William J. Edenfield

Axitinib and/or bevacizumab with modified FOLFOX‐6 as first‐line therapy for metastatic colorectal cancer: A randomized phase 2 study

In this multicenter, open‐label, randomized phase 2 trial, the authors evaluated the vascular endothelial growth factor receptor inhibitor axitinib, bevacizumab, or both in combination with chemotherapy as first‐line treatment of metastatic colorectal cancer (mCRC).

PD-L1 Expression by Two Complementary Diagnostic Assays and mRNA In Situ Hybridization in Small Cell Lung Cancer

Introduction: Therapeutic antibodies to immune checkpoints show promising results. Programmed death‐ligand 1 (PD‐L1), an immune checkpoint ligand, blocks the cancer immunity cycle by binding the PD‐L1 receptor (programmed death 1). We investigated PD‐L1 protein expression and messenger RNA (mRNA) levels in SCLC. Methods: PD‐L1 protein expression and mRNA levels were determined by immunohistochemistry (IHC) with SP142 and Dako 28‐8 PD‐L1 antibodies and in situ hybridization in primary tumor tissue microarrays in both tumor cells and tumor‐infiltrating immune cells (TIICs) obtained from a limited‐disease SCLC cohort of 98 patients. An additional cohort of 96 tumor specimens from patients with extensive‐disease SCLC was assessed for PD‐L1 protein expression in tumor cells with Dako 28‐8 antibody only. Results: The overall prevalence of PD‐L1 protein expression in tumor cells was 16.5%. In the limited‐disease cohort, the prevalences of PD‐L1 protein expression in tumor cells with SP142 and Dako 28‐8 were 14.7% and 19.4% (tumor proportion score cutoff ≥1%) and PD‐L1 mRNA ISH expression was positive in 15.5% of tumor samples. Increased PD‐L1 protein/mRNA expression was associated with the presence of more TIICs (p < 0.05). The extensive‐disease cohort demonstrated a 14.9% positivity of PD‐L1 protein expression in tumor cells with Dako 28‐8 antibody. Conclusions: A subset of SCLCs is characterized by positive PD‐L1 and/or mRNA expression in tumor cells. Higher PD‐L1 and mRNA expression correlate with more infiltration of TIICs. The prevalence of PD‐L1 in SCLC is lower than that published for NSCLC. The predictive role of PD‐L1 expression in SCLC treatment remains to be established.

Long-term effects of crizotinib in ALK-positive tumors (excluding NSCLC): A phase 1b open-label study

Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), MET, and ROS1, is approved for treatment of patients with ALK‐positive or ROS1‐positive advanced non‐small‐cell lung cancer (NSCLC). However, ALK rearrangements are also implicated in other malignancies, including anaplastic large‐cell lymphoma and inflammatory myofibroblastic tumors (IMTs). In this ongoing, multicenter, single‐arm, open‐label phase 1b study (PROFILE 1013; NCT01121588), patients with ALK‐positive advanced malignancies other than NSCLC were to receive a starting dose of crizotinib 250 mg twice daily. Primary endpoints were safety and objective responses based on Response Evaluation Criteria in Solid Tumors version 1.1 or National Cancer Institute International Response Criteria. Forty‐four patients were enrolled (lymphoma, nu2009=u200918; IMT, nu2009=u20099; other tumors, nu2009=u200917). The objective response rate was 53% (95% confidence interval [CI], 28–77) for lymphoma, with 8 complete responses (CRs) and 1 partial response (PR); 67% (95% CI, 30–93) for IMTs, with 1 CR and 5 PRs; and 12% (95% CI, 2–36) for other tumors, with 2 PRs in patients affected by colon carcinoma and medullary thyroid cancer, respectively. The median duration of treatment was almost 3 years for patients with lymphoma and IMTs, with 2‐year progression‐free survival of 63% and 67%, respectively. The most common treatment‐related adverse events were diarrhea (45.5%) and vision disorders (45.5%), mostly grade 1. These findings indicate strong and durable activity of crizotinib in ALK‐positive lymphomas and IMTs. The safety profile was consistent with the known safety profile of crizotinib even with long‐term treatment.

Irinotecan-induced dysarthria: A case report and review of the literature.

Irinotecan-induced dysarthria has been reported in the literature, but the underlying mechanism of this neurotoxicity remains unclear. Here, we present a 35-year-old female with metastatic colon cancer who experienced dysarthria during irinotecan infusion. Her symptoms were decreased and eventually eliminated with subsequent increases in infusion time. When the patient returned to original 90u2009min infusion time, symptoms were significantly reduced in both severity and duration as compared to the first infusion. We suggest infusion time as a potential intervention for patients experiencing dysarthria, and we review the existing literature, explore treatment options, and discuss proposed mechanisms surrounding this unusual adverse drug reaction.

Macrophage incorporation into a 3D perfusion tri-culture model of human breast cancer

Meeting abstractsnnImmunotherapy has recently shown promising clinical activity in multiple tumor types but standard in vitro immuno-oncology models for preclinical and clinical predictivity are lacking. Macrophages have been shown to have both tumor promoting and tumor preventing properties

Abstract A120: A Phase Ib study of CC-486 (Oral Azacitidine) as a priming agent for carboplatin or NAB-paclitaxel in subjects with relapsed and refractory solid tumors.

Background: CC-486, an oral formulation of 5-azacitidine, induces global genomic hypomethylation and clinical responses in MDS patients at doses of 200 mg and 300 mg/day for 14 or 21/28 days with acceptable safety. This non-randomized, multi-center Phase Ib study was designed to determine whether CC-486 can be delivered safely as priming for carboplatin or NAB-Paclitaxel (ABI-007) in patients with solid tumors.nnMethods: In Part 1 of this study, patients with refractory solid tumors were assigned to Arm A: CC-486 days 1 - 14 with carboplatin AUC 4 on day 8 of a 21 day cycle (n = 13) or Arm B: CC-486 days 1 - 14 with ABI-007 100 mg/m2 given weekly starting on Day 8 of Cycle 1 (n = 24). 200 mg and 300 mg dose levels (DLs) of CC-486 were evaluated in cohorts of 6 to identify a recommended Part 2 dose (RP2D).nnResults: On Arm A, 200 mg and 300 mg doses of CC-486 were tolerated. There was one DLT (Grade 3 pericardial effusion) at the 300 mg DL. Other related treatment-emergent adverse events (TEAEs) included anemia (53.8%) and neutropenia (46.3%). On Arm B, there were 2 DLTs of neutropenia at the 200 mg DL. The protocol was amended to give ABI-007 on days 8 and 15/21. No DLTs were encountered on 200 mg of CC-486 with intermittent ABI-007. At 300 mg, the MTD was exceeded with 2 DLTs of neutropenia (cholangiocarcinoma, pancreatic). Other common TEAEs in Arm B included nausea/vomiting (45.8%) and peripheral neuropathy (50%). Evidence of activity seen at both DLs included hypomethylation in PBMCs, 3 PRs in Arm B and 5 subjects with stable disease (> 4 mos) in Arm A. CC-486 plasma exposure showed high interpatient variability but was higher at 300 mg than 200 mg. Incidence and severity of AEs did not differ significantly between the 2 DLs. 300 mg was selected as the RP2D in combination with carboplatin and 200 mg in combination with ABI-007.nnConclusion: CC-486 dosed 14/21 days is tolerated as a priming agent with carboplatin and ABI-007. Both combinations show evidence of clinical activity. Expansion cohorts at the RP2D of Arm A (relapsed/refractory bladder or ovarian carcinoma) and Arm B (relapsed/refractory NSCLC or pancreatic carcinoma) are enrolling to further characterize safety, PK/PD and anti-tumor activity.nnCitation Information: Mol Cancer Ther 2013;12(11 Suppl):A120.nnCitation Format: Patricia LoRusso, Drew Rasco, Johanna Bendell, Jasgit Sachdev, Ramesh Ramanathan, Glenn Weiss, Pamela Munster, William J. Edenfield, Kejian Liu, Anne Blackwood-Chirchir, Jorge DiMartino, Jorge DiMartino, Daniel D. Von Hoff. A Phase Ib study of CC-486 (Oral Azacitidine) as a priming agent for carboplatin or NAB-paclitaxel in subjects with relapsed and refractory solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A120.

Phase I Study of CC-486 Alone and in Combination With Carboplatin or nab‑paclitaxel in Patients With Relapsed or Refractory Solid Tumors

Purpose: This large two-part, three-arm phase I study examined the safety and tolerability of CC-486 (an oral formulation of azacitidine, a hypomethylating agent) alone or in combination with the cytotoxic agents, carboplatin or nab-paclitaxel, in patients with advanced unresectable solid tumors. Patients and Methods: Part 1 (n = 57) was a dose escalation of CC-486 alone (arm C) or with carboplatin (arm A) or nab-paclitaxel (arm B). The primary endpoint was safety, MTD, and recommended part 2 dose (RP2D) of CC-486. In part 2 (n = 112), the primary endpoint was the safety and tolerability of CC-486 administered at the RP2D for each treatment arm, in tumor-specific expansion cohorts. Secondary endpoints included pharmacokinetics, pharmacodynamics, and antitumor activity of CC-486. Results: At pharmacologically active doses CC-486 in combination with carboplatin or nab-paclitaxel had a tolerable safety profile and no drug–drug interactions. The CC-486 RP2D was determined as 300 mg (every day, days 1–14/21) in combination with carboplatin (arm A) or as monotherapy (arm C); and 200 mg in the same dosing regimen in combination with nab-paclitaxel (arm B). Albeit limited by the small sample size, CC-486 monotherapy resulted in partial responses (three/eight) and stable disease (four/eight) in patients with nasopharyngeal cancer. Three of the stable disease responses lasted more than 150 days. Conclusions: CC-486 is well tolerated alone or in combination with carboplatin or nab-paclitaxel. Exploratory analyses suggest clinical activity of CC-486 monotherapy in nasopharyngeal cancer and provided the basis for an ongoing phase II clinical trial (ClinicalTrials.gov identifier: NCT02269943). Clin Cancer Res; 24(17); 4072–80. ©2018 AACR.

Safety and Pharmacokinetics of Bendamustine Rapid‐Infusion Formulation

Bendamustine hydrochloride (BDM) is approved in the United States to treat chronic lymphocytic leukemia and relapsed indolent B‐cell non‐Hodgkin lymphoma. The first formulation marketed in the United States (original BDM) was a lyophilized product requiring reconstitution prior to dilution to the final admixture. A liquid formulation of BDM was subsequently introduced that did not require reconstitution before dilution. Both formulations are administered as a 500 mL admixture with a recommended infusion time of 30 or 60 minutes for chronic lymphocytic leukemia and indolent B‐cell non‐Hodgkin lymphoma, respectively. A newer liquid BDM formulation (rapid BDM) is a ready‐to‐dilute solution not requiring reconstitution that dilutes into an admixture of only 50 mL and can be safely administered in a shorter infusion time (10 minutes). Rapid BDM admixture also has longer stability at room temperature than both lyophilized and liquid BDM formulations (6 vs 2 to 3 hours). This phase 1, open‐label, randomized, crossover (3‐period, partially replicated) study, conducted in “end‐of‐life” cancer patients at 10 oncology centers in the United States, demonstrates that rapid BDM is bioequivalent to original BDM as determined by area under the curve. Expected differences in maximum plasma concentration and time to maximum plasma concentration were observed between study treatments, given the substantially shorter infusion time of rapid BDM. No clinically relevant differences in other evaluated pharmacokinetic parameters were found. Rapid BDM infusions were safe and tolerable for cancer patients in this study. The overall safety profiles of the 2 BDM formulations were comparable, with no new safety signals identified and no differences in infusion‐related adverse events.

Abstract CT056: Preliminary safety, efficacy, and pharmacodynamics of a highly selective PI3Kδ inhibitor, INCB050465, in patients with previously treated B-cell malignancies

Background: PI3Kδ inhibitors have demonstrated efficacy in the treatment of B-cell malignancies, but off-target toxicity and/or the inability to achieve near-complete inhibition of the PI3Kδ pathway may affect the depth and duration of response. INCB050465 is a novel, potent, and selective PI3Kδ inhibitor (Shin et al. AACR 2015. Abstract 2671), with a differentiated profile for potency (whole blood IC50 = 10 nM), dose ( 10-fold). An open-label phase 1 study was initiated to evaluate INCB050465 alone or in combination with other agents in patients with previously treated B-cell malignancies; preliminary results of the dose escalation of INCB050465 monotherapy are reported. Methods: Adult patients with B-cell malignancies who were refractory to or for whom available treatments had failed were eligible. Dose escalation was conducted with a 3 + 3 design after an initial single patient cohort. Patients were observed for 21 days before enrollment of the next cohort. Results: As of the data cutoff, 15 patients were enrolled and treated with INCB050465 at doses ranging from 5 to 30 mg once daily. The median age was 64 years and 47% were men. Patients received a median of 2 prior treatment regimens and the median time since initial diagnosis was 4.9 years. Disease subtypes included DLBCL (n = 6), CLL (n = 3), FL (n = 2), MZL (n = 2), MCL (n = 1), and HL (n = 1). Median exposure to INCB050465 was 15.4 weeks (range, 6.9 to 36.4+ weeks) and no patients required dose reduction. INCB050465 was well tolerated with no DLTs observed. Five patients discontinued treatment, 4 due to disease progression and 1 due to an adverse event (grade 2 exfoliative dermatitis). Ten grade 3 or greater treatment-emergent adverse events were seen in 6 patients: anemia (n = 2), bacteremia, Escherichia infection, hypotension, neutropenia, pneumonia, sepsis, syncope, and WBC count decreased (n = 1 each). To date, only grade 1 transaminase elevations have been observed. Responses were observed in DLBCL (3/6 patients), CLL (1/3), FL (2/2), MZL (2/2), and MCL (1/1). Clinical benefit was observed early in the course of treatment, and the longest duration of response was 27+ weeks. Terminal half-life and suppression of PI3Kδ signaling at trough support once daily dosing. Conclusions: INCB050465 monotherapy was generally well tolerated at all doses tested. Robust and durable signaling pathway inhibition was achieved at all doses and INCB050465 showed promising efficacy in FL, DLBCL, and other lymphomas, with a potentially favorable toxicity profile vs other PI3Kδ inhibitors. Enrollment in dose-escalation, combination therapy, and disease-specific cohorts is ongoing. Citation Format: Andres Forero-Torres, Michael S. Wertheim, Tycel J. Phillips, Martin E. Gutierrez, William J. Edenfield, Swamy Yeleswaram, Maureen Bleam, Li Zhou, Jennifer H. Pulini, Thea Faivre, Harry Miao, Matt Spear, Rod Ramchandren. Preliminary safety, efficacy, and pharmacodynamics of a highly selective PI3Kδ inhibitor, INCB050465, in patients with previously treated B-cell malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT056.

Abstract B217: A Phase I study of CC-486 (oral azacitidine) to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of azacitidine administered alone and in combination with carboplatin or ABI-007 (NAB-paclitaxel) in subjects with solid tumors.

Background: CC-486 is an orally bioavailable formulation of azacitidine that has demonstrated clinical activity in subjects with Myelodysplastic Syndromes (MDS) and Acute Myleoid Leukemia (AML). In these patient populations, CC-486 in extended dosing regimens, 200 mg and 300 mg given daily on a 14 or 21 out of 28-day schedule, induces sustained global genomic hypomethylation.nnMethods: This Phase I, multicenter, open-label study was conducted in subjects with solid tumors to evaluate: 1) the effect of carboplatin or ABI-007 on the PK of CC-486; 2) the effect of CC-486 on the PK of carboplatin or ABI-007; and 3) the PD (DNA methylation) effects of CC[[Unable to Display Character: ‑]]486 as a single agent and in combination with carboplatin or ABI-007. Safety and efficacy information of this trial are presented in a separate abstract submission.nnSubjects received CC-486 on Days 1-14 with carboplatin AUC 4 on Day 8 of a 21-day cycle (Arm A), CC-486 on Days 1-14 with ABI-007 100 mg/m2 given weekly starting on Day 8 of a 21-day cycle (Arm B), or CC-486 on Days 1-21 of a 21-day cycle (Arm C).nnResults: High inter-subject variability was observed in PK concentrations and parameters. In subjects from Arms A and B, following administration of CC-486 alone or in combination with carboplatin or ABI-007, CC-486 was rapidly absorbed and reached Tmax within approximately 1.0 hour post-dose (median); azacitidine PK parameters (AUC, Cmax, half-life elimination, apparent clearance, and volume of distribution) were comparable following administration of CC-486 alone or in combination. Similarly, carboplatin and ABI-007 PK parameters were similar following administration of carboplatin or ABI-007 alone or in combination with CC-486. In subjects from the 3 Arms, global genomic hypomethylation was observed in PBMCs, with maximum effect on Day 15. A PK/PD (AUC/hypomethylation change on Day 15) correlation was noted (r>0.5; p<0.01).nnConclusion: Carboplatin and ABI-007 had minimal to no effect on CC-486 PK parameters, and vice-versa. Following administration of CC-486, global genomic hypomethylation was correlated with plasma AUC.nnCitation Information: Mol Cancer Ther 2013;12(11 Suppl):B217.nnCitation Format: Eric Laille*, Aaron N. Nguyen*, Gengxi Chen, Drew Rasco, Patricia LoRusso, Daniel D. Von Hoff, Johanna Bendell, Pamela Munster, William J. Edenfield, Ramesh Ramanathan, Michael B. Gonzalez, Anne Blackwood-Chirchir, Jorge DiMartino. A Phase I study of CC-486 (oral azacitidine) to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of azacitidine administered alone and in combination with carboplatin or ABI-007 (NAB-paclitaxel) in subjects with solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B217.