Clinical Predictors of Early Trial Discontinuation for Patients Participating in Phase I Clinical Trials in Oncology

Despite stringent eligibility criteria for trial participation, early discontinuation often occurs in phase I trials. To better identify patients unlikely to benefit from phase I trials, we investigated predictors for early trial discontinuation. Data from 415 patients with solid tumors who participated in 66 trials were pooled for the current analysis. Early trial discontinuation was defined as (i) trial discontinuation within 28 days after start of treatment or (ii) discontinuation before administration of the first dosage in eligible patients. Multilevel logistic regression analyses were conducted to identify predictors for early trial discontinuation. Eighty-two participants (20%) demonstrated early trial discontinuation. Baseline sodium level below the lower limit of normal (OR = 2.95, 95%CI = 1.27–6.84), elevated alkaline phosphatase level >2.5 times the upper limit of normal (OR = 2.72, 95%CI = 1.49–4.99), performance score ≥ 1 (OR = 2.07, 95%CI = 1.03–4.19) and opioid use (OR = 1.82, 95%CI = 1.07–3.08) were independent predictors for early trial discontinuation. Almost 50% of the patients with hyponatremia and all four patients in whom all four predictors were present together discontinued the trial early. Hyponatremia, elevated alkaline phosphatase level, performance score ≥1 and opioid use were identified as significant predictors for early trial discontinuation. Hyponatremia was the strongest predictor and deserves consideration for inclusion in eligibility criteria for future trials.

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Case 14.26

Mayo Clinic Body MRI Case Review ◽

10.1093/med/9780199915705.003.0381 ◽

2014 ◽

pp. 723-724

Author(s):

Christine U. Lee ◽

James F. Glockner

Keyword(s):

Alkaline Phosphatase ◽

Bone Scintigraphy ◽

Prostate Carcinoma ◽

Alkaline Phosphatase Level ◽

Elevated Alkaline Phosphatase ◽

Pelvic Mri ◽

Axial Diffusion ◽

Diffusion Weighted Images ◽

Vertebral Bodies ◽

Ct Contrast

64-year-old man with recently diagnosed prostate carcinoma and elevated alkaline phosphatase level; abdominal pelvic MRI was requested to screen for metastases in this patient with a severe allergy to iodinated CT contrast Axial diffusion-weighted images (b=800 s/mm2) (Figure 14.26.1) reveal multiple small hyperintense lesions involving lower thoracic and lumbar vertebral bodies, bilateral ribs, and the left iliac bone. Anterior and posterior views from bone scintigraphy (...

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Smartphone measurements of physical activity and fitness are associated with early trial discontinuation of patients in (hemato)oncology phase I/II clinical trials

Supportive Care in Cancer ◽

10.1007/s00520-020-05902-2 ◽

2020 ◽

Author(s):

Joeri A. J. Douma ◽

Sonja Zweegman ◽

Mieke Alberts ◽

Sandy Kruyswijk ◽

Niels C. W. J. van de Donk ◽

...

Keyword(s):

Physical Activity ◽

Clinical Trials ◽

Physical Fitness ◽

Phase I ◽

Walking Distance ◽

Optimal Cutoff ◽

Early Trial ◽

Cutoff Values ◽

Steps Per Day ◽

Trial Discontinuation

Abstract Background Patients, who discontinue early, do not benefit from phase I/II clinical trials (early-phase clinical trials (EPCT)). In this study, associations between objective smartphone measurements of physical activity and fitness and early trial discontinuation in patients with cancer participating in EPCT were investigated. Methods Before start of treatment, physical activity (steps/day) and physical fitness (meters walked in 6 min) were measured with a smartphone, and patient-reported physical function (PRO-PF) was assessed (EORTC QLQ-C30-PF). Early trial discontinuation was defined as discontinuation ≤ 28 days. Univariable logistic regression analyses were performed to study associations of physical activity, fitness, and function with early trial discontinuation. Optimal cutoff values of physical activity and fitness were assessed with ROCs, based on positive predictive values (PPV). Results Median (interquartile range (IQR)) step count was 4263 (2548–6897) steps/day, mean ± standard deviation 6-min walking distance was 477 ± 120 m and median (IQR) PRO-PF score was 83 (67–95) points. Fourteen patients (12%) discontinued the trial early. Smartphone measurements of physical activity in units of 100 steps per day (odds ratio (OR) = 0.96, 95% CI = 0.94–0.99, p = 0.01), physical fitness (OR = 0.99, 95% CI = 0.98–0.99, p < 0.01), and PRO-PF (OR = 0.97, 95% CI = 0.94–1.00, p = 0.03) were associated with early trial discontinuation. Optimal cutoff values were < 900 steps for physical activity and < 285 m for physical fitness. PPV for early trial discontinuation was 100% in patients who walked both < 1500 steps per day and < 300 m in 6 min. Conclusions Objective smartphone measurements of physical activity and fitness are associated with early trial discontinuation. However, cutoff values should be externally validated in a larger cohort before implementation in clinical practice.

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Characteristics and outcome of patients (pts) enrolled on phase I trials: A report from the Pediatric Oncology Branch, NCI

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.9550 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 9550-9550

Author(s):

A. Kim ◽

E. Fox ◽

K. Warren ◽

S. Blaney ◽

S. Berg ◽

...

Keyword(s):

Multivariate Analysis ◽

Phase I ◽

Performance Status ◽

Median Number ◽

Maximum Tolerated Dose ◽

Drug Dose ◽

Cell Transplant ◽

Phase I Trials ◽

Eligibility Criteria ◽

Increased Risk

9550 Background: Knowledge of the characteristics and outcomes of pts enrolled on pediatric phase I trials may aid in the design of future phase I trials and selection of pts. Methods: Pre-enrollment characteristics and treatment outcomes (toxicity, response, survival) were retrospectively analyzed from pts with refractory solid tumors enrolled in 16 phase I trials with similar eligibility criteria from 1992 to 2005. The relationship between patient characteristics and dose-limiting toxicity (DLT) was evaluated using multivariate analysis. Results: Of 262 pts (62% M, 38% F) eligible for analysis, 147 were on trials of myelosuppressive drugs (MS) and 115 were enrolled on trials of non-MS. 50 pts (19%) participated in =2 separate trials. Median (range) or (frequency) entry characteristics were: age 13.5 yrs (1–24); ECOG performance score 0 (30%), 1 (50%), 2 (19%); prior regimens 2 (0–9); prior stem cell transplant (20%); prior radiation (66%); concomitant medications 1 (0–12); and presence of metastatic disease (65%). 94% of pts were evaluable for the primary trial outcome, and 92% participated in pharmacokinetic (PK) studies. 17% of pts had grade 3 as their highest-grade toxicity. 22% of pts had grade 4 as their highest-grade toxicity, of which 91% were hematological. DLT rate was 18%. 5% of pts came off study due to toxicity, and treatment related death occurred in 0.3%. Age, prior radiation, medications, prior regimens, performance status, gender, transplant history, and drug dose expressed as a fraction of the maximum tolerated dose were included in the multivariate analysis. Only drug dose (OR 14.2, 95% CI 3.0–67.8) and prior radiation (OR 3.4, 95% CI 1.1–10.7) were statistically significantly associated with increased risk of developing DLT after adjusting for all other variables. The median number of cycles was 1 (range 0–31). Complete and partial response rate was 3%, however, 18% of pts had stable disease (received = 3 cycles). The median survival (Kaplan Meier analysis) from time of enrollment was 5 months. Conclusion: Standard phase I eligibility criteria selected a population of pts who tolerated the investigational agents well and >90% were evaluable for the toxicity and PK endpoints. Prior radiation was associated with a greater risk for DLT. No significant financial relationships to disclose.

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Re-evaluating eligibility criteria: Analysis of factors leading to nonparticipation and outcomes of patients (pt) with advanced cancer who signed consent but were not treated in early-phase immunotherapy (IO) trials.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2552 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2552-2552

Author(s):

Roberto Carmagnani Pestana ◽

Ishwaria Mohan Subbiah ◽

Kenneth R. Hess ◽

Le Huang ◽

Shuang Liu ◽

...

Keyword(s):

Phase I ◽

Advanced Cancer ◽

Early Phase ◽

Detailed Examination ◽

Median Number ◽

Phase I Trials ◽

Eligibility Criteria ◽

Alternate Therapy ◽

Modifiable Factors ◽

Metastatic Sites

2552 Background: Eligibility criteria protect the safety of trial pt and delineate the study population. Excessively restrictive criteria, however, can negatively impact accrual and prevent access to beneficial investigational treatments. Recently, ASCO issued a statement on the need to broaden eligibility criteria and make trials more representative. We aim to characterize the factors leading to non-participation and the outcomes of pt who signed consent for phase I IO trials but ultimately did not receive any therapy on that trial. Methods: We identified 696 consecutive pt w/ advanced cancer who consented to participate on IO phase I trials from 10/2015-12/2017, and collected pt characteristics as well as clinical outcomes, and compared participants (P) to non-participants (NP). Results: Among the 696 pt who initially consented to participate on IO phase I trials, 178 (25.6%) were never treated. Median age was 60 in both groups, and there were no differences regarding median number of metastatic sites (n = 2 vs 2 ) or sex distribution (F 53% vs 54%); NP had received less lines of therapy (median = 3 vs 4, p = 0.016). Reasons for non-participation were: 48 (26%) alternate therapy (for 18, geography was the main reason), 29 (16%) clinical progression/ decline in PS, 14 (8%) did not have enough biopsy tissue, 13 (7%) new lab abnormality, 11 (6%) new brain mets, 63 (35%) had other reasons (death, concurrent medications, financial factors). Median time from signature of consent to final exclusion of trial was 19 days (0-82). 54 of NP eventually enrolled in other trial, including 29 in immunotherapy trial. Median overall survival (OS) was significantly lower for NP vs P (median 6.9 vs 18.0, HR 0.5; p < .0001). Conclusions: One quarter of patients who signed consent for early-phase immunotherapy trials were unable to start on study. NP had significantly decreased OS. Detailed examination of these reasons can lead to recognition of modifiable factors and streamline the pretrial period, to guarantee this vulnerable population has maximal access to start therapy on study.

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Revisiting Risk and Benefit in Early Oncology Trials in the Era of Precision Medicine: A Systematic Review and Meta-Analysis of Phase I Trials of Targeted Single-Agent Anticancer Therapies

JCO Precision Oncology ◽

10.1200/po.20.00214 ◽

2021 ◽

pp. 17-26

Author(s):

Michael P. Mackley ◽

Nicholas R. Fernandez ◽

Benjamin Fletcher ◽

Christy G. Woolcott ◽

Conrad V. Fernandez

Keyword(s):

Phase I ◽

Targeted Therapies ◽

Response Rate ◽

Single Agent ◽

Objective Response ◽

P Value ◽

Phase I Trials ◽

Eligibility Criteria ◽

Tumor Types ◽

Single Tumor

PURPOSE Phase I trials are a crucial step in the evaluation of new cancer therapies. Historically, low rates of response (5%) and comparably high rates of death from toxicities (0.5%) have contributed to debates on the ethics and orientation of these trials. With the introduction of novel targeted therapies, a contemporary estimate is needed. METHODS We systematically searched PubMed, Embase, and ClinicalTrials.gov for reports of phase I oncology trials of single-agent targeted immunomodulators, molecularly targeted therapies, and antiangiogenic agents, published between January 2015 and July 2018. Adult and pediatric trials of solid and hematological malignancies were eligible. Treatment-related adverse events (grades 3, 4, and 5) and response rates (objective, complete, and partial) were extracted and analyzed. RESULTS One hundred and fifty-eight trial reports, covering 6,707 patients, were included. The rate of treatment-related deaths was 0.0% (95% CI, 0.0 to 0.1), while 13.2% of patients (9.5 to 17.3) experienced a grade 3 or 4 treatment-related toxicity. The combined objective response rate was 6.4% (4.6 to 8.5). Among trials using tumor biomarkers as eligibility criteria, the objective response rate was higher (12.0% [7.3 to 17.6] compared to 4.9% [2.5 to 5.7], P value < .01). The same was true of trials focusing on a single tumor type (13.4% [8.2 to 19.4]) compared to multiple tumor types (3.8% [2.5 to 5.3], P value < .01). CONCLUSION Reduced grade 5 risk and improved benefit appears to exist in modern phase I oncology trials, particularly in trials that target single tumor types and integrate biomarkers as eligibility criteria. These findings provide information to support informed consent discussions, highlight the need for improved reporting of phase I oncology trials, and provide direction for optimizing their design.

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Predictors for early trial discontinuation of patients with cancer participating in phase I clinical trials

Annals of Oncology ◽

10.1093/annonc/mdz244.058 ◽

2019 ◽

Vol 30 ◽

pp. v187 ◽

Cited By ~ 1

Author(s):

J.A.J. Douma ◽

L.M. Buffart ◽

M. Labots ◽

C.W. Menke-van derHouven van Oordt ◽

M. Skardhamar ◽

...

Keyword(s):

Clinical Trials ◽

Phase I ◽

Phase I Clinical Trials ◽

Patients With Cancer ◽

Early Trial ◽

Trial Discontinuation

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A 31‐Year‐Old Man With A Fungal Infection, Elevated Alkaline Phosphatase Level, and Polyarthritis

Arthritis Care & Research ◽

10.1002/acr.23812 ◽

2020 ◽

Vol 72 (5) ◽

pp. 601-606 ◽

Cited By ~ 1

Author(s):

Talha Khawar ◽

Carsten R. Hamann ◽

Arezoo Haghshenas ◽

Allie Blackburn ◽

Karina D. Torralba

Keyword(s):

Alkaline Phosphatase ◽

Fungal Infection ◽

Alkaline Phosphatase Level ◽

Elevated Alkaline Phosphatase

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Conduct of phase I trials in children with cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.3.966 ◽

1998 ◽

Vol 16 (3) ◽

pp. 966-978 ◽

Cited By ~ 69

Author(s):

M Smith ◽

M Bernstein ◽

W A Bleyer ◽

J D Borsi ◽

P Ho ◽

...

Keyword(s):

Phase I ◽

Phase Ii ◽

Maximum Tolerated Dose ◽

Primary Objective ◽

Phase I Trials ◽

Phase Ii Trials ◽

Children With Cancer ◽

Eligibility Criteria ◽

New Agents ◽

Childhood Malignancies

PURPOSE AND METHODS: Future progress in the care of children with cancer requires appropriate evaluations of promising new agents for pediatric indications, beginning with well-conducted phase I trials. This report summarizes current guidelines for the conduct of pediatric phase I trials and represents a consensus between American and European investigators. The primary objective of pediatric phase I trials is to define safe and appropriate doses and schedules of new agents that can subsequently be used in phase II trials to test for activity against specific childhood malignancies. Prioritization of agents for evaluation in children is critical, since many more investigational agents are evaluated in adult patients than can be systematically evaluated in children. Considerations used in prioritizing agents include activity in xenograft models, novel mechanism of action, favorable drug-resistance profile, and activity observed in adult trials of the agent. RESULTS AND CONCLUSION: Distinctive characteristics of pediatric phase I trials, in comparison to adult phase I trials, include the necessity for multiinstitutional participation and their higher starting dose (typically 80% of the adult maximum-tolerated dose [MTD]), both of which reflect the relative unavailability of appropriate patients. The application of uniform eligibility criteria and standard definitions for MTD and dose-limiting toxicity (DLT) help to assure that pediatric phase I trials are safely conducted and reliably identify appropriate doses and schedules of agents for phase II evaluation. Where possible, pediatric phase I trials also define the pharmacokinetic behavior of new agents in children.

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