Patient experience of early high grade symptomatic adverse events on early phase clinical trials using the PRO-CTCAE.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 12051-12051
Author(s):  
Geoffrey Alan Watson ◽  
Zachary William Neil Veitch ◽  
Daniel Shepshelovich ◽  
Zhihui (Amy) Liu ◽  
Anna Spreafico ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Phase I ◽  
Early Phase ◽  
Daily Life ◽  
High Grade ◽  
Negative Experience ◽  
Patient Reported ◽  
Grade 3 ◽  
Early Phase Clinical Trials

12051 Background: There are limited data describing the patients’ experience of symptomatic adverse events (syAEs) on early phase clinical trials. This information is critical to understand the tolerability of experimental agents. The patient reported outcome version of the CTCAE (PRO-CTCAE) evaluates syAE components such as severity and interference in daily life. The aim of this study was to correlate clinician reported early, high grade (grade 3-4) AEs with patients’ reported experience of these toxicities. Methods: Advanced solid tumor patients (pts) enrolled on early phase clinical trials at Princess Margaret Cancer Centre were surveyed electronically using the full library of 78 items for PRO-CTCAE v1.0, which was administered at baseline (prior to therapy), mid-cycle 1, and mid-cycle 2. AEs on study were recorded by physicians using the CTCAE v4.0. Worst responses for severity items are ‘severe’ and ‘very severe’ and for interference items are ‘quite a bit’ and ‘very much’. A logistic regression model was used to assess the association between CTCAE grade and PRO-CTCAE severity and interference. Results: A total of 292 pts were approached in phase 1 clinics from May 2017 to January 2019, and 219 pts were included in the analysis: median age 60 years (range 18-82), 111 (51%) were male; all were ECOG ≤1. A total of 140 pts (64%) received combination therapy (immunotherapy and targeted therapy), and 73 pts (33%) had received ≥3 previous lines of treatment. In terms of patient reported syAEs, a total of 114 pts (52%) reported a symptomatic AE as either severe or very severe at any timepoint and 79 pts (36%) reported a syAE with an interference that was either ‘quite a bit’ or ‘very much’. With regards to clinician reported AEs, a total of 82 pts (37%) had a clinician reported grade 3 or 4 syAE, and of these 34 pts (41%) reported these as either severe or very severe; and 26 pts (32%) found these AEs interfered with daily life either ‘quite a bit’ or ‘very much’. Additionally 137 pts (66%) had a clinician reported grade 1 or 2 syAE, and of these 39 pts (28%) reported these as either severe or very severe; and 19 (14%) found these AEs interfered with daily life either ‘quite a bit’ or ‘very much’. Higher grade clinician reported syAEs (CTCAE grade 3-4 vs 1-2) was associated with higher patient reported severity levels (odds ratio, OR = 1.78, 95% CI 1-3.16, p = 0.049), and was associated with higher patient reported interference levels (OR = 2.88, 95% CI 1.47-5.64, p = 0.002). Conclusions: A majority of patients had a very negative experience of syAEs on a phase I trial. Higher grades of clinician reported AEs correlated with greater severity and interference with daily living. Future phase I studies could incorporate the PRO-CTCAE and other PRO tools which could inform the tolerability of experimental regimens and enhance the description of symptomatic AEs.

scholarly journals Efficacy and Safety of Histone Deacetylase Inhibitors in Multiple Myeloma - a Systematic Review of Early Phase Clinical Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5629-5629
Author(s):  
Sharoon Samuel ◽  
Muhammad Junaid Tariq ◽  
Muhammad Usman ◽  
Amna Khalid ◽  
Muhammad Asad Fraz ◽  
...  
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
Adverse Events ◽  
Phase I ◽  
Hdac Inhibitors ◽  
Complete Response ◽  
Number Of Patients ◽  
Grade 3 ◽  
Early Phase Clinical Trials

Abstract Introduction Recent studies in novel therapies have created opportunities for new treatment regimens to be used in the management of multiple myeloma. Histone deacetylase (HDAC) inhibitors lead to epigenetic manipulation of multiple myeloma (MM) cells by reducing resistance to pro-apoptotic signals. Panobinostat is an FDA approved HDAC inhibitor for multiple myeloma. The aim of this article is to study the safety, efficacy and dose limiting toxicities of HDAC inhibitors in the early phase clinical trials in multiple myeloma. Methods We performed a comprehensive literature search for phase I & I/II trials of HDAC inhibitors during last ten years using following databases: PubMed, Embase, AdisInsight, and Clinicaltrials.gov. Studies involving HDAC inhibitors in multiple myeloma other than panobinostat irrespective of the age, sex or specific eligibility criteria were included. Results Out of 2537 studies, we included 25 trials (23 phase I, 2 phase I/II) of HDAC inhibitors in this systematic review having a total of 518 patients. Of these, 471(90.9%) patients were evaluable for response. Vorinostat (Vor) is the most studied drug used in 13 trials (n=281). Two trials had Vor-only regimen and the remaining 11 had combination regimens mostly with lenalidomide and bortezomib. Vor, in combination with lenalidomide (R), bortezomib (V) and dexamethasone (d) has showed 100% overall response rate (ORR) in 30 newly diagnosed multiple myeloma (NDMM) patients, (Kaufmann et al., 2016), fifty two percent patients achieved very good partial response (VGPR) and 28% patients showed complete response (CR). Another study using Vor + R regimen after autologous stem cell transplant in 16 NDMM patients showed VGPR in 7, stringent complete response (sCR) in 4, partial response (PR) in 2 and CR in 3 patients (Sborov et al.). Grade 3 neutropenia was seen in 1 patient in this study. Richter et al, 2011 showed an ORR of 24% in 29 relapsed refractory multiple myeloma (RRMM) patients with Vor only regimen. Another study (Kaufmann et al., 2012) with Vor only regimen used in 10 RRMM patients showed stable disease (SD) in 9 and minimal response (MR) in 1 patient. ORR of 65% was achieved in 31 RRMM patients receiving Vor in combination with doxorubicin & bortezomib (Vorhees et al, 2017). Thrombocytopenia & neutropenia were reported in 94% and 59% patients respectively. Ricolinostat in combination with Rd and Vd achieved an ORR of 55% and 29% respectively in two studies with 38 and 57 evaluable patients (NCT01583283, NCT01323751). Another ricolinostat regimen with pomalidomide & dexamethasone achieved ≥PR in 6/11 RRMM patients (Madan et al., 2016). Table 1 illustrates the efficacy, number of patients and regimens used in all the studies in this systematic review. Quisinostat in a 2017 study by Moreau P et al. (NCT01464112) showed an ORR of 88% in a combination regimen with Vd in RRMM patients (N=18). Drug related adverse events were seen in 13 patients, thrombocytopenia being most common in 11 patients, 2 patients had grade 3 cardiac disorders and 1 patient had a cardiac arrest. Romidepsin in a phase I/II study (Harrison et al., 2011) combined with Vd was used in 25 RRMM patients. ORR was 60% with VGPR n=7, CR n=2, PR n=6, SD n=5 and PD n=1. Grade ≥3 thrombocytopenia in 16, neutropenia in 9 and peripheral neuropathy in 2 patients was seen. Popat et al used combination of two HDAC inhibitors CHR 3996 and tosedostat in 20 RRMM patients. ORR was 10% and SD was seen in 30% patients. Grade 3/4 toxicities seen were thrombocytopenia (n=12), leukopenia (n=6) and diarrhea (n=5). A phase I study on AR-42 drug in 17 RRMM patients (Sborov et al., 2017) showed SD in 10, PD in 4, MR in 3 patients with progression free survival (PFS) of 8.2 months. Thrombocytopenia, neutropenia and lymphopenia were seen in 11, 10 and 6 patients respectively. A detail of all grade 3 and higher adverse events along with dose limiting toxicity is given in table 2. Three trials (NCT02576496, NCT01947140, NCT03051841) of Edo-S101, romidepsin and CKD-581 are currently recruiting with 84, 93 and 18 planned number of patients. Conclusion Regimens containing vorinostat have shown an ORR up to 100% in NDMM patients. HDAC inhibitors have also shown promising efficacy up to 88% ORR in RRMM population. Majority of the patients developed cytopenias as hematological adverse events. Disclosures No relevant conflicts of interest to declare.

Immuno-oncology and the elderly: A comparative analysis of participation and toxicities of senior adults aged 65 years and above vs mid age and adolescent/young adult patients on immunotherapy-based phase I clinical trials.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10034-10034
Author(s):  
Ishwaria Mohan Subbiah ◽  
Kenneth R. Hess ◽  
Takeo Fujii ◽  
Anas Alshawa ◽  
Anna Lui ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Young Adult ◽  
Adverse Events ◽  
Phase I ◽  
Early Phase ◽  
Low Grade ◽  
Phase I Trials ◽  
High Grade ◽  
Senior Adults ◽  
Phase I Clinical Trials

10034 Background: Senior adults ≥ 65 yrs remain underrepresented in early phase clinical trials in particular trials with novel immunotherapies. One general limitation to enrollment is the concern for immune-related toxicities in the context of older age and comorbidities. We analyzed the enrollment and incidence of toxicities of seniors in comparison to mid age and adolescent/young adult (AYA) pts enrolled in phase 1 immunotherapy trials. Methods: We identified 422 consecutive pts w advanced cancer treated on immunotherapy-based phase I trials bw 04/2009-09/2015. We divided pts into 3 cohorts based on age at start of trial (AYA 15-39y, mid age 40-64y, seniors 65y+) and collected pt/disease characteristics and immune-related adverse events (irAE) including endocrinopathies, diarrhea/colitis, pneumonitis, constitutional (eg fatigue, fever, anorexia), myalgia, and dermatitis. Results: Of 422 patients treated, 116 were seniors (27%, median 70y), 50 AYA (12%, median 30y), 256 mid age (61%, median 56y). Most common cancers were GI (n = 108, 26%), thoracic/head/neck (n = 84, 20%), GU (n = 54, 13%), and GYN (n = 47, 11%). Median PFS was comparable in all 3 cohorts (2.4m seniors, 2.1m AYA, 2.1m mid age). The incidence of irAE was higher in elderly than mid age or AYA (low grade [G1/2] 49% vs 34% vs 34%, p 0.02; high grade [G3/4] 19% vs 11% vs 12%. p 0.14). When comparing irAE rates of seniors to AYA and mid age pts, the odds ratio of high grade events was 1.81 (95% CI 1.01, 3.24; p 0.05) and low grade events was 1.85 (95% CI 1.20, 2.85; p 0.0055). Most common G1/2 irAE among all cohorts was fatigue (n = 76, 18%), dermatitis (n = 59, 14%), fever (n = 29, 7%) and anorexia (n = 28, 7%) with seniors having a greater incidence of low grade fatigue (25% vs 15%, OR 1.84, 95% CI 1.09, 3.10, p 0.025). Conclusions: Senior adults accounted for < 1/3 of pts on immunotherapy-based phase I trials. When compared to mid age and AYA pts, seniors had a higher likelihood of experiencing a toxicity. Early phase immunotherapy trials may be an option for older adults but with a particular vigilance for adverse events in this population.

scholarly journals P05.08 High-grade gliomas and immunotherapeutic early phase clinical trials: a single-center experience

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii35-iii36
Author(s):  
M Simonelli ◽  
P Persico ◽  
A Dipasquale ◽  
E Lorenzi ◽  
L Giordano ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Early Phase ◽  
Univariate Analysis ◽  
Methylation Status ◽  
High Grade ◽  
Clinical Factors ◽  
Lymphocyte Ratio ◽  
High Grade Gliomas ◽  
Early Phase Clinical Trials

Abstract BACKGROUND Patients with high-grade gliomas (HGGs) have historically been excluded from immunotherapeutic early-phase clinical trials (ieCTs) due to unavailability of serial bioptic sampling, the frequent need of corticosteroids, concerns regarding activity of immunotherapy in central nervous system, and rapid clinical deterioration. MATERIAL AND METHODS We retrospectively reviewed data of all recurrent HGG patients enrolled in ieCTs at Humanitas Cancer Center Phase I Unit between 2014 and 2019. Disease control rate (DCR) according to RANO criteria, six-months progression-free and overall survival (PFS-6; OS-6), and treatment-related adverse events (TRAEs), were evaluated. A control-cohort (CC) of patients treated with standard treatments (temozolomide, fotemustine, lomustine and procarbazine, bevacizumab) matched (1:1) for sex, age, line of treatment, MGMT methylation status, and IDH mutational status, was selected for comparison. A series of clinical parameters with an established prognostic value for patients with solid tumors treated into ieCTs were correlated with survivals through an univariate analysis. These include: use of steroids, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, lactate dehydrogenase, albumin, total protein. RESULTS Five among the 23 ieCTs conducted at our Phase I Unit allowed inclusion of HGG patients. 25 patients were enrolled in the experimental cohort (EC): 22 (88%) glioblastoma, 3 (12%) anaplastic astrocytoma. Median age was 50 years (range 25–71); 16 patients (64%) were men, 9 (36%) women; 17 pts (68%) required steroid therapy, with a median baseline dexamethasone dose of 2 mg (range 1–6). The median number of prior systemic therapies was 1 (range 1–2). Twelve patients (48%) received monotherapies (anti PD-1, anti CSFR-1, anti TGF-ß, anti cereblon), 13 (52%) combination regimens (anti PD-L1 + anti CD38, anti PD-1 + anti CSFR-1). DCR was 40% (1 CR + 2 PR + 7 SD) and 37% (9 SD), in EC and CC, respectively. Four patients (16%) in EC had grade ≥3 TRAEs (1 neutropenia, 1 pneumonia, 2 hepatitis). With a median follow-up of 14 months PFS-6 were 35% and 16% (p=0.075), in EC and CC respectively, while OS-6 was significantly improved in the EC (82% vs 44%, p=0.004). In our small series, none of clinical factors resulted prognostic. CONCLUSION Survival outcomes of ourHGG patients treated into ieCTs compared very favorably with a matched CC. Inclusion of HGGs patients into ieCTs should be strongly encouraged. Identification of clinical factors to select who may benefit from ieCTs still remains crucial.

Association of serious adverse events with type and sponsorship of clinical trials in patients with lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6576-6576
Author(s):  
T. L. Koeneke ◽  
J. O. Armitage ◽  
P. J. Bierman ◽  
R. Bociek ◽  
J. M. Vose ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Phase I ◽  
Phase Ii ◽  
Medical Center ◽  
Stage Iv ◽  
Large Cell ◽  
Phase Iii ◽  
Serious Adverse Events ◽  
Early Phase Clinical Trials

6576 Background: Arguments have been made against early phase clinical trials (CTs) as possibly being unethical because its risk may outweigh its potential benefits. Whether this is true in the light of newer biological treatment for cancer is unknown. We therefore examined the association between the incidence of serious adverse events according to type and sponsorship of CTs in pts with lymphoma. Methods: All IRB approved CTs at the University of Nebraska Medical Center from Jan 2000-June 2005 classified as therapeutic for lymphoma involving a biological agent were included. CTs were classified in two ways: by type of CTs (phase I vs II vs III) and sponsorship (Investigator-initiated vs Industry-initiated. Multivariate logistic regression was used to evaluate the association between types/sponsorship of CTs with the incidence of IRB serious adverse events (SAE; no vs yes) and fatal adverse events (FAE; no vs yes) while adjusting for age, sex, race, lymphoma type and stage, interval from dx to tx, co-morbid conditions, and previous tx. Results: 357 pts with lymphoma enrolled in 29 CTs were included. The median age of pt was 54y (21–88). 41% of the pts had follicular lymphoma, 36% diffuse large cell, 14% mantle cell and 9% were other types. 59% had Stage IV lymphoma. 71% of the pts participated in investigator-initiated CTs, while 29% participated in industry-initiated CTs. 21% of pts were enrolled in phase I, 65% in phase II and 14% in phase III studies. SAEs were seen in 49 pts (14%), while FAEs occurred in 13 pts (4%). Multivariate analysis showed the risk of having SAE was independent of the type or sponsor of CTs. Additionally, the risk of FAEs was not associated with the type of CTs. However, the risk of having FAEs was less in investigator- iniatiated CTs than in industry-iniatiated trials (Odds Ratio: 0.13 (95% CI, 0.03–0.61, p = 0.01). Conclusions: Our study showed that in CTs involving biological treatments, the incidence of SAEs was not associated with the type or sponsor of CTs suggesting that use of biological agents in phase I studies may have similar risks to phase II/III trials. Further studies should be done in other types of malignancies to evaluate further the decrease frequency of FAEs seen in investigator-initiated trials. No significant financial relationships to disclose.

scholarly journals Phase I prognostic online (PIPO): A web tool to improve patient selection for oncology early phase clinical trials

2021 ◽  
Vol 155 ◽  
pp. 168-178
Author(s):  
Ignacio Matos ◽  
Guillermo Villacampa ◽  
Cinta Hierro ◽  
Juan Martin-Liberal ◽  
Roger Berché ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Patient Selection ◽  
Early Phase ◽  
Web Tool ◽  
Improve Patient Selection ◽  
Selection For ◽  
Early Phase Clinical Trials ◽  
Improve Patient

A pilot study of the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) in a phase I clinical trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6587-6587 ◽  
Author(s):  
Rui Qin ◽  
Amylou C. Dueck ◽  
Daniel Satele ◽  
Julian R. Molina ◽  
Charles Erlichman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Pilot Study ◽  
Adverse Events ◽  
Phase I ◽  
Patient Reported Outcomes ◽  
Point Of View ◽  
Phase I Clinical Trial ◽  
Phase I Clinical Trials ◽  
Patient Reported

6587 Background: Recently the Patient-Reported Outcomes version of the CTCAE was developed to augment clinically graded adverse events with information reported directly by patients on clinical trials (Basch, 2009). The validation and potential application of PRO-CTCAE in phase I clinical trials are of great interest as toxicity is the primary endpoint. Methods: Selected PRO-CTCAE items (21 items measuring 12 symptomatic adverse events) corresponding to the major adverse events required to be graded clinically were collected in an ongoing phase I clinical trial of weekly cilengitide and paclitaxel in patients with advanced solid malignancies (NCT01276496). PRO-CTCAE was administered in a paper booklet by a clinical research associate prior to treatment on days 1, 8 and 15 of their regular visits. These PRO-CTCAE items were summarized descriptively in comparison to clinician-assessed CTCAE ver 4.0 (NCI, 2009) during the first cycle. As a pilot study to assess feasibility of PRO-CTCAE in phase I trials, PRO-CTCAE was not intended for determination of dose-limiting toxicity. Results: Twelve patients were accrued to two separate doses of cilengitide and paclitaxel. The median age was 56 (range 36—67) and half of patients were female. All patients had an ECOG performance score <= 1. Over 90% of patients had received prior surgery and chemotherapy. All but one patient completed weekly PRO-CTCAE during the first cycle, the only patient refused to complete weeks 2 and 3 did not give a reason. PRO-CTCAE captured most of the symptomatic adverse events reflected in clinician-assessed CTCAE. Some symptomatic adverse events were not reported clinically by CTCAE but were reported by patients by PRO-CTCAE. Overall, PRO-CTCAE items indicated slightly more severe degree of symptoms experienced by patients than those reported in CTCAE. Conclusions: This is the first study that PRO-CTCAE items were integrated within regular study visits in a phase I trial. The administration of PRO-CTCAE has been proved feasible and fruitful, providing consistent and enhanced symptomatic toxicity from the patient point of view. The addition of PRO-CTCAE did not significantly increase patient burden. Clinical trial information: NCT01276496.

scholarly journals Outcome of high-grade gliomas (HGGs) treated into immunotherapeutic early-phase clinical trials (ieCTs): A single-center experience

2019 ◽  
Vol 30 ◽  
pp. v155-v156
Author(s):  
M. Simonelli ◽  
P. Persico ◽  
A. Dipasquale ◽  
E. Lorenzi ◽  
L. Giordano ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Early Phase ◽  
High Grade ◽  
Single Center ◽  
Single Center Experience ◽  
High Grade Gliomas ◽  
Early Phase Clinical Trials

scholarly journals Patient (pt) selection for immunotherapeutic early-phase clinical trials (ieCTs): A single phase I unit experience

2019 ◽  
Vol 30 ◽  
pp. v186
Author(s):  
M. Simonelli ◽  
E. Lorenzi ◽  
A. Dipasquale ◽  
P. Persico ◽  
G. Ninatti ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Early Phase ◽  
Single Phase ◽  
Selection For ◽  
Early Phase Clinical Trials
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