonstrated by cardiac MRI and transthoracic echocardiogram. In addition, cardiac MRI and CT scan of the chest revealed the large mediastinal mass completely surrounding and eroding into the superior vena cava (SVC) wall causing a collar of stokes. The cardiac and SVC infiltration created a significant therapeutic challenge as lymphomas are very responsive to chemotherapy, and treatment could potentially lead to vascular wall rupture and hemorrhage. Despite the lack of conclusive data on chemotherapy-induced hemodynamic compromise in such scenarios, her progressive severe SVC syndrome and respiratory distress necessitated urgent intervention. In addition to the unique presentation of this rare lymphoma, our case report highlights the safety of R-CHOP treatment.