Improving patient selection for immuno‐oncology phase 1 trials: External validation of six prognostic scores in a French Cancer Center

2020 ◽  
Author(s):  
Ghassan Al Darazi ◽  
Elodie Martin ◽  
Jean‐Pierre Delord ◽  
Iphigenia Korakis ◽  
Sarah Betrian ◽  
...  
Keyword(s):  
Patient Selection ◽  
Phase 1 ◽  
External Validation ◽  
Prognostic Scores ◽  
Cancer Center ◽  
Phase 1 Trials ◽  
Selection For

scholarly journals Prospective validation of prognostic scores to improve patient selection for immuno-oncology trials

2018 ◽  
Vol 29 ◽  
pp. viii144 ◽  
Author(s):  
C. Massard ◽  
N.H. Segal ◽  
D.C. Cho ◽  
V.A. Papadimitrakopoulou ◽  
N.A. Rizvi ◽  
...  
Keyword(s):  
Patient Selection ◽  
Prognostic Scores ◽  
Improve Patient Selection ◽  
Selection For ◽  
Improve Patient

Precision oncology in sarcoma drug development: Impact of genomic matching on response, clinical benefit, and survival in sarcoma patients on phase 1 trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11018-11018 ◽  
Author(s):  
Shiraj Sen ◽  
Roberto Pestana ◽  
Kenneth R. Hess ◽  
David S. Hong ◽  
Filip Janku ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Benefit ◽  
Phase 1 ◽  
Cancer Center ◽  
Precision Oncology ◽  
Sequencing Data ◽  
Time To Progression ◽  
Phase 1 Trials ◽  
Clinical Benefit Rate ◽  
Bone Sarcomas

11018 Background: Genomic analyses have revealed many potentially actionable mutations across sarcoma subtypes. Whether sarcoma patients enrolled on genomically matched early phase trials have improved clinical outcomes over patients enrolled on non-genomically matched trials remains unclear. Methods: We analyzed clinical and next gen sequencing data from sarcoma patients on phase 1 trials at MD Anderson Cancer Center (MDACC) and performed logistic and Cox proportional hazards regression analyses to compare response rate (RR), median time to progression (mTTP), clinical benefit rate (CBR = CR, PR, or SD > 6 months), and median overall survival (mOS) between patients treated on genomically-matched and non-genomically matched trials. Results: Among the 406 patients with advanced sarcomas (321 soft tissue sarcoma [STS], 85 bone sarcomas) treated on phase 1 trials at MDACC from May 2006 to May 2018, median age was 53 (range 11-84), 48% were female, and patients had a median 3 prior lines of therapy (range 0-9). The most commonly treated STS subtypes were leiomyosarcoma (n = 66; 16%), liposarcoma (n = 52; 13%), GIST (n = 44; 11%), and synovial sarcoma (n = 11; 3%) and most commonly treated bone sarcomas were osteosarcoma (n = 34; 8%), chondrosarcoma (n = 28; 7%), and Ewing's sarcoma (n = 25; 6%). 23% (n = 93) of sarcoma patients treated on phase 1 trials were treated on genomically-matched trials. RR on non-genomically matched trials was 6% compared to 11% on genomically-matched trials, OR 1.97 (95% CI 0.88, 4.44), p = 0.10. Responses on genomically-matched trials were seen with novel agents targeting TRK, LRRC15, cMET, mTOR, VEGF, MDM2, KIT/PDGFRA, and FGFR. mTTP on non-genomically matched trials was 2.7 months compared to 3.7 months on genomically-matched trials, HR 0.72 (95% CI 0.57, 0.91), p = 0.0048. CBR on non-genomically matched trials was 19% compared to 41% on genomically-matched trials, OR 2.91 (95% CI 1.77, 4.80), p < 0.0001. mOS on non-genomically matched trials was 15.5 months compared to 22.1 months on genomically-matched trials, HR 0.70 (95% CI 0.50,0.98), p = 0.031. Conclusions: Enrollment on genomically-matched phase 1 trials is associated with an improvement in clinical benefit rate, time to progression, and overall survival in heavily pretreated, metastatic sarcoma patients. While RR remained low, we report the mutations associated with responses on genomically-matched trials. A prospective, biomarker-driven genomically-matched basket trial for these alterations is warranted in advanced sarcomas.

scholarly journals Exposure-Response Analyses and Disease Modeling for Selection and Confirmation of Optimal Dosing Regimen of Isatuximab in Combination Treatment in Patients with Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1897-1897 ◽  
Author(s):  
Fatiha Rachedi ◽  
Kimiko Koiwai ◽  
Nadia Gaudel-Dedieu ◽  
Bernard Sebastien ◽  
Hoai-Thu Thai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase 1 ◽  
Single Agent ◽  
M Protein ◽  
Dosing Regimen ◽  
Phase 3 ◽  
Phase 1 Trials ◽  
Exposure Response ◽  
Selection For ◽  
Time Since Diagnosis

Background: Isatuximab (Isa) is an anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells through direct tumor targeting and immune cell engagement. Exposure-Response (E-R) analysis and disease modelling of tumor burden were performed to evaluate the relationship between Isa exposure and efficacy outcomes. This analysis also supports the Isatuximab dosing regimen selection/confirmation when administered in combination in relapsed/refractory multiple myeloma (RRMM) patients. Methods: To determine the optimal dose for the Phase 3 ICARIA-MM study, E-R analyses were conducted in 44 and 52 RRMM evaluable patients from two Phase 1 trials of Isa in combination with pomalidomide/dexamethasone (Pd) (NCT02283775) or with lenalidomide/dexamethasone (Rd) (NCT01749969), respectively. Isa was administered intravenously at doses from 3 to 20 mg/kg every 2 weeks or weekly for 4 weeks then every 2 weeks (QW/Q2W). In the E-R analyses, several Isa exposure parameters were tested to evaluate if they were predictors of response (partial response [PR] or better). Baseline covariates were also considered in the model to evaluate potential confounding effects. In addition, a second type of analysis was performed on 2 pooled datasets of 153 (single agent and combination with Pd) and 162 (single agent and combination with Rd) evaluable RRMM patients: disease response was also captured by modeling the dynamics of the serum M-protein using a joint model of tumor growth inhibition and drop-out. Trial simulations were then performed to evaluate different dosing regimens of interest. To confirm the dose, E-R analyses were conducted in 297 evaluable RRMM patients from the phase 3 trial (ICARIA-MM; NCT02990338) comparing Isa-Pd (N=148) and Pd (N=149). Isa was administered intravenously at 10 mg/kg QW/Q2W in the Isa-Pd arm. Cox and Weibull (Progression-Free Survival [PFS]) or logistic regression (overall response rate [ORR]) models were used. Results: In the two combination Phase 1 trials, Isa appeared to be well tolerated with no clear dose response relationship between 10 and 20 mg/kg. E-R analyses suggested that higher Isa exposure represented by log Ctrough at 4 weeks (CT4W) was associated with increased ORR. Both models predicted an increased ORR with decreased beta-2 microglobulin and lower number of prior lines of therapy (Rd only), together with higher log CT4W. Clinical trial simulations showed that the probability of success to reach the targeted ORR was high with 10 mg/kg QW/Q2W for both Pd (83% for ORR ≥60%) and Rd (96% for ORR ≥50%). Serum M-protein reduction was greater at doses ≥10 mg/kg compared to doses <10 mg/kg, with minimal differences between 10 and 20 mg/kg QW/Q2W. These analyses supported the rationale for 10 mg/kg QW/Q2W selection for the Phase 3 combination study. In the Phase 3 ICARIA-MM study, the E-R analysis showed that higher CT4W was associated with higher ORR (predicted ORR below and above the median CT4W being 52% and 72%, respectively). The final model also included time since diagnosis and Revised International Staging System (R-ISS) stage at baseline and an interaction between time since diagnosis and R-ISS; ORR increased as time since diagnosis increased and decreased with higher R-ISS stage. For PFS, in addition to CT4W, the model included plasmacytomas, serum albumin level and R-ISS at baseline. The predicted distribution of PFS indicated that patients with greater Isa CT4W had longer PFS, patients with R-ISS Stage III and plasmacytomas had shorter PFS. Matched analyses to Pd indicated that even patients with concentrations ≤median CT4W benefited from Isa treatment (PFS hazard ratio: 0.773). Conclusion: Model-based drug development was successfully applied to support Phase 3 Isa dosing regimen selection for use in combination with Pd in RRMM patients. E-R and clinical data from the Phase 3 ICARIA-MM study confirmed the efficacy and safety of 10 mg/kg QW/Q2W dose/regimen selected. Disclosures Rachedi: Sanofi: Employment. Koiwai:Sanofi: Employment. Gaudel-Dedieu:Sanofi: Employment. Sebastien:Sanofi: Employment. Thai:Sanofi: Employment. El-Cheikh:Sanofi: Employment. Brillac:Sanofi: Employment. Fau:Sanofi: Employment. Nguyen:Sanofi: Employment. Liu:Sanofi: Employment. Campana:Sanofi: Employment. van de Velde:Sanofi: Employment. Semiond:Sanofi: Employment.

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