Showing papers by "Sagun Parakh published in 2016"

Antibody-Drug Conjugates for Cancer Therapy

Abstract: Antibody-drug conjugates (ADCs) take advantage of the specificity of a monoclonal antibody to deliver a linked cytotoxic agent directly into a tumour cell. The development of these compounds provides exciting opportunities for improvements in patient care. Here, we review the key issues impacting on the clinical success of ADCs in cancer therapy. Like many other developing therapeutic classes, there remain challenges in the design and optimisation of these compounds. As the clinical applications for ADCs continue to expand, key strategies to improve patient outcomes include better patient selection for treatment and the identification of mechanisms of therapy resistance.

Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy.

Abstract: Recent phase III clinical trials have established the superiority of the anti-PD-1 antibodies pembrolizumab and nivolumab over the anti-CTLA-4 antibody ipilimumab in the first-line treatment of patients with advanced melanoma. Ipilimumab will be considered for second-line treatment after the failure of anti-PD-1 therapy. We retrospectively identified a cohort of 40 patients with metastatic melanoma who received single-agent anti-PD-1 therapy with pembrolizumab or nivolumab and were treated on progression with ipilimumab at a dose of 3 mg kg−1 for a maximum of four doses. Ten percent of patients achieved an objective response to ipilimumab, and an additional 8% experienced prolonged (>6 months) stable disease. Thirty-five percent of patients developed grade 3–5 immune-related toxicity associated with ipilimumab therapy. The most common high-grade immune-related toxicity was diarrhoea. Three patients (7%) developed grade 3–5 pneumonitis leading to death in one patient. Ipilimumab therapy can induce responses in patients who fail the anti-PD-1 therapy with response rates comparable to previous reports. There appears to be an increased frequency of high-grade immune-related adverse events including pneumonitis that warrants close surveillance.

Antibody-mediated delivery of therapeutics for cancer therapy

Abstract: Introduction: Antibody-conjugated therapies (ACTs) combine the specificity of monoclonal antibodies to target cancer cells directly with highly potent payloads, often resulting in superior efficacy and/or reduced toxicity. This represents a new approach to the treatment of cancer. There have been highly promising clinical trial results using this approach with improvements in linker and payload technology. The breadth of current trials examining ACTs in haematological malignancies and solid tumours indicate the potential for clinical impact.Areas covered: This review will provide an overview of ACTs currently in clinical development as well as the principles of antibody delivery and types of payloads used, including cytotoxic drugs, radiolabelled isotopes, nanoparticle-based siRNA particles and immunotoxins.Expert opinion: The focus of much of the clinical activity in ACTs has, understandably, been on their use as a monotherapy or in combination with standard of care drugs. This will continue, as ...

Molecular Imaging and Quantitation of EphA2 Expression in Xenograft Models with 89Zr-DS-8895a

Abstract: Subtype A2 of the erythropoietin-producing hepatocellular tyrosine kinase (EphA2) cell surface receptor is expressed in a range of epithelial cancers. This study evaluated the molecular imaging of EphA2 expression in vivo in mouse tumor models using SPECT/MR and PET/MR and a humanized anti-EphA2 antibody, DS-8895a. Methods: DS-8895a was labeled with 111In, 125I, and 89Zr and assessed for radiochemical purity, immunoreactivity (Lindmo analysis), antigen-binding affinity (Scatchard analysis), and serum stability in vitro. In vivo biodistribution, imaging, and pharmacokinetic studies were performed with SPECT/MR and PET/MR. A dose-escalation study was also performed to determine EphA2 receptor saturability through tissue and imaging quantitative analysis. Results: All conjugates demonstrated good serum stability and specific binding to EphA2-expressing cells in vitro. In vivo biodistribution studies showed high uptake of 111In-CHX-A″-DTPA-DS-8895a and 89Zr-Df-Bz-NCS-DS-8895a in EphA2-expressing xenograft models, with no specific uptake in normal tissues. In comparison, retention of 125I-DS-8895a in tumors was lower because of internalization of the radioconjugate and dehalogenation. These results were confirmed by SPECT/MR and PET/MR. EphA2 receptor saturation was observed at the 30 mg/kg dose. Conclusion: Molecular imaging of tumor uptake of DS-8895a allows noninvasive measurement of EphA2 expression in tumors in vivo and determination of receptor saturation. 89Zr-Df-Bz-NCS-DS-8895a is suited for human bioimaging trials on the basis of superior imaging characteristics and will inform DS-8895a dose assessment and patient response evaluation in clinical trials.

Non‐HIV‐associated Kaposi sarcoma in an immunosuppressed melanoma patient treated with dabrafenib

Abstract: SummaryWhat is known and objective Cutaneous toxicities are commonly seen with BRAF inhibitors, frequently involving painful hyperkeratosis of the feet. We illustrate an unexpected diagnosis of extensive bilateral pedal Kaposi sarcoma masquerading as BRAF inhibitor-related toxicity in a patient treated with dabrafenib for metastatic melanoma. Case Summary A HIV-negative, non-diabetic, Italian man with a history of myasthenia gravis and metastatic melanoma presented with enlarging macular/plaque-like rash on his feet preceded by bilateral plantar shooting pains. The rash progressed in the context of acute-on-chronic immunosuppression and was initially thought due to commencement of the BRAF inhibitor (BRAFi) dabrafenib. Histopathological findings from skin biopsies revealed Kaposi sarcoma. The patient was continued on dabrafenib and received superficial radiotherapy to the feet with prompt relief of pain. What is new and conclusion This case illustrates the diagnostic pitfalls in patients treated with targeted therapies and highlights the importance of broad differentials for unusual presentations and early biopsy.

Temozolomide-associated liver fibrosis

Abstract: Temozolomide is generally well tolerated, and severe hepatic toxicities associated with temozolomide are rare. We report a case of liver fibrosis in a patient on temozolomide for the treatment of glioblastoma multiforme (GBM). A 64-year-old man was diagnosed with a WHO grade IV astrocytoma after presenting with seizures and left-sided weakness. At diagnosis the patient was commenced on levetiracetam, clonazepam, dexamethasone, and pantoprazole. The patient had not previously been on any regular medication and had no history of alcohol intake or liver disease. Two weeks after diagnosis, the patient commenced radiotherapy and received 100 mg temozolomide concurrently as well as trimethoprim-sulfamethoxazole (TMP-SMZ) 3 times a week as prophylaxis. Baseline laboratory tests prior to commencing treatment including viral hepatitis serology were normal apart from a mildly elevated alanine aminotransferase (ALT) of 116 IU/L (<41 U/L). The patient did not have prior liver function tests (LFTs) available for comparison. Five weeks into treatment, routine blood tests revealed deranged LFTs with a mixed cholestatic and hepatitic picture: ALT 664 U/L, serum total bilirubin 10 μmol/L (<18μmol/L), γ -glutamyltransferase (GGT) 1115 U/L (<60 U/L); alkaline phosphatase (ALP) 151 U/L (40–130 U/L), and aspartate aminotransferase (AST) 241 IU/L (<40 U/L). No new medications were commenced during the intervening period. Investigations including viral serology, autoimmune screening, and an abdominal ultrasound were normal. Transient elastography findings were consistent with advanced fibrosis with an elevated reading of 15.3 kilopascals (kPa) (<7.0 kPa). Temozolomide and TMP-SMZ were discontinued. The patient did not proceed to have postradiation temozolomide. Three months postcessation of drug there has been a gradual improvement in LFTs, with repeat transient elastography showing an improved, though elevated, reading of 12.0 kPa (Figure 1). To our knowledge this is the first suspected case of temozolomide-associated liver fibrosis. The diagnosis is supported by the timing of liver dysfunction, which was in close temporal relation to commencing temozolomide, findings on transient elastography, and near-normal blood tests 2 weeks after commencing potentially hepatotoxic drugs. The significance of an elevatedALT at baseline is unknown. Although it could indicate some preexisting undiagnosed hepatic injury that may have predisposed to this problem, our experience is that many patients with similar asymptomatic abnormalities have been treated with temozolomide without problems. The clinical picture is not consistent with TMP-SMZ–induced liver fibrosis, which is extremely rare, typically has features of hypersensitivity, and usually resolves within 4 weeks of onset. This patient was on a prophylactic dose, whereas previously described cases of hepatotoxicity have been at full treatment doses.1 Furthermore, review of safety data from phase 2-3 trials of levetiracetam did not show it