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Third part of the appendix

Purpose: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non–small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase Ib study was conducted to test safety, MTD, pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC.Patients and Methods: An initial dose escalation phase was used to determine the MTD of twice-daily oral abemaciclib (150, 200 mg) plus pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each drug combination. Pemetrexed and gemcitabine were administered according to label. The abemaciclib plus ramucirumab study examined two dosing schedules.Results: The three study parts enrolled 86 patients; all received ≥1 dose of combination therapy. Across arms, the most common treatment-emergent adverse events were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. The trial did not identify an abemaciclib MTD for the combination with pemetrexed or gemcitabine but did so for the combination of abemaciclib with days 1 and 8 ramucirumab (8 mg/kg). Plasma sample analysis showed that abemaciclib did not influence the pharmacokinetics of the combination agents and the combination agents did not affect abemaciclib exposure. The disease control rate was 57% for patients treated with abemaciclib–pemetrexed, 25% for abemaciclib–gemcitabine, and 54% for abemaciclib–ramucirumab. Median progression-free survival was 5.55, 1.58, and 4.83 months, respectively.Conclusions: Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies. Clin Cancer Res; 24(22); 5543–51. ©2018 AACR.

First part of the appendix

Second part of the appendix

Purpose: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non–small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase Ib study was conducted to test safety, MTD, pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC. Patients and Methods: An initial dose escalation phase was used to determine the MTD of twice-daily oral abemaciclib (150, 200 mg) plus pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each drug combination. Pemetrexed and gemcitabine were administered according to label. The abemaciclib plus ramucirumab study examined two dosing schedules. Results: The three study parts enrolled 86 patients; all received ≥1 dose of combination therapy. Across arms, the most common treatment-emergent adverse events were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. The trial did not identify an abemaciclib MTD for the combination with pemetrexed or gemcitabine but did so for the combination of abemaciclib with days 1 and 8 ramucirumab (8 mg/kg). Plasma sample analysis showed that abemaciclib did not influence the pharmacokinetics of the combination agents and the combination agents did not affect abemaciclib exposure. The disease control rate was 57% for patients treated with abemaciclib–pemetrexed, 25% for abemaciclib–gemcitabine, and 54% for abemaciclib–ramucirumab. Median progression-free survival was 5.55, 1.58, and 4.83 months, respectively. Conclusions: Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies. Clin Cancer Res; 24(22); 5543–51. ©2018 AACR.

Rad17 is a subunit of the Rad9-Hus1-Rad1 clamp loader complex, which is required for Chk1 activation after DNA damage. Rad17 has been shown to be regulated by the ubiquitin-proteasome system. We have identified a deubiquitylase, USP20 that is required for Rad17 protein stability in the steady-state and post DNA damage. We demonstrate that USP20 and Rad17 interact, and that this interaction is enhanced by UV exposure. We show that USP20 regulation of Rad17 is at the protein level in a proteasome-dependent manner. USP20 depletion results in poor activation of Chk1 protein by phosphorylation, consistent with Rad17 role in ATR-mediated phosphorylation of Chk1. Similar to other DNA repair proteins, USP20 is phosphorylated post DNA damage, and its depletion sensitizes cancer cells to damaging agents that form blocks ahead of the replication forks. Similar to Chk1 and Rad17, which enhance recombinational repair of collapsed replication forks, we demonstrate that USP20 depletion impairs DNA double strand break repair by homologous recombination. Together, our data establish a new function of USP20 in genome maintenance and DNA repair.

Smokers experience aberrant gene promoter methylation in their bronchial cells, which may predispose to the development of neoplasia. Hydralazine is a DNA demethylating agent, and valproic acid is a histone deacetylase inhibitor, and both have modest but synergistic anticancer activity in vitro. We conducted a phase I trial combining valproic acid and hydralazine to determine the maximally tolerated dose (MTD) of hydralazine in combination with a therapeutic dose of valproic acid in patients with advanced, unresectable, and previously treated solid cancers. Twenty females and nine males were enrolled, with a median age of 57 years and a median ECOG performance status of 0. Grade 1 lymphopenia and fatigue were the most common adverse effects. Three subjects withdrew for treatment-related toxicities occurring after the DLT observation period, including testicular edema, rash, and an increase in serum lipase accompanied by hyponatremia in one subject each. A true MTD of hydralazine in combination with therapeutic doses of valproic acid was not reached in this trial, and the planned upper limit of hydralazine investigated in this combination was 400 mg/day without grade 3 or 4 toxicities. A median number of two treatment cycles were delivered. One partial response by Response Evaluation Criteria In Solid Tumors criteria was observed, and five subjects experienced stable disease for 3 to 6 months. The combination of hydralazine and valproic acid is simple, nontoxic, and might be appropriate for chemoprevention or combination with other cancer treatments. This trial supports further investigation of epigenetic modification as a new therapeutic strategy.

Psoralen 4 (Pso4) is an evolutionarily conserved protein that has been implicated in a variety of cellular processes including RNA splicing and resistance to agents that cause DNA interstrand cross-links. Here we show that the hPso4 complex is required for timely progression through S phase and transition through the G2/M checkpoint, and it functions in the repair of DNA lesions that arise during replication. Notably, hPso4 depletion results in delayed resumption of DNA replication after hydroxyurea-induced stalling of replication forks, reduced repair of spontaneous and hydroxyurea-induced DNA double strand breaks (DSBs), and increased sensitivity to a poly(ADP-ribose) polymerase inhibitor. Furthermore, we show that hPso4 is involved in the repair of DSBs by homologous recombination, probably by regulating the BRCA1 protein levels and the generation of single strand DNA at DSBs. Together, our results demonstrate that hPso4 participates in cell proliferation and the maintenance of genome stability by regulating homologous recombination. The involvement of hPso4 in the recombinational repair of DSBs provides an explanation for the sensitivity of Pso4-deficient cells to DNA interstrand cross-links.

mTOR inhibitors are emerging as important anti-neoplastic agents with a wide range of clinical applications. The topoisomerase I inhibitor irinotecan is a potent DNA damaging drug, with a broad spectrum of anticancer activities. mTOR appears to enhance cancer cell survival following DNA damage, thus the inhibition of mTOR after irinotecan could theoretically show synergistic activities in patients. Both mTOR inhibitors and irinotecan have been used as single agents in soft tissue sarcomas with limited efficacy. We completed a phase I trial of the combination of the mTOR inhibitor, temsirolimus, and irinotecan in patients with advanced soft tissue sarcoma. Seventeen patients were recruited. The Phase II recommended dose is 20 mg of temsirolimus and 80 mg/m2 of irinotecan administered on weekly basis for three out of four weeks. Most frequently encountered toxicities include cytopenias, fatigue, and gastrointestinal toxicities. Two patients (one with leiomyosarcoma and one with high grade undifferentiated sarcoma) had stable disease for more than 12 months.