scholarly journals 176 POSTER Outcome of three Phase I trials of the marine compound ES-285 (3 hour infusion) in patients with refractory solid tumors

2008 ◽  
Vol 6 (12) ◽  
pp. 56 ◽  
Author(s):  
P. Schöffski ◽  
V. Grünwald ◽  
G. Giaccone ◽  
R. Salazar ◽  
M. Majem ◽  
...  
2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3020-3020 ◽  
Author(s):  
A. Jimeno ◽  
P. Kulesza ◽  
G. Cusatis ◽  
A. Howard ◽  
Y. Khan ◽  
...  

3020 Background: Pharmacodynamic (PD) studies, using either surrogate or tumor tissues, are frequently incorporated in Phase I trials. However, it has been less common to base dose selection, the primary endpoint in Phase I trials, in PD effects. We conducted a PD-based dose selection study with rapamycin (Rap). Methods: We used the modified continuous reassessment method (mCRM), a computer-based dose escalation algorithm, and adapted the logit function from its classic toxicity-based input data to a PD-based input. We coupled this design to a Phase I trial of Rap with 2 parts: a dose estimation phase where PD endpoints are measured in normal tissues and a confirmation phase where tumor tissue is assessed. Patients (pts) had solid tumors refractory to standard therapy. Rap was given starting at 2 mg/day continuously in 3-pt cohorts. The PD endpoint was pP70S6K in skin and tumor. Biopsies were done on days 0 and 28 of cycle 1, and a PD effect was defined as ≥ 80% inhibition from baseline. The first 2 dose levels (2 and 3 mgs) were evaluated before implementing the mCRM. The data was then fed to the computer that based on the PD effect calculated the next dose level. The mCRM was set so escalation continued until a dose level elicited a PD effect and the mCRM assigned the same dose to 8 consecutive pts, at which point the effect of that dose will be confirmed in tumor biopsies. Other correlates were PET-CT and pharmacokinetics. Results: Ten pts were enrolled at doses of 2 mg (n = 4), 3 mg (n = 3) and 6 mg (n = 3). Toxicity was anemia (4 G1, 1 G2), leucopenia (1 G1, 2 G2), low ANC (2 G2), hyperglycemia (2 G1, 1 G2), hyperlipidemia (4 G1), and mucositis (1 G1, 1 G2). PD responses were seen in 2 and 1 pt at 2 and 3 mg dose levels. Input of data to the mCRM selected a dose of 6 mg for the third cohort, where PD effect was seen in 1 pt, and thus a fourth dose around 9 mg will be tested. No responses by RECIST occurred, but 2 pts had a response by PET. The PK was consistent with prior data (t1/2 24.6 ± 10.2 h, CL 31.4 ± 12.0 L/h, vol of distribution 235 ± 65 L), and exposure increased with dose. Steady-state concentration were in the 5–20 nM range. Conclusions: mCRM-based dose escalation based on real-time PD assessment is feasible and permits the exploitation of PD effects for dose selection in a rational manner. No significant financial relationships to disclose.


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10536-10536 ◽  
Author(s):  
Raghav Sundar ◽  
Terri Patricia McVeigh ◽  
Ann Petruckevitch ◽  
Nikolaos Diamantis ◽  
Joo Ern Ang ◽  
...  

10536 Background: AYA cancer patients are relatively under-represented in clinical trials, with no published data regarding their outcomes in phase I studies. Trials utilizing novel therapeutic agents are often considered in these patients, due to their tendency to have good organ reserve, and ability to tolerate additional lines of therapy. This study describes the experience of AYA patients with advanced solid tumors treated in a specialized drug development unit. Methods: Patient characteristics and clinical outcomes of AYA patients (defined as age 15 to 39 years at time of initial cancer diagnosis) treated at the Drug Development Unit, Royal Marsden Hospital, United Kingdom, between 2002 and 2016, were captured and analyzed from case and trial records. Results: From a database of 2631 patients treated on phase I trials, 219 AYA patients (8%) were identified. Major tumor types included gynaecological cancer (24%), sarcoma (18%), gastrointestinal (16%) and breast cancer (11%). Patients had a median of 3 previous lines of systemic chemotherapy (range 0 – 6), and 19% participated in 2 or more phase I studies. Twenty (9%) had a known hereditary cancer syndrome (most commonly BRCA), 27% had a family history (FH) of cancer, 15% no FH and 49% no FH documented. Molecular characterization of tumors (n = 45) identified mutations most commonly in p53 (33%) , PI3KCA (18%) and KRAS (9%) . Major trial categories included DNA damage repair (16%), PI3K (16%) and anti-angiogenesis (15%) agents. Grade 3/4 toxicities were experienced in 25% of patients (10% hematological). Of the 214 evaluable patients, objective response rate was 12%, with clinical benefit rate at 6 months of 22%. Median progression free survival was 2.3 months (95% CI: 1.9 to 2.8), median OS was 7.6 months (95% CI: 6.3 to 9.5), and 2-year OS was 11%. Of patients with responses, 35% were matched to phase I trials based on germline or somatic genetic aberrations. Conclusions: A sub-group of AYA patients with advanced solid tumors derive considerable benefit from participating in trials involving novel therapeutics. Future research must focus on predictive biomarkers and molecular profiling to identify those that would benefit from novel therapies.


2007 ◽  
Vol 12 (4) ◽  
pp. 426-437 ◽  
Author(s):  
Dirk Strumberg ◽  
Jeffrey W. Clark ◽  
Ahmad Awada ◽  
Malcolm J. Moore ◽  
Heike Richly ◽  
...  

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. e13035-e13035
Author(s):  
R. Morgan ◽  
F. Valdes-Albini ◽  
T. W. Synold ◽  
P. H. Frankel ◽  
C. Ruel ◽  
...  

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e24005-e24005
Author(s):  
Ramy Sedhom ◽  
Alison Turnbull ◽  
Amanda L. Blackford ◽  
Arjun Gupta ◽  
Janet Heussner ◽  
...  

e24005 Background: Patients participating in phase I trials represent a population with advanced cancer and symptoms, with QOL implications from both disease and treatment. Transitions to end of life for these patients has received little attention. Good empirical data is needed to better understand the role of advanced care planning (ACP) and palliative care (PC) during phase I trial transitions. We investigated how physician-patient communication at time of progression, patient characteristics, and patterns of care were associated with EOL care. Methods: Retrospective chart review of all patients with solid tumors enrolled in phase I trials at a comprehensive cancer center from Jan 2015 to Dec 2017. We captured physician-patient communication during disease progression, and for all patient deaths, assessed PC referral, ACP, place of death, health care utilization in the final month of life, hospice enrollment and LOS. Factors independently associated with a short hospice LOS (defined as ≤3 days) were estimated from a multivariable model building approach. Results: Among 207 participants, median age was 61 (range 31-91), 48% were female and 20% were ethnic minorities. Predominant diagnoses were GI (40%), GU (14%), and lung cancer (15%). 40% of patients were referred from an outside institution. At the time of disease progression, 64% had goals of care documented, 57% were referred to PC, and 54% discussed hospice with their oncologist. Overall, 82% of patients died within 1 year of study enrollment. Of all patients who died, 85% enrolled in hospice and 76% died at home. In the last 30 days of life, 37% were hospitalized, 21% received chemotherapy, and 8% were admitted to the ICU. 15% had a short hospice LOS. The multivariable model revealed that increased age > 65 was positively associated with short hospice length of service (odds ratio (OR) 1.12 [95% CI 1.01, 1.24], p = 0.03), while remaining at the same institution (OR 0.72 [95% CI 0.65, 0.8], p < 0.001), and referral to PC before progression (OR 0.83 [95% CI 0.75, 0.92], p < 0.001) were associated with a decreased risk of short hospice LOS. Conclusions: This data supports the benefit of PC for patients on phase I trials and the danger of transitions for all patients, with particular attention needed for older adults, regardless of care received. Leaving a clinical trial is a time when clear communication is paramount. Phase 1 studies will continue to be vital in advancing cancer treatment. It is equally important to advance the support provided to patients who transition off these trials.


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