MUC1 is a mucinous glycoprotein which is overexpressed and under or aberrantly glycosylated in many human malignancies. MUC1
is associated with cellular transformation and can confer resistance to ...genotoxic agents. L-BLP25 is a peptide vaccine strategy
that targets the exposed core peptide of MUC1. In preclinical studies, L-BLP25 induced a cellular immune response characterized
by T-cell proliferation in response to MUC1 and production of IFN-γ. Phase I and II trials have established the dose and schedule
of the vaccine as well as its excellent safety profile. A randomized phase II trial of maintenance L-BLP25 versus best supportive
care in patients with stage IIIB/IV non–small cell lung cancer who experienced clinical benefit from initial therapy has been
reported. Updated survival analysis of this trial continues to show a strong survival trend in favor of L-BLP25 (median survival,
30.6 versus 13.3 months) in a subgroup of patients with locoregional stage IIIB disease. These promising results will be tested
in a phase III trial of L-BLP25 versus placebo in patients with stage III non–small cell lung cancer after response to primary
chemoradiotherapy.
Summary Background Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody–drug conjugate ...containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). Methods In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1–2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m2 . Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov , number NCT01290549. Findings Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3–4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3–4 adverse events were neutropenia (18 40% of 45), anaemia (five 11%), and peripheral sensory neuropathy (four 9%). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3–4 adverse event, with neutropenia (five 56%), anaemia (two 22%), and febrile neutropenia (two 22%) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients two treatment related, and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. Interpretation Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. Funding Genentech.
There is limited information on the treatment trajectory and outcomes of patients with advanced cEGFRm NSCLC treated with osimertinib in routine clinical practice in Canada. By using and analyzing ...population-based administrative data and detailed chart abstraction in the province of Alberta, our objective was to capture Canadian-specific real-world treatment patterns, health outcomes, and healthcare resource utilization (HCRU) in advanced cEGFRm NSCLC patients who were (a) treated with osimertinib and (b) those receiving treatment after osimertinib. In our study cohort, we found that the overall survival rates for real-world patients receiving osimertinib were less favorable than those observed in clinical trials (24.0 versus 38.6 months). The attrition rate after osimertinib was substantial and high HCRU persisted across many years after diagnosis and treatment. This study provides important real-world evidence on contemporary survival, treatment patterns, and healthcare use among cEGFRm NSCLC patients treated with osimertinib and suggests that further research efforts are needed to improve therapeutic options in both the first and subsequent line settings.
This study examined safety, pharmacokinetics, and efficacy of veliparib, a PARP inhibitor, combined with carboplatin and etoposide in patients with extensive-stage (ED) small cell lung cancer (SCLC) ...and other solid tumors.
The 3 + 3 design was used for dose escalation of oral veliparib in combination with carboplatin (AUC 5 on day 1) and etoposide (100 mg/m
on days 1-3) in 21-day cycles. Veliparib dose was explored from 80 to 240 mg b.i.d. on 7-day, 14-day, or continuous schedules. Patients without disease progression continued on maintenance monotherapy (veliparib 400 mg b.i.d.) until disease progression or unacceptable toxicity.
Thirty-nine patients were enrolled to determine the recommended phase II dose of 240 mg veliparib for 14 days combined with carboplatin and etoposide based on long-term tolerability. Dose-limiting toxicity occurred in 1 patient (grade 2 toxic motor polyneuropathy) at veliparib 240 mg b.i.d. for 7 days. Most common adverse events related to veliparib were nausea (39%), fatigue (39%), and hematologic toxicities. Continuous dosing of veliparib 240 mg b.i.d. with carboplatin and etoposide resulted in excessive chemotherapy dose delays due to hematologic toxicity (grade 3/4 neutropenia/thrombocytopenia). Etoposide pharmacokinetics was not affected by veliparib. Confirmed responses occurred in 17 of 39 (44%) and 16 of 25 (64%) of all enrolled and ED SCLC patients, respectively. At the RP2D, confirmed responses occurred in 6 of 13 (46%) and 5 of 6 (83%) of all enrolled and ED SCLC patients, respectively.
Veliparib (240 mg b.i.d. 14 days) plus carboplatin/etoposide can be safely combined. Phase II of this study is ongoing in first-line patients with ED SCLC.
To determine the safety, pharmacokinetics, and recommended phase II dose of an antibody-drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to ...monomethyl auristatin F (MMAF) in subjects with advanced metastatic renal cell carcinoma (mRCC).
Two phase I studies were conducted sequentially with 2 ADCs considered equivalent, hybridoma-derived AGS-16M8F and Chinese hamster ovary-derived AGS-16C3F. AGS-16M8F was administered intravenously every 3 weeks at 5 dose levels ranging from 0.6 to 4.8 mg/kg until unacceptable toxicity or progression. The study was terminated before reaching the MTD. A second study with AGS-16C3F started with the AGS-16M8F bridging dose of 4.8 mg/kg given every 3 weeks.
The AGS-16M8F study (
= 26) closed before reaching the MTD. The median duration of treatment was 12 weeks (1.7-83 weeks). One subject had durable partial response (PR; 83 weeks) and 1 subject had prolonged stable disease (48 weeks). In the AGS-16C3F study (
= 34), the protocol-defined MTD was 3.6 mg/kg, but this was not tolerated in multiple doses. Reversible keratopathy was dose limiting and required multiple dose deescalations. The 1.8 mg/kg dose was determined to be safe and was associated with clinically relevant signs of antitumor response. Three of 13 subjects at 1.8 mg/kg had durable PRs (range, 100-143 weeks). Eight subjects at 2.7 mg/kg and 1.8 mg/kg had disease control >37 weeks (37.5-141 weeks).
AGS-16C3F was tolerated and had durable antitumor activity at 1.8 mg/kg every 3 weeks.
.
Summary Background Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess ...whether dacomitinib improved overall survival in heavily pretreated patients with this disease. Methods In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov , number NCT01000025. Findings Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6–29·6) for patients in the dacomitinib group and 24·4 months (11·5–38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months 95% CI 6·08–7·49 for dacomitinib vs 6·31 months 5·32–7·52 for placebo; hazard ratio HR 1·00 95% CI 0·83–1·21; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months 1·91–3·32 vs 1·38 months 0·99–1·74, respectively; HR 0·66 95% CI 0·55–0·79; p<0·0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 7% of 480 patients vs three 1% of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR -mutation-positive tumours (HR 0·98, 95% CI 0·67–1·44) and EGFR wild-type tumours (0·93, 0·71–1·21; p interaction =0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS -mutation-positive tumours (2·10, 1·05–4·22) and patients with KRAS wild-type tumours (0·79, 0·61–1·03; p interaction =0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0·0001), dyspnoea (p=0·049), and pain (p=0·041). 185 (39%) of 477 patients who received dacomitinib and 86 (36%) of 239 patients who received placebo had serious adverse events. The most common grade 3–4 adverse events were diarrhoea (59 12% patients on dacomitinib vs no controls), acneiform rash (48 10% vs one <1%), oral mucositis (16 3% vs none), and fatigue (13 3% vs four 2%). Interpretation Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor. Funding Canadian Cancer Society Research Institute and Pfizer.
Purpose: Gemcitabine monotherapy is the standard palliative chemotherapy for pancreatic adenocarcinoma. Gemcitabine requires plasma
membrane nucleoside transporter proteins to efficiently enter cells ...and exert it cytotoxicity. In vitro studies have demonstrated that deficiency of human equilibrative nucleoside transporter 1 (hENT1), the most widely abundant
and distributed nucleoside transporter in human cells, confers resistance to gemcitabine toxicity, but the distribution and
abundance of nucleoside transporters in normal and malignant pancreatic tissue is unknown.
Experimental Design: We studied tumor blocks from normal pancreas and 21 Alberta patients with gemcitabine-treated pancreatic cancer. Immunohistochemistry
on the formalin-fixed, paraffin-embedded tissues was performed with specific hENT1 and human Concentrative Nucleoside Transporter
3 monoclonal antibodies and scored by a pathologist blinded to clinical outcomes.
Results: hENT1 was detected in normal Langerhan cells and lymphocytes but not in normal glandular elements. Patients in whom all adenocarcinoma
cells had detectable hENT1 had significantly longer median survivals from gemcitabine initiation than those for whom hENT1
was absent in a proportion (10 to 100%) of adenocarcinoma cells (median survival, 13 versus 4 months, P = 0.01). Immunohistochemistry for human Concentrative Nucleoside Transporter 3 revealed moderate to high-intensity staining
in all adenocarcinoma tissue samples.
Conclusions: Patients with pancreatic adenocarcinoma with uniformly detectable hENT1 immunostaining have a significantly longer survival
after gemcitabine chemotherapy than tumors without detectable hENT1. Immunohistochemistry for hENT1 shows promise as a molecular
predictive assay to appropriately select patients for palliative gemcitabine chemotherapy but requires formal validation in
prospective, randomized trials.
Skeletal muscle radio-density (SMD) measures muscle radiation attenuation (in Hounsfield Units, HU) on computed tomography (CT) scans. Low SMD is prognostic of poor survival in melanoma, however its ...significance is unknown for hematologic malignancies. We performed a single institution, retrospective review of all follicular lymphoma (FL) patients who received chemoimmunotherapy from 2004-2009. Patient demographics, FL International Prognostic Index 1 (FLIPI-1), progression free (PFS) and overall survival (OS) were collected as primary endpoints. Objective response rates (ORR) were secondary. SMD was calculated using pre-treatment CT scans. In 145 patients reviewed, median values were age 59, FLIPI-1 of 2, stage III, and 8 chemoimmunotherapy cycles received. Median PFS for those with low SMD (<36.6 and <33.1 HU for patients with BMI ≤ 25 and > 25 kg/m2, respectively) compared to those with high SMD was profoundly worse, 69.6 vs. 106.7 months (hazard ratio HR 1.85; p = 0.01), respectively. Median OS was not reached in patients with high SMD vs. 92.7 months in low SMD patients (HR 4.02; p = 0.0002). Multivariate analysis supported lower SMD's OS detriment (HR = 3.40; p = 0.002) independent of FLIPI-1 (HR 1.46-2.76, p = 0.05) or gender. Low SMD predicted lower ORR, 83 vs. 96% (p = 0.01). SMD predicts survival independent of FLIPI-1 and potentially chemoimmunotherapy response. SMD is an inexpensive and powerful tool that can complement FLIPI-1.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) have limited treatment options, particularly if they are transplantation or chimeric antigen receptor (CAR) T-cell ...ineligible, and novel therapeutics are needed. An 86-year-old woman with relapsed DLBCL received a novel, first-in-class small molecule inhibitor of N-myristoyltransferase (NMT) as the initial patient on a phase I dose escalation trial. Daily oral administration of 20 mg PCLX-001 tablets produced a pharmacokinetic profile suitable for single daily dosing: rapid oral absorption, followed by an apparent elimination half-life of 16 h, without systemic accumulation of drug by day 15. Pharmacodynamic tests showed no clear change in NMT1 and NMT2 levels or selected NMT substrate Lyn and HGAL protein levels in normal circulating blood mononuclear cells, suggesting a higher dose will be required for normal tissue toxicity. The patient did not experience any dose-limiting toxicities but had disease progression after 28 days of study therapy. Dose escalation continues in other patients in this first-in-human study of a new class of anticancer drug. We conclude that PCLX-001 oral monotherapy has suitable pharmacokinetic parameters for dose escalation, and that higher doses are required to achieve pharmacodynamic evidence of on-target activity in normal tissues. The current protocol is appropriately designed to achieve these ends, and the study proceeds without modification.
Background
Cancer is a systemic catabolic condition affecting skeletal muscle and fat. We aimed to determine whether cardiac atrophy occurs in this condition and assess its association with cardiac ...function, symptoms, and clinical outcomes.
Methods
Treatment naïve metastatic non‐small cell lung cancer patients (n = 50) were assessed prior to and 4 months after commencement of carboplatin‐based palliative chemotherapy. Methods included echocardiography for left ventricular mass (LVM) and LV function LV ejection fraction, global longitudinal strain (GLS), diastolic function, computed tomography to quantify skeletal muscle and total adipose tissue, Eastern Cooperative Oncology Group Performance Status (ECOG‐PS), validated questionnaires for dyspnoea and fatigue, plasma biomarkers, tumour response to therapy, and overall survival.
Results
During 112 ± 6 days, the median change in LVM was −8.9% 95% confidence interval (95% CI) −10.8 to −4.8, P < 0.001. Quartiles of LVM loss were −20.1%, −12.9%, −4.8%, and +5.5%. Losses of muscle, adipose tissue, and LVM were frequently concurrent; LVM loss > median value was associated with loss of skeletal muscle odds ratio (OR) = 4.5, 95% CI: 1.4–14.8, P=0.01 and loss of total adipose tissue (OR = 10.0, 95% CI: 2.7–36.7, P < 0.001). LVM loss was associated with decreased GLS (OR = 6.6, 95% CI: 1.9–22.7, P=0.003) but not with LV ejection fraction or diastolic function. In the population overall, plasma levels of C‐reactive protein (P=0.008), high sensitivity troponin T (hs‐TnT) (P=0.03), and galectin‐3 (P=0.02) increased over time, while N‐terminal pro B‐type natriuretic peptide and hs‐cTnI did not change over time. C‐reactive protein was the only biomarker associated with LVM loss but at the univariate level only. Independent predictors of LVM loss were prior weight loss (adjusted OR = 10.2, 95% CI: 2.2–46.9, P=0.003) and tumour progression (adjusted OR = 14.6, 95% CI: 1.4–153.9, P=0.02). LVM loss was associated with exacerbations of fatigue (OR = 6.6, 95% CI: 1.9–22.7, P=0.003), dyspnoea (OR = 9.3, 95% CI: 2.4–35.8, P<0.001), and deterioration of performance status (OR = 4.8, 95% CI: 1.3–18.3,P=0.02). Patients with concurrent loss of LVM, skeletal muscle, and fat were more likely to deteriorate in all three symptom domains and to have reduced survival (P=0.05).
Conclusions
Intense LVM atrophy is associated with non‐small cell lung cancer‐induced cachexia. Loss of LVM was associated with emerging alterations of GLS, indicating subtle changes in left ventricular function. Longer term studies are needed to assess the full scope of cardiac atrophy and its impact. LVM atrophy arises in conjunction with losses of fat and skeletal muscle and is temporally associated with meaningful declines in performance status, worsening of fatigue, and dyspnoea, as well as poorer tumour response and decreased survival. The specific contribution of LVM atrophy to these outcomes requires further study.
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