Oncologists’ reflections on patient rights and access to compassionate use drugs: A qualitative interview study from an academic cancer center

The U.S. Food and Drug Administration (FDA) allows patients with serious illnesses to access investigational drugs for “compassionate use” outside of clinical trials through expanded access (EA) Programs. The federal Right-to-Try Act created an additional pathway for non-trial access to experimental drugs without institutional review board or FDA approval. This removal of oversight amplifies the responsibility of physicians, but little is known about the role of practicing physicians in non-trial access to investigational drugs. We undertook semi-structured interviews to capture the experiences and opinions of 21 oncologists all with previous EA experience at a major cancer center. We found five main themes. Participants with greater EA experience reported less difficulty accessing drugs through the myriad of administrative processes and drug company reluctance to provide investigational products while newcomers reported administrative hurdles. Oncologists outlined several rationales patients offered when seeking investigational drugs, including those with stronger health literacy and a good scientific rationale versus others who remained skeptical of conventional medicine. Participants reported that most patients had realistic expectations while some had unrealistic optimism. Given the diverse reasons patients sought investigational drugs, four factors—scientific rationale, risk-benefit ratio, functional status of the patient, and patient motivation—influenced oncologists’ decisions to request compassionate use drugs. Physicians struggled with a “right-to-try” framing of patient access to experimental drugs, noting instead their own responsibility to protect patients’ best interest in the uncertain and risky process of off-protocol access. This study highlights the willingness of oncologists at a major cancer center to pursue non-trial access to experimental treatments for patients while also shedding light on the factors they use when considering such treatment. Our data reveal discrepancies between physicians’ sense of patients’ expectations and their own internal sense of professional obligation to shepherd a safe process for patients at a vulnerable point in their care.

Small molecule splicing modifiers with systemic HTT-lowering activity

Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin (HTT) gene. Consequently, the mutant protein is ubiquitously expressed and drives pathogenesis of HD through a toxic gain-of-function mechanism. Animal models of HD have demonstrated that reducing huntingtin (HTT) protein levels alleviates motor and neuropathological abnormalities. Investigational drugs aim to reduce HTT levels by repressing HTT transcription, stability or translation. These drugs require invasive procedures to reach the central nervous system (CNS) and do not achieve broad CNS distribution. Here, we describe the identification of orally bioavailable small molecules with broad distribution throughout the CNS, which lower HTT expression consistently throughout the CNS and periphery through selective modulation of pre-messenger RNA splicing. These compounds act by promoting the inclusion of a pseudoexon containing a premature termination codon (stop-codon psiExon), leading to HTT mRNA degradation and reduction of HTT levels.

Factors of feasibility: an interview study of physicians’ experiences of expanded access to investigational drugs in three countries

Seriously ill patients who have exhausted all approved treatment regimens and who cannot be enrolled in clinical trials may resort to expanded access programmes in order to gain access to unapproved, investigational drugs. It seems that in some countries, expanded access to investigational drugs is offered in clinical practice on a more routine basis than in other countries. This study is the first to investigate the experiences of physicians with expanded access to investigational drugs in different healthcare systems, with a focus on factors that facilitate or hinder expanded access. Semi-structured interviews (n = 36) were carried out with medical specialists in the Netherlands (n = 14), Turkey (n = 9) and the United States of America (n = 13), and analysed thematically. This study identifies five sets of factors pointed out by physicians that determine the degree to which expanded access to investigational drugs is deemed feasible in clinical practice: the suitability of investigational treatments, the application process, hospital policies, support by pharmaceutical companies, and funding and reimbursement arrangements. Based on the interviews conducted, we conclude that, while legally allowed and technically possible, expanded access is not always feasible for—and not always considered an option by—treating physicians. This is mainly due to lack of familiarity with expanded access, the extensive time and effort required for the application process, willingness or ability of pharmaceutical companies to supply the drugs, and funding issues.

CTIM-32. IMMUNE CHECKPOINT INHIBITOR NIVOLUMAB IN PEOPLE WITH RECURRENT SELECT RARE CNS CANCERS: RESULTS OF INTERIM ANALYSIS IN A HEAVILY PRETREATED COHORT

INTRODUCTION Standard and experimental therapies for patients with rare CNS tumors are scarce. Nivolumab (PD-1 inhibitor) is approved for several non-CNS cancers. This ongoing Phase II trial (NCT03173950) will determine the efficacy of nivolumab in adults with recurrence/progression of one of 11 selected rare primary CNS tumors. Efficacy is measured by Disease Control Rate (DCR; confirmed CR/PR or durable SD for ≥ 6 months) in 2 cohorts: heavily and non-heavily pretreated patients (heavily pretreated: ≥ 3 prior therapies; non-heavily pretreated: ≤ 2). We report efficacy and safety results of a preplanned interim analysis in the heavily pretreated cohort. METHODS Eligibility includes recurrence/progression of an eligible tumor; age ≥ 18 years; tumor tissue available for histopathology, molecular and immune profiling; KPS ≥ 70; and no steroids at study entry. A total of 150 evaluable patients will be enrolled (75 to each cohort). Prior therapies include radiation and/or standard or investigational drugs. Nivolumab treatment is 240 mg IV every 2 weeks (4 doses); then 480 mg every 4 weeks (14 additional doses). Interim analysis was planned when sample size reached 32 in each cohort. RESULTS As of March 10, 2021, DCR exceeded the minimum required for interim analysis in the heavily pretreated cohort. Among 30 patients, 4 achieved SD > 6 months (medulloblastoma, anaplastic ependymoma, myxopapillary ependymoma, metastatic atypical meningioma). Safety profile (related AEs): grade 3 = 7; grade 4 = 1. Most frequent grade 3-5 AEs regardless of attribution: tumor progression (6); anemia, hydrocephalus, lymphopenia (3 each); cerebral edema, headache (2 each). CONCLUSION DCR exceeded the “go” boundary (i.e., > 2) in the heavily pretreated cohort. Nivolumab showed safety profile consistent with other studies. This cohort will continue to stage 2 and complete total accrual of 75 patients. The trial is currently being expanded to 10 additional sites across the BTTC/NCI-CONNECT consortium.

LINCS Dataset-Based Repositioning of Dutasteride as an Anti-Neuroinflammation Agent

Neuroinflammation is often accompanied by central nervous system (CNS) injury seen in various CNS diseases, with no specific treatment. Drug repurposing is a strategy of finding new uses for approved or investigational drugs, and can be enabled by the Library of Integrated Network-based Cellular Signatures (LINCS), a large drug perturbation database. In this study, the signatures of Lipopolysaccharide (LPS) were compared with the signatures of compounds contained in the LINCS dataset. To the top 100 compounds obtained, the Quantitative Structure-Activity Relationship (QSAR)-based tool admetSAR was used to identify the top 10 candidate compounds with relatively high blood–brain barrier (BBB) penetration. Furthermore, the seventh-ranked compound, dutasteride, a 5-α-reductase inhibitor, was selected for in vitro and in vivo validation of its anti-neuroinflammation activity. The results showed that dutasteride significantly reduced the levels of IL-6 and TNF-α in the supernatants of LPS-stimulated BV2 cells, and decreased the levels of IL-6 in the hippocampus and plasma, and the number of activated microglia in the brain of LPS administration mice. Furthermore, dutasteride also attenuated the cognitive impairment caused by LPS stimulation in mice. Taken together, this study demonstrates that the LINCS dataset-based drug repurposing strategy is an effective approach, and the predicted candidate, dutasteride, has the potential to ameliorate LPS-induced neuroinflammation and cognitive impairment.

Introduction

In addition to setting out the themes of the book, the Introduction tells the story of cancer patient Abigail Burroughs and the case of Abigail Alliance v. von Eschenbach (2008), a suit against the FDA brought by a patient advocacy group founded by Abigail’s father after her death. In this case, the US Court of Appeals for the DC Circuit denied terminally ill patients the right to obtain investigational drugs prior to FDA approval. Using a test established by the Supreme Court in its physician-assisted suicide decision, Washington v. Glucksberg (1997), the DC Circuit held that a right to access unapproved drugs is not “deeply rooted in this Nation’s history and tradition.” The Introduction asserts that the Abigail Alliance court’s version of history was incomplete and one-dimensional, as the rest of the book will demonstrate.

New actionable targets and investigational drugs in chronic lymphocytic leukemia

SummaryThe treatment landscape of chronic lymphocytic leukemia (CLL) has shifted from chemotherapy-based approaches to targeted agents in the last decade. However, evolving drug resistance and accumulating toxicity remain challenges that still limit patients’ clinical outcomes. Furthermore, currently licensed targeted agents such as inhibitors of Bruton’s tyrosine kinase (BTK) and anti-apoptotic protein B‑cell lymphoma 2 (BCL2) do not adequately compensate for the poor clinical outcomes associated with high-risk genetics such as TP53 alterations. New insights into disease biology facilitated design and investigation of several new targeted agents with encouraging results in early clinical trials. This short review focuses on novel actionable targets and investigational drugs aimed at circumventing acquired resistance and avoiding accumulating toxicity.