Supplement:Phase I Study of Veliparib (ABT-888) Combined with Cisplatin andVinorelbine in Advanced Triple-Negative Breast Cancer and/or BRCA Mutation-Associated Breast Cancer
Patients and Methods: Trial Design:
Treatment
Antiemetic therapy included aprepitant, 5-HT3 antagonists, and dexamethasone.
The veliparibmonotherapy dose was initially the same dose that the patient received on enrollment. It was increased to 150 mg BID in March 2011, then to 300 mg BID in July 2012, based on updated safety data from CTEP trial 8282 [NCT00892736], and finally increased to 400 mg BID in June 2013 based on safety results of the NCI phase I trial (1)which established this as the recommended dose for veliparib monotherapy.
Dose escalation
The starting dose of veliparib was 20 mg orally twice daily (BID). This dose and subsequent escalating doses in the lower dose cohorts were based on the PK and pharmacodynamic (PD) data from the Phase 0, first-in-human clinical trial of veliparib conducted by the National Cancer Institute (NCI IND) (2) and preliminary data from the phase I study utilizing veliparib and temozolomide (3). Dose escalation of veliparib proceeded more conservatively than a Fibonacci scheme due to concern for potential toxicities from the common renal elimination of cisplatin and veliparib.No within-patient dose escalation was performed during combination therapy.
Safety
A history and physical exam, including vital signs and performance status, were conducted at baseline and repeated on day 1, 8, and 15 of the first 3 cycles, and then on day 1 and 8 of each cycle of combined therapy thereafter. A complete neurological exam was carried out on the first day of each cycle in the setting of using cisplatin and the concern for possible overlapping toxicity with veliparib. In addition, an audiogram was performed before the first dose of cisplatin and repeated after cycle 4 of treatment, or earlier if symptoms of ototoxicity developed. 12-lead electrocardiogram was done at baseline and repeated on cycle 2 day 8, cycle 3 day 8 and at the final visit to study the potential impact of veliparib on QTc interval. For female patients of childbearing potential, a serum pregnancy test was performed at screening and a urine pregnancy test was done prior to the first dose of cisplatin/vinorelbine.
Patients and Methods:Eligibility Criteria
Adequate organ function is defined as absolute neutrophil count (ANC) > 1,500/mm3 , platelets > 100,000/mm3, hemoglobin > 9.0 g/dL, serum creatinine < 1.5 × upper limit of normal (ULN), AST and/or ALT < 2.5 × ULN, except patients with liver metastases, may have AST and/or ALT<5 × ULN, bilirubin <1.5 × ULN, PTT ≤ 1.5 × ULN, and INR < 1.5.
Systemic therapies must have been completed within either 28 days or 5 half lives of a targeted therapy (whichever is shorter), prior to study drug administration. Radiation therapy must have been completed at least 2 weeks prior to the enrollment date.
Patients were excluded if they had baseline peripheral neuropathy that exceeded grade 1, clinically significant and uncontrolled major medical conditions, or were pregnant or lactating.
Patients and Methods:Pharmacogenetic evaluation
Whole-genome DASL (WG-DASL) Assay
For gene expression profiling, tissue sections were macrodissected to enrich for the invasive tumor components and reduce contamination from non-tumor cells. RNA was isolated from FFPE sections using the RNeasy FFPE kit (Qiagen) with modifications as previously described (4) and from fresh/frozen tissue using the AllPrep DNA/RNA MicroKit (Qiagen) with modifications. Expression of 29,361 well-annotated RefSeq transcripts (probes) were assessed using the WG-DASL®(HumanHT-12 v4) Assay (Illumina, Inc., San Diego CA) which enables the interrogation of up to 96 samples in parallel on the SentrixBeadChip detection platform (4, 5). Per manufacturer’s protocol, the target input for each sample for degraded RNA from FFPE tissue and intact RNA from fresh/frozen tissue is at least 200 ng and 100 ng, respectively, normalized to 40 ng/uL. In total, samples from thirty patients were run on the WG-DASL assay: 24 pre-treatment samples and seven post-treatment samples. Several samples were run in replicate to assess reproducibility of the assay and assess variability across batches. The samples were processed through the WG-DASL assay by the Fred Hutchinson Cancer Research Center Shared Resources Genomics Core. The samples were then hybridized to HumanHT-12 v4 Expression BeadChip Array (Illumina). After hybridization, the BeadChips were scanned using the Illumina iScan System, and the image data files were directly downloaded into GenomeStudio Gene Expression (GX) Module (Illumina Inc., v 2011.1) for preliminary data visualization and quality assessment (Illumina GenomeStudio Framework User Guide v 2008.1). GenomeStudio produces output files containing probe and gene lists, associated hybridization intensities, and control summary reports. The raw array data were then exported to the R v3.0.3 statistical software Bioconductor lumi package for pre-processing (6), and the gene expression values were log2 transformed. Probes were identified to be low signal if the log2 expression values were below the median of negative controls for each sample. Probes with more than 1/3 low signal across samples were excluded. A median normalization was carried out. As the data were processed in batches, including the batch effect from FFPE vs. Frozen samples, the “ComBat” algorithm was used to remove the batch effect before combining data from different batches (7). Data were then subjected to “shorth” (8) variance filtering to remove probes that have no or little variation across samples (9). In this filtering, probes with a standard deviation less than the mean of the standard deviations of arrays within the “shorth” interval were removed from further analysis. Of the starting 29,361 probes in the WG-DASL assay, after preprocessing there were 19,168 probes left for analysis.
Results: Pharmacokinetics
Veliparib pharmacokinetics are summarized in Table S4, and are comparable to previous reports (10). Figure S1 shows dose proportionality of veliparibCmax and AUC0-6for C1D1 and C4D1. Figure S2 shows veliparib PK parameters for C1D0 and C4D1, by dose cohort. Total and ultrafilterable platinum pharmacokinetics are summarized in Table S5and are consistent with previous reports (11-14). Ultrafilterable platinum PK parameters (dividing by dose to accommodate 7/31 patients analyzed with reduced cisplatin dose at cycle 4) are shown in Figure S3.
Results: Efficacy
Long-Term responders
Two patients who achieved a CR are long-term responders. A patient in the 60 mg dose cohort with a BRCA1 mutation (exon 13 insert 6kb rearrangement) received 6 cycles of combination therapy with cycle 5 day 8 dose of vinorelbine held, and subsequent vinorelbine dose reduction to 20 mg/m2 at cycle 6. Complete radiographic response of liver and distant lymph node lesions occurred at 36 weeks, and has been maintained through 57 cycles of monotherapy (40 months since starting study therapy) and she remains on trial. Her stage IV disease was diagnosed 5.5 years after primary diagnosis. She started study therapy at age 48 after approximately 1 year and two chemotherapy regimens (nab-paclitaxel and bevacizumab; erlotinib and bevacizumab) for stage IV disease. Her highest grade AE to date is grade 3 fatigue.
The second long-term responder with radiographic CR (120 mg dose cohort) tested negative for a BRCA1/2 mutation. Distant disease in the supraclavicular and mediastinal lymph nodes was diagnosed 28 months after primary disease, and she received one line of therapy (capecitabine) prior to study enrollment. She received 6 cycles of combination therapy, with cisplatin reduced to 60 mg/m2 at cycle 6 and vinorelbine dose reduced starting cycle 4 day 8 through the last 2 cycles of combined therapy, due to grade 2 thrombocytopenia. Radiographic complete response was achieved at 54 weeks. She remains on veliparib monotherapy 32 months after starting study therapy (37 cycles). This patient had tumor tissue sampled at the time of stage IV diagnosis and had a basal-like phenotype by IHC. A DNA sequencing test, (BROCA, University of Washington, Division of Medical Genetics, Laboratory) was performed on DNA isolated from blood of the participant and showed no mutations damaging to gene function in 40 genes in the Fanconi anemia/DNA repair pathway, in addition to BRCA1 and BRCA2.
Results: Pharmacodynamics (IHC)
Pretherapy tissue was assessed for 28 patients. Twenty-five (89%) showed a basal-like phenotype by IHC (Table S6). For the 3 without a basal-like phenotype, the tissue samples were from 3-6 months prior to study registration (none from the initial breast cancer diagnosis), and included one ER+ tumor in a patient with a BRCA1 mutation, and two tumors negative for both EGFR and CHK5/6 (one from a patient without a BRCA mutation, the other from a patient with a BRCA1 mutation).
References:
[1] Puhalla SL, Beumer JH, Appleman LJ, Tawbi HA, Stoller RG, Lin Y, et al. A phase I study of chronically dosed, single-agent veliparib (ABT-888) in patients (pts) with either BRCA 1/2-mutated cancer (BRCA+), platinum-refractory ovarian cancer, or basal-like breast cancer (BRCA-wt). J ClinOncol 2012; 30:(suppl; abstr 3054).
[2] Kummar S, Kinders R, Gutierrez ME, Rubinstein L, Parchment RE,
Phillips LR, et al. Phase 0 clinical trial of the Poly(ADP-Ribose) polymerase
inhibitor ABT-888 in patients with advanced malignancies. J ClinOncol 2009; 27(16):2705-2711.
[3] Information for Clinical Investigators (Clinical Brochure) for ABT-888
(A-861695), Edition No. 3, Abbott Park, Illinois: Abbott, 2009.
[4] Abramovitz M, Ordanic-Kodani M, Wang Y, et al. Optimization of RNA extraction from FFPEtissues for expression profiling in the DASL assay. Biotechniques 2008;44(3):417-423.
[5] Oliphant A, Barker DL, Stuelpnagel JR, Chee MS. BeadArray technology: enabling an accurate, cost-effective approach to high-throughput genotyping. Biotechniques 2002;suppl:56-1.
[6] Du P, Kibbe WA, Lin SM. lumi: a pipeline for processing Illumina microarray.Bioinformatics2008;24(13):1547-1548.
[7] Johnson WE, Rabinovic A, and Li C. Adjusting batch effects in microarray expression data using Empirical Bayes methods. Biostatistics 2007; 8(1):118-127.
[8] Grubel R. The length of the shorth. The Annals of Statistics 1988;16(2):619-628.
[9] Genefilter: Methods for filtering genes from microarray experiments. Version 1.46.1. 2011.
[10]Kummar S, Ji J, Morgan R, Lenz HJ, Puhalla SL, Belani CP, et al. A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas. Clin Cancer Res. 2012; 18(6):1726-34.
[11] Urien S, Lokiec F. Population pharmacokinetics of total and unbound plasma cisplatin in adult patients.Br J ClinPharmacol. 2004; 57(6):756-63.
[12] Loos WJ, de Jongh FE, Sparreboom A, de Wit R, van Boven-van Zomeren DM, Stoter G, et al. Evaluation of an alternate dosing strategy for cisplatin in patients with extreme body surface area values. J ClinOncol. 2006; 24(10):1499-506.
[13] Specenier PM, Ciuleanu T, Latz JE, Musib LC, Darstein CL, Vermorken JB.
Pharmacokinetic evaluation of platinum derived from cisplatin administered alone and with pemetrexed in head and neck cancer patients. Cancer ChemotherPharmacol. 2009; 64(2):233-41.
[14] Reece PA, Stafford I, Russell J, Khan M, Gill PG. Creatinine clearance as a
predictor of ultrafilterable platinum disposition in cancer patients treated with cisplatin: relationship between peak ultrafilterable platinum plasma levels and nephrotoxicity. J ClinOncol. 1987; 5(2):304-309.
Table S1: Schedule of pharmacokinetic analysis
Cycle 1, Day 0: Veliparib PK alone *Cycle 1, Day 1: Veliparib* and Cisplatin PK**
Cycle 1, Day 2: Veliparib* and Cisplatin** 24 hour sample
Cycle 4, Day 1: Veliparib* and Cisplatin** PK (long-term evaluation for effect of chronic nephrotoxicity)
Cycle 4, Day 2: Veliparib* and Cisplatin** 24 hour sample
* Blood plasma (t=0, 30 min, 1, 1.5, 2, 4, 6, 24 hours after dosing)
Urine collection (0-3 hours, and 3-6 hours, 6-12 hours after dosing)
** Blood plasma (t=0, 30 min, 1, 1.25, 2, 4, 6, 24 hours after start of infusion)
Table S2: Overview of study dose levels (N=50). Study design was 3+3 dose escalation, with patients “replaced” (not evaluable for DLT) when received <75% of any study drug and did not experience a DLT.
Level / Veliparib
(mg BID)
Days 1 -14 / Cisplatin
(mg/m2)
Day 1 / Vinorelbine
(mg/m2)
Days 1, 8 / Pts
(n) / DLT Events / Ineligible for dose escalation
1 / 20 / 75 / 25 / 4 / 1 died of progressive disease cycle 1, day 8
2 / 30 / 75 / 25 / 3
3 / 40 / 75 / 25 / 6 / Grade 4 Thrombocytopenia
4 / 60 / 75 / 25 / 8 / Grade 4 Neutropenic fever / 1 withdrew for worsening disease after C1D0
5 / 80 / 75 / 25 / 5 / 1 noncompliant with C1 medication diary; 1 withdrew C1 for insurance reasons
6 / 120 / 75 / 25 / 6 / 2 held C1D8 vinorelbine*; 1 withdrew consent during C1
7 / 160 / 75 / 25 / 3
8 / 200 / 75 / 25 / 7 / Grade 3 Neutropenic fever / 1 held C1D8 vinorelbine*
9 / 300 / 75 / 25 / 3
E / 300 / 75 / 25 / 5
* Not all adverse events with protocol-specified holds or reductions were also defined as a DLT
DLT = dose limiting toxicity (defined in Supplement)
E = expansion cohort
BID = bis in die (two times a day)
C1D1 = cycle 1, day 1
Table S3.Adverse events reported at any time during study therapy: grade 3-4 adverse events. There were no grade 5 adverse events.
Veliparib dose (N)Adverse Event / 20
(4) / 30
(3) / 40
(6) / 60
(8) / 80
(5) / 120
(6) / 160
(3) / 200
(7) / 300
(8) / N (%)
Neutrophil count decreased / 1 / 1 / 3 / 2 / 2 / 2 / 1 / 2 / 4 / 18 (36%)
Anemia / 2 / 0 / 1 / 1 / 2 / 2 / 2 / 3 / 2 / 15 (30%)
Platelet count decreased / 1 / 0 / 2 / 1 / 0 / 1 / 0 / 1 / 0 / 6 (12%)
White blood cell decreased / 1 / 1 / 0 / 1 / 0 / 0 / 0 / 0 / 0 / 3 (6%)
Nausea / 0 / 1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 1 (2%)
Fatigue / 0 / 0 / 0 / 1 / 0 / 0 / 0 / 0 / 0 / 1 (2%)
Dehydration / 0 / 0 / 1 / 0 / 0 / 0 / 0 / 0 / 0 / 1 (2%)
Hypophosphatemia / 1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 1 (2%)
Aspiration / 0 / 0 / 0 / 1 / 0 / 0 / 0 / 0 / 0 / 1 (2%)
Hypertension / 0 / 0 / 1 / 0 / 0 / 0 / 0 / 0 / 0 / 1 (2%)
Vomiting / 0 / 1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 1 (2%)
Table S4: Veliparib pharmacokinetic (PK) parameters by cohort
C1D0 / C1D1PK Parameter / N / Tmax (hrs) / Cmax (ng/mL) / AUC0-6 (hr*ng/mL) / AUC0-∞ (hr*ng/mL) / t1/2 (hr) / CL/F (L/hr) / Cmax (ng/mL) / AUC0-6 (hr*ng/mL)
Cohort 1 (20 mg BID)
Cycle 1 / 4 / 2.7± 1.5 / 173 ± 63 / 612 ± 102 / 1366 ± 339 / 5.3 ± 3.1 / 15.3 ± 3.64 / 248 ± 31 / 864 ± 80
C4D1 / 3 / 2.2 ± 1.8 / 159 ± 74 / 555 ± 296 / 1019 ± 165 / 4.1 ± 2.2 / 19.9 ± 3.02 / 159 ± 74 / 555 ± 296
Geomeana / 3 / 0.80 / 0.83 / 0.80 / 0.83 / 0.99 / 1.20 / 0.59 / 0.57
Cohort 2 (30 mg BID)
Cycle 1 / 3 / 2.8 ± 2.0 / 227 ± 154 / 842 ± 329 / 2857 ± 512b / 10.5 ± 5.7b / 10.7 ± 1.91b / 264 ± 77 / 1018 ± 220
C4D1 / 3 / 1.2 ± 0.3 / 227 ± 44 / 798 ± 167 / 1662 ± 497 / 6.6 ± 4.7 / 19.4 ± 6.99 / 227 ± 44 / 798 ± 167
Geomeana / 3 / 0.57 / 1.14 / 0.98 / 0.69b / 0.83b / 1.46b / 0.87 / 0.79
Cohort 3 (40 mg BID)
Cycle 1 / 6 / 1.8 ± 2.1 / 443 ± 101 / 1364 ± 416 / 2735 ± 1343c / 5.4 ± 2.7c / 18.0 ± 9.14c / 469 ± 188 / 1617 ± 661
C4D1 / 4 / 1.5 ± 0.6 / 289 ± 84 / 1008 ± 204 / 1494 ± 355 / 3.3 ± 0.7 / 27.8 ± 6.04 / 289 ± 84 / 1008 ± 204
Geomeana / 4 / 1.37 / 0.67 / 0.77 / 0.69c / 0.75c / 1.44c / 0.63c / 0.69c
Cohort 4 (60 mg BID)
Cycle 1 / 8 / 1.3 ± 0.8 / 554 ± 145 / 1803 ± 348 / 3619 ± 1731 / 6.9 ± 6.4 / 19.6 ± 7.73 / 532 ± 101d / 1920 ± 451d
C4D1 / 5 / 1.8 ± 1.3 / 377 ± 85 / 1245 ± 184 / 2265 ± 783 / 4.4 ± 1.8 / 30.1 ± 13.5 / 377 ± 85 / 1245 ± 184
Geomeana / 5 / 1.79 / 0.77 / 0.78 / 0.69 / 0.70 / 1.46 / 0.77 / 0.73
Cohort 5 (80 mg BID)
Cycle 1 / 5 / 1.0 ± 0.5 / 618 ± 196 / 2134 ± 422 / 3226 ± 451 / 3.8 ± 0.8 / 25.2 ± 3.35 / 682 ± 262 / 2498 ± 578
C4D1 / 3 / 1.6 ± 0.6 / 771 ± 289 / 2512 ± 1327 / 3338 ± 1736 / 2.6 ± 0.1 / 27.9 ± 11.5 / 771 ± 289 / 2512 ± 1327
Geomeana / 3 / 1.73 / 2.20 / 1.16 / 1.01 / 0.71 / 0.99 / 1.11 / 1.00
Cohort 6 (120 mg BID)
Cycle 1 / 6 / 1.3 ± 0.6 / 801 ± 181 / 3393 ± 714 / 7718 ± 2284 / 6.1 ± 2.3 / 17.7 ± 8.78 / 1219 ± 627 / 4232 ± 1368
C4D1 / 4 / 1.3 ± 0.5 / 840 ± 139 / 3104 ± 481 / 6794 ± 2788 / 6.7 ± 3.2 / 19.6 ± 6.33 / 840 ± 139 / 3104 ± 481
Geomeana / 4 / 0.94 / 1.64 / 0.88 / 0.72 / 0.85 / 0.93 / 0.70 / 0.71
Cohort 7 (160 mg BID)
Cycle 1 / 3 / 1.2 ± 0.6 / 1571 ± 290 / 5229 ± 174 / 8589 ± 2420 / 4.0 ± 1.6 / 19.5 ± 4.80 / 1535 ± 143 / 5552 ± 641
C4D1 / 3 / 2.2 ± 1.6 / 1285 ± 366 / 3966 ± 474 / 9248 ± 3229 / 4.8 ± 2.4 / 19.1 ± 7.63 / 1285 ± 366 / 3966 ± 474
Geomeana / 3 / 1.75 / 0.81 / 0.75 / 1.05 / 1.18 / 0.96 / 0.82 / 0.71
Cohort 8 (200 mg BID)
Cycle 1 / 7 / 1.5 ± 0.6 / 1071 ± 370 / 4271 ± 970 / 8874 ± 2591 / 6.0 ± 2.4 / 24.7 ± 8.99 / 1298 ± 436 / 4722 ± 1039
C4D1 / 7 / 2.7 ± 1.6 / 850 ± 384 / 3380 ± 1492 / 8590 ± 2602e / 6.5 ± 2.7e / 25.8 ± 10.6e / 850 ± 384 / 3380 ± 1492
Geomeana / 7 / 1.71 / 0.76 / 0.74 / 0.92e / 1.02e / 1.08e / 0.62 / 0.67
Cohort 9 (300 mg BID)
Cycle 1 / 3 / 2.3 ± 1.5 / 2037 ± 908 / 7327 ± 1976 / 17,683 ± 4005 / 6.7 ± 0.8 / 17.5 ± 3.71 / 2384 ± 692 / 9240 ± 2539
C4D1 / 0 / -- / -- / -- / -- / -- / -- / -- / --
Geomeana / 0 / -- / -- / -- / -- / -- / -- / -- / --
Data as mean ± SD
aC4:C1 geometric mean ratio.
bn=2 (1 subject’s concentrations did not decline over the observed sampling period and half-life, CL/F, and AUC0-∞ could not be determined). cn=5 (1 subject had increasing concentrations throughout sampling and half-life, AUC0-∞, and CL/F could not be determined). dn=7 (1 subject withdrew from the study for worsening disease after C1D0).
Abbreviations: C1D0: cycle 1, day 0; C1D1: cycle 1, day 1; C4D1: cycle 4, d
Table S5: Total and ultrafilterable platinum pharmacokinetic parameters by cohort
PK Parameter / N / Total Platinum / Ultrafilterable PlatinumCmax (µg/mL) / AUC0-24h (hr*µg/mL) / Cmax (µg/mL) / AUC0-24h (hr*µg/mL) / AUC0-∞ (hr*µg/mL) / t1/2 (hr) / CL (L/hr/m2)
Cohort 1 (Veliparib 20 mg BID)
C1 / 3 / 3.25 ± 0.68 / 35.77 ± 2.67 / 1.77 ± 0.63 / 6.07 ± 1.78 / 7.33 ± 1.00 / 9.3 ± 4.7 / 10.4 ± 1.3
C4 / 3 / 3.51 ± 0.55 / 32.05 ± 13.39 / 2.15 ± 0.33 / 6.18 ± 2.90 / 13.17 ± 8.07 / 40.4 ± 38.6 / 6.6 ± 4.4
Geomeana / 2 / 1.25 / 0.78 / 1.62 / 1.44 / 1.73 / 1.78 / 0.58
Cohort 2 (Veliparib 30 mg BID)
C1 / 3 / 4.03 ± 0.60 / 43.13 ± 2.93 / 2.52 ± 0.63 / 7.04 ± 1.79 / 10.82 ± 3.46 / 15.5 ± 6.3 / 7.5 ± 2.9
C4 / 3 / 4.08 ± 0.33 / 50.15 ± 5.15 / 2.78 ± 0.52 / 8.16 ± 0.63 / 15.05 ± 2.01 / 22.0 ± 2.0 / 4.7 ± 1.1
Geomeana / 3 / 1.10 / 1.25 / 1.19 / 1.27 / 1.55 / 1.49 / 0.64
Cohort 3 (Veliparib 40 mg BID)
C1 / 6 / 4.36 ± 0.77 / 32.55 ± 12.74 / 2.80 ± 0.64 / 4.70 ± 0.65 / 5.78 ± 1.50 / 18.2 ± 9.8 / 13.6 ± 3.4
C4 / 4 / 3.21 ± 0.66 / 18.70 ± 14.33 / 2.37 ± 0.35 / 3.98 ± 0.29 / 5.21 ± 0.61 / 23.6 ± 8.8 / 14.5 ± 1.6
Geomeana / 4 / 0.70 / 0.47 / 0.79 / 0.90 / 1.06 / 1.55 / 0.94
Cohort 4 (Veliparib 60 mg BID)
C1 / 7 / 4.10 ± 0.31 / 43.54 ± 6.38 / 2.77 ± 0.87 / 5.33 ± 1.59 / 7.62 ± 2.26 / 33.4 ± 21.9 / 10.7 ± 3.4
C4 / 5 / 2.32 ± 0.79 / 7.36 ± 6.40 / 2.68 ± 0.40 / 6.06 ± 1.96 / 8.35 ± 1.34 / 35.6 ± 23.5 / 9.1 ± 1.4
Geomeana / 5 / 0.54 / 0.13 / 0.96 / 1.10 / 1.19 / 1.20 / 0.84
Cohort 5 (Veliparib 80 mg BID)
C1 / 5 / 3.46 ± 0.70 / 31.43 ± 5.41 / 2.30 ± 0.45 / 3.72 ± 0.38 / 4.81 ± 0.87 / 26.2 ± 8.5 / 15.5 ± 2.7
C4 / 3 / 2.84 ± 0.85 / 12.39 ± 7.56 / 2.36 ± 0.15 / 3.67 ± 0.19 / 5.88 ± 2.79 / 41.9 ± 46.9 / 13.8 ± 4.8
Geomeana / 3 / 0.83 / 0.31 / 0.96 / 0.97 / 1.17 / 1.04 / 0.86
Cohort 6 (Veliparib 120 mg BID)
C1 / 6 / 3.41 ± 1.00 / 31.42 ± 9.11 / 2.99 ± 1.73 / 5.30 ± 3.25 / 6.33 ± 3.11 / 24.2 ± 14.4 / 13.4 ± 4.1
C4 / 4 / 3.91 ± 0.87 / 40.44 ± 9.29 / 2.19 ± 0.37 / 3.94 ± 0.44 / 5.47 ± 1.46 / 30.9 ± 11.0 / 13.6 ± 3.3
Geomeana / 4 / 1.00 / 1.15 / 0.70 / 0.72 / 0.82 / 1.62 / 1.21
Cohort 7 (Veliparib 160 mg BID)
C1 / 3 / 3.50 ± 0.33 / 36.03 ± 11.27 / 2.24 ± 0.24 / 4.34 ± 0.13 / 5.30 ± 0.43 / 19.3 ± 8.4 / 14.2 ± 0.9
C4 / 3 / 3.14 ± 0.47 / 34.94 ± 9.41 / 2.09 ± 0.49 / 4.16 ± 0.30 / 6.87 ± 1.58 / 33.0 ± 17.0 / 9.8 ± 2.0
Geomeana / 3 / 1.04 / 1.14 / 1.07 / 1.11 / 1.48 / 1.66 / 0.68
Cohort 8 (200 mg BID)
C1 / 7 / 3.18 ± 0.76 / 33.34 ± 10.14 / 2.12 ± 0.27 / 3.53 ± 0.61 / 4.33 ± 1.09 / 18.8 ± 5.2 / 17.8 ± 4.2
C4 / 6 / 3.68 ± 0.50 / 33.49 ± 7.58 / 2.06 ± 0.27 / 3.54 ± 0.45 / 4.58 ± 0.88 / 23.8 ± 4.6 / 15.6 ± 2.3
Geomeana / 3 / 1.27 / 1.08 / 1.06 / 1.06 / 1.18 / 1.31 / 0.85
Cohort 9 (300 mg BID)
C1 / 3 / 3.73 ± 0.59 / 40.92 ± 4.96 / 2.37 ± 0.47 / 3.82 ± 0.66 / 4.55 ± 1.03 / 18.0 ± 3.3 / 17.0 ± 3.8
C4 / 0 / -- / -- / -- / -- / -- / -- / --
Geomeana / 0 / -- / -- / -- / -- / -- / -- / --
Data as mean ± SD
aC4:C1 geometric mean ratio for cisplatin dose-normalized, paired comparisons only
Abbreviations: C1: Cycle 1, Day 1; C4: Cycle 4, Day 1
Table S6: Immunohistochemistry results for 28 pre-therapy samples.
ER / PR / HER2 / EGFR / CK56 / basal-likeIHC phenotype / Frequency
- / - / IND / - / - / no / 1
- / - / - / - / - / no / 1
+ / - / - / + / + / no / 1
- / - / IND / + / - / yes / 1
- / - / IND / + / + / yes / 2
- / - / - / - / + / yes / 6
- / - / - / + / - / yes / 2
- / - / - / + / + / yes / 14
Figure S1:VeliparibCmax (ng/mL, panel A) and veliparib AUC0-6 (hr*ng/mL, panel B) by dose cohort. The fitted line is from a linear mixed effects model with log(PK parameter) estimated by a random patient intercept, categorical time (C1D1=cycle 1 day 1, C4D1=cycle 4 day 1), and log(dose).
Figure S2: Veliparib pharmacokinetic parameters (A) Cmax and (B) AUC0-6 at cycles 1 and 4 by cohort. Abbreviations: C1 = cycle 1, day 0. C4 = cycle 4, day 1.
A)
B)
Figure S3: Ultrafilterableplatinum pharmacokinetic parameters Cmax and AUC0-24 at cycles 1 and 4 by cohort. (A) Filled black circles and (B) filled black diamonds show subjects who had cisplatin dose reduction from 75 mg/m2 to 60 mg/m2 by cycle 4.
Abbreviations: C1 = cycle 1, day 1. C4 = cycle 4, day 1.
A)
B)
Figure S4: Consort 2010 flow diagram for exploratory efficacy analysis comparing germline BRCA mutation positive to wild type.
Figure S5: PAR assay results (pg/mL) for 14 patients in dose cohorts 6-8 (120-200 mg). PBMCs were sampled at two screening (SCR) timepoints, and 2, 4, 6 and 24 hours post administration of the first oral dose of veliparibfor day 0 cycle 1 and day 1 cycle 4.
1