Article Figures & Data
Figures
- Figure 1.
Patient enrollment and disposition. Abbreviation: ECOG PS, Eastern Cooperative Oncology Group Performance Status.
- Figure 2.
PK and PD features of talazoparib. A–D, Mean concentration–time profiles of talazoparib. Linear mean talazoparib plasma concentration–timeprofiles over the initial 24 hours after dose and log-linear mean talazoparib plasma concentration–time profiles over the complete sampling interval following (A and B) single doses of talazoparib and (C and D) multiple daily doses of talazoparib. E–H, Dose proportionality of talazoparib PK and dose–response and exposure–response relationships between talazoparib and PBMC PARP activity. E, Plasma Cmax following multiple daily doses ranging from 0.025 to 1.1 mg. F, AUC0–24 following multiple daily doses ranging from 0.025 to 1.1 mg. Filled circles represent the mean value at each dose level, and error bars represent the standard deviations. Solid line represents the power model fit through the data. G, Dose–response relationship between talazoparib and PBMC PARP activity. H, Exposure–response relationship between talazoparib and PBMC PARP activity. Percentage baseline PBMC PARP activity defined as the mean of the predose PARP activity assessments during the multiple dosing assessment phase (i.e., predose assessments on days 15, 22, and 35 of cycle 1). Abbreviations: AUC0–24, AUC from 0 to 24 h; IC50, half maximal inhibitory concentration; ID50, inhibitory dose 50%; PD, pharmacodynamic.
- Figure 3.
Percentage change in target lesion for patients undergoing treatment with talazoparib who have (A) gBRCA breast cancer and (B) gBRCA ovarian cancer. Positive values indicate tumor growth, negative values indicate tumor reduction, and the dashed line represents the definition of partial response from RECIST guidelines. Abbreviations: gBRCA, germline BRCA mutated; SLD, sum of longest diameter.
Tables
- Table 1.
Demographics and baseline clinical characteristics
Demographic parameter Dose escalation (Part 1; n = 39) Dose expansion (Part 2; n = 71) Overall (N = 110) Median age, years (range) 58.0 (19–81) 57.0 (18–88) 57.0 (18–88) Male, n (%) 6 (15.4) 28 (39.4) 34 (30.9) ECOG performance status, n (%) 0 23 (59.0) 37 (52.1) 60 (54.5) 1 16 (41.0) 34 (47.9) 50 (45.5) Tumor type, n (%) Breast 8 (20.5) 12 (16.9) 20 (18.2) Ovarian/peritoneal 23 (59.0) 11 (15.5) 34 (30.9) Prostate 1 (2.6) 3 (4.2) 4 (3.6) Pancreatic 3 (7.7) 10 (14.1) 13 (11.8) Ewing sarcoma 2 (5.1) 12 (16.9) 14 (12.7) SCLC 0 23 (32.4) 23 (20.9) Colorectal 2 (5.1) 0 2 (1.8) Deleterious mutation, n (%) gBRCA1 16 (41.0) 13 (18.3) 29 (26.4) gBRCA2 7 (17.9) 20 (28.2) 27 (24.5) gBRCA1/2 1 (2.6) 2 (2.8) 3 (2.7) Median prior chemotherapy regimens, n (range) 4.0 (1.0–13.0) 2.0 (0.0–6.0) 2.5 (0.0–13.0) Median prior platinum regimens, n (range) 2.0 (0.0–4.0) 1.0 (0.0–4.0) 1.0 (0.0–4.0) Abbreviations: ECOG, Eastern Cooperative Oncology Group; gBRCA, germline BRCA mutated.
- Table 2.
Part 1 dose escalation schema, DLTs, dose reductions, and common AEs (>15%) or grade 3 to 4 AEs (>4%) assessed by investigator as related at the recommended dose
Dose level Patients (n = 39) DLTs in first cycle Dose reductions (any cycle) Number of treatment days Number Description Number Median (range) 0.025 mg 3 0 — 2 35 (35–98) 0.05 mg 3 0 — 2 99 (34–205) 0.10 mg 3 0 — 2 119 (65–253) 0.20 mg 3 0 — 2 281 (35–427) 0.40 mg 3 0 — 1 226 (97–268) 0.60 mg 6 0 — 4 185 (58–289) 0.90 mg 6 1 Grade 3 TCP 5 261 (30–1114) 1.00 mg 6 0 — 5 214 (84–960) 1.10 mg 6a 2 Grade 3–4 TCP 4 60 (14–196) Adverse event All grade (n = 71) Grade 3–4 (n = 71) Any treatment-emergent AE, n (%) 55 (77) 32 (45) Blood and lymphatic system disorders, n (%) 40 (56) 30 (42) Anemia 25 (35) 16 (23) TCP 15 (21) 13 (18) Neutropenia 11 (15) 7 (10) Gastrointestinal disorders, n (%) 27 (38) — Nausea 23 (32) — General disorders and administration site conditions, n (%) 27 (38) 2 (3) Fatigue 26 (37) 2 (3) Skin and subcutaneous tissue disorders, n (%) 19 (27) — Alopecia 14 (20) — Abbreviation: TCP, thrombocytopenia.
↵aOne patient discontinued from the trial on study day 21 for progressive disease, having received only 8 days of continuous dosing.
- Table 3.
PK parameters and PARP inhibition following single and multiple daily dosing
Single talazoparib dose, mg PK parameter 0.025 (n = 3) 0.05 (n = 3) 0.1 (n = 3) 0.2 (n = 3) 0.4 (n = 3) 0.6 (n = 6) 0.9 (n = 6) 1.0 (n = 5) 1.1 (n = 7) Tmax, median (min, max), h 7.92 (1.95, 9.95) 1.00 (0.80, 1.02) 1.02 (1.00, 3.98) 1.03 (1.00, 2.32) 2.03 (0.75, 2.95) 0.835 (0.75, 1.95) 2.00 (1.02, 9.98) 1.03 (0.73, 2.07) 1.00 (0.73, 2.05) Cmax, mean (SD), pg/mL 60.0 (15.9) 79.7 (7.50) 214 (50.9) 788 (369) 1,830 (699) 4,100 (1,400) 6,100 (3,060) 10,600 (4,220) 13,200 (3,220) AUC0–24, mean (SD), pg·h/mL 952 (386) 1,160 (166) 3,160 (1,270) 9,130 (3,540) 13,500 (5,200) 37,900 (12,900) 58,200 (24,300) 85,100 (29,100) 91,600 (31,800) AUC0–t, mean (SD), pg·h/mL 3,600 (1,360) 5,340 (1,960) 16,600 (5,320) 39,300 (11,700) 43,700 (15,000) 97,900 (30,000) 160,000 (66,100) 182,000 (62,400) 201,000 (93,400) AUC0-∞, mean (SD), pg·h/mL 5,330 (1,840) 8,320 (1,960) 37,600 (6,620) 92,700 (48,500) 60,100 (15,900) 120,000 (26,000) 188,000 (85,700) 200,000 (64,000) 235,000 (111,000) t1/2, mean (SD), h 100 (11.9) 129 (42.6) 229 (158) 212 (126) 102 (27.2) 58.6 (17.3) 60.4 (10.9) 52.9 (13.4) 71.0 (20.6) CL/F, mean (SD), L/h 5.17 (2.10) 6.27 (1.66) 2.72 (0.532) 2.61 (1.35) 6.95 (1.71) 5.19 (0.99) 5.49 (2.08) 5.39 (1.59) 5.32 (1.64) Vz/F, mean (SD), L 756 (351) 1,240 (742) 839 (487) 678 (217) 1,050 (431) 441 (143) 468 (169) 415 (170) 549 (232) Multiple daily talazoparib dosing, mg/day 0.025 (n = 3) 0.05 (n = 2) 0.1 (n = 2) 0.2 (n = 3) 0.4 (n = 3) 0.6 (n = 6) 0.9 (n = 5) 1.0 (n = 6) 1.1 (n = 4) Tmax, median (min, max), h 1.02 (0.58, 3.98) 5.43 (0.77, 10.1) 0.76 (0.75, 0.82) 1.97 (1.00, 3.02) 0.98 (0.75, 2.00) 1.04 (0.73, 5.98) 1.02 (0.97, 2.07) 1.02 (0.75, 2.00) 1.48 (0.98, 2.00) Cmax, mean (SD), pg/mL 300 (78.8) 615 (74.2) 1,880 (332) 5,620 (3,530) 6,560 (1,500) 11,300 (3,230) 15,400 (1,540) 21,000 (7,990) 23,400 (4,810) AUC0-24, mean (SD), pg·h/mL 3,960 (759) 9,770 (2,440) 30,000 (4,490) 83,100 (49,300) 67,300 (22,600) 119,000 (19,900) 157,000 (24,500) 202,000 (54,000) 188,000 (29,200) t1/2, mean (SD), h 107 (84.2) 132 (12.3) 98.2 (4.83) 50.9 (19.1) 90.7 (32.7) 63.7 (12.7) 71.0 (14.5) 50.0 (16.6) 52.8 (23.2) CLss/F, mean (SD), L/h 6.43 (1.23) 5.28 (1.32) 3.37 (0.502) 3.12 (1.91) 6.40 (2.07) 5.15 (0.897) 5.86 (0.951) 5.24 (1.39) 5.96 (0.837) Vz/F, mean (SD), L 1,070 (971) 1,020 (345) 475 (47.8) 264 (249) 818 (326) 477 (136) 604 (169) 373 (144) 472 (254) Cmin, mean (SD), pg/mL 169 (58.0) 299 (133) 1,020 (107) 2,880 (1,710) 2,230 (957) 3,470 (1,050) 3,180 (802) 3,720 (1,590) 2,910(803) PARP activity, % baseline 0.025 (n = 3) 0.05 (n = 3) 0.1 (n = 3) 0.2 (n = 3) 0.4 (n = 3) 0.6 (n = 4) 0.9 (n = 4) 1.0 (n = 4) 1.1 (n = 2) PARP activity, mean (SD) 172 (206) 141 (52.5) 102 (98.0) 14.7 (5.04) 111 (96.5) 24.7 (8.19) 34.7 (27.4) 21.1 (14.9) 16.3 (5.63) Abbreviations: AUC0–24, AUC from 0 to 24 h; AUC0–∞, AUC from time 0 extrapolated to infinity; AUC0–t, AUC from time 0 to last quantifiable concentration; CLss/F, CL/F at steady state; SD, standard deviation; Tmax, time to Cmax.
- Table 4.
Clinical response rate (RECIST) by cancer type in patients treated with talazoparib 1.0 mg/day (recommended phase II dose)
Response Breasta (n = 14) Ovarian/peritoneala (n = 12) SCLC (n = 23) Pancreatic (n = 10) Ewing sarcoma (n = 13) ORR,% 50.0 41.7 8.7 20.0 0 CR, n 1 1 0 0 0 PR, n 6 4 2 2 0 SD, n 5 3 4 1 3 CBR,%b 85.7 66.7 26.1 30.0 23.1 Median PFS, weeks 34.6 36.4c 11.1 ND ND Abbreviations: ND, not determined; SD, stable disease.
↵aPatients had BRCA1/2 mutation.
↵bClinical benefit = CR + PR + SD ≥24 weeks for breast and ovarian cancers, and CR + PR + SD ≥16 weeks for SCLC, pancreatic cancer, and Ewing sarcoma.
↵cAnalysis on 14 patients, as 2 patients who did not have measurable disease at baseline were included in the PFS analysis but not in the response analysis.
Supplementary Data
- Supplementary Methods - Supplementary Methods includes additional details on these topics: tumors eligible for dose escalation phase; tumors eligible for dose expansion phase; patients enrolled using a local laboratory; study design and participants; additional inclusion criteria; full list of exclusion criteria; study treatment; study procedures; pharmacodynamic (PD) analysis; inhibition of PBMC PARP activity.
- Supplementary Figure S1 - Supplementary Figure S1. Talazoparib inhibition of PBMC PARP activity.
- Supplementary Table S1 - Supplementary Table S1. Dose-response and exposure-response parameters.
Volume 7, Issue 6
