- Email: [email protected]
Demonstrating the changing trends in phase I clinical trials
abstracts CI 1.39-5.10; Wald test p¼.003), while pts who received 2 lines of treatment in the metastatic setting presented with higher ORR (OR 2.37; 95%, CI 1.03-5.44; Wald test p¼.004). Conclusions: Our results confirmed the consistent improvement in terms of CBR and ORR of the new generation Ph1 as compared to historical reported data. Better outcomes were observed in less pre-treated pts with lower burden of disease, suggesting that Ph1 should be proposed in earlier lines of therapy to derive a greater benefit. Further analyses on a larger cohort of Ph1 patients are currently ongoing. Legal entity responsible for the study: Istituto Europeo di Oncologia. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Patient (pt) selection for immunotherapeutic early-phase clinical trials (ieCTs): A single phase I unit experience
M. Simonelli1, E. Lorenzi2, A. Dipasquale1, P. Persico1, G. Ninatti1, L. Giordano2, M. Bertossi2, A. Santoro1 1 Department of Biomedical Sciences, Humanitas University, Humanitas Clinical and Research Hospital - IRCCS, Pieve Emanuele, Italy, 2Oncology and Hematology, Humanitas Clinical and Research Hospital, Rozzano, Italy Background: Selecting which pts may benefit from ieCTs is challenging. Few prognostic indexes have been proposed so far and none qualifying as a predictor of response. The Gustave Roussy Immune Score (GRImS) identifies two prognostic categories based on three objective variables (albumin<3.5 g/dL¼1; LDH>ULN¼1; NLR>6¼1). Methods: We retrospectively reviewed data of all pts enrolled into ieCTs at the Humanitas Cancer Center Phase I Unit between 2014 and 2019. A large series of demographic and clinical variables were correlated with overall survival (OS) and objective response rate (ORR) through univariate and multivariate analysis (UVA; MVA). Laboratory parameters were calculated either as baseline values and as dynamic sixweeks (6wks) changes. Finally, we explored the performance of the GRImS in our cohort. Results: A total of 111 pts (M/F:63/48; median age: 62) with advanced solid tumors treated into ieCTs have been selected. The most frequent histologies were hepatocellular carcinoma (34%), lung carcinoma (22%), glioblastomas (13%). With a median follow-up (FU) of 14.3 months (mos), the OS was 12.9 mos, and the ORR 12.6%. In the UVA ECOG PS < 1 (HR ¼ 0.53; IC 0.30-0.94; p ¼ 0.030) and higher baseline value of albumin (HR ¼ 0.40; IC 0.21-0.77; p ¼ 0.006) were significantly associated with a better OS, while baseline total protein level (OR ¼ 1.47; IC 1.24 - 2.10; p ¼ 0.030), and increase in lymphocytes count at 6wks (OR ¼ 1.02; IC 1.00-1.04; p ¼ 0.029) were predictive of response. In the MVA only higher baseline value of albumin seems to confirm its independent prognostic value (HR ¼ 0.48; IC 0.23-1.01; p ¼ 0.054), as well as baseline total protein level its predictive role (OR ¼ 1.52; IC 1-2.33; p ¼ 0.052). The GRImS resulted prognostic, with pts at low-risk (1) having a significant better OS compared to pts with a high-risk score (>1) (14.3 mos vs 7.3 mos; p ¼ 0.029), but not predictive. Conclusions: We assessed the prognostic accuracy of GRImS in our ieCTs cohort. With limitations due to small sample size, short FU and few events recorded we identified additional static and dynamic variables with a potential prognostic and predictive relevance to be further explored in larger series and to be eventually included in new scores. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: M. Simonelli: Advisory / Consultancy: AbbVie. A. Santoro: Advisory / Consultancy: Bristol-Myers-Squibb; Advisory / Consultancy: Servier; Advisory / Consultancy: Gilead; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eisai; Advisory / Consultancy: Bayer; Advisory / Consultancy: Merck Sharp & Dohme; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Bristol-Myers-Squibb; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert Testimony: Abbvie; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony: Servier; Speaker Bureau / Expert testimony: Gilead; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Arqule; Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: SANDOZ. All other authors have declared no conflicts of interest.
493P
Improving patient selection for immuno-oncology phase I trials: An external validation of five prognostic scores at Claudius Regaud Institute of Toulouse, Oncopoˆle (IUCT-O)
G. Al Darazi1, E. Martin2, J-P. Delord3, I. Korakis3, S. Betrian1, M. Poublanc2, F. Ollivier4, T. Filleron2, C.A. Gomez-Roca3 1 Medical Oncology & Clinical Research, Institut Claudius Regaud, Toulouse, France, 2 Statistics, Institut Claudius Regaud, Toulouse, France, 3Medical Oncology & Clinical Research, Institut Claudius Regaud, Toulouse, Haute-Garonne, France, 4Clinical Research Department, Institut Claudius Regaud, Toulouse, France Background: We aimed to compare the performance of 5 prognostic scores (RMH: Royal Marsden Hospital, MDACC: MD Anderson Clinical Center, MDA-ICI: MD Anderson Immune Checkpoint Inhibitors, GRIm: Gustave Roussy Immune Score and LIPI: Lung Immune Prognostic Index) in predicting overall survival (OS) in phase 1 patients treated with immune checkpoint inhibitors (ICI).
v186 | Developmental Therapeutics
Methods: We reviewed records of patients with advanced solid tumors enrolled in phase 1 ICI trials between 2015 and 2018 at IUCT-O. We compared the performance of prognostic scores using Akaike criterion, discriminatory ability (Harrell’s C, the Royston’s D) and proportion of explained variation (R2) statistics. Primary endpoint was OS. ANC: Absolute Neutrophil Count ALC: Absolute Lymphocyte count (d)NLR: (Derived) Neutrophil / Lymphocyte ratio PS: Performance status
Table: 493P
Sites of metastases > 2 LDH > ULN LDH > 466 Albumin < 35 G/L Gastrointestinal tumor PS 1 PS > 1 Age > 52 years Platelet count > 300 ANC > 4.9 ALC < 1.8 liver metastases NLR > 6 dNLR > 3 AIC CH Dadj R2 adj
RMH
MDACC
MDA-ICI
GRIm
LIPI
1310.7 0.60 0.67 0.096
1290.0 0.67 0.94 0.176
1296.4 0.64 0.81 0.136
1293.5 0.66 0.98 0.186
1296.9 0.65 0.84 0.145
Results: A total of 259 patients were included. Median age was 63 years (range 18-83). Main primary cancers were melanoma (18.5%), head and neck (16.2%), lung (12.7%) and bladder (9.7%). With a median follow up of 15 months (95% CI: [11.6;17.5]), median OS was 12.5 months (95%CI ¼ [10.3;16.0]). All scores were associated with OS: Hazard Ratio (HR)¼1.98 [1.41;2.78] for RMH score 2-3 vs 0-1, HR ¼ 1.68 [1.09;2.60] for MDA score 2 and 3.65 [2.42;5.51] for score 3-5 vs 0-1, HR ¼ 1.18 [0.77;1.81] for MDA-ICI score 3; HR ¼ 2.70 [1.74;4.17] for score 4 and HR ¼ 4.85 [2.62;8.98] for 5-6 vs 0-2, HR ¼ 2.70 [1.92;3.79] for GRIm score 2-3 vs 0-1 and finally 1.86 [1.25;2.78] for LIPI score 1 and HR ¼ 3.86[2.43;6.13] for score 2 vs 0. MDA and GRIm scores obtained more significant results for discrimination than RMH, MDAICI and LIPI (Table). Conclusions: The utilization of theses scores could allow a better patients selection in early trials, especially during the critical periods of dose escalation and proof-of-concept expansion cohorts. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
494P
Demonstrating the changing trends in phase I clinical trials
C. Guo, R. Kelly, J. Desai, B. Tran Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia Background: Early drug development and phase 1 (P1) clinical trials have changed dramatically in the past decade, as targeted therapies and then immune-oncology evolved. Understanding the changing trends in P1 trials allows more targeted resource investment at the site level, but also at the industry level. We describe the changes in the P1 trial landscape in solid tumours over the past decade. Methods: P1 trials registered on ClinicalTrials.gov to start between 1/1/2009-31/12/ 2018 were extracted using the parameters: cancer, 18 years (yr) old, active, recruiting, completed, (early) P1 and interventional. Of the 7,870 trials identified, 3,031 were excluded on the following basis: not conducted in patients with solid tumours, directed at supportive care, solely involving radiotherapy (RT), testing of a device or procedure or solely involving dietary interventions. The 4,839 eligible studies were categorized by treatment type, tumor type, start date and study location. Studies were independently reviewed by two clinicians. Results: In the past decade, there was an average increase of 5%/yr in the number of P1 registered, reflected by substantial increases in trials investigating immune-oncology agents (IO) (average increase: 36%/year) and cell therapies (CT) (average increase: 17%/yr). P1 trials using chemotherapy (C) (average decrease: 1%/yr) or targeted therapies (T) (average decrease: 1%/yr) have plateaued. Clinical trials combining IO with T or C or RT increased by an average of 45%/yr. Most P1 studies (41%) enrolled multiple tumour types. Studies frequently involved North American (68.5%), European
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz244.056/5576555 by guest on 27 October 2019
492P
Annals of Oncology
abstracts
Annals of Oncology (29.3%) and Asia Pacific sites (34%). The inclusion of Asia Pacific sites increased most substantially (average increase: 8%/year). P1 Trials Classified by Type of Therapy (2009-2018)
Table: 494P
1
C1
T1
CT1
Total
4% (30) 12% (89) 17% (141) 33% (364) 44% (581)
39% (324) 36% (276) 32% (258) 29% (320) 23% (305)
66% (557) 64% (491) 57% (467) 48% (529) 40% (524)
5% (39) 3% (25) 6% (47) 9% (98) 11% (140)
839 767 814 1095 1324
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz244.056/5576555 by guest on 27 October 2019
2009-10 2011-12 2013-14 2015-16 2017-18
IO1
Includes P1 trials using a combination of treatments.
Conclusions: The conduct of P1 trials has increased markedly over the past decade, driven by growing interest in IO. Legal entity responsible for the study: Peter MacCallum Cancer Centre. Funding: Has not received any funding. Disclosure: J. Desai: Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Novartis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bionomics; Research grant / Funding (institution): MedImmune; Advisory / Consultancy, Research grant / Funding (institution): BeiGene; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (institution), Advisory / Consultancy: Eisai; Advisory / Consultancy: Ignyta. B. Tran: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astella; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen-Cilag; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy: Tolmar; Advisory / Consultancy: Ipsen. All other authors have declared no conflicts of interest.
Volume 30 | Supplement 5 | October 2019
doi:10.1093/annonc/mdz244 | v187
Patient (pt) selection for immunotherapeutic early-phase clinical trials (ieCTs): A single phase I unit experience
M. Simonelli1, E. Lorenzi2, A. Dipasquale1, P. Persico1, G. Ninatti1, L. Giordano2, M. Bertossi2, A. Santoro1 1 Department of Biomedical Sciences, Humanitas University, Humanitas Clinical and Research Hospital - IRCCS, Pieve Emanuele, Italy, 2Oncology and Hematology, Humanitas Clinical and Research Hospital, Rozzano, Italy Background: Selecting which pts may benefit from ieCTs is challenging. Few prognostic indexes have been proposed so far and none qualifying as a predictor of response. The Gustave Roussy Immune Score (GRImS) identifies two prognostic categories based on three objective variables (albumin<3.5 g/dL¼1; LDH>ULN¼1; NLR>6¼1). Methods: We retrospectively reviewed data of all pts enrolled into ieCTs at the Humanitas Cancer Center Phase I Unit between 2014 and 2019. A large series of demographic and clinical variables were correlated with overall survival (OS) and objective response rate (ORR) through univariate and multivariate analysis (UVA; MVA). Laboratory parameters were calculated either as baseline values and as dynamic sixweeks (6wks) changes. Finally, we explored the performance of the GRImS in our cohort. Results: A total of 111 pts (M/F:63/48; median age: 62) with advanced solid tumors treated into ieCTs have been selected. The most frequent histologies were hepatocellular carcinoma (34%), lung carcinoma (22%), glioblastomas (13%). With a median follow-up (FU) of 14.3 months (mos), the OS was 12.9 mos, and the ORR 12.6%. In the UVA ECOG PS < 1 (HR ¼ 0.53; IC 0.30-0.94; p ¼ 0.030) and higher baseline value of albumin (HR ¼ 0.40; IC 0.21-0.77; p ¼ 0.006) were significantly associated with a better OS, while baseline total protein level (OR ¼ 1.47; IC 1.24 - 2.10; p ¼ 0.030), and increase in lymphocytes count at 6wks (OR ¼ 1.02; IC 1.00-1.04; p ¼ 0.029) were predictive of response. In the MVA only higher baseline value of albumin seems to confirm its independent prognostic value (HR ¼ 0.48; IC 0.23-1.01; p ¼ 0.054), as well as baseline total protein level its predictive role (OR ¼ 1.52; IC 1-2.33; p ¼ 0.052). The GRImS resulted prognostic, with pts at low-risk (1) having a significant better OS compared to pts with a high-risk score (>1) (14.3 mos vs 7.3 mos; p ¼ 0.029), but not predictive. Conclusions: We assessed the prognostic accuracy of GRImS in our ieCTs cohort. With limitations due to small sample size, short FU and few events recorded we identified additional static and dynamic variables with a potential prognostic and predictive relevance to be further explored in larger series and to be eventually included in new scores. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: M. Simonelli: Advisory / Consultancy: AbbVie. A. Santoro: Advisory / Consultancy: Bristol-Myers-Squibb; Advisory / Consultancy: Servier; Advisory / Consultancy: Gilead; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eisai; Advisory / Consultancy: Bayer; Advisory / Consultancy: Merck Sharp & Dohme; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Bristol-Myers-Squibb; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert Testimony: Abbvie; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony: Servier; Speaker Bureau / Expert testimony: Gilead; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Arqule; Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: SANDOZ. All other authors have declared no conflicts of interest.
493P
Improving patient selection for immuno-oncology phase I trials: An external validation of five prognostic scores at Claudius Regaud Institute of Toulouse, Oncopoˆle (IUCT-O)
G. Al Darazi1, E. Martin2, J-P. Delord3, I. Korakis3, S. Betrian1, M. Poublanc2, F. Ollivier4, T. Filleron2, C.A. Gomez-Roca3 1 Medical Oncology & Clinical Research, Institut Claudius Regaud, Toulouse, France, 2 Statistics, Institut Claudius Regaud, Toulouse, France, 3Medical Oncology & Clinical Research, Institut Claudius Regaud, Toulouse, Haute-Garonne, France, 4Clinical Research Department, Institut Claudius Regaud, Toulouse, France Background: We aimed to compare the performance of 5 prognostic scores (RMH: Royal Marsden Hospital, MDACC: MD Anderson Clinical Center, MDA-ICI: MD Anderson Immune Checkpoint Inhibitors, GRIm: Gustave Roussy Immune Score and LIPI: Lung Immune Prognostic Index) in predicting overall survival (OS) in phase 1 patients treated with immune checkpoint inhibitors (ICI).
v186 | Developmental Therapeutics
Methods: We reviewed records of patients with advanced solid tumors enrolled in phase 1 ICI trials between 2015 and 2018 at IUCT-O. We compared the performance of prognostic scores using Akaike criterion, discriminatory ability (Harrell’s C, the Royston’s D) and proportion of explained variation (R2) statistics. Primary endpoint was OS. ANC: Absolute Neutrophil Count ALC: Absolute Lymphocyte count (d)NLR: (Derived) Neutrophil / Lymphocyte ratio PS: Performance status
Table: 493P
Sites of metastases > 2 LDH > ULN LDH > 466 Albumin < 35 G/L Gastrointestinal tumor PS 1 PS > 1 Age > 52 years Platelet count > 300 ANC > 4.9 ALC < 1.8 liver metastases NLR > 6 dNLR > 3 AIC CH Dadj R2 adj
RMH
MDACC
MDA-ICI
GRIm
LIPI
1310.7 0.60 0.67 0.096
1290.0 0.67 0.94 0.176
1296.4 0.64 0.81 0.136
1293.5 0.66 0.98 0.186
1296.9 0.65 0.84 0.145
Results: A total of 259 patients were included. Median age was 63 years (range 18-83). Main primary cancers were melanoma (18.5%), head and neck (16.2%), lung (12.7%) and bladder (9.7%). With a median follow up of 15 months (95% CI: [11.6;17.5]), median OS was 12.5 months (95%CI ¼ [10.3;16.0]). All scores were associated with OS: Hazard Ratio (HR)¼1.98 [1.41;2.78] for RMH score 2-3 vs 0-1, HR ¼ 1.68 [1.09;2.60] for MDA score 2 and 3.65 [2.42;5.51] for score 3-5 vs 0-1, HR ¼ 1.18 [0.77;1.81] for MDA-ICI score 3; HR ¼ 2.70 [1.74;4.17] for score 4 and HR ¼ 4.85 [2.62;8.98] for 5-6 vs 0-2, HR ¼ 2.70 [1.92;3.79] for GRIm score 2-3 vs 0-1 and finally 1.86 [1.25;2.78] for LIPI score 1 and HR ¼ 3.86[2.43;6.13] for score 2 vs 0. MDA and GRIm scores obtained more significant results for discrimination than RMH, MDAICI and LIPI (Table). Conclusions: The utilization of theses scores could allow a better patients selection in early trials, especially during the critical periods of dose escalation and proof-of-concept expansion cohorts. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
494P
Demonstrating the changing trends in phase I clinical trials
C. Guo, R. Kelly, J. Desai, B. Tran Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia Background: Early drug development and phase 1 (P1) clinical trials have changed dramatically in the past decade, as targeted therapies and then immune-oncology evolved. Understanding the changing trends in P1 trials allows more targeted resource investment at the site level, but also at the industry level. We describe the changes in the P1 trial landscape in solid tumours over the past decade. Methods: P1 trials registered on ClinicalTrials.gov to start between 1/1/2009-31/12/ 2018 were extracted using the parameters: cancer, 18 years (yr) old, active, recruiting, completed, (early) P1 and interventional. Of the 7,870 trials identified, 3,031 were excluded on the following basis: not conducted in patients with solid tumours, directed at supportive care, solely involving radiotherapy (RT), testing of a device or procedure or solely involving dietary interventions. The 4,839 eligible studies were categorized by treatment type, tumor type, start date and study location. Studies were independently reviewed by two clinicians. Results: In the past decade, there was an average increase of 5%/yr in the number of P1 registered, reflected by substantial increases in trials investigating immune-oncology agents (IO) (average increase: 36%/year) and cell therapies (CT) (average increase: 17%/yr). P1 trials using chemotherapy (C) (average decrease: 1%/yr) or targeted therapies (T) (average decrease: 1%/yr) have plateaued. Clinical trials combining IO with T or C or RT increased by an average of 45%/yr. Most P1 studies (41%) enrolled multiple tumour types. Studies frequently involved North American (68.5%), European
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz244.056/5576555 by guest on 27 October 2019
492P
Annals of Oncology
abstracts
Annals of Oncology (29.3%) and Asia Pacific sites (34%). The inclusion of Asia Pacific sites increased most substantially (average increase: 8%/year). P1 Trials Classified by Type of Therapy (2009-2018)
Table: 494P
1
C1
T1
CT1
Total
4% (30) 12% (89) 17% (141) 33% (364) 44% (581)
39% (324) 36% (276) 32% (258) 29% (320) 23% (305)
66% (557) 64% (491) 57% (467) 48% (529) 40% (524)
5% (39) 3% (25) 6% (47) 9% (98) 11% (140)
839 767 814 1095 1324
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz244.056/5576555 by guest on 27 October 2019
2009-10 2011-12 2013-14 2015-16 2017-18
IO1
Includes P1 trials using a combination of treatments.
Conclusions: The conduct of P1 trials has increased markedly over the past decade, driven by growing interest in IO. Legal entity responsible for the study: Peter MacCallum Cancer Centre. Funding: Has not received any funding. Disclosure: J. Desai: Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Novartis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bionomics; Research grant / Funding (institution): MedImmune; Advisory / Consultancy, Research grant / Funding (institution): BeiGene; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (institution), Advisory / Consultancy: Eisai; Advisory / Consultancy: Ignyta. B. Tran: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astella; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen-Cilag; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy: Tolmar; Advisory / Consultancy: Ipsen. All other authors have declared no conflicts of interest.
Volume 30 | Supplement 5 | October 2019
doi:10.1093/annonc/mdz244 | v187