Use of Expansion Cohorts in Phase I Trials and Probability of Success in Phase II for 381 Anticancer Drugs

e14505 Background: ADG106 is a fully human agonistic anti-CD137 monoclonal IgG4 antibody that mediates anti-tumor activities via unique mechanisms of action. Here we provide safety and efficacy updates from our phase I trials and report the findings of a predictive biomarker and two pharmacodynamic biomarkers which correlate with patients’ clinical responses to ADG106 treatment and demonstrate target engagement, respectively. Methods: Formalin fixed and paraffin embedded (FFPE), blood and plasma specimens were collected from 92 patients enrolled in our phase I trials. We measured expression across a panel of protein biomarkers in FFPE specimens using three highly sensitive detection technologies: multiple immunohistochemical (IHC) staining of protein expression, the BD Multitest 6-color TBNK reagent for profiling immune cell subpopulations, and the MSD-ECL electrochemiluminescence assay for detection of soluble CD137. Objective tumor responses were determined using RECIST v1.1 for solid tumor patients and Lugano classification for lymphoma patients. Results: As of November 30, 2020, ADG106 has demonstrated a favorable safety profile and efficacy in the phase I clinical trials with a disease control rate of 56%. From a retrospective analysis of 28 pretreatment FFPE specimens, we identified a predictive biomarker that correlated with tumor shrinkage upon ADG106 treatment. We identified four biomarker positive specimens from two patients with lymphoma and two with solid tumors. Three out of four biomarker positive patients achieved greater than 30% tumor shrinkage after 3mg/kg or 5mg/kg ADG106 treatment. One biomarker positive patient with stable disease received a low dose ADG106 treatment at 0.5mg/kg during dose escalation. None of the 24 biomarker negative patients showed significant clinical response. A tissue microarray study confirmed expression of this predictive biomarker in a variety of tumor types suggesting a broad indication for ADG106 therapy. Our biomarker studies also demonstrated target engagement with increased NK cell proliferation and soluble CD137 upon ADG106 treatment. Analysis of safety, efficacy, PK and PD data allowed us to select a recommended dose for the upcoming phase II study. Conclusions: We identified a biomarker predictive of response to antitumor CD137 blockade by ADG106, as well as demonstrated the involvement of NK cells in ADG106 mediated anti-tumor activities. In upcoming phase II trials, we plan to enrich for populations expressing this predictive biomarker to demonstrate a clinical benefit to ADG106 therapy further validating early biomarker-based patient stratification. We will also explore the potential of selecting patients for combination treatment with anti-PD-1 therapies. Clinical trial information: NCT03802955.

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Evolution of Clinical Trial Design in Early Drug Development: Systematic Review of Expansion Cohort Use in Single-Agent Phase I Cancer Trials

Journal of Clinical Oncology ◽

10.1200/jco.2012.47.4957 ◽

2013 ◽

Vol 31 (33) ◽

pp. 4260-4267 ◽

Cited By ~ 53

Author(s):

Arif Manji ◽

Irene Brana ◽

Eitan Amir ◽

George Tomlinson ◽

Ian F. Tannock ◽

...

Keyword(s):

Systematic Review ◽

Phase I ◽

Phase Ii ◽

Data Extraction ◽

Single Agent ◽

Clinical Trial Design ◽

Phase I Trials ◽

Phase Ii Studies ◽

Cancer Trials ◽

Expansion Cohort

Purpose To evaluate the use and objectives of expansion cohorts in phase I cancer trials and to explore trial characteristics associated with their use. Methods We performed a systematic review of MEDLINE and EMBASE, limiting studies to single-agent phase I trials recruiting adults and published after 2006. Eligibility assessment and data extraction were performed by two reviewers. Data were assessed descriptively, and associations were tested by univariable and multivariable logistic regression. Results We identified 611 unique phase I cancer trials, of which 149 (24%) included an expansion cohort. The trials were significantly more likely to use an expansion cohort if they were published more recently, were multicenter, or evaluated a noncytotoxic agent. Objectives of the expansion cohort were reported in 74% of trials. In these trials, safety (80%), efficacy (45%), pharmacokinetics (28%), pharmacodynamics (23%), and patient enrichment (14%) were cited as objectives. Among expansion cohorts with safety objectives, the recommended phase II dose was modified in 13% and new toxicities were described in 54% of trials. Among trials aimed at assessing efficacy, only 11% demonstrated antitumor activity assessed by response criteria that was not previously observed during dose escalation. Conclusion The utilization of expansion cohorts has increased with time. Safety and efficacy are common objectives, but 26% fail to report explicit aims. Expansion cohorts may provide useful supplementary data for phase I trials, particularly with regard to toxicity and definition of recommended dose for phase II studies.

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Experience in Phase I Trials and an Upcoming Phase II Study with uPA Inhibitors in Metastatic Breast Cancer

Breast Care ◽

10.1159/000151733 ◽

2008 ◽

Vol 3 (2) ◽

pp. 6-6 ◽

Cited By ~ 9

Author(s):

Lori J. Goldstein

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Phase I ◽

Phase Ii ◽

Phase Ii Study ◽

Metastatic Breast ◽

Phase I Trials

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A Population-Based Clinical Trial of Irinotecan and Carboplatin

Journal of Oncology ◽

10.1155/2009/458528 ◽

2009 ◽

Vol 2009 ◽

pp. 1-5

Author(s):

Derick Lau ◽

Minh Huynh ◽

Jewel Johl

Keyword(s):

Phase I ◽

Normal Distribution ◽

Anticancer Drugs ◽

Dose Level ◽

Dose Intensity ◽

Maximum Tolerated Dose ◽

Population Based ◽

Phase I Trials ◽

Dose Levels ◽

Carboplatin Auc

Purpose. Phase I trials of anticancer drugs are commonly conducted using the method of modified Fibonacci. We have developed a population-based design for phase I trials of combining anticancer drugs such as irinotecan and carboplatin.Patients and Methods. Intrapatient dose escalation of irinotecan and carboplatin was performed according to a predetermined schema to reach individual dose-limiting toxicity (DLT) in 50 patients with solid tumors refractory to previous chemotherapy. The individual toxicity-limiting dose levels were analyzed for normal distribution using the method of Ryan-Joiner and subsequently used to determine a population-based maximum tolerated dose (pMTD). For comparison, a simulation study was performed using the method of modified Fibonacci.Results. The most common dose-limiting toxicities (DLTs) included neutropenia (58%), thrombocytopenia (16%), and diarrhea (8%). The frequency of individual toxicity-limiting dose levels of 50 patients approximated a normal distribution. The dose levels associated with individual limiting toxicities ranged from level 1 (irinotecan 100 mg/m2and carboplatin AUC = 4 mg/mLxmin) to level 8 (irinotecan 350 mg/m2and carboplatin AUC = 6). The pMTD was determined to be dose level 3 (150 mg/m2for irinotecan and AUC = 5 for carboplatin). In contrast, the MTD was determined to be dose level 4 (200 mg/m2for irinotecan and AUC 5 for carboplatin) by modified-Fibonacci simulation.Conclusions. The population-based design of phase I trial allows optimization of dose intensity and derivation of a pMTD. The pMTD has been applied in phase II trial of irinotecan and carboplatin in patients with small-cell lung cancer.

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The changing face of phase I protocols: A closer look at study requirements

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.3061 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 3061-3061

Author(s):

B. S. Craft ◽

R. Kurzrock ◽

R. Herbst ◽

K. Culotta ◽

C. Stewart ◽

...

Keyword(s):

Clinical Trials ◽

Phase I ◽

Phase Ii ◽

Medical Oncology ◽

Current Phase ◽

Recent Experience ◽

Phase I Trials ◽

Phase I Clinical Trials ◽

Phase Ii Trials ◽

Versus Phase

3061 Background: We have studied our recent experience in the MDACC Clinical Translational Research Center (CTRC), the Phase I Program, and the Dept. of Thoracic/Head & Neck Medical Oncology to compare the extent of regulatory and other requirements for current phase I and II cancer clinical trials. Methods: We developed a comprehensive database, together with a Microsoft Excel spreadsheet matrix to analyze the number and extent of diagnostic and therapeutic requirements for each protocol. We then examined the demands for pharmacokinetic (PK) sampling as well as electrocardiography (ECG) in the first cycle of a protocol as a surrogate for study complexity. Results: Since October, 2002, 250 protocols have been conducted in the CTRC; 54.6% were Phase I clinical trials. We reviewed 65 trials, approximately one quarter of the total. Of these, 48 were phase I trials carried out by the Phase I Program. For comparison, we identified 17 phase II trials managed by the Dept. of Thoracic/Head & Neck Medical Oncology during the same time period. In the phase I trials there were significantly more PKs (mean ± SE = 16.69 ± 1.93) than in the phase II trials (mean ± SE = 1.82 ± 1.17) (p<0.0001). Similarly, there were more ECGs in the phase I versus phase II trials (4.46 ± 1.18 vs. 1.41 ± 0.35; p=0.017). Conclusions: Pharmacokinetic collection and ECG monitoring in Phase I trials are complex and labor-intensive. In addition, they represent only a small portion of time-intensive requirements, with increasingly complicated correlates and monitoring (physical exams, imaging, etc.). Successful and accurate Phase I clinical trials require resources and commitment for research infrastructure considerably greater than later phase studies. No significant financial relationships to disclose.

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The relationship between response and dose in published, contemporary phase 1 oncology trials.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14583 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14583-e14583

Author(s):

Antonious Ziad Hazim ◽

Emerson Yu-sheng Chen ◽

Gordon B. Mills ◽

Vinay Prasad

Keyword(s):

Phase I ◽

Treatment Response ◽

Dose Level ◽

Phase Ii ◽

Response Rate ◽

Drug Dose ◽

Phase I Trials ◽

Recommended Phase Ii Dose ◽

Dose Levels ◽

The Relationship

e14583 Background: Traditional dose-escalation trial designs have changed little even as diverse classes of oncology drugs have been developed. We aimed to examine whether the association of drug dose to preliminary clinical efficacy previously established in cytotoxic chemotherapies remains true in contemporary phase I dose-escalation oncology trials. Methods: We conducted a systematic review of recent early-phase, dose-finding clinical trials of oncology drugs from November 15, 2015 to November 15, 2018 to examine the relationship between the dose of the investigational drug and objective response rate. We searched PubMed using “cancer” or “oncology” search terms and selected studies that enrolled adults with advanced cancer, determined maximum tolerated dose (MTD) and/or recommended phase II dose, and reported efficacy results by drug dose level. Trials testing combination therapies, single dose level, and non-pharmacologic therapies were excluded. Information related to the study drug, study design, cancer type, dose levels, MTD, and recommended phase II dose were all collected. Treatment response for every dose level was categorized into: complete response, partial response, stable disease, and progressive disease. Dose level was categorized into four categories: < = 40%, 41-80%, 81-120%, and > 120% of the recommended phase II dose. Results: We identified 93 trials with 2506 participants having both dose and treatment response data. Of these trials, 71 (76%) were testing targeted agents, 7 (8%) were immunotherapy, and 6 (7%) were cytotoxic chemotherapy. Median response rate across trials was 5% (range 0-83%). Among the dose range of < = 40%, the response rate was 12% (57 of 491), 41-80% was 17% (95 of 562), 81-120% was 23% (272 of 1206), and > 120% was 29% (71 of 247). Conclusions: Observed treatment response across dose levels in recent phase I trials should cause us to re-examine the toxicity-benefit ratio and influence how we design phase I trials testing novel classes of oncology drugs.

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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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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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