Iyer, Renuka

The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, and cancer of the bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Due to the multiple modalities that can be used to treat the disease and the complications that can arise from comorbid liver dysfunction, a multidisciplinary evaluation is essential for determining an optimal treatment strategy. A multidisciplinary team should include hepatologists, diagnostic radiologists, interventional radiologists, surgeons, medical oncologists, and pathologists with hepatobiliary cancer expertise. In addition to surgery, transplant, and intra-arterial therapies, there have been great advances in the systemic treatment of HCC. Until recently, sorafenib was the only systemic therapy option for patients with advanced HCC. In 2020, the combination of atezolizumab and bevacizumab became the first regimen to show superior survival to sorafenib, gaining it FDA approval as a new frontline standard regimen for unresectable or metastatic HCC. This article discusses the NCCN Guidelines recommendations for HCC.

AbstractIn this phase I, dose‐escalation study, we sought to determine the maximum tolerated dose (MTD) of the anaplastic lymphoma kinase/c‐ROS oncogene 1 receptor (ALK/ROS1) inhibitor ceritinib in combination with gemcitabine‐based chemotherapy in patients with advanced solid tumors. Secondary objectives were characterization of the safety profile, pharmacokinetics and preliminary efficacy of these combinations, and identification of potential biomarkers of efficacy. Ceritinib was combined with gemcitabine (Arm 1), gemcitabine/nab‐paclitaxel (Arm 2) or gemcitabine/cisplatin (Arm 3). Drug concentrations in plasma were measured by tandem mass spectrometric detection (LC‐MS/MS). We analyzed archival tumor tissue for ALK, ROS1, hepatocyte growth factor receptor (c‐MET) and c‐Jun N‐terminal kinase (JNK) expression by immunohistochemistry. Arm 2 closed early secondary to toxicity. Twenty‐one patients were evaluable for dose‐limiting toxicity (DLT). There was one DLT in Arm 1 (grade 3 ALT increase) and three DLTs in Arm 3 (grade 3 acute renal failure, grade 3 thrombocytopenia, grade 3 dyspnea). The MTD of ceritinib was determined to be 600 mg (Arm 1) and 450 mg orally daily (Arm 3). Main toxicities were hematologic, constitutional and gastrointestinal as expected by the chemotherapy backbone. The apparent clearance for ceritinib decreased substantially after repeated dosing; cisplatin did not significantly affect the pharmacokinetics of ceritinib. The overall response rate was 20%; the median progression‐free survival was 4.8 months. Three out of five response‐evaluable cholangiocarcinoma patients had clinical benefit. Increased expression of c‐MET was associated with a lack of clinical benefit. Ceritinib in combination with gemcitabine and gemcitabine/cisplatin has a manageable toxicity profile. Further development of this strategy in tumors with ALK or ROS1 fusions is warranted.

TPS358 Background: The anti–PD-L1 antibody ATEZO prevents PD-L1 from interacting with PD-1 and B7.1, thus reinvigorating antitumor T cell activity. Anti-VEGF BEV can increase dendritic cell maturation, enhance T cell infiltration, and reduce myeloid-derived suppressor cells and regulatory T-cells in tumors. This combination has been FDA approved for first-line treatment of advanced HCC based on the IMbrave 150 study. On the other hand, locoregional radiotherapy (e.g., Y90 TARE) enhances the diversity of the intratumoral T cell receptor repertoire. It is the standard of care for pts with intermediate-stage HCC (iHCC). Based on preclinical and clinical data, we hypothesize that the combination of Y90 TARE, BEV, and ATEZO induces synergistic tumor-killing. Methods: This is an open-label, multicenter, randomized phase II study of Y90 TARE and BEV plus ATEZO compared with Y90 TARE alone in pts with unresectable IHCC. The primary study objective is to assess and compare the progression-free survival (PFS) (per mRECIST 1.1) of pts in each arm. The main secondary objective is to determine the safety and tolerability (CTCAE v5) of TARE combined with ATEZO and BEV in pts with HCC. Exploratory objectives are to assess the role of the immunoscore and PD-L1 expression levels in the prediction of improved clinical outcome in pts receiving Y-90 TARE and BEV plus ATEZO; the composition of tumor-infiltrating immune cell subtypes in predicting response to a chosen therapy; how Y90 therapy affects the proportion of antigen-presenting cells in the tumor; and symptoms experienced by pts receiving TARE and BEV plus ATEZO treatment, using patient-reported outcomes. Eligible pts have either HCC that is not amenable to surgical resection, confirmed by pathology review, or at least BCLC stage B HCC outside of downstaging criteria. Other standard eligibility criteria apply. Pts must have a pretreatment liver biopsy taken and then be randomized 1:1 to TARE (Arm A) or TARE followed by ATEZO and BEV (Arm B). Pts will have TARE mapping during week (wk) 1 and TARE treatment during wk 2. In Arm B, pts will start BEV plus ATEZO 4 wks (±1 wk) after TARE treatment. Pts will have abdominal MRI or CT scans every 12 weeks, CT scans of the chest every 24 wks, and a second tumor biopsy at 4 wks. Disease progression will be captured by both RECIST 1.1 and mRECIST. We plan to assess the safety of TARE with BEV and ATEZO in the first 10 pts randomized to Arm B for two cycles. If there are no grade ≥ 3 unexpected toxicities possibly, probably or definitely related to combined TARE plus BEV plus ATEZO, the study will continue to accrue 128 pts in total. Pts will continue study treatment (Arm B) for a total of 24 months from initiation of TARE or until intolerable toxicity or disease progression occur, whichever is earlier. Enrollment began in September 2020. Clinical trial information: NCT04541173.

Abstract Introduction: Cer is an oral ALK/ROS1 inhibitor. Aberrancies in ALK and ROS1 have been observed in many cancer types and ALK inhibition has synergistic effects with chemotherapy in ALK or ROS1 rearranged tumors in preclinical models. We launched a Phase I study of Cer in combination with Gem-based chemotherapy in advanced solid tumors. Herein we present initial results of this study. Methods: Phase I, dose-escalation study of Cer in combination with A1: Gem 1000 mg IV D1/8/15 q28 days; A2: Gem 1000 mg IV + nanoparticle albumin-bound Paclitaxel 125 mg IV both D1/8/15 q28 days; A3: Gem 1000 mg IV + Cisplatin 60 mg IV D1/8 q21 days in pts with advanced, solid malignancies until disease progression, intolerable toxicity or withdrawal. A 3 + 3 dose-escalation design was used starting at Cer 450 mg once daily (DL1) in all arms; DL2 was 600 mg once daily. Primary objective was to determine the maximum tolerated dose (MTD) of Cer. Key inclusion criteria: diagnosis of advanced solid malignancy for which Gem-based treatment was appropriate, >18 years old, ECOG PS 0/1, adequate bone marrow/renal/liver function. Key exclusion criteria: interstitial lung fibrosis/disease, recent acute coronary event, CHF NYHA III/IV, corrected QTc > 450 ms. Pts in A3 could have up to 2 prior lines of therapy. Prior use of ALK inhibitors allowed. Plasma was collected for PK on C1D1, C2D1, and C1D15. Archival tumor tissue was tested for ALK/ROS1/JNK/MET by IHC. Results: Thirty-eight patients were enrolled with 21 evaluable for dose-limiting toxicity (DLT) in A1 and A3. A2 (n=4) closed to accrual for toxicity. Median age was 61 years. Seven pts (41%) had cholangiocarcinoma. A1 had one DLT (G3 ALT increase) in DL2; MTD was 600 mg. A3 had one DLT in DL1 (G3 acute renal failure) and two DLTs in DL2 (G3 thrombocytopenia and G3 dyspnea); MTD was 450 mg. G3-5 AEs in all pts: anemia (A1: 3/19, A3: 2/15), nausea (A1: 1/19, A3: 2/15), emesis (A1: 1/19, A3: 1/15), neutropenia (A1: 2/19, A3: 8/15), thrombocytopenia (A1: 1/19, A3: 4/15), hyperbilirubinemia (A3: 3/15), pneumonia (A1: 2/19), acute renal failure (A3: 1/15), fatigue (A3: 2/15). Fifteen patients were evaluable for response; the overall response rate was 20% with two PR (pt with head and neck carcinoma in A1 and pt with carcinoma of unknown primary in A3) - and one CR in a pt with cholangiocarcinoma (A3) lasting 10.3 months. Overall, disease control rate was 47%. Of 5 evaluable pts with cholangiocarcinoma 3 had clinical benefit. Median PFS 3.4 mo (A1)/4.8 mo (A3) and OS 13.7 mo (A1)/29.1 mo (A3). PK and IHC data will be presented at the conference. Conclusions: The MTD of Cer is 600 mg in combination with Gem and 450 mg in combination with Gem/Cisplatin. Further evaluation of Cer plus Gem-based chemotherapy is planned in ALK/ROS1 positive cholangiocarcinomas. Citation Format: Christos Fountzilas, Alex Adjei, Mateusz Opyrchal, Rachel Evans, Kristopher Attwood, Andrew Goey, John Wilton, Wen Wee Ma, Renuka Iyer. Ceritinib (Cer) in combination with gemcitabine (Gem)-based chemotherapy in patients (pts) with advanced solid tumors, a phase I study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT139.

Background: Patients with cholangiocarcinoma often have indwelling biliary stents or catheters which are prone to obstructions and/or infections; studies show that 20–40% present with fever and/or jaundice requiring urgent treatment in the outpatient setting for which there are no uniform guidelines. The goal was to develop an expert panel consensus on this topic using the modified RAND/UCLA Delphi process to rate treatment appropriateness. Methods: Thirteen expert physicians from relevant specialties, geography, and practice settings were recruited for the panel. Patient scenarios were developed and panelists rated the therapies before and after a face-to-face discussion. The appropriateness of various therapies was rated on a scale from 1–9 and classified as appropriate, inappropriate, or uncertain. Scenarios with greater than 2 (>2) ratings of 1–3 (inappropriate) and greater than 2 (>2) ratings of 7–9 (appropriate) were considered to have disagreement and were not assigned an appropriateness rating. Results: Panelists were from all US regions and the UK (8%) and had practiced for a mean 16.5 years (4–33 years). Panelists rated 480 scenarios before the meeting and re-rated 288 of the clinical scenarios after the meeting. The panelists agreed that ongoing treatment with chemotherapy did not influence decision-making and, therefore, 192 scenarios were excluded from the final list. Disagreement decreased from 37.5% before to 10.4% after the meeting. Consensus on stent/tube manipulation and inpatient antibiotic therapy was obtained and summarized in patients as “appropriate” or “maybe appropriate” based on a patient’s bilirubin level at presentation. Conclusions: The Delphi process produced consensus guidelines to fill an unmet need in the urgent management of ascending cholangitis in patients with cholangiocarcinoma.

3583 Background: The novel curaxin CBL0137 intercalates into DNA, interfering with histone/DNA binding. Consequent trapping of histone chaperone FACT leads to MYC, NF-kB, and HSF1 inhibition, p53 activation, and an IFN response. CBL0137 shows broad nonclinical antitumor activity (Gasparian et al. Sci Transl Med. 2011; 3(95):95ra74). Methods: This dose-ranging study assessed the CBL0137 maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) and CBL0137 safety, pharmacokinetics (PK), and efficacy in adults with advanced treatment-refractory solid tumors. CBL0137 was administered IV on Days 1, 8, and 15 of repeated 28-day cycles until progressive disease (PD) or unacceptable toxicity. Doses were escalated using a 3+3 design based on Cycle 1 dose-limiting toxicities (DLTs). PK was assessed through 168 hours after Day 1. Efficacy was evaluated every 8 weeks. Results: The study enrolled 83 pts (M/F [n] = 49/34; median [range] age = 64 [33-85] years; ECOG status [n] = 1/2 [32/51]), with cancer types (n) of colorectal (23), prostate (7), glioblastoma (6), liver (6), non-small-cell (5), and others (36) across 17 dose levels from 10 to 700 mg/m2/infusion. Durations of therapy ranged to 24 months. Cycle 1 DLTs (n type) were observed at 240 mg/m2 (1 Gr 3 photosensitivity), 400 mg/m2 (1 Gr 3 anemia), 700 mg/m2 (1 Gr 4 thrombocytopenia, 1 Gr 4 neutropenia/Gr 4 thrombocytopenia), and 650 mg/m2 (1 Gr 3 thrombocytopenia, 1 Gr 4 neutropenia/Gr 3 thrombocytopenia). Nausea and vomiting were successfully prevented with dexamethasone/serotonin antagonists. Photosensitization was effectively managed with sun protection. Peripheral venous thrombosis required central vein infusion in subjects with glioblastoma. PK showed dose-proportional increases in plasma CBL0137 area under the concentration-time curve (AUC), a high mean (range) volume of distribution (Vd) of 1,030 (655-1460) L/m2 consistent with extensive tissue distribution and DNA intercalation, and an average mean (range) half-life (t1/2) of 24.7 (10.3-40.7) hours without dose dependence. The best response was stable disease: 2 pts with liver cancer had tumor control for 9 and 24 months and a maximum tumor regression of 10%; 2 pts with prostate cancer had tumor regressions by 11% and 22%; 1 pt with uterine cancer had a 20% tumor regression. Conclusions: CBL0137 administered IV was generally well tolerated with manageable toxicities The MTD and RP2D were estimated at 540 mg/m2 due to myelosuppressive DLTs. PK were predictable. Preliminary evidence of antitumor activity supports Phase 2 testing. Clinical trial information: NCT01905228 .

4038 Background: GEM has served as the chemotherapy platform for most phase III clinical trials in APC, inc. CALGB 80303 (GEM +/- BEV). However, GEM-based combination regimens may confer superior outcomes in select pts and represent a preferred backbone in clinical trial design testing targeted agents. Methods: Data was pooled from 5 phase II trials evaluating GEM-based cytotoxic doublets plus BEV in APC. 1o endpoint was OS. 2o endpoints included ORR, CA19-9 response, and adverse events (AEs). Kaplan-Meier methods estimated time-to-event endpoints. The Cox proportional hazard model estimated univariate hazard ratios (HR) of death. Results: Of 261 pts, 90.7% were Caucasian, 95.4% had an ECOG PS 0-1, and 91.6% had metastatic disease. Median age = 60y. Pooled OS data (in mos), stratified for PS and stage, is shown in the table. ORR across all trials: CR 1.6%, PR 22.9%, SD 50.8%, PD 20.2%, NA 4.7%. HR for pts who achieved disease control (CR/PR/SD) was 0.35 vs. those with PD (95% CI 0.23-0.54, p<0.001). 76.5% of pts had elevated baseline CA19-9; of these, 62% achieved ≥50% reduction (HR 0.50; 95% CI 0.34-0.73, p<0.001). BEV-related AEs ≥grade 3: HTN (10.6%), hemorrhage (9.5%), VTE (10.1%), cardiac events (3.4%), and bowel perforation (2.2%). Median OS in pts with grade 3-4 HTN was 13.4 mos vs. 9.8 mos in those without (HR 0.77; 95% CI 0.48-1.24, p=0.29). Conclusions: Recognizing the limitations of single-arm phase II trial design and cross-study comparisons, these results compare favorably to those from CALGB 80303. The standard paradigm of GEM +/- drug X in clinical trial development for APC needs to be reconsidered. Based on our data as well as the recent phase III FOLFIRINOX study, building on more intensive combination chemo regimens in future trials may represent a better strategy, especially for pts with good PS. [Table: see text]

The NCCN Guidelines for Hepatobiliary Cancers provide treatment recommendations for cancers of the liver, gallbladder, and bile ducts. The NCCN Hepatobiliary Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s discussion and updated recommendations regarding systemic therapy for first-line and subsequent-line treatment of patients with hepatocellular carcinoma.

Objectives: Preclinical studies demonstrated antitumor activity of dovitinib in pancreatic cancer models. This phase Ib study aimed to determine the maximum tolerated dose (MTD) of dovitinib in combination with gemcitabine and capecitabine and to characterize the safety and pharmacokinetic profile in patients with advanced pancreatic and biliary tract cancers and solid malignancies. Materials and Methods: Patients received gemcitabine 1000 mg/m² intravenously on days 1 and 8, capecitabine 1300 mg/m² oral daily from day 1 to 14, and dovitinib oral daily 5 days on and 2 days off, every 21-day cycle. The standard 3+3 dose escalation design was utilized and the study expanded to treat an additional 20 advanced pancreatic and biliary tract cancers patients at MTD. Results: A total of 29 patients were enrolled. One patient experienced dose-limiting grade 3 colitis. Two patients developed clinically significant neuropathy after the first cycle requiring dose reduction. The MTD was not reached and dovitinib 300 mg was declared the recommended dose for expansion. The most frequent grade 2 or worse adverse events were fatigue (45%), neutropenia (41%), thrombocytopenia (34%), anemia (24%), nausea (24%), and palmer-plantar erythrodysaesthesia syndrome (21%). Partial responses were observed in 5 patients. Pharmacokinetic studies showed no drug-drug interaction between dovitinib, capecitabine and gemcitabine. Fibroblast growth factor 23 plasma level increased in 4 of 5 patients during the first cycle of treatment. Conclusions: Dovitinib 300 mg daily is the recommended dose when combined with gemcitabine and capecitabine, achieving clinically relevant plasma concentrations. The study combination demonstrated encouraging efficacy signals in advanced pancreatic cancer.

e15641 Background: CC pts with biliary stents or catheters are prone to have obstruction/infection and studies show 20-40% present with fever/or jaundice requiring urgent treatment for which there is no uniform guideline. We aimed to develop an expert panel consensus on this topic using the modified RAND/UCLA Delphi process to rate treatment appropriateness. Methods: We recruited 13 physician experts from relevant specialty, geography, and practice settings. Patient scenarios were developed and panelists rated the therapies before and after a face-to-face discussion. The appropriateness of various therapies was rated on a 1-9 scale and classified as appropriate, inappropriate, or uncertain. Scenarios with > 2 ratings of 1-3 (inappropriate) and > 2 ratings of 7-9 (appropriate) were considered to have disagreement and were not assigned an appropriateness rating. Results: Panelists were from all US regions (92%) and the UK (8%); had practiced for a mean 16.5 years (4-33 years). Panelists rated 480 scenarios before the meeting, but re-rated only 288 clinical scenarios as they felt that ongoing treatment with chemotherapy did not influence decision-making. Disagreement decreased from 37.5% before the meeting to 10.4% after. Consensus statements are summarized in the table below. Conclusions: The Delphi process produced consensus guidelines to fill an unmet need in urgent management of ascending cholangitis in pts with CC. (Support: The Cholangiocarcinoma Foundation). [Table: see text]