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

3088 Background: We studied clinical and radiological parameters influencing DIP in patients (pts) participating in phase I clinical trials, aiming to investigate predictive factors affecting DIP, in particular those affecting outcome. Methods: 2439 consecutive stage IV cancer pts on phase I clinical trials from 2007 to 2017 were identified. Pts with respiratory symptoms or abnormal lung imaging were reviewed in detail, with longitudinal analysis of imaging by an experienced radiologist. R-DIP was categorized according to internationally recognized criteria. Results: 60 pts developed R-DIP (overall incidence 2.5%); most frequent in pts receiving drug conjugates (31.1%) followed by targeted therapies (8.3%). Hypersensitivity pneumonitis was most common (33.3%) followed by non-specific interstitial pneumonitis (30%) and cryptogenic organising pneumonitis (26.7%). 45% pts who developed R-DIP were clinically asymptomatic. The number of affected lobes (OR 1.47, 95% CI: 1.19-1.81, p < 0.001) and the pattern of R-DIP (OR 5.83 for ARDS, 95% CI: 0.38-90.26, p = 0.002) were significantly associated with a higher CTCAE pneumonitis grading. 23% pts (14/60) had investigational medicinal product (IMP) temporarily discontinued or had a dose reduction while 42% pts (25/60) had IMP permanently discontinued. 48% pts were treated with steroids. The number of affected lobes, pattern of R-DIP and steroid therapy did not influence an improvement in R-DIP (p = 0.65, 0.27 and 0.23 respectively). Continuation of treatment resulted in worsening of DIP in 42.9% of cases. The only predictive factor for an improvement in DIP was an interruption of treatment (OR 0.05, 95% CI: 0.01-0.35, p = 0.01). 14 pts were retreated with a reoccurrence of R-DIP in 4 pts (28.6%). Conclusions: R-DIP from novel agents in early phase clinical trials presents in varied radiological patterns, with findings often preceding clinical symptoms. Treatment interruption leads to improvement of DIP and should be considered early. Close clinical and radiological surveillance is recommended should IMP be restarted.

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

Neuro-Oncology ◽

10.1093/neuonc/noz126.122 ◽

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.

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Utility of ctDNA to support patient selection for early phase clinical trials: the TARGET study

Nature Medicine ◽

10.1038/s41591-019-0380-z ◽

2019 ◽

Vol 25 (5) ◽

pp. 738-743 ◽

Cited By ~ 66

Author(s):

Dominic G. Rothwell ◽

Mahmood Ayub ◽

Natalie Cook ◽

Fiona Thistlethwaite ◽

Louise Carter ◽

...

Keyword(s):

Clinical Trials ◽

Patient Selection ◽

Early Phase ◽

Selection For ◽

Early Phase Clinical Trials

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Therapeutic outcome of early-phase clinical trials in multiple myeloma: a meta-analysis

Blood Cancer Journal ◽

10.1038/s41408-021-00441-3 ◽

2021 ◽

Vol 11 (3) ◽

Author(s):

Niels van Nieuwenhuijzen ◽

Rowan Frunt ◽

Anne M. May ◽

Monique C. Minnema

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

Phase I ◽

Phase Ii ◽

Early Phase ◽

Meta Analysis ◽

Cochrane Library ◽

Phase I Trials ◽

Phase Ii Trials ◽

Early Phase Clinical Trials

AbstractGreat progress in the treatment of patients with multiple myeloma (MM) has been made due to the development of novel drugs. Patients with relapsed/refractory MM (RRMM) can be enrolled in early-phase clinical trials, but their performance across the last decade is unknown. We conducted a meta-analysis on the overall response rate (ORR) and toxicity. PubMed, Embase, and Cochrane Library were systematically searched for phase I and phase II trials investigating an experimental compound as a single agent or in combination with dexamethasone, published from January 1, 2010 to July 1, 2020. Eighty-eight articles were included, describing 61 phase I trials involving 1835 patients and 37 phase II trials involving 2644 patients. There was a high degree of heterogeneity. Using a random-effects model, the 95% CIs of the estimated ORR were 8–17% for phase I trials and 18–28% for phase II trials. There were significant subgroup differences in ORR between the years of publication in phase I trials and between drug classes in both phase I and phase II trials. The ORR in early-phase clinical trials in RRMM is substantial, especially in phase II trials, but due to high heterogeneity a general assessment of clinical benefit before participation is difficult to offer to patients.

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A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia

Pediatric Blood & Cancer ◽

10.1002/pbc.26351 ◽

2016 ◽

Vol 64 (6) ◽

pp. e26351 ◽

Cited By ~ 9

Author(s):

B. Vormoor ◽

G. J. Veal ◽

M. J. Griffin ◽

A. V. Boddy ◽

J. Irving ◽

...

Keyword(s):

Clinical Trials ◽

Acute Leukemia ◽

Phase I ◽

Early Phase ◽

Aurora Kinase ◽

Selective Inhibitor ◽

Early Phase Clinical Trials

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

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.12051 ◽

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.

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