Predictors of early treatment discontinuation in patients enrolled on Phase I oncology trials.
ABSTRACT: Patients who do not complete one cycle of therapy on Phase I trials for reasons other than dose limiting toxicity (DLT) are considered inevaluable for toxicity and must be replaced.Individual records from patients enrolled to NCI-sponsored Phase I trials activated between 2000 and 2010 were used. Early discontinuation was defined as the failure to begin cycle 2 for reasons other than a DLT during cycle 1. A multinomial logistic regression with a 3-level nominal outcome (early discontinuation, DLT during cycle 1, and continuation to cycl1e 2) was used with continuation to cycle 2 serving as the reference category. The final model was used to create two risk scores. An independent external cohort was used to validate these models.Data from 3079 patients on 127 Phase I trials were analyzed. ECOG performance status (1, ? 2, two-sided P = .0315 and P = .0007), creatinine clearance (<60 ml/min, P = .0455), alkaline phosphatase (>2.5xULN, P = .0026), AST (>ULN, P = .0076), hemoglobin (<10 g/dL, P < .0001), albumin (<3.5 g/dL, P < .0001), and platelets (<400x109/L, P = .0732) were predictors of early discontinuation. The c-index of the final model was 0.63.Knowledge of risk factors for early treatment discontinuation in conjunction with clinical judgment can help guide Phase I patient selection.
Project description:Background:Data generated by phase I trials is richer than the classical binary DLT measured at the first cycle used as primary endpoints. Several works developed designs for more informative endpoints, e.g. ordinal toxicity grades and/or longitudinal data which relied however on strong assumptions, in particular the proportional odds (PO) assumption. Methods:We evaluated this PO assumption for the dose and cycle on a large database of individual patient data from 54 phase I clinical trials of molecularly targeted agents. The PO model is a specific case of the continuation ratio logit model (CRLM) with null parameters. We compared the PO and CRLM models using the widely applicable information criterion (WAIC). We considered a longitudinal multivariate ordinal toxicity outcome (cutaneous, digestive, hematological, general disorders, and other toxicities). Results:WAIC suggested that the CRLM model (WAIC = 30911.58) outperformed the PO model (WAIC = 31432.10). Deviance from PO assumption for dose was observed for digestive and general disorder toxicities. There was moderate cycle effect with slight deviance from PO assumption for the other type of toxicity. Conclusions:Designs based on PO for dose should be a useful tool for drug with low expected digestive or general disorder toxicity dose-related incidence.
Project description:BACKGROUND:ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The first-in-human trial of ONC201 previously established a recommended phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of weekly ONC201. METHODS:Patients ≥ 18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of weekly ONC201, which was confirmed in an 11-patient dose expansion cohort. RESULTS:Twenty patients were enrolled: three at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. PK profiles were consistent with every-three-week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 induction were detected, along with intratumoral integrated stress response activation and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effectors was higher in patients who received ONC201 once weekly versus once every three weeks. Stable disease of > 6 months was observed in several prostate and endometrial cancer patients. CONCLUSIONS:Weekly, oral ONC201 is well-tolerated and results in enhanced immunostimulatory activity that warrants further investigation. TRIAL REGISTRATION:NCT02250781 (Oral ONC201 in Treating Patients With Advanced Solid Tumors), NCT02324621 (Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors).
Project description:To evaluate the impact of discontinuation of adalimumab (ADA) for 1?year in Japanese patients with early rheumatoid arthritis (RA).This 52-week postmarketing study, HOPEFUL-2, enrolled patients who had completed HOPEFUL-1 for early RA, in which patients received either ADA + methotrexate (MTX) or MTX alone in a 26-week randomised phase, followed by ADA+MTX in a 26-week open-label phase.A total of 220 patients (ADA discontinuation: 114 patients vs ADA continuation: 106 patients) were enrolled in this study. The proportion of patients with sustained low disease activity (LDA) in the ADA discontinuation group was significantly lower than that in the continuation group (80% (64/80 patients) vs 97% (71/73 patients); p=0.001); however, most patients sustained LDA in both groups. In patients with 28-joint disease activity score (DAS28)-C reactive protein ?2.0 at week 52, the proportion of patients who achieved sustained LDA at week 104 was 93%, suggesting that DAS28 remission may be a predictor to indicate biological-free disease control in patients with early RA. The incidence of adverse events (AE) was significantly lower in the ADA discontinuation group than in the continuation group (34.2% (39/114 patients) vs 48.1% (51/106 patients); p=0.04), most notably for infection (14.9% vs 27.4%, p=0.031).Although ADA discontinuation was associated with an increase in disease activity, a large proportion of patients maintained LDA with MTX monotherapy after ADA discontinuation. Since ADA discontinuation was associated with a lower AE incidence, physicians should weigh the risks and benefits of ADA discontinuation.NCT01163292.
Project description:PURPOSE:MET and AXL mediate resistance to EGFR TKI in NSCLC. Foretinib, a MET/RON/AXL/TIE-2/VEGFR kinase inhibitor may overcome EGFR kinase resistance. This dose escalation study combined foretinib and erlotinib in advanced pretreated NSCLC patients. EXPERIMENTAL DESIGN:The primary endpoint was to define the RP2D of foretinib plus erlotinib as continuous oral daily dosing. Secondary objectives included safety, pharmacokinetics, response and potential biomarkers of response including EGFR, KRAS genotype, MET, AXL expression, and circulating HGF levels. Erlotinib (E100-150 mg) was commenced on day 1 cycle 1; if well tolerated, foretinib (F30-45 mg) was added on day 15 cycle 1, using standard 3+3 dose escalation. RESULTS:Of 31 patients enrolled in 3 dose levels, 6 were inevaluable for DLT and replaced. DLT occurred in 3/15 patients at DL2 (E150 mg, F30 mg): Gr3 pain, mucositis, fatigue and rash. Cycle 1 DLT was not seen at DL3 (E150 mg, F45 mg) but 27% experienced dose reduction/interruption. Adverse events in ?20% included diarrhea, fatigue, anorexia, dry skin, rash and hypertension. No PK interaction was seen with the combination. RP2D was defined as erlotinib 150 mg daily x 14 days with foretinib 30 mg added on day 15 (continuous dosing in 28-day cycles). Responses were seen in 17.8% of response evaluable patients (5/28). In 18 samples, baseline MET expression uncontrolled for EGFR genotype appeared associated with response. AXL expression was associated with neither EGFR mutation nor response. CONCLUSION:Combining foretinib and erlotinib demonstrated response in unselected advanced NSCLC but also incremental toxicity. Future development will require molecular patient selection.
Project description:BACKGROUND:Antipsychotic medication is effective for symptomatic treatment in schizophrenia-spectrum disorders. After symptom remission, continuation of antipsychotic treatment is associated with lower relapse rates and lower symptom severity compared to dose reduction/discontinuation. Therefore, most guidelines recommend continuation of treatment with antipsychotic medication for at least 1 year. Recently, however, these guidelines have been questioned as one study has shown that more patients achieved long-term functional remission in an early discontinuation condition-a finding that was not replicated in another recently published long-term study. METHODS/DESIGN:The HAMLETT (Handling Antipsychotic Medication Long-term Evaluation of Targeted Treatment) study is a multicenter pragmatic single-blind randomized controlled trial in two parallel conditions (1:1) investigating the effects of continuation versus dose-reduction/discontinuation of antipsychotic medication after remission of a first episode of psychosis (FEP) on personal and social functioning, psychotic symptom severity, and health-related quality of life. In total 512 participants will be included, aged between 16 and 60?years, in symptomatic remission from a FEP for 3-6?months, and for whom psychosis was not associated with severe or life-threatening self-harm or violence. Recruitment will take place at 24 Dutch sites. Patients are randomized (1:1) to: continuation of antipsychotic medication until at least 1?year after remission (original dose allowing a maximum reduction of 25%, or another antipsychotic drug in similar dose range); or gradual dose reduction till eventual discontinuation of antipsychotics according to a tapering schedule. If signs of relapse occur in this arm, medication dose can be increased again. Measurements are conducted at baseline, at 3, and 6 months post-baseline, and yearly during a follow-up period of 4?years. DISCUSSION:The HAMLETT study will offer evidence to guide patients and clinicians regarding questions concerning optimal treatment duration and when to taper off medication after remission of a FEP. Moreover, it may provide patient characteristics associated with safe dose reduction with a minimal risk of relapse. TRIAL STATUS:Protocol version 1.3, October 2018. The study is active and currently recruiting patients (since September 2017), with the first 200 participants by the end of 2019. We anticipate completing recruitment in 2022 and final assessments (including follow-up 3.5 years after phase one) in 2026. TRIAL REGISTRATION:European Clinical Trials Database, EudraCT number 2017-002406-12. Registered 7 June 2017.
Project description:BACKGROUND:Pediatric phase I oncology trials have historically focused on safety and toxicity, with objective response rates (ORRs) <10%. Recently, with an emphasis on targeted approaches, response rates may have changed. We analyzed outcomes of recent phase I pediatric oncology trials. MATERIALS AND METHODS:This was a systematic review of phase I pediatric oncology trials published in 2012-2017, identified through PubMed and EMBASE searches conducted on March 14, 2018. Selection criteria included full-text articles with a pediatric population, cancer diagnosis, and a dose escalation schema. Each publication was evaluated for patient characteristics, therapy type, trial design, toxicity, and response. RESULTS:Of 3,431 citations, 109 studies (2,713 patients) met eligibility criteria. Of these, 78 (72%) trials incorporated targeted therapies. Median age at enrollment/trial was 11?years (range 3-21?years). There were 2,471 patients (91%) evaluable for toxicity, of whom 300 (12.1%) experienced dose-limiting toxicity (DLT). Of 2,143 patients evaluable for response, 327 (15.3%) demonstrated an objective response. Forty-three (39%) trials had no objective responses. Nineteen trials (17%) had an ORR >25%, of which 11 were targeted trials and 8 were combination cytotoxic trials. Targeted trials demonstrated a lower DLT rate compared with cytotoxic trials (10.6% vs. 14.7%; p = .003) with similar ORRs (15.0% vs. 15.9%; p = .58). CONCLUSION:Pediatric oncology phase I trials in the current treatment era have an acceptable DLT rate and a pooled ORR of 15.3%. A subset of trials with target-specific enrollment or combination cytotoxic therapies showed high response rates, highlighting the importance of these strategies in early phase trials. IMPLICATIONS FOR PRACTICE:Enrollment in phase I oncology trials is crucial for development of novel therapies. This systematic review of phase I pediatric oncology trials provides an assessment of outcomes of phase I trials in children, with a specific focus on the impact of targeted therapies. These data may aid in evaluating the landscape of current phase I options for patients and enable more informed communication regarding risk and benefit of phase I clinical trial participation. The results also suggest that, in the current treatment era, there is a rationale to increase earlier access to targeted therapy trials for this refractory patient population.
Project description:<h4>Background</h4>Little is known on factors predicting sunitinib toxicity. Recently, the condition of low muscle mass, named sarcopenia, was identified as a significant predictor of toxicity in metastatic renal cell cancer (mRCC) patients treated with sorafenib. We investigated whether sarcopenia could predict early dose-limiting toxicities (DLTs) occurrence in mRCC patients treated with sunitinib.<h4>Methods</h4>Consecutive mRCC patients treated with sunitinib were retrospectively reviewed. A DLT was defined as any toxicity leading to dose reduction or treatment discontinuation. Body composition was evaluated using CT scan obtained within 1 month before treatment initiation.<h4>Results</h4>Among 61 patients eligible for analysis, 52.5% were sarcopenic and 32.8% had both sarcopenia and a body mass index (BMI)<25?kg?m(-2). Eighteen patients (29.5%) experienced a DLT during the first cycle. Sarcopenic patients with a BMI<25?kg?m(-2) experienced more DLTs (P=0.01; odds ratio=4.1; 95% CI: (1.3-13.3)), more cumulative grade 2 or 3 toxicities (P=0.008), more grade 3 toxicities (P=0.04) and more acute vascular toxicities (P=0.009).<h4>Conclusion</h4>Patients with sarcopenia and a BMI<25?kg?m(-2) experienced significantly more DLTs during the first cycle of treatment.
Project description:This article addresses the concern regarding late-onset dose-limiting toxicities (DLT), moderate toxicities below the threshold of a DLT and cumulative toxicities that may lead to a DLT, which are mostly disregarded or handled in an ad hoc manner when determining the maximum tolerated dose (MTD) in dose-finding cancer clinical trials. An extension of the Time-to-Event Continual Reassessment Method (TITE-CRM) which allows for the specification of toxicity constraints on both DLT and moderate toxicities, and can account for partial information is proposed. The method is illustrated in the context of an Erlotinib dose-finding trial with low DLT rates, but a significant number of moderate toxicities leading to treatment discontinuation in later cycles. Based on simulations, our method performs well at selecting the dose level that satisfies both the DLT and moderate-toxicity constraints. Moreover, it has similar probability of correct selection compared to the TITE-CRM when the true MTD based on DLT only and the true MTD based on grade 2 or higher toxicities alone coincide, but reduces the probability of recommending a dose above the MTD.
Project description:OBJECTIVE:In patients with Alzheimer's disease (AD) with psychosis or agitation that respond to haloperidol treatment, to evaluate the risk of relapse following discontinuation. METHODS:In outpatients with AD with symptoms of psychosis or agitation, responders to 20 weeks of haloperidol (0.5-5?mg daily) were randomized to a 24-week, double-blind pilot trial of discontinuation on placebo versus continuation haloperidol. Phase A response criteria were minimum 50% reduction in three target symptoms, and improvement on the Clinical Global Impression-Change (CGI-C) score for psychosis/agitation. Phase B relapse criteria required 50% worsening in target symptoms and on the CGI-C. ??=?0.1 was the significance criterion in this pilot study. RESULTS:Of 44 patients, 22 patients responded in Phase A. The sum score of target symptoms, and Brief Psychiatric Rating Scale (BPRS) psychosis and hostile suspiciousness factor scores, decreased in Phase A (p's?<?0.001). Extrapyramidal signs increased in Phase A (p?<?0.01). Of 22 responders, 21 patients entered Phase B, and 20 had at least one follow-up visit. Four of 10 patients (40%) on continuation haloperidol relapsed compared to eight of 10 patients on placebo (80%, ?(2) ?=?3.3, p?=?0.07). In survival analyses, time to relapse was shorter on placebo than haloperidol (?(2) ?=?4.1, p?=?0.04). CONCLUSIONS:Haloperidol open treatment was efficacious, and relapse was greater on placebo than with haloperidol continuation. In patients with AD who have psychosis or agitation and respond to antipsychotic medication, the increased risk of relapse after discontinuation needs to be weighed against the side effects associated with continuing the medication.
Project description:Interferon has antiproliferative and antiangiogenic properties. We sought to evaluate preliminary efficacy and determine the recommended phase II dose (RP2D) for pegylated interferon-?-2b (PI) in patients with unresectable progressive or symptomatic plexiform neurofibromas (PN).PI was administered weekly in cohorts of 3-6 patients during the dose-finding phase and continued for up to 2 years. Twelve patients were treated at the RP2D to further evaluate toxicity and activity.Thirty patients (median age 9.3 years, range 1.9-34.7 years) were enrolled. No dose-limiting toxicity (DLT) was seen in patients treated at the 3 ?g/kg dose level (DL) during the first 4 weeks. All 5 patients treated at the 4.5 ?g/kg DL came off study or required dose reductions for behavioral toxicity or fatigue. Similar DLT on the 3 ?g/kg DL became apparent over time. There was 1 DLT (myoclonus) in 12 patients enrolled at the 1.0 ?g/kg DL. Eleven of 16 patients with pain showed improvement and 13 of 14 patients with a palpable mass had a decrease in size. Five of 17 patients (29%) who underwent volumetric analysis had a 15%-22% decrease in volume. Three of 4 patients with documented radiographic progression prior to enrollment showed stabilization or shrinkage.The RP2D of PI for pediatric patients with PN is 1 ?g/kg/wk. Clinical and radiographic improvement and cessation of growth can occur.This study provides Class III evidence that pegylated interferon-?-2b in patients with unresectable, progressive, symptomatic, or life-threatening PNs results in radiographic reduction or stabilization of PN size.