Changes in Patient-reported Neuropsychiatric Outcomes during the SENSE Trial: First-line Treatment with Two Nucleoside Analogues plus Etravirine or Efavirenz

TPS351 Background: Biliary tract cancer (BTC) carries a poor prognosis and no first-line treatments are approved. The accepted global standard of care is gemcitabine + cisplatin (GemCis). NUC-1031 is a phosphoramidate transformation of gemcitabine designed to overcome key cancer resistance mechanisms that are associated with gemcitabine. Promising efficacy has been observed with single-agent NUC-1031 in a phase I study in advanced solid tumors and in the phase Ib ABC-08 study of NUC-1031 + cisplatin for first-line treatment of advanced BTC. Of 14 patients enrolled in 2 cohorts (NUC-1031 625 mg/m2 or 725 mg/m2 + cisplatin 25 mg/m2 on Days 1 and 8 of 21-day cycle), 1 had a CR and 6 had PRs, resulting in an unconfirmed ORR of 50%. This represents an approximate doubling of ORR over SoC. The combination was well-tolerated with no unexpected AEs or DLTs. The RP2D of NUC-1031 with cisplatin was 725 mg/m2. The tolerability profile, together with encouraging efficacy, suggested NUC-1031 + cisplatin may represent a more effective therapy than GemCis for BTC and led to initiation of a global registrational study. Methods: NuTide:121 is a Phase III, open-label, randomized study of NUC-1031 + cisplatin vs GemCis for first-line treatment of advanced BTC. Patients ≥18 years with histologically- or cytologically-confirmed BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), who have had no prior systemic chemotherapy for locally advanced/metastatic disease, are eligible. A total of 828 patients are being randomized (1:1) to either 725 mg/m2 NUC-1031 or 1000 mg/m2 gemcitabine, both with 25 mg/m2 cisplatin, administered on days 1 and 8 of 21-day cycles. Primary objectives are OS and ORR. Secondary objectives include PFS, safety, PK and patient-reported quality of life. In addition to the final analysis, three interim analyses, including two designed to support accelerated approval, are planned. The study has passed an initial safety analysis, with no protocol changes required. NuTide:121 is being conducted at approximately 130 sites across North America, Europe and Asia Pacific countries. Clinical trial information: NCT04163900.

Download Full-text

Randomized Comparison of Pazopanib and Doxorubicin as First-Line Treatment in Patients With Metastatic Soft Tissue Sarcoma Age 60 Years or Older: Results of a German Intergroup Study

Journal of Clinical Oncology ◽

10.1200/jco.20.00714 ◽

2020 ◽

Vol 38 (30) ◽

pp. 3555-3564 ◽

Cited By ~ 1

Author(s):

Viktor Grünwald ◽

Annika Karch ◽

Markus Schuler ◽

Patrick Schöffski ◽

Hans-Georg Kopp ◽

...

Keyword(s):

Soft Tissue ◽

Soft Tissue Sarcoma ◽

Febrile Neutropenia ◽

Geriatric Assessment ◽

Group Performance ◽

Life Questionnaire ◽

Line Treatment ◽

First Line ◽

Patient Reported ◽

First Line Treatment

PURPOSE Doxorubicin is a standard of care in patients with advanced, inoperable soft tissue sarcoma (STS). We tested whether pazopanib has efficacy comparable to that of doxorubicin in elderly patients with STS and offers superior tolerability for hematologic toxicity. PATIENTS AND METHODS Patients age 60 years or older without previous systemic treatment for progressive advanced or metastatic STS who had Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function were included. Treatment consisted of pazopanib 800 mg once per day or doxorubicin 75 mg/m2 once every 3 weeks (≤ 6 cycles) after being randomly assigned in a 2:1 ratio. Noninferiority was assumed for progression-free survival (PFS), if the upper limit of the 95% CI for the hazard ratio (HR) was less than 1.8. Neutropenia and febrile neutropenia were key secondary end points. The European Organisation for Research and Treatment of Cancer (30-item) Quality of Life Questionnaire and geriatric assessment were used to measure patient-reported outcomes. Cox regression analysis and Kaplan-Meier curves were used for analysis. RESULTS Pazopanib and doxorubicin were given to 81 and 39 patients, respectively. The median age was 71 years (range, 60-88 years). PFS was noninferior (HR, 1.00; 95% CI, 0.65 to 1.53) and the incidence of grade 4 neutropenia and febrile neutropenia favored pazopanib. Objective response rates for pazopanib and doxorubicin were 12.3% and 15.4%, respectively. Overall survival did not differ significantly between arms (HR, 1.08; 95% CI, 0.68 to 1.72; P = .735). Geriatric assessment revealed 2 or more comorbidities in 15.8% of the patients and impairment of activities of daily living in 28.3% of patients. CONCLUSION Pazopanib was noninferior to doxorubicin, rendering pazopanib a putative therapeutic option in the first-line treatment of STS in patients age 60 years or older. The distinct adverse event profile may be used to counsel patients and tailor therapy to individual needs.

Download Full-text

INDUCE-3: A randomized, double-blind study of GSK3359609 (GSK609), an inducible T-cell co-stimulatory (ICOS) agonist antibody, plus pembrolizumab (PE) versus placebo (PL) plus PE for first-line treatment of PD-L1-positive recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps6591 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS6591-TPS6591 ◽

Cited By ~ 1

Author(s):

Aaron Richard Hansen ◽

Thomas S. Stanton ◽

Min Hee Hong ◽

Ezra E.W. Cohen ◽

Hisham Mohamed Mehanna ◽

...

Keyword(s):

T Cell ◽

Adaptive Design ◽

Double Blind Study ◽

Line Treatment ◽

First Line ◽

Eligibility Criteria ◽

Double Blind ◽

Hpv Status ◽

Patient Reported ◽

First Line Treatment

TPS6591 Background: Pembrolizumab as part of first-line treatment for patients (pts) with R/M HNSCC has improved survival. However, in order to further improve outcomes in this population investigation of rational combinations targeting different mechanisms that cancers exploit to evade the immune system is required. ICOS, a member of the CD28/B7 immunoglobulin receptor superfamily, provides a co-stimulatory signal augmenting T-cell proliferation, cytokine production, cytotoxic function and survival. GSK609 is a humanized IgG4 antibody selected for its potent agonist activity and non-depleting properties. The rationale for targeting ICOS with GSK609 plus PD-1 blockade with PE is supported by preclinical and clinical evidence (Rischin, et al. Annals of Oncol 2019;30[Supplement_5]:v454–5). INDUCE-3 trial (NCT04128696) will explore if the addition of GSK609 to PE improves outcomes of pts with R/M HNSCC. Methods: INDUCE-3 uses a 2-in-1 adaptive design that has the option to seamlessly expand from an initial Phase 2 to a Phase 3 study. Pts (n = 600) will be stratified by PD-L1 status and HPV status (oropharynx only) then randomly assigned in a 1:1 ratio to receive GSK609 plus PE or PL plus PE, every 3 weeks until progression, unacceptable toxicity, or up to 35 cycles. GSK609 plus PE will be assessed for superiority versus PL plus PE in overall survival (OS) and progression-free survival (PFS) per RECISTv1.1 as dual primary endpoints; secondary endpoints include PFS per immune-based RECIST; milestone OS; safety and tolerability; time to deterioration in patient-reported physical function and pain. Efficacy and patient-reported outcome endpoints will be assessed in the PD-L1 combined positive score (CPS) ≥1 and ≥20 populations. Key eligibility criteria are aged ≥18 years; locally incurable R/M HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx; no prior systemic therapy in the R/M setting; PD-L1 CPS ≥1 by central testing; measurable disease per RECIST v1.1 and ECOG PS 0/1. Recruitment is ongoing in countries across the globe. Funding: Study is funded by GlaxoSmithKline and in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Clinical trial information: NCT04128696 .

Download Full-text

d4T: keep it or abandon it?

Asian Biomedicine ◽

10.2478/abm-2010-0068 ◽

2010 ◽

Vol 4 (4) ◽

pp. 541-546 ◽

Cited By ~ 1

Author(s):

Andrew Hill

Keyword(s):

Body Weight ◽

Adverse Events ◽

World Health ◽

Nucleoside Analogues ◽

Line Treatment ◽

First Line ◽

The World ◽

Dose Ranging ◽

Health Organization ◽

First Line Treatment

Abstract Stavudine is a nucleoside analogue used widely for first-line treatment of HIV in developing and middleincome countries. The World Health Organization recommended that all patients should switch to stavudine (30mg BID). However, there is evidence from the dose-ranging trials that patients with body weight below 60kg should use a dose of 20mg BID. For patients who show adverse events on stavudine, a switch to other nucleoside analogues can be considered. This article reviews d4T to study if it should be kept or abandoned.

Download Full-text

Role and relevance of quality indicators in the selection of first-line treatment of patients with metastatic renal cell carcinoma: a position paper of the MeetURO Group

Future Oncology ◽

10.2217/fon-2018-0857 ◽

2019 ◽

Vol 15 (22) ◽

pp. 2657-2666

Author(s):

Giuseppe Procopio ◽

Sandro Pignata ◽

Amelia Altavilla ◽

Laura Attademo ◽

Delia De Lisi ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Kinase Inhibitors ◽

Line Treatment ◽

First Line ◽

Patient Reported ◽

Related Quality ◽

First Line Treatment

Tyrosine kinase inhibitors still play a very important role in the treatment of metastatic renal cell carcinoma despite a continuously changing scenario, in which immunotherapy and several combination-based approaches are also available. In this light, patient-reported outcomes and health-related quality of life are important factors in the selection of the best first-line treatment. This Review focuses on the existing evidence on patient-reported outcomes and health-related quality of life with several tyrosine kinase inhibitors (pazopanib, sunitinib, cabozantinib and tivozanib) used as first-line treatment for metastatic renal cell carcinoma.

Download Full-text

Design of a randomized controlled trial to evaluate effectiveness of methotrexate versus prednisone as first-line treatment for pulmonary sarcoidosis: the PREDMETH study

BMC Pulmonary Medicine ◽

10.1186/s12890-020-01290-9 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Vivienne Kahlmann ◽

◽

Montse Janssen Bonás ◽

Catharina C. Moor ◽

Coline H. M. van Moorsel ◽

...

Keyword(s):

Side Effects ◽

Patient Reported Outcomes ◽

Controlled Trial ◽

Pulmonary Sarcoidosis ◽

Response To Therapy ◽

Line Treatment ◽

First Line ◽

Patient Reported ◽

First Line Treatment

Abstract Background Treatment of pulmonary sarcoidosis is recommended in case of significant symptoms, impaired or deteriorating lung function. Evidence-based treatment recommendations are limited and largely based on expert opinion. Prednisone is currently the first-choice therapy and leads to short-term improvement of lung function. Unfortunately, prednisone often has side-effects and may be associated with impaired quality of life. Methotrexate is presently considered second-line therapy, and appears to have fewer side-effects. Objective The primary objective of this trial is to investigate the effectiveness and tolerability of methotrexate as first-line therapy in patients with pulmonary sarcoidosis compared with prednisone. The primary endpoint of this study will be the change in hospital-measured Forced Vital Capacity (FVC) between baseline and 24 weeks. Secondary objectives are to gain more insights in response to therapy in individual patients by home spirometry and patient-reported outcomes. Blood biomarkers will be examined to find predictors of response to therapy, disease progression and chronicity, and to improve our understanding of the underlying disease mechanism. Methods/design In this prospective, randomized, non-blinded, multi-center, non-inferiority trial, we plan to randomize 138 treatment-naïve patients with pulmonary sarcoidosis who are about to start treatment. Patients will be randomized in a 1:1 ratio to receive either prednisone or methotrexate in a predefined schedule for 24 weeks, after which they will be followed up in regular care for up to 2 years. Regular hospital visits will include pulmonary function assessment, completion of patient-reported outcomes, and blood withdrawal. Additionally, patients will be asked to perform weekly home spirometry, and record symptoms and side-effects via a home monitoring application for 24 weeks. Discussion This study will be the first randomized controlled trial comparing first-line treatment of prednisone and methotrexate and provide valuable data on efficacy, safety, quality of life and biomarkers. If this study confirms the hypothesis that methotrexate is as effective as prednisone as first-line treatment for sarcoidosis but with fewer side-effects, this will lead to improvement in care and initiate a change in practice. Furthermore, insights into the immunological mechanisms underlying sarcoidosis pathology might reveal new therapeutic targets. Trial registration The study was registered on the 19th of March 2020 in the International Clinical Trial Registry, www.clinicaltrials.gov; ID NCT04314193.

Download Full-text