Yang Liu, Anne Chain, Rebecca Wrishko, How to Inform and Revise Dose Levels in an Ongoing Pediatric Program --- Some Statistical and Strategic Thinking Yang Liu, Anne Chain, Rebecca Wrishko, Mandy Jin, Elizabeth Schaeffer, Kara Bickham Merck Research Laboratories

Introduction Pediatric Clinical Development Challenges FDA Guidance Study Design Dose Selection Sample Size FDA Guidance Recruiting pediatric patients in clinical trials is difficult due to the small size of this population.

Study Design -PKPD 12 -17 yr old (n~16) 6 -<12 yr old (n~16) 2 -<6 yr old (n~16) <2 yr old (n~16) MK Dose 1 (150 mg) Total n=64 MK Dose 2 (60 mg) MK Dose 3(20 mg) Screen patients Standard of Care Phase IIb, active comparator-controlled, PK/PD, dose-ranging study Interim analysis was performed to verify the dose for opening 0 - < 2 year old age cohort based on PK data from older age cohorts (2-17 years old) and adjusting dose levels for 2-17 years old cohorts.

Dose Selection Initial Dose Revise Dose Based on Interim Data Well correlated to adult data Body weight/body surface area normalized dose Do children function like little adults? Metabolize differently Population PK model and Modeling&Simulations was used to help pick 3 initial doses. (FDA required us to test at least 3 different dose levels) Revise Dose Based on Interim Data Predefined PK criteria To “match” adult PK Within some clinical bounds Safety profile Exploratory efficacy endpoints Infants and children do not exhibit pharmacokinetics of Blittle adults,^ due in large part to differences in enzyme expression, physiology, and exposure-response as a function of age in pediatric patients. For example, children often process medications differently than adults. Therefore, it is often difficult to estimate safe and efficacious pediatric drug doses based on adult data. Many pharmacokinetic processes, such as drug absorption and drug metabolism, change as a function of age. These age dependent differences may be investigated directly, through pediatric clinical studies, or indirectly through application of model-based simulation.

Dose Selection Example Dose Arm Adult Equivalent Dose Age-Specific Dose Adjustments 12 to 17 years of age 2 to <12 years of age 0 to <2 years of age 4 months to <2 years† 1 to <4 months† 0 to <1 month† Dose 1 150 mg 3 mg/kg (up to 150 mg)   1.5 mg/kg 0.75 mg/kg Dose 2 60 mg 1.2 mg/kg (up to 60 mg) 0.6 mg/kg 0.3 mg/kg Dose 3 20 mg 0.4 mg/kg (up to 20 mg) 0.2 mg/kg 0.1 mg/kg Phase II B, active comparator controlled, PK/PD dose ranging study with 3 dose levels in pediatric patients. N=256 patients Four age groups: <2, 2-6, 6-12, and 12-17 yrs. <2 will not be permitted to participate until PK and safety data from the old age groups are available. PK: AUC0-inf, Cmax, C24hr PD: proportion of patients with complete response Treatments for patients 0 to <2 years of age may be adjusted either upwards or downwards based on data obtained from the older age groups in this study and other ongoing studies with pediatric patients. These allowed dose adjustments will be solely to achieve similar pharmacokinetic exposure in the 0 to <2 year pediatric age group to older patient groups.

Interim Analysis: AUC0-inf Age Group N Mean SD Median GM (95%CI) GMR vs. Adult (90%) Dose 1 (3 mg/kg up to 150 mg) 2<6 Yrs 4 30147.2 27711.2 20111.6 22310.7 ( 5512.8, 90293.5) 0.64 (0.23, 1.78) 6<12 Yrs 8 29347.1 18534.2 20195.4 24903.1 (15040.1, 41234.1) 0.71 (0.47, 1.07) 12<17 Yrs 37468.4 10766.9 35689.1 36290.7 (29120.3, 45226.6) 1.03 (0.85, 1.25) Adult (150mg) 41 37375.1 14753.2 32841.0 35108.9 (31478.7, 39157.7) Dose 2 (1.2 mg/kg up to 60 mg) 5 15778.1 7651.8 20907.6 13749.8 ( 6176.5, 30609.3) 0.39 (0.21, 0.72) 7 9733.4 5671.3 7590.0 8371.6 ( 4769.6, 14693.7) 0.24 (0.15, 0.37) 10479.9 3815.6 9691.7 9940.6 ( 7228.4, 13670.3) 0.28 (0.22, 0.37) Dose 3 (0.4 mg/kg up to 20 mg) 6 1927.2 702.5 1665.2 1830.1 ( 1272.5, 2632.2) 0.05 (0.04, 0.07) 4814.5 6962.3 2446.1 2964.7 ( 1414.0, 6215.8) 0.08 (0.05, 0.15) 2943.8 984.1 2578.8 2821.1 ( 2032.5, 3915.6) 0.08 (0.06, 0.10) AUC0-inf was log transformed and analyzed via a linear mixed-effects model containing fixed effect for age (2 to <6 years, 6 to <12 years, 12 to 17 years, adult data) for each dose level tested. Conclusion: Compared to historical data in adults, exposures in adolescents ages 12 to 17 years at the highest dose (150 mg) are generally similar, whereas in younger children at the highest dose (3 mg/kg) appear to be less (GMR ~0.6-0.7).

Interim Analysis Data from this study and other studies suggest: in adolescents ages 12 to 17 years, the adult dose (150 mg) is likely to achieve similar PK exposures as observed in adults; combined with preliminary efficacy data (response rate 70%-90%) this dose is reasonable and appropriate for further evaluation in the pivotal efficacy/safety study in pediatric patients < 12 years old, these data suggest that higher doses than those initially predicted are necessary to approximate the adult target exposures No new safety signal was identified during the interim analysis FDA feedback FDA thought it was reasonable to proceed with an evaluation of the 150 mg dose in patients 12-17  in the Phase III efficacy/safety study. Based on similar PK and some exploratory efficacy FDA did not object to our plan to evaluate a higher dose ( > 3 mg/kg) in current study based on targeting similar exposures to adults However, they do not support that only matching exposure would be sufficient in identifying the appropriate dose to evaluate in the efficacy/safety study. They requested that we continue to collect  both PK and PD data in this study.

Interim Analysis PK target AUC=35108; log-AUC= 10.47 A little short…. Age Group (Years) N Planned Dose (mg/kg) Actual Mean Weight Based Dose (mg/kg) 12 to <18 8 3.0 3.20 7 1.2 1.13 6 0.4 0.34 6 to <12 2.96 1.20 0.40 2 to <6 4 3.02 5 1.22 AUC unit PK target AUC=35108; log-AUC= 10.47 A little short….

Interim Analysis PK target AUC=35108; log-AUC= 10.47 How to predict the dose? Extrapolation? At risk. Combine the two age groups?

Inverse Regression Estimate X from a response Y with CI for the true value of X. CI depends on uncertainty of b0 and b1 (intercept and slope) Y (a single measurement or average of m repeated measurements) Reference: Irma Lavagnini and Franco Magno, Mass Spectrometry Reviews, 2007, 26, 1-18 Other methods were introduced

Inverse Regression AUC0-inf Overall regression line Log-AUC=7.82+0.82 dose/weight Target log-AUC 10.47 Estimated weight based dose is 3.24 95% CI (3.06, 3.42)

Inverse Regression Cmax Overall regression line Log-Cmax=5.81+0.72 dose/weight Target log-Cmax is 8.30 Estimated weight based dose is 3.45. 95% CI (3.24, 3.66)

Interim Analysis Population PK model and modeling/simulations What dose level to add ?? Considering both PK and efficacy , in patients 2 - <6 and 6 - <12 years old, the dose ~5.0 mg/kg (up to the maximum adult dose of 150 mg) was added in the second half of the study. See efficacy data in the back.

New Dose 5.0 mg/kg Data

Inverse Regression Revisit AUC0-inf PK target AUC=35108; log-AUC= 10.47

Inverse Regression Revisit AUC0-inf Combined the two age groups? The dose is now well within the range of X. Overall regression line Log-AUC=8.13+0.54 weight based dose Target log-AUC 10.47 Weight based dose is 4.30 95% CI (3.91, 4.68)

Inverse Regression Predicts Dose PK parameter PK target Estimated Dose 95% CI AUC 0-inf 35100 4.30 (3.91, 4.68) AUC 0-24hr 24500 3.64 (3.26, 4.01) Cmax 4010 4.80 (4.30, 5.30) C24hr 577 4.28 (3.74, 4.82) Overall regression 2 to 6 years regression PK parameter PK target Estimated Dose 95% CI AUC 0-inf 35100 4.57 (4.07, 5.07) AUC 0-24hr 24500 3.86 (3.30, 4.43) Cmax 4010 5.02 (3.35, 5.68) C24hr 577 4.66 (3.82, 5.50) PK parameter PK target Estimated Dose 95% CI AUC 0-inf 35100 3.97 (3.59, 4.38) AUC 0-24hr 24500 3.56 (3.16, 3.97) Cmax 4010 4.61 (4.07, 5.15) C24hr 577 3.98 (3.49, 4.48) 6 to 12 years regression

Summary At interim stage, compared to historical data in adults, exposures in adolescents ages 12 to 17 years at the highest dose (3mg/kg up to 150 mg) are generally similar, whereas in younger children at the highest dose (3 mg/kg) appear to be less (GMR ~0.6-0.7). A higher dose of 5.0 mg/kg was added in younger age groups. At the end of the study, PK data was again compared with the same historical adult control data. The PK targets were well covered within the dose range up to 5.0 mg/kg. Based on the inverse regression analysis on AUC0-inf, it seems that 4.0 mg/kg is reasonable in 6 to 12 years old; and higher dose such as 4.60 or higher considering other factors may needed in 2-6 years old. Population PK/Modeling and Simulation and exploratory efficacy were all used to predict the final proposed dose.

Discussion Pediatric clinical development and dose selection are much more challenging. Adaptive design with interim analysis should be considered to be able to adjust dose when initial data are available. The method of inverse regression can be used to facilitate dose selection. Extrapolation should be avoided if possible. There are limitations with this approach, such as When sample size is small, the CI is relatively wide Additional assumptions linear relationship between PK and dose though other models could also be used depending on the known relationships in adult information

Back Up

Other Design Example -Open Label PK Age Cohort Age Range 1 (n=6) 12 to <18 years 2 (n=6) 6 to <12 years 3 (n=6) 2 to <6 years 4 (n=8) 3 months to <2 yearsb 5 (n=18) Birth to <3 monthsd Initial doses in Cohorts 4 and 5 will be selected based data from Cohorts 1 through 3 during the second interim PK review. Cohorts 4 and 5 will be further subdivided 3 months to <1 year; at least 4 subjects, 4 weeks to <3 months of age; at least 6 subjects, 1 to <4 weeks of age; at least 6 subjects, <1 week of age; at least 6 subjects.

Interim Analysis: Cmax Age Group N Mean SD Median GM (95%CI) GMR vs. Adult (90%) Dose 1 (3 mg/kg up to 150 mg) 2<6 Yrs 4 2916.7 1629.0 2533.9 2599.6 ( 1081.6, 6247.8) 0.65 (0.34, 1.24) 6<12 Yrs 8 3023.5 1569.9 2522.7 2655.7 ( 1663.9, 4238.7) 0.66 (0.45, 0.97) 12<17 Yrs 3845.0 995.7 4126.9 3724.0 ( 2955.1, 4693.1) 0.93 (0.77, 1.13) Adult (150mg) 41 4154.4 1152.0 4000.0 4006.3 ( 3675.3, 4367.2) Dose 2 (1.2 mg/kg up to 60 mg) 5 1412.7 537.7 1503.1 1324.8 ( 793.5, 2212.0) 0.33 (0.22, 0.49) 7 996.6 624.0 796.2 871.7 ( 533.3, 1424.9) 0.22 (0.15, 0.32) 1234.7 424.4 1172.5 1169.8 ( 835.9, 1637.0) 0.29 (0.22, 0.38) Dose 3 (0.4 mg/kg up to 20 mg) 6 280.4 61.2 263.0 275.5 ( 223.4, 339.7) 0.07 (0.06, 0.08) 396.0 355.9 294.5 293.5 ( 147.3, 584.5) 0.07 (0.04, 0.13) 349.1 149.9 342.6 316.2 ( 182.4, 548.0) 0.08 (0.05, 0.12) Cmax was log transformed and analyzed via a linear mixed-effects model containing fixed effect for age (2 to <6 years, 6 to <12 years, 12 to 17 years, adult data) for each dose level tested.

Efficacy at Interim Review From Other Study   3.0 mg/kg (<12 years) 150 mg (12-17 years) Phase n/m % ( CI) Acute 16 / 22 72.7 (49.8, 89.3) 10 / 11 90.9 (58.7, 99.8) Delayed 4 / 22 18.2 (5.2, 40.3) 8 / 11 72.7 (39.0, 94.0) Overall Number (%) of Subjects responsed by Phase CI = 95% exact Clopper-Pearson confidence interval for the proportion. n/m = Number of subjects with desired response/number of subjects included in time point. Acute Phase: 0 to 24 hours following initiation of chemotherapy infusion. Delayed Phase: 25 to 120 hours following initiation of chemotherapy infusion. Overall Phase: 0 to 120 hours following initiation of chemotherapy infusion.

At the end: 3 mg/kg data PK Parameter Age Group N GM (95% CI) GMR vs. Adult (90% CI) AUC0-inf (ng•hr/mL) 2 to <6 years 5 13100 ( 6550, 26300) 0.37 (0.22, 0.64) 6 to <12 years 8 29200 (17300, 49200) 0.83 (0.54, 1.27) 12 to 17 years 3 33300 (19600, 56600) 0.95 (0.69, 1.31) Adult 41 35100 (31500, 39200)   AUC0-24hr (ng•hr/mL) 6 15900 ( 6860, 36800) 0.65 (0.34, 1.25) 14 26000 (19400, 35000) 1.06 (0.83, 1.37) 12 29400 (25000, 34600) 1.20 (1.04, 1.39) 24500 (22700, 26300) Cmax (ng/mL) 1960 ( 1010, 3790) 0.49 (0.29, 0.82) 2930 ( 2040, 4210) 0.73 (0.54, 0.99) 3360 ( 2740, 4110) 0.84 (0.70, 1.00) 4010 ( 3680, 4370) C24hr (ng/mL) 115 ( 26, 512) 0.20 (0.06, 0.64) 419 ( 243, 723) 0.73 (0.46, 1.14) 675 ( 511, 892) 1.17 (0.92, 1.49) 577 ( 510, 654) Log transformed PK parameters were analyzed via a linear mixed-effects model containing fixed effect for age (2 to <6 years, 6 to <12 years, 12 to 17 years and Adult).

At the end: 1.2 mg/kg data PK Parameter Age Group N GM (95% CI) GMR vs. Adult (90% CI) AUC0-inf (ng•hr/mL) 2 to <6 years 5 13400 ( 5590, 32200) 0.38 (0.20, 0.75) 6 to <12 years 9 9370 ( 6030, 14600) 0.27 (0.19, 0.38) 12 to 17 years 8 11600 ( 8460, 15800) 0.33 (0.25, 0.43) Adult 41 35100 (31500, 39200)   AUC0-24hr (ng•hr/mL) 14700 ( 7550, 28500) 0.60 (0.35, 1.02) 13 9310 ( 6130, 14100) 0.38 (0.27, 0.54) 12 8860 ( 6660, 11800) 0.36 (0.29, 0.46) 24500 (22700, 26300) Cmax (ng/mL) 1600 ( 906, 2840) 0.40 (0.25, 0.63) 1140 ( 786, 1650) 0.28 (0.21, 0.39) 1110 ( 869, 1420) 0.28 (0.22, 0.34) 4010 ( 3680, 4370) C24hr (ng/mL) 170 ( 56.6, 513) 0.30 (0.12, 0.72) 110 ( 56.4, 213) 0.19 (0.11, 0.33) 124 ( 89.1, 172) 0.21 (0.16, 0.28) 577 ( 510, 654) Log transformed PK parameters were analyzed via a linear mixed-effects model containing fixed effect for age (2 to <6 years, 6 to <12 years, 12 to 17 years and Adult).

At the end: 0.4mg/kg data PK Parameter Age Group N GM (95% CI) GMR vs. Adult (90% CI) AUC0-inf (ng•hr/mL) 2 to <6 years 4 1890 ( 857, 4170) 0.05 (0.03, 0.10) 6 to <12 years 8 2650 ( 1840, 3820) 0.08 (0.06, 0.10) 12 to 17 years 9 3310 ( 2560, 4280) 0.09 (0.08, 0.12) Adult 41 35100 (31500, 39200)   AUC0-24hr (ng•hr/mL) 5 1730 ( 1080, 2760) 0.07 (0.05, 0.10) 12 3090 ( 1960, 4860) 0.13 (0.09, 0.18) 13 3110 ( 1920, 5030) 0.13 (0.09, 0.19) 24500 (22700, 26300) Cmax (ng/mL) 6 309 ( 219, 436) 407 ( 272, 610) 0.10 (0.07, 0.14) 467 ( 310, 703) 0.12 (0.08, 0.16) 4010 ( 3680, 4370) C24hr (ng/mL) 8.78 ( 3.48, 22.2) 0.02 (0.01, 0.03) 28.3 ( 12.6, 63.8) 34.5 ( 15.9, 74.8) 0.06 (0.03, 0.11) 577 ( 510, 654) Log transformed PK parameters were analyzed via a linear mixed-effects model containing fixed effect for age (2 to <6 years, 6 to <12 years, 12 to 17 years and Adult).