230 Feasibility study of targeted sequencing-based molecular prescreening of patients for Phase I clinical trials. Trial of Oncopanel for Introduction into Clinical Study Phase 1 (TOPICS-1)

364 Background: The prognosis of cholangiocarcinoma (CC) and gallbladder carcinoma (GC) remains grim. The purpose of this study was to report the presenting characteristics and outcomes of patients with CC and GC treated on phase 1 clinical trials focused on targeted agents at a major cancer center. Methods: We reviewed the records of consecutive patients with GC and CC in the Phase I Clinical Trials Program at the M. D. Anderson Cancer Center from Nov 2004. We assessed the relationship between overall survival, patients' tumor types, and mutations, demographic and clinical characteristics. Results: Fifty-two patients were identified (7 with GC, 45 with CC). The median age was 58 yrs (range, 20-75 yrs). ECOG performance status (PS) was 0, 1, 2, and 3 in 9 (17%), 30 (58%), 7 (13%), and 6 (12%) pts, respectively. Median number of prior therapies was 3 (range 0-17). The median time from diagnosis of metastatic disease to primary Phase I clinic evaluation was 14.6 months. Of 52 patients, 17 (33%) were not enrolled on a Phase I trial due to decline in PS (n=13) or decision to pursue other treatments (n=4). Of 35 patients evaluable for response, 2 (6%) had a partial response (PR), and 3 (9%) had stable disease > 4 months. Prognostic factors analyzed include Hg < 10.5 g/dL, elevated CA 19-9 (>47 ng/mL), ECOG PS > 3, LDH > 618 IU/L, albumin < 3.5 g/dL, platelets < 150 K/UL, and number of metastatic sites. Full analysis including the mutational analysis for PIK3CA, KRAS, BRAF, TP53 is in progress. Median survival since presentation to the Phase I clinic was 4.1 months (range 2.3 - 30.8 months). Median overall survival from diagnosis was 23.9 months. The median survival since enrollment in a Phase I trial was 4.6 months w the median time to disease progression on Phase I treatment was 2.2 months (range 0.6 - 25.6 months). Conclusions: Prognosis of pts with CC and GC referred for phase I studies remains poor. Further analysis including complete mutational profiles of CC and GC patients will be reported.

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The role of phase I clinical trials in advanced malignant melanoma: Retrospective analysis of CTEP-sponsored trials 1995-2011.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2606 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2606-2606

Author(s):

Jason John Luke ◽

Larry Rubinstein ◽

Gary L Smith ◽

S. Percy Ivy ◽

Pamela Jo Harris

Keyword(s):

Clinical Trials ◽

Phase I ◽

Phase 1 ◽

Therapeutic Benefit ◽

Phase Iii ◽

Phase I Trials ◽

Toxicity Data ◽

Phase I Clinical Trials ◽

Exact Test ◽

Phase Iii Clinical Trials

2606 Background: Standard chemotherapy for melanoma is DTIC (RR ~10%). Many physicians do not refer to phase I due to perceived limited clinical benefit (CB=CR+PR+SD) and increased toxicity. To understand the actual experience of melanoma patients (pts) in phase I trials, we analyzed the outcomes of melanoma pts treated on CTEP phase 1 trials (1995-2011) and compared them to DTIC. Methods: We queried the CTMS of CTEP for phase I trials in which advanced melanoma pts were treated. Trials were separated into targeted (T), chemo (C) and immunotherapy (I). Pt characteristics, response and toxicity data were collected. Chemotherapy included chemo with targeted or immunotherapy. Toxicity was drug related if attributed possibly, probably or definitely to drug. Fisher’s Exact Test (2-sided p) was used to compare groups. DTIC data was pooled from 6 modern phase III clinical trials (1999-2011). Results: 937 pts (M595:F342) participated in 148 trials (T: 68, C: 53, I: 27). Characteristics included (median) Age: 51.5 yrs; ECOG status: 0; Prior therapies: 2 (majority receiving prior DTIC); LDH: 206 and albumin: 4.1. Response and toxicity data are shown in the Table. Targeted therapy was associated with lower RR (p=.01), immuno with lower CB rate (p<.001) and chemo with higher incidence of G4 toxicity (p<.001) relative to the other groups. Comparing phase 1 to DTIC, RR and CB were not clinically different (phase I: 6.3% and 26.8% vs. DTIC: 8.8% and 27.9%) but G3-4 toxicity was significantly higher (54% vs. 28%) in phase I (p<.0001). Conclusions: Melanoma pts in prior CTEP phase I trials, a majority DTIC pre-treated, had similar therapeutic benefit but more toxicity compared to DTIC naïve pts in modern clinical trials. [Table: see text]

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Targeted agents matched with tumor molecular aberrations: Review of 160 patients with advanced melanoma treated in a phase I clinic.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.8551 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 8551-8551

Author(s):

Haby Adel Henary ◽

David S. Hong ◽

Gerald Steven Falchook ◽

Apostolia Maria Tsimberidou ◽

Goldy George ◽

...

Keyword(s):

Clinical Trials ◽

Phase I ◽

Systemic Therapy ◽

Phase I Trial ◽

Phase 1 ◽

Targeted Agents ◽

Phase I Clinical Trials ◽

Kit Mutation ◽

Targeted Agent ◽

Molecular Aberrations

8551 Background: Identification of activating mutations in melanoma has increased the number of novel targeted agents for this disease. Methods: Weretrospectively reviewed clinical outcomes of 160 consecutive metastatic melanoma patients (pts) treated in the Dept of Investigational Cancer Therapeutics (Phase I program) at M. D. Anderson since 2008, and compared their median progression free survival (PFS) to their first and last standard systemic therapy PFS. In addition, we compared those pts’ outcomes tested for tumor molecular aberrations on a phase I trial with a matched targeted agent with those of pts who were treated without regard for their molecular profiles. Results: Of 160 pts treated on 35 different phase 1 clinical trials, 110 pts (69%) had ≥ 1 molecular aberration. Of those pts who had adequate tissue for molecular analysis, 63% (85/134) pts had BRAF mutation, 20% (22/109) NRAS mutation, 20% (1/5) GNAQ mutation, 11% (1/9) P53 mutation, 2.5% (1/39) PIK3CA and 1.3% (1/76) had KIT mutation. 77 (48%) pts were treated on a phase I trial with a matched targeted agent and 83 (52%) pts were treated on a non-matched phase 1 trial. The overall response rate was 39% (complete response [CR], 9%; partial response [PR], 30%) in the 77 pts treated with matched therapy and 9% (all PRs) in the 83 pts treated without matched therapy (P = 0.0018). 139 (87%) pts received at least one systemic therapy before referral to phase I, median PFS was longer on phase 1 therapy than on last line standard therapy prior to referral to phase 1 (4.2 vs. 2.8 months, P = 0.002). Median PFS was greater for pts on matched vs. non-matched therapy (5.3 vs. 3.7 months, log rank P = 0.004). Also, median PFS was longer on phase 1 matched trial than on first standard treatment (5.3 vs. 3.9 months, log rank P = 0.045).PFS did not differ between first standard and non-matched phase 1 study. Univariate analyses with the log rank test revealed that matched therapy (P = 0.004) was positively associated with longer PFS on phase I clinical trials. Conclusions: Matching melanoma pts with targeted drugsbased on specific molecular aberrations in the phase I setting can be associated with superior outcomes compared to prior standard systemic therapies.

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Integration of supportive care in immuno-oncology trials: Investigating the incidence and severity of immune-related toxicities among older adults versus mid-age patients on immunotherapy-based phase I clinical trials.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.31_suppl.152 ◽

2017 ◽

Vol 35 (31_suppl) ◽

pp. 152-152

Author(s):

Ishwaria Mohan Subbiah ◽

Kenneth R. Hess ◽

Takeo Fujii ◽

Anna Lui ◽

Vivek Subbiah ◽

...

Keyword(s):

Older Adults ◽

Clinical Trials ◽

Adverse Events ◽

Supportive Care ◽

Phase I ◽

Phase 1 ◽

Low Grade ◽

Phase I Trials ◽

High Grade ◽

Phase I Clinical Trials

152 Background: Older adults (65y+) with cancer are underrepresented in trials of novel drugs notably in phase I clinical trials with immunotherapies. The trepidation over immune-related toxicities in the context of older age and associated comorbidities may function as a barrier to participation. To that end, we investigated the enrollment and incidence of immune related adverse events of older adults enrolled in phase 1 immunotherapy trials. Methods: We identified 422 consecutive pts w advanced cancer treated on immunotherapy-based phase I trials bw 04/2009-09/2015, and collected pt/disease characteristics and immune-related adverse events (irAE) such as endocrinopathies, diarrhea/colitis, pneumonitis, constitutional (fatigue, fever, anorexia), myalgia, and dermatitis. Results: Older adults comprised 27% of trial participants (116 of 422 pts, median age 70y) while 256 pts were mid age (61%, median 56y). Most common cancers were GI (n = 108, 26%), thoracic/head/neck (n = 84, 20%), GU (n = 54, 13%), and GYN (n = 47, 11%). Median PFS was comparable among older pts (2.4m) and mid age (2.1m). Older adults had a higher incidence of irAE than mid age (low grade [G1/2] 49% vs 34%, p 0.02; high grade [G3/4] 19% vs 11%. p 0.14). The odds ratio of high grade events among older adults vs mid age pts was 1.81 (95% CI 1.01, 3.24; p 0.05) and low grade events was 1.85 (95% CI 1.20, 2.85; p 0.0055). Most common G1/2 irAE among all patients was fatigue (n = 76, 18%), dermatitis (n = 59, 14%), fever (n = 29, 7%) and anorexia (n = 28, 7%) with older adults having a greater incidence of low grade fatigue (25% vs 15%, OR 1.84, 95% CI 1.09, 3.10, p 0.025). Conclusions: Older adult participation remained under 30% for immunotherapy-based phase I trials. This early analysis suggests a higher incidence of toxicities among older adults, which calls for the urgent integration of comprehensive supportive care strategy to guide seniors through therapy. This work lays the foundation for future studies investigating the early involvement of supportive care through treatment on early phase clinical trials with immunotherapeutic agents.

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Investigating the disparate enrollment of older adults on phase I clinical trials: Evolving participation patterns of patients 65 years and older w advanced cancer on phase I trials.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.12044 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 12044-12044

Author(s):

Ishwaria Mohan Subbiah ◽

Aman Buzdar ◽

Ecaterina Elena Ileana Dumbrava ◽

Siqing Fu ◽

Filip Janku ◽

...

Keyword(s):

Older Adults ◽

Clinical Trials ◽

Phase I ◽

Oldest Old ◽

Phase 1 ◽

Single Agent ◽

Primary Objective ◽

Dose Finding ◽

Phase I Trials ◽

Phase I Clinical Trials

12044 Background: While safety and dose-finding remain the primary objective of Phase 1 trials, the potential for clinical benefit has taken a greater meaning in the last decade with the novel therapies. With data from phase I trials being submitted for regulatory approval, the finer details of these studies are under even more scrutiny: in particular, do the trial participants reflect the general patient population for whom the drug may be indicated? To that end, we investigated age-based enrollment on phase I clinical trials over time. Methods: We queried a prospectively maintained database at a major phase I trials center to identify eligible patients and demographic + clinical variables including phase I trial characteristics, age at date of enrollment into 3 age-based cohorts: AYA ages 15-39y, mid-age 40-64y, older adults aged 65y+. We calculated descriptive statistics, and explored correlations (Pearson/Spearman) and associations (linear regression) between age and independent variables. Results: Over a 3-year period (1/1/17 to 12/31/19), we identified 6267 pts enrolled on 338 phase I trials. Median overall age 58.4y (range 15.5-95.1y). 729 (12%, median age 34.8y) were AYA, 3652 (58%, median age 55.4y) mid-age and 1886 (30%, median 70y) older adults, of whom 870 pts were aged 70-79y and 76 pts aged 80y+ (18 being >85y). There was no association b/w senior participation and year of enrollment (2017 31%, 2018 29%, 2019 30%, b/w age and type of therapy (i.e. targeted vs immunotherapy, etc.) or b/w age and # of drugs given on trial (single agent vs combo) (all p > 0.05). Conclusions: Older adults remain underrepresented on phase I trials esp. when compared to incidence of cancer in that age group (30% enrollment vs 60% incidence), a discordance more staggering in the oldest old pts (85y+; only 18 pts enrolled over 3 yrs when compared to 140,690 pts 85y+ w a new cancer dx in just 2019). Once enrolled, older adults received similar types of phase I therapies with comparable number of drugs as compared to middle age patients, i.e. older adults were just as likely to get immunotherapy or targeted therapy as well mono- vs combo therapy as mid-age pts. [Table: see text]

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Optimal biological dose: a systematic review in cancer phase I clinical trials

BMC Cancer ◽

10.1186/s12885-021-07782-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

J. Fraisse ◽

D. Dinart ◽

D. Tosi ◽

C. Bellera ◽

C. Mollevi

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Phase I ◽

Dose Escalation ◽

Phase 1 ◽

Dose Finding ◽

Cancer Clinical Trials ◽

Phase I Clinical Trials ◽

Cancer Trial ◽

Biological Dose

Abstract Background Classical phase 1 dose-finding designs based on a single toxicity endpoint to assess the maximum tolerated dose were initially developed in the context of cytotoxic drugs. With the emergence of molecular targeted agents and immunotherapies, the concept of optimal biological dose (OBD) was subsequently introduced to account for efficacy in addition to toxicity. The objective was therefore to provide an overview of published phase 1 cancer clinical trials relying on the concept of OBD. Methods We performed a systematic review through a computerized search of the MEDLINE database to identify early phase cancer clinical trials that relied on OBD. Relevant publications were selected based on a two-step process by two independent readers. Relevant information (phase, type of therapeutic agents, objectives, endpoints and dose-finding design) were collected. Results We retrieved 37 articles. OBD was clearly mentioned as a trial objective (primary or secondary) for 22 articles and was traditionally defined as the smallest dose maximizing an efficacy criterion such as biological target: biological response, immune cells count for immunotherapies, or biological cell count for targeted therapies. Most trials considered a binary toxicity endpoint defined in terms of the proportion of patients who experienced a dose-limiting toxicity. Only two articles relied on an adaptive dose escalation design. Conclusions In practice, OBD should be a primary objective for the assessment of the recommended phase 2 dose (RP2D) for a targeted therapy or immunotherapy phase I cancer trial. Dose escalation designs have to be adapted accordingly to account for both efficacy and toxicity.

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Left versus right: Does location matter for refractory metastatic colorectal cancer (mCRC) patients in phase I clinical trials?

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.771 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 771-771

Author(s):

Sukeshi R. Patel ◽

Norma S. Ketchum ◽

Joel Michalek ◽

Jonathan Gelfond ◽

Devalingam Mahalingam

Keyword(s):

Clinical Trials ◽

Growth Factor ◽

Phase I ◽

Primary Tumor ◽

Phase 1 ◽

Cohort Analysis ◽

Rank Test ◽

Phase I Clinical Trials ◽

Historical Cohort ◽

Heavily Pretreated

771 Background: Location of the primary tumor is prognostic and predictive of efficacy with VEGF-inhibitors (I) vs EGFR-I given first-line to mCRC patients (pts) (ASCO 2016). However, little is known regarding the effect of location on prognosis and prediction in heavily pretreated mCRC pts. We assessed the efficacy of VEGF-I and EGFR-I in regards to location of the primary tumor in pts with refractory mCRC enrolled in early phase studies. Methods: A historical cohort analysis of mCRC pts enrolled amongst 44 phase I trials at the IDD from 3/2004 - 9/2012. Median Progression free survival (mPFS) and overall survival (mOS) were estimated from Kaplan-Meier curves and groups were statistically compared with the log rank test. The magnitude of association between dichotomous factors and survival was estimated with the hazard ratio (HR). Results: 139 pts, median age 59 (33-81), KRAS mut 20 %, wt 31 %, unknown 49 %. ≥ 3 prior lines therapy 73.9 %; Prior EGFR-I 75.5% (100% of KRAS wt). Location: Right 20.9 %, Left 61.9 %, Transverse 4.3 %, Unknown 12.9 %. Phase I agents: VEGF I 19.4%, EGFR/Growth Factor I 9.3%. For survival analysis, transverse were included with right. Of 112 pts, mOS: Left (n = 80) 6.6 months (mo) vs Right (n = 32) 5.9 mo, p = 0.18. mPFS: Left (n = 86) 2.0 mo vs Right (n = 35) 2.0 mo, p = 0.76. Survival in regards to location or biologic agent (table). Conclusions: In phase 1 clinical trials, although location alone was not prognostic in heavily pretreated pts, left-sided mCRC had improved survival with EGFR-I. Despite progression on EGFR I, left-sided KRAS wild mCRC pts should be considered for phase 1 studies of agents targeting the growth factor pathways. [Table: see text]

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Phase I clinical trials in refractory colorectal cancer (CRC): Do older adult patients benefit?

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.784 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 784-784

Author(s):

Sukeshi Patel Arora ◽

Norma S. Ketchum ◽

Jonathan Gelfond ◽

Joel Michalek ◽

Devalingam Mahalingam

Keyword(s):

Risk Factors ◽

Clinical Trials ◽

Phase I ◽

Phase 1 ◽

Cohort Analysis ◽

Clinical Trial Data ◽

The Elderly ◽

Rank Test ◽

Phase I Clinical Trials ◽

Historical Cohort

784 Background: Current clinical trial data are largely driven by younger participants, yet half the population diagnosed with CRC are 70+. Upon progression, many CRC patients (pts) with refractory cancer are referred to phase 1 clinical trials; however, tolerability and clinical benefit is unclear in the elderly. Given our robust phase 1 program, we assessed the efficacy and safety of early therapeutics in the elderly CRC pts. Methods: A historical cohort analysis included mCRC pts enrolled amongst 44 phase I trials from 3/2004 - 9/2012. Median Progression free survival (mPFS) and overall survival (mOS) were estimated from Kaplan-Meier curves and groups were statistically compared with the log rank test. The magnitude of association between dichotomous factors and survival was estimated with the hazard ratio (HR). Results: 139 pts, median age 59 (33-81), 70+ 16.5% (n = 23); KRAS mut 39.4 %. ≥3 prior lines of therapy 73.9 %; Prior EGFR-I 75.5% (100% of KRAS wt). Location: Right 20.9 %, Left 61.9 %, Transverse 4.3 %, Unknown 12.9 %. Phase I agents: VEGF I 19.4%, EGFR/Growth Factor I 9.3%. mOS for < 70 (n = 108) vs 70+ (n = 22): 6.5 vs 4.2 months (HR 1.88, p 0.007). mPFS for < 70 (n = 116) vs 70+ (n = 23): 2.0 months vs x 1.5 months (HR 1.73, P 0.03). There was not a statistical difference between < 70 versus 70+ in regards to dose cohort, number of cycles completed, or adverse events. Survival analysis in terms of risk factors in pts 70+ are in the Table below. Conclusions: Elderly CRC pts are underrepresented (16.5%) in phase 1 clinical trials and have worse survivals than non-elderly pts. Elderly CRC pts with liver and hematologic toxicities had a trend toward worse PFS but no OS. Phase I studies should incorporate prospective assessments to identify risk factors of morbidity and mortality in elderly CRC pts. [Table: see text]

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Justification of participation of human subjects in Phase 1 clinical trials: an ethical analysis

Bangladesh Journal of Bioethics ◽

10.3329/bioethics.v2i2.9543 ◽

1970 ◽

Vol 2 (2) ◽

pp. 26-29

Author(s):

Inayat Ullah Memon

Keyword(s):

Clinical Trials ◽

Phase I ◽

Ethical Issues ◽

Human Subjects ◽

Phase 1 ◽

Therapeutic Interventions ◽

Research Subjects ◽

Phase I Clinical Trials ◽

Healthy Human

In the process of clinical trials, after ascertaining the safety of drugs or other therapeutic interventions in animals or in vivo, phase I clinical trials are conducted as initial step on healthy human volunteers (or patients with specific disease) to observe pharmacokinetics, safety and side effects associated with escalating doses of the drugs. Participation of human subjects having different biological system than animals is not without risks in these trials; this fact raises some important ethical issues. In the light of international research ethics guidelines, this paper analyses moral justification of use of humans as research subjects in phase I clinical trials, discusses what groups of participants should be involved, their economic status, questionable coercive effect of monetary remuneration on the subjects and soundness of informed consent obtained for the trials. These issues are also discussed in the perspective of four founding principles of bioethics i.e. autonomy, justice, beneficence and non-maleficence. DOI: http://dx.doi.org/10.3329/bioethics.v2i2.9543 Bangladesh Journal of Bioethics 2011; 2(2): 26-29

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Retrospective study of phase I clinical trials participation in patients at least 65 years of age at Karmanos Cancer Institute (KCI), Wayne State University, Detroit, Michigan

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e20626 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e20626-e20626

Author(s):

P. Vishnu ◽

P. Jasti ◽

L. Ding ◽

L. K. Heilbrun ◽

R. Venkatramanamoorthy ◽

...

Keyword(s):

Clinical Trials ◽

Phase I ◽

Phase 1 ◽

Performance Status ◽

The Elderly ◽

Primary Objective ◽

Biologic Agent ◽

Tumor Type ◽

Phase I Clinical Trials

e20626 Background: It is important to increase our understanding of recruitment barriers in the elderly population to improve their participation in clinical trials. The primary objective of this study was to describe the demographics, treatment, toxicity, and overall survival (OS) of all patients ≥ 65 years who presented to the Phase I clinical trials service at KCI between 1995–2005. Methods: Patient demographics, co-morbidities, tumor type, reason not enrolled on a Phase 1 clinical trial, toxicities, and OS were obtained by retrospective chart reviews. The patients were divided into 3 mutually exclusive groups: patients considered but not enrolled (PC), enrolled but not treated (PE), and treated (PT). OS was compared across these three groups. Results: 216 patients met the study criteria. Of these, there were 114 PC, 7 PE, and 95 PT. Lack of enrollment was due to ineligibility (30%), loss to follow-up (12%), refusal (8%), or no trial available (2%). Median age was 71 years, 63% were males and 87% were Caucasian. 59% had performance status (PS) 1; 16% had PS 2. 66% of patients had a history of cardiovascular disease but renal, liver, hematological diseases were found in less than 7% of patients at baseline. Colorectal (27%), lung (15%) and prostate (8%) were the 3 most common cancers. 54% received a cytotoxic agent, 62% a biologic agent, and 17% combination therapy. The 3 most common Grade 3–4 toxicities were: 15% leucopenia, 11% electrolyte abnormalities, and 4% anemia. The median OS for PC, PE, and PT was 3.9 mos, 2.2 mos, and 8.4 mos, respectively (p < 0.001 between any pair). However, PS 0–1 patients comprised 47%, 75%, and 73% of those 3 patient subgroups, respectively. Conclusions: More than half of the elderly patients initially considered for Phase 1 clinical trials at KCI were not enrolled due to ineligibility, refusal, or lost to follow up. Phase I chemotherapy appears feasible in patients age ≥ 65 years old. OS was significantly longer for patients treated on Phase I trials compared to those who were not, although that may be confounded by PS differences. More detailed OS comparisons will be presented. No significant financial relationships to disclose.

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