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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 Data from Clinical Activity of Single-Agent Cabozantinib (XL184), a Multi-receptor Tyrosine Kinase Inhibitor, in Patients with Refractory Soft-Tissue Sarcomas

Purpose:Soft-tissue sarcomas (STS) are a rare, heterogeneous group of mesenchymal tumors. For decades the mainstay of treatment for advanced, unresectable STS has been palliative chemotherapy. High levels of activated MET receptor have been reported in various sarcoma cell lines, together with elevated vascular endothelial growth factor (VEGF) levels in patients with STS, suggesting that dual targeting of the VEGF and MET pathways with the multi-receptor tyrosine kinase inhibitor cabozantinib would result in clinical benefit in this population.Patients and Methods:We performed an open-label, multi-institution, single-arm phase II trial of single-agent cabozantinib in adult patients with advanced STS and progressive disease after at least 1 standard line of systemic therapy. Patients received 60 mg oral cabozantinib once daily in 28-day cycles, and dual primary endpoints of overall response rate and 6-month progression-free survival (PFS) were assessed. Changes in several circulating biomarkers were assessed as secondary endpoints.Results:Six (11.1%; 95% CI, 4.2%–22.6%) of the 54 evaluable patients enrolled experienced objective responses (all partial responses). Six-month PFS was 49.3% (95% CI, 36.2%–67.3%), with a median time on study of 4 cycles (range, 1–99). The most common grade 3/4 adverse events were hypertension (7.4%) and neutropenia (16.7%). Patients' levels of circulating hepatocyte growth factor (HGF), soluble MET, and VEGF-A generally increased after a cycle of therapy, while soluble VEGFR2 levels decreased, regardless of clinical outcome.Conclusions:Cabozantinib single-agent antitumor activity was observed in patients with selected STS histologic subtypes (alveolar soft-part sarcoma, undifferentiated pleomorphic sarcoma, extraskeletal myxoid chondrosarcoma, and leiomyosarcoma) highlighting the biomolecular diversity of STS.

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

3067 Background: M6620 (M), a potent ATR inhibitor, has synergistic activity with cisplatin (C) in multiple preclinical models, resulting in DNA damage and antitumor activity. We hypothesize that inhibition of both homologous recombination and base excision repair through the combination of M6620 and veliparib (V, a potent inhibitor of PARP1/2) would result in accumulation of lethal double stranded breaks induced by cisplatin and increased antitumor activity and initiated a phase-1 dose escalation trial of this combination in patients (pts) with advanced solid tumors (NCT02723864). Methods: This is a standard 3+3 dose escalation design with 21-day cycles. M is given IV day 2 (D2) and D9; V orally twice daily D1-3 and D8-10; C IV D1 (and D8 from dose level 3 [DL3] onwards) at 40 mg/m2 (with option of holding after cycle 6). Primary objectives: safety; tolerability; maximum tolerated dose (MTD). Secondary objectives: pharmacodynamic (PD) biomarkers; antitumor activity. Dose-limiting toxicity (DLT) evaluated during cycle 1, response using RECIST 1.1. Results: Thirty-seven patients enrolled, median 5 lines of prior therapy (Range 1-12). MTD: V 200 mg, M 210 mg/m2, C 40 mg/m2 (DL6). DLT: grade (gr) 4 thrombocytopenia (DL4), hypophosphatemia (not resolved in 24 hrs., DL3), infusion reaction (DL7). Common gr 3/4 toxicities: anemia (41%), thrombocytopenia (30%), neutropenia (27%), hyponatremia (11%) and hypophosphatemia (8%). Of 34 pts evaluable for response: 2 partial response (PR) (6%, 1 confirmed & 1 transient), 22 stable disease (SD) (65%, median 4 cycles, range 2-11). Of 24 pts with PR/SD, 22 had prior platinum chemotherapy. After July 2018, V was held for gr ≥2 anemia until improved to gr 1, followed by dose reduction. Of 5 pts treated in this period, 3 required V held. PD analysis of circulating tumor cells is underway to elucidate biomarkers of DNA damage and apoptosis. Conclusions: This combination of M6620, veliparib and cisplatin is safe, with activity seen in pts having received prior platinum. The most common toxicity was anemia, which prevented adequate delivery of veliparib. While MTD was established in a heavily pretreated population, consideration should be given to continued dose escalation in pts who have received fewer prior lines of therapy. Funded in part by NCI Contract No. HHSN261200800001E. Clinical trial information: NCT02723864.

This article discusses the problems in basic design, conduct, and interpretation associated with phases I, II, and III of the cancer clinical trials and explains the various statistical solutions to these problems. The fundamental problem common to all three trials is achieving a correct and precise answer to the question posed to inform future testing and treatment while protecting trial patients from receiving treatment that has demonstrated excessive toxicity or lack of clinical efficacy. This shared problem gives rise to statistical designs with basic similarities across the three trial types.

Occurrences of malignancy in 308 patients who were clinically free of cancer 60 months or more after surgical treatment of T1 N0 non-small-cell lung cancer are summarized. At last report, 210 patients remained alive with no evidence of malignant disease, 43 patients died of nonmalignant causes, and 55 patients had 59 occurrences of malignant disease. Late lung cancer recurrence was observed in 22 patients (concurrent with nasopharyngeal cancer in one patient and with laryngeal cancer in one patient). Metachronous second lung cancer was noted in 20 patients (including concurrent colon cancer in one patient and metastatic recurrence in one patient). Other nonpulmonary malignant tumors appeared in 13 patients. Including second lung cancer, 25 cancers of aerodigestive epithelium were observed in 23 patients. The malignancy-free survival advantage for patients with squamous cancer observed until 60 months after resection was not sustained at 60 months and beyond. At the time of last follow-up, 84 patients (27%) had died; 43 were free of malignancy, and 41 had malignancy (14 patients were alive with malignancy and 210 with no evidence of disease). These data reinforce two conclusions: (1) The probability of lung cancer recurrence or appearance of new lung cancer 5 years or more after successful operation in this select subpopulation of patients with lung cancer is of concern. (2) The malignancy-free survival advantage of patients with squamous cancer disappears after 5 years.

Modern postoperative mortality rates for resectional operations for lung cancer are not readily available. In recent publications estimating the risk factors for surgical resection, mortality rates of 10% to 15% for pneumonectomy and 5% to 7% for lobectomy are frequently quoted. In order to determine modern operative mortality rates (up to 30 days postoperatively), the Lung Cancer Study Group (LCSG) analyzed the surgical mortality rates of the various participating centers during the years 1979 to 1981. A total of 2,200 resections for lung cancer were available for analysis. Of the 2,220 resections performed, 1,058 were lobectomies, 569 were pneumonectomies, and 143 were lesser resections (segmental or wedge). Eighty-one postoperative deaths occurred from among the 2,220 resections (3.7%). The mortality rate for pneumonectomy was 6.2% and for lobectomy, 2.9%. Lesser resections carried a 1.4% mortality rate, not statistically different from lobectomy. In patients under the age of 60 years, the mortality rate was 1.3%, 60 to 69 years, 4.1%, and over 70 years, 7.1%, all significantly different (p less than 0.01). The postoperative mortality rate for patients 70 years or older was 7.1% (pneumonectomy 5.9% and lobectomy 7.3%). It is obvious that greater care was taken in selection among the older pneumonectomy patients. The striking similarity of postoperative mortality rates for resectional operations for lung cancer among the various centers of the LCSG and among the various institutions within these centers suggest that these data are a reasonably accurate analysis of modern surgical mortality rates in the treatment of lung cancer.

The purpose of this trial was to investigate the impact of systemic combination chemotherapy on survival and recurrence patterns in incompletely resected non-small-cell lung cancer. Incomplete resection was defined as presence of residual tumor in the resection margin or by presence of metastasis in the highest paratracheal lymph node sampled during protocol-directed surgical staging of the mediastinum. One hundred seventy-two patients were randomized to receive either postoperative radiotherapy (RT) alone or postoperative RT plus chemotherapy with CAP (Cytoxan [cyclophosphamide; Bristol Myers, Evansville, IN], Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH], and Platinol [cisplatin; Bristol Myers]) for 6 months. One hundred sixty-four patients were eligible for analysis at a mean time since randomization of 3.7 years. The chemotherapy arm showed significantly longer recurrence-free survival (two-sided Mantel-Haenszel log rank test, P = .004). This difference holds true for nonsquamous patients (P = .01), and approaches significance for squamous patients as well (P = .08). There was a 14% difference in survival rate favoring the chemotherapy arm 1 year after randomization. Analysis of sites of recurrence showed a significant decrease in distant metastases in the chemotherapy arm. Median survival for the entire group was approximately 17 months, and 35% are alive 2 years after resection. Toxicity of treatment consisted of esophagitis (mild-moderate by Eastern Cooperative Oncology Group [ECOG] criteria) and predictable hematologic, gastrointestinal (GI), and skin toxicity expected from CAP.