Clinical outcome and prognosis of metastatic colorectal cancer (mCRC) patients (pts) on phase 1 trials: A single institution experience from 1999 to 2016.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 828-828
Author(s):  
Audrey E. Kam ◽  
Gopichand Pendurti ◽  
Umang H. Shah ◽  
Mohammad Haroon Ghalib ◽  
Imran Chaudhary ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Phase I ◽  
Risk Score ◽  
Phase 1 ◽  
Median Number ◽  
Direct Bilirubin ◽  
P Value ◽  
Phase I Trials ◽  
Phase 1 Trials ◽  
Valuable Treatment

828 Background: Pts with mCRC who progress on all standard therapies have a poor prognosis and limited therapy options. Phase 1 trials represent a valuable treatment option. Herein we report the characteristics and outcomes of mCRC patients treated at our institution. Methods: We reviewed records of pts with mCRC enrolled on phase I trials at our institution from January 1999 to December 2016. Treatment-related response, toxicity, and deaths were recorded. Prognostic factors for overall survival (OS) were calculated using univariate (UVA) and multivariable Cox PH analysis (MVA). Results: We observed 187 enrollments with 152 unique patients accrued on 37 phase I trials. Median age was 59 years (range 29-83) and median number of prior therapies was 3 (range 0-8). 144 patients were evaluable for response. The clinical benefit rate (SD+response, CBR) was 33.2% and the ORR was 4.3%. Grade 3/4 non-hematological and hematological AE were seen in 25.5% and 17.3% of patients, respectively. Treatment-related mortality was 0.5%. Median PFS was 1.7 mos and OS was 8.2 mos. In UVA, the following variables predicted a shorter OS: age (p = 0.049); PS > 1 (p < 0.01); sites of metastases > 2 (p = 0.04); LDH > ULN (p < 0.001); albumin < 3.5 (p < 0.001); direct bilirubin > ULN (p = 0.02); WBC > 5.2 (p = 0.001); anemia (p = 0.046). In MVA, age > 60 (HR 1.63, p < 0.004), albumin < 3.5 (HR 3.69, p < 0.001), direct bilirubin > ULN (HR1.69, p < 0.01), and WBC > 5.2 (HR 1.97, p < 0.001) were negative prognostic factors for OS, adjusted for race and sex. A risk score based on MVA revealed that patients with a score of 0-1 had an improved OS (12.5mos) compared to a score of 2 (9.1mos, p-value < 0.005) and 3 (3.2 mos, p-value < 0.001). Conclusions: Patients with mCRC enrolled on phase 1 trials had a CBR of 33.2% and median OS of 8.2 mos, which exceeds third line therapies including regorafenib and trifluridine/tipiracil. Negative prognostic factors for OS were: age > 60, albumin < 3.5, direct bilirubin > ULN, and WBC > 5.2. A risk score based on these parameters showed that patients with a higher score had a significantly shorter OS, which may be useful in selecting patients for phase 1 trials.

Rethinking Risk-Benefit Assessment for Phase I Multiple Myeloma Trials

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1146-1146
Author(s):  
Ehsan Malek ◽  
Caner Saygin ◽  
Rebecca Ye ◽  
Byung-gyu Kim ◽  
Fahrettin Covut ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Response Rate ◽  
Single Agent ◽  
Median Number ◽  
Therapeutic Benefit ◽  
P Value ◽  
Phase I Trials ◽  
The Past ◽  
Increasing Trend

Abstract The recent number of US Food and Drug Administration (FDA) drug approvals for the treatment of multiple myeloma (MM) is unprecedented.Four new therapeutic agents,panobinostat,daratumumab,elotuzumab, andixazomibwere approved in 2015 matching the record of seven new-agents and 16 regulatory approvals during the past 12 years. New therapies have dramatically improved life expectancy for patients with MM. The therapeutic benefit of newer agents, combined with the incurable and relapse-remission nature of disease, has further propagated the interest of pharmaceuticaland academic investigations. Thus, a multitude of anti-myeloma compounds have been proposed, evaluated in pre-clinical studies and tested in phase I trials. A major hurdle to recruiting patients onto phase I oncology trials has the assumption that these trials offer low therapeutic benefit, which makes phase I trial recruitment a last resort(Simon et al. JCO, 2004).The status of MM phase I trials in the past 12 years has not been reviewed in detail. The aim of this study is to determine overall therapeutic benefit and risks forptsrecruited in phase I trials from 2004 to 2015 and to analyze the role of potential factors affecting outcomes. Methods: Phase I trials for MM conducted from 2004-2015 were identified from searches of MEDLINE, Cochrane Library and scientific meetings (Fig. 1). Data was extracted by two independent reviewers based upon the same algorithm and significant overlap in assignment to assess inter-observer heterogeneity. Results: Trials (n=74) were selected and included a total of 2408 enrolled pts (Fig. 1). The median number of pts/trial was 29 (range: 5-84), 56% of pts male, 44% female, median age was 67 years (range: 55-71) with increasing trend toward the end of the study period. The performance status was 2 or better in all trials. 39% of the trials evaluated a single agent (excluding corticosteroids) and the remainder evaluated combination therapies (Fig. 2A). 12 (42%) trials tested small molecules and 16 (68%) used monoclonal antibodies as single agent. 90% of the trials were conducted based on 3+3 design. The proportion of industry-sponsored trials increased progressively in the study period (Fig. 2B). The ratio of the initial dose to the Maximum Tolerated Dose (MTD) was 0.29 indicating significant portion of enrolled pts were potentially undertreated, most likely due to dominance of 3+3 design. 1107 of the 2408 pts responded to the study drugs which resulted in overall response rate (ORR) of 42% (range: 0-91). Median ORR was significantly different in trials with single agent vs. combination therapy (20% vs. 40%, respectively, p-value<0.01). The Median number of prior treatment lines showed an increasing trend toward the end of the study period (Fig. 2D) that correlated inversely with response rate (Fig. 3A). The effect of number of prior lines of therapy on response rate remained significant after multivariate analysis taking age, the year of publication and ratio of initial dose to the MTD into account. There were 7 therapy-related in all studies (overall death rate: 0.4 %). Pts who participated in combination therapy phase I clinical trials had more SAEs than single agents (29% vs 16%, HR: 1.35, p-value: 0.04). Median serious adverse events (SAE) was 22% (range: 0-44) (Fig. 2C). Response rates and SAE rate were not statistically difference between the 4 periods of the study (2004-06, 2007-09, 2010-12 and 2013-15, p-value=0.3).Daratumuab,ixazomib,pomalidomide,Isatuximab,marizomib,oprozomib,filanesib,dinaciclib,venetoclax and LGH-447, had single agent anti-myeloma activity and proceeded to later phase clinical trials (Fig. 3B). Conclusions: Our analysis indicates that the therapeutic benefit for patients recruited onto MM phase I trials was significantly higher than that reported for phase I trial of all cancer types (Horstmann et al. NEJM. 2005).Our results suggest an inverse correlation between the number of prior lines of therapies and the response rate that support earlier patient entry onto phase I studies to increase the therapeutic benefit.Also, our analysis shows that despite an increase in the number of compounds tested in MM phase I trials during the past 12 years, the overall toxicity from these trials has not increased. It is also possible that less patients would be undertreated by utilizing phase I designs other than 3+3 that deliver therapeutic dosage to a larger portion of enrolled patients. Disclosures No relevant conflicts of interest to declare.

Long-term follow up of patients with mesothelioma treated with dendritic cell therapy in three phase I trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2618-2618
Author(s):  
Daphne W Dumoulin ◽  
Robin Cornelissen ◽  
Koen Bezemer ◽  
Sara Baart ◽  
Joachim Aerts
Keyword(s):  
Phase I ◽  
Phase 1 ◽  
Phase I Trials ◽  
Tumor Lysate ◽  
Phase 1 Trials ◽  
Three Phase ◽  
Long Term Follow Up ◽  
Vaccination Therapy

2618 Background: Immunotherapy targeting PD-(L)1 has become indispensable in the treatment of many malignant tumors. Recently, checkpoint inhibition using anti-PD-1 in combination with anti-CTLA-4 was proved to be effective in patients with malignant pleural mesothelioma (MPM). However, the minority of patients benefit from this treatment. The lack of immunotherapy efficacy in the majority of patients with mesothelioma can be explained by the fact that mesothelioma is a tumor with an “immune-desert” phenotype, meaning a non-inflamed tumor characterized by low T-cell infiltration. By administration of dendritic cells (DCs), which were cultured, activated, and exposed to antigens ex-vivo, this “immune-desert” phenotype might be turned into an “inflamed” phenotype. Previously, we performed and published three phase I trials using activated DCs, which support this concept. Here, we report the long-term survival of the patients treated with DCs in these three phase 1 studies. Methods: We collected the survival data of the phase 1 trials using DC therapy in patients with MPM. In the first two trials, DCs loaded with autologous tumor lysate were used, while in the third allogeneic tumor lysate was used to load the DCs (Mesopher). Results: Between 2006 and 2015, in the three studies combined, 29 patients with MPM were treated with DC vaccination. At data cut-off, the median OS was 27 months (95% confidence interval (CI): 21 – 47 months). OS at 2 years was 55.2% (95% CI: 39.7%-76.6%), OS at 5 years was 20.7% (95% CI: 10.1%-42.2%). Conclusions: The long-term follow up of MPM patients treated with DC vaccination in the three separate phase 1 trials show a promising signal, with a 2-year OS of over 50% and a 5-year OS of over 20%. In addition, 2 patients are alive after 10 years of treatment. In our opinion, these findings show the potency of DC vaccination therapy in long-term activation of the immune system. DC vaccination therapy in patients with MPM is currently being investigated in a large, randomized phase II-III trial (NCT03610360) and in pancreatic cancer. Additional biomarker studies, as well as treatment combinations with for example ICI, could further improve the outcomes of DC-vaccination therapy. Clinical trial information: NCT02395679. [Table: see text]

Prognostic factors among cancer patients with good performance status screened for phase I trials

2007 ◽  
Vol 26 (1) ◽  
pp. 53-58 ◽  
Author(s):  
Nicolas Penel ◽  
Marie Vanseymortier ◽  
Marie-Edith Bonneterre ◽  
Stéphanie Clisant ◽  
Eric Dansin ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Phase I ◽  
Cancer Patients ◽  
Performance Status ◽  
Phase I Trials ◽  
Good Performance Status

scholarly journals Phase i trials in melanoma: A framework to translate preclinical findings to the clinic

2015 ◽  
Author(s):  
Eunjung Kim ◽  
Vito W. Rebecca ◽  
Keiran S.M. Smalley ◽  
Alexander R.A. Anderson
Keyword(s):  
Mathematical Model ◽  
Clinical Trial ◽  
Combination Therapy ◽  
Phase I ◽  
Phase 1 ◽  
Cell Populations ◽  
Model Parameters ◽  
Phase I Trials ◽  
Virtual Patients ◽  
Akt Inhibitor

We present a, mathematical model driven, framework to implement virtual or imaginary clinical trials (phase i trials) that can be used to bridge the gap between preclinical studies and the clinic. The trial implementation process includes the development of an experimentally validated mathematical model, generation of a cohort of heterogeneous virtual patients, an assessment of stratification factors, and optimization of treatment strategy. We show the detailed process through application to melanoma treatment, using a combination therapy of chemotherapy and an AKT inhibitor, which was recently tested in a phase 1 clinical trial. We developed a mathematical model, composed of ordinary differential equations, based on experimental data showing that such therapies differentially induce autophagy in melanoma cells. Model parameters were estimated using an optimization algorithm that minimizes differences between predicted cell populations and experimentally measured cell numbers. The calibrated model was validated by comparing predicted cell populations with experimentally measured melanoma cell populations in twelve different treatment scheduling conditions. By using this validated model as the foundation for a genetic algorithm, we generated a cohort of virtual patients that mimics the heterogeneous combination therapy responses observed in a companion clinical trial. Sensitivity analysis of this cohort defined parameters that discriminated virtual patients having more favorable versus less favorable outcomes. Finally, the model predicts optimal therapeutic approaches across all virtual patients.  

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

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.

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.

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.

scholarly journals 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

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.

scholarly journals Use of the Pallia 10 score in patients enrolled in phase I trials at Gustave Roussy Cancer Center.

2021 ◽  
Vol 39 (28_suppl) ◽  
pp. 23-23
Author(s):  
Kaissa Ouali ◽  
Christine Mateus ◽  
Ariane Laparra ◽  
Elena Pavliuc ◽  
Patricia Martin Romano ◽  
...  
Keyword(s):  
Palliative Care ◽  
Prognostic Factors ◽  
Phase I ◽  
Subsequent Treatment ◽  
Palliative Care Unit ◽  
Cancer Center ◽  
Phase I Trials ◽  
Double Blind ◽  
Palliative Care Consultation ◽  
Systemic Treatments

23 Background: Early phase clinical trials usually include patients (pts) with advanced disease who have failed to standard therapies. Early palliative care (EPC) for these pts has shown to improve quality of life and even survival. Pallia 10 score (from 1 to 10) is a tool developed by the French Palliative Care Society to identify the best time to introduce palliative care. Methods: We assessed the Pallia 10 score and other prognostic factors (age, ECOG, Royal Marsden Hospital (RMH) score, LDH and albumin levels, number (nb) of prior systemic treatments and metastatic sites) in pts enrolled in phase I trials (P1CT) prospectively during 2 periods of time (cohort 1 (C1) and 2 (C2)). A double-blind assessment of the Pallia 10 score was done during 15 days by a member of the palliative care unit in C2. A Pallia 10 > 3 motivated a dedicated palliative care consultation. Results: From 01/07/2018 to 01/11/2018 (C1) and from 01/12/2020 to 16/04/2021 (C2), a total of 85 pts were assessed in C1 and 302 in C2. Gastro-intestinal (23%), hematological (14%) and lung (11%) cancer were the most frequent tumor types. Pallia 10 score and prognostic factors were similar between both cohorts (Table). On C1 and C2, 12% and 4% of pts had a dedicated palliative consultation with median time of referral of 18 and 2 months (m) after the P1CT onset (p = 0.003), with a median Pallia 10 score of 1.5 and 2 (p = 0.65), respectively. Overall, 75% and 76% of pts in C1 and C2 were still alive beyond 3m after discontinuation of the P1CT (p = 0.91), followed by at least one subsequent treatment in 56% and 54% of pts. In C2, assessment of Pallia 10 score was significantly different between palliative care physician (median 5, range 3-8), phase I physician (median 1, range 1 -6) and phase I nurse (median 3, range 1-8) (p < 0.001). Conclusions: Only a few patients included in P1CT were referred to the palliative care unit. Median Pallia 10 score was low when assessed by the phase I physician which suggests the need for a better tool to implement EPC in clinical practice and trials.[Table: see text]

scholarly journals Comparison of prognostic factors in patients in phase I trials of cytotoxic drugs vs new noncytotoxic agents

2003 ◽  
Vol 89 (7) ◽  
pp. 1166-1171 ◽  
Author(s):  
C Han ◽  
J P Braybrooke ◽  
G Deplanque ◽  
M Taylor ◽  
D Mackintosh ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Phase I ◽  
Cytotoxic Drugs ◽  
Phase I Trials
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