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Supplementary Table 1 Pharmacokinetic parametersa of veliparib and its main metabolite (A- 925088) when veliparib was given orally alone on cycle 2 day -1 or in combination with irinotecan on cycle 2 day 8

Supplementary Figure Legends

Supplementary Figure S2. Dose-exposure relationships.

Supplementary Methods, including numbered supplementary methods figures and figure legends

Supplementary Table 2 Pharmacokinetic parametersa of irinotecan and its main active metabolite SN-38 when irinotecan was administered as a 1.5-h intravenous infusion (100 mg/m2) alone on cycle 1 day 1 or in combination with veliparib on cycle 2 day 8

Purpose: PARP is essential for recognition and repair of DNA damage. In preclinical models, PARP inhibitors modulate topoisomerase I inhibitor–mediated DNA damage. This phase I study determined the MTD, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib, an orally bioavailable PARP1/2 inhibitor, in combination with irinotecan.Experimental Design: Patients with advanced solid tumors were treated with 100 mg/m2 irinotecan on days 1 and 8 of a 21-day cycle. Twice-daily oral dosing of veliparib (10–50 mg) occurred on days 3 to 14 (cycle 1) and days −1 to 14 (subsequent cycles) followed by a 6-day rest. PK studies were conducted with both agents alone and in combination. Paired tumor biopsies were obtained after irinotecan alone and veliparib/irinotecan to evaluate PARP1/2 inhibition and explore DNA damage signals (nuclear γ-H2AX and pNBS1).Results: Thirty-five patients were treated. DLTs included fatigue, diarrhea, febrile neutropenia, and neutropenia. The MTD was 100 mg/m2 irinotecan (days 1 and 8) combined with veliparib 40 mg twice daily (days −1–14) on a 21-day cycle. Of 31 response-evaluable patients, there were six (19%) partial responses. Veliparib exhibited linear PK, and there were no apparent PK interactions between veliparib and irinotecan. At all dose levels, veliparib reduced tumor poly(ADP-ribose) (PAR) content in the presence of irinotecan. Several samples showed increases in γ-H2AX and pNBS1 after veliparib/irinotecan compared with irinotecan alone.Conclusions: Veliparib can be safely combined with irinotecan at doses that inhibit PARP catalytic activity. Preliminary antitumor activity justifies further evaluation of the combination. Clin Cancer Res; 22(13); 3227–37. ©2016 AACR.

Supplementary Figure S4. Assessment of pNBS1 in the exploratory multiplex immunofluorescence assay.

Supplementary Figure S3. pNBS1 staining post-combination treatment is limited to tumor cells.

We study biased random walk on subcritical and supercritical Galton-Watson trees conditioned to survive in the transient, sub-ballistic regime. By considering offspring laws with infinite variance, we extend previously known results for the walk on the supercritical tree and observe new trapping phenomena for the walk on the subcritical tree which, in this case, always yield sub-ballisticity. This is contrary to the walk on the supercritical tree which always has some ballistic phase.\ud

We prove that the speed of a biased random walk on a supercritical Galton-Watson tree conditioned to survive is analytic within the ballistic regime. This extends the previous work arXiv:1906.07913 in which it was shown that the speed is differentiable within the range of bias for which a central limit theorem holds., Comment: Error, the argument of compact convergence is insufficient to prove analyticity for real functions

We prove that the speed of a $\lambda$-biased random walk on a supercritical Galton-Watson tree is differentiable for $\lambda$ such that the walk is ballistic and obeys a central limit theorem, and give an expression of the derivative using a certain $2$-dimensional Gaussian random variable. The proof heavily uses the renewal structure of Galton-Watson trees that was introduced by Lyons-Pemantle-Peres., Comment: 33 pages, 1 figure

In this paper we consider the one-dimensional, biased, randomly trapped random walk when the trapping times have infinite variance. We prove sufficient conditions for the suitably scaled walk to converge to a transformation of a stable L\'{e}vy process. As our main motivation, we apply subsequential versions of our results to biased walks on subcritical Galton-Watson trees conditioned to survive. This confirms the correct order of the fluctuations of the walk around its speed for values of the bias that yield a non-Gaussian regime., Comment: 29 pages

We prove CLTs for biased randomly trapped random walks in one dimension. In particular, we will establish an annealed invariance principal by considering a sequence of regeneration times under the assumption that the trapping times have finite second moment. In a quenched environment, an environment dependent centring is determined which is necessary to achieve a central limit theorem. As our main motivation, we apply these results to biased walks on subcritical Galton-Watson trees conditioned to survive and prove a tight bound on the bias required to obtain such limiting behaviour., Comment: 34 pages

Purpose: PARP is essential for recognition and repair of DNA damage. In preclinical models, PARP inhibitors modulate topoisomerase I inhibitor–mediated DNA damage. This phase I study determined the MTD, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib, an orally bioavailable PARP1/2 inhibitor, in combination with irinotecan. Experimental Design: Patients with advanced solid tumors were treated with 100 mg/m2 irinotecan on days 1 and 8 of a 21-day cycle. Twice-daily oral dosing of veliparib (10–50 mg) occurred on days 3 to 14 (cycle 1) and days −1 to 14 (subsequent cycles) followed by a 6-day rest. PK studies were conducted with both agents alone and in combination. Paired tumor biopsies were obtained after irinotecan alone and veliparib/irinotecan to evaluate PARP1/2 inhibition and explore DNA damage signals (nuclear γ-H2AX and pNBS1). Results: Thirty-five patients were treated. DLTs included fatigue, diarrhea, febrile neutropenia, and neutropenia. The MTD was 100 mg/m2 irinotecan (days 1 and 8) combined with veliparib 40 mg twice daily (days −1–14) on a 21-day cycle. Of 31 response-evaluable patients, there were six (19%) partial responses. Veliparib exhibited linear PK, and there were no apparent PK interactions between veliparib and irinotecan. At all dose levels, veliparib reduced tumor poly(ADP-ribose) (PAR) content in the presence of irinotecan. Several samples showed increases in γ-H2AX and pNBS1 after veliparib/irinotecan compared with irinotecan alone. Conclusions: Veliparib can be safely combined with irinotecan at doses that inhibit PARP catalytic activity. Preliminary antitumor activity justifies further evaluation of the combination. Clin Cancer Res; 22(13); 3227–37. ©2016 AACR.

Background: The nuclear enzyme PARP is essential in recognition and repair of DNA damage. Preclinical evidence suggests that PARP inhibitors work as sensitizing agents for DNA-damaging agents such as irinotecan. Veliparib is an orally bioavailable PARP 1 and 2 inhibitor. This expansion to a phase I study, which demonstrated veliparib reduces PAR levels in tumor after irinotecan exposure, was conducted to assess the safety, tolerability and preliminary anti-tumor activity of the combination of veliparib and irinotecan in triple negative breast cancer (TNBC) patients (pts), as well as to apply next generation sequencing technologies to define a signature of response. Methods: Pts were enrolled to two breast cancer cohorts: (1) TNBC, germline BRCA-mutant positive and (2) TNBC, non-BRCA mutated (wt). Eligibility included performance status 0-2; ≥ age 18; adequate bone marrow, hepatic and renal function. Cycles were 21 days. Irinotecan was given i.v. 100 mg/m2 over 90 min on Days 1 and 8. Twice daily (BID) oral dosing of 40 mg veliparib occurred Days 2-15 (Cycle 1) and Days 1-15 (subsequent cycles) followed by a 6-day rest. Tumor biopsies were collected at baseline, 4-6 hours after the first dose of irinotecan (day 1) and the combination (day 8) in cycle 1. Whole exome and transcriptome sequencing was performed using both normal and tumor tissue. Circulating tumor cells (CTC) were evaluated using the CellSearch platform. Results: 24 TNBC pts were enrolled, with 20 pts treated and evaluable for response (8 germline BRCA-mutation positive, 10 non-BRCA mutated, 2 suspected deleterious). Median age was 51 (range 31-63). Median number of prior treatments was 4 (range 1-7). Most frequent drug-related toxicities included: leukopenia (60%), neutropenia (60%), nausea (55%), diarrhea (40%), fatigue (40%), anemia (30%), and vomiting (30%). Best responses were as follows: Germline BRCA-mutant positive 7/8 PR (88%; median number of days on study = 330; range 148-594 days), 1/8 PD (12%); suspected deleterious 2/2 PD (100%); non-BRCA mutated 7/10 SD (70%; median number of days on study = 70; range 42-98 days), 3/10 PD (30%). Exploratory molecular profiling has been performed in a subset of these pts and the results will be presented. EpCAM+ CTC numbers were evaluable in 11 of 22 enrolled pts, and nuclear γH2Ax+, a pharmacodynamic biomarker of DNA damage, was identified in a fraction of CTCs from all 11 of these pts. Conclusions: Veliparib in combination with irinotecan was safe and tolerable in TNBC pts. Although the cohort in this trial is small, the preliminary response rate of 88% in pts with germline BRCA mutation is encouraging and higher than that historically reported with PARP inhibitor monotherapy in this population. Deep molecular profiling among BRCA mutant carriers will be validated in a larger, independent cohort to define potential biomarkers of response. Support: NCI U01-CA062487, NCI U01-CA062490, Komen KG120001, NCI R21-CA135572, and HHSN261200800001E. Citation Format: Patricia M. LoRusso, Sara M. Tolaney, Shukmei Wong, Ralph E. Parchment, Robert J. Kinders, Lihua Wang, Jessica Aldrich, Alice Chen, Diane Durecki, Scott A. Boerner, Tina Guthrie, Adam Bowditch, Lance K. Heilbrun, Mary Jo Pilat, David Craig, Dongpo Cai, Tracy Bell, John Carpten, Geoffrey Shapiro. Combination of the PARP inhibitor veliparib (ABT888) with irinotecan in patients with triple negative breast cancer: Preliminary activity and signature of response. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT325. doi:10.1158/1538-7445.AM2015-CT325