Search

PURPOSE National Cancer Institute (NCI)–sponsored clinical trial network studies frequently require biopsy specimens for pharmacodynamic and molecular biomarker analyses, including paired pre- and post-treatment samples. The purpose of this meeting of NCI-sponsored investigators was to identify local institutional standard procedures found to ensure quantitative and qualitative specimen adequacy. METHODS NCI convened a conference on best biopsy practices, focusing on the clinical research community. Topics discussed were (1) criteria for specimen adequacy in the personalized medicine era, (2) team-based approaches to ensure specimen adequacy and quality control, and (3) risk considerations relevant to academic and community practitioners and their patients. RESULTS AND RECOMMENDATIONS Key recommendations from the convened consensus panel included (1) establishment of infrastructure for multidisciplinary biopsy teams with a formalized information capture process, (2) maintenance of standard operating procedures with regular team review, (3) optimization of tissue collection and yield methodology, (4) incorporation of needle aspiration and other newer techniques, and (5) commitment of stakeholders to use of guideline documents to increase awareness of best biopsy practices, with the goal of universally improving tumor biopsy practices.

e17114 Background: Adrenocortical carcinoma (ACC) is a rare cancer with an incidence of 0.7 – 2 cases per million persons per year, and generally has a poor prognosis with a 5-year survival rate of 20-25%. In a previous review of 330 patients with ACC, the median overall survival time of patients with Stage IV ACC was 0.9 years. Currently, complete surgical resection is the only curative treatment for ACC. Cases of recurrent or metastatic ACC are infrequently curable by surgery alone and systemic therapies have limited benefit. A previous study has suggested that local interventions to resect liver metastases improve survival. We hypothesize that local therapies increase survival of patients with metastatic ACC and here we describe the characteristics of various types of regional therapies. Methods: We conducted a retrospective chart review of 26 patients with ACC who were seen at the National Institutes of Health (NIH) between 2002 and 2019 and who are currently alive. These patients had multiple interventions that were performed including surgeries, radiofrequency ablations/embolizations/cryoablations and systemic therapies. Results: The group of patients we studied were 92% female and 8% male. The ages ranged from 23 to 77, with an average age of 57. Out of the 26 patients, 11 (42%) patients had liver metastases, 17 (65%) patients had lung metastases, 4 (15%) patients had retroperitoneal recurrence, and 5 (19%) patients had lymph node involvement. All patients with lung, retroperitoneum, liver, and lymph node metastases underwent surgical intervention. In patients with liver metastases, 73% underwent liver-directed therapies and 91% received systemic therapy. In patients with lung metastases, 59% underwent radiofrequency ablation or cryoablation and 94% had systemic therapy. Among the systemic therapies, 15% of patients received zero lines of treatment, 50% of patients received one line, 12% of patients received two lines, 19% of patients received three lines, and 4% of patients received more than three lines of treatment. Conclusions: The analysis of this cohort indicates that multiple local therapies could increase patient survival. ACC metastases are most common in the liver, followed by the lungs. Patients with recurrent/metastatic ACC should be considered for regional therapies such as metastasectomy/ablation in experienced hands which can increase long-term survival in selected patients.

336 Background: Prognosis in advanced HCC and BTC is unfavorable, and 5-year overall survival (OS) rate is less than 20% and 10%, respectively. Single agent ICI in HCC has response rates (RR) of 20%, while early data in BTC reported 17.4% RR. Dual ICI has increased RR in other malignancies. The purpose of this study was to explore the efficacy of the combination of anti-CTLA4 (tremelimumab) with anti-PD-L1 (durvalumab) in advanced HCC and BTC. Methods: Eligible patients with advanced HCC or BTC who had received (or refused) at least one prior therapy, received monthly tremelimumab 75 mg in combination with durvalumab 1500 mg for 4 doses followed by monthly durvalumab 1500 mg monotherapy until progression of disease or unacceptable toxicity. Response was assessed with CT scan every 8 weeks. Adverse events (AEs) were recorded and managed. The primary endpoint is 6-month progression free survival (PFS). Results: Twenty-two patients were enrolled, 10 with advanced HCC and 12 with advanced BTC. Male to female ratio was 14:8, with median age of 62.5 years (range 19-80). Grade 3/4 treatment-related AEs included lymphocytopenia, hyponatremia, bullous dermatitis, maculopapular rash, mucositis, hypophosphatemia, anaphylaxis, dyspnea, pleural effusion, and pain. Twenty patients were evaluable for response analysis. Two patients (2/10, 20%) achieved a confirmed partial response (both with HCC, lasting 6.9 and 17.6 months), while 9 patients (4 [40%] with HCC and 5 [41.7%] with BTC) had stable disease, with the longest duration of 9.3 months (in an HCC patient). Disease control rate is 60% in HCC and 41.7% in BTC, respectively. In this small pilot cohort, median PFS was 3.1 months (95% CI 0.8 to 4.6 months) and median OS was 5.45 months (95% CI 4.60 to 8.3 months) among BTC patients, while HCC patients median PFS was 7.8 months (95% CI 2.6 to 10.6 months) and median OS was 15.9 (95% CI 7.1 to 16.3 months). Conclusions: Combined ICI with tremelimumab and durvalumab is well tolerated and demonstrates promising activity in patients with advanced HCC and BTC. Clinical trial information: NCT02821754.

2549Background: Ataxia-telangiectasia-related (ATR) protein kinase is central to the repair of damaged DNA through the homologous recombination (HR) pathway, activating phosphorylation cascades tha...

365 Background: Treatment option for patients with advanced BTC is limited and prognosis is poor with a median survival of less than 1 year in the locally advanced or metastatic setting. It has been shown deregulation of the immune system plays an important role in the pathogenesis of BTC. This study aimed to investigate whether tremelimumab (Treme), anti-CTLA4, could be combined safely and feasibly with microwave ablation therapy to enhance the effect of anti-CTLA4 treatment in patients with advanced BTC. Methods: Patients with refractory BTC were enrolled in a study of monthly Treme (10mg/kg, IV, 6 doses), followed by 3-monthly infusions until off-treatment criteria were met. On day 36, patients underwent subtotal microwave ablation. Staging image was performed every 8 weeks. Adverse events (AEs) were collected and managed. Tumor samples and peripheral blood samples were collected to perform immune monitoring. Results: Twenty patients with refractory BTC were enrolled. Male: female ratio was 10:10 with median age 56.5 years (range 37-67). Six patients had extrahepatic cholangiocarcinoma (ECC), two patients had gallbladder cancer, whereas the remaining 12 patients had intrahepatic cholangiocarcinoma (ICC). No dose-limiting toxicities were encountered. The common AEs included lymphocytopenia, colitis, adrenal insufficiency, anemia, and elevated transaminases. The most common clinical toxicity was diarrhea. Sixteen patients were evaluable for response analysis, one (6%) patient achieved a confirmed partial response (lasting for 8 months), 6 (37.5%) achieved stable disease with the longest lasting for 9.2 months. Among all 20 patients, median progression free survival, time to progression, and overall survival were 3.4 months (95% CI 2.5-5.2 months), 3.3 months (95% CI: 2.5-4.6 months) and 6.0 months (95% CI 3.8-8.8 months) respectively in this small pilot cohort. T cell receptor (TCR) b screening showed Treme expanded TCR repertoire though non-significantly. RNA seq is ongoing and will be presented. Conclusions: Treme in combination with tumor ablation is a potential new treatment for patients with advanced BTC. TCR repertoire expansion induced by Treme may contribute to treatment benefit. Clinical trial information: NCT01853618.

e20000 Background: Thermal ablation [radiofrequency ablation (RFA), cryoablation, microwave ablation (MWA)] has been used effectively for control of hepatic metastases from various solid tumors. However, these interventions have not been systematically evaluated in patients (pts) with TETs. We present our experience of the safety and clinical efficacy of thermal ablation in pts with advanced TETs and limited sites of disease progression. Methods: Pts with metastatic TETs followed at the National Cancer Institute were considered for thermal ablation if extrathoracic disease progression was limited to 3 or fewer anatomic sites amenable to percutaneous thermal ablative techniques. Appropriate imaging studies were used to evaluate for recurrence, and recurrence-free survival (RFS) was calculated. Biopsies were performed prior to ablation to study mutational and signaling events that may predispose to benefit. Results: From November 2012 to June 2016, 11 metastases (9 liver, 2 chest wall) in 4 pts (3 male, 1 female; median age 59.5 (range, 59-67); 3 thymic carcinoma, 1 WHO B2 thymoma; all Masaoka stage IVB) were treated with thermal ablation (6 MWA, 3 RFA, 2 cryoablation). Median size of metastasis was 1.5 cm (range, 1-4 cm). Local recurrence occurred at 2 (18%) of 11 treated sites, 11.5 months and 10 months after thermal ablation. All pts experienced distant recurrence (1 mesenteric/pelvic mass, 1 lung, 1 malignant pleural effusion, 1 liver) with a median RFS of 7 months (range, 2.5-14). Treatment was well tolerated with no serious adverse events. One pt died due to disease progression 9 months after thermal ablation; 3 pts are alive at the time of reporting (23.5, 37.5 and 38 months after treatment). Conclusions: Thermal ablation is well tolerated and largely successful in achieving local control in pts with advanced, unresectable TETs. Further studies are needed to assess the clinical benefit of thermal ablation compared with systemic therapy and surgery in specific pts with recurrent, oligometastatic TETs. The exact role of thermal ablation tools remains to be defined in this population. The potential for local thermally-induced cell death to induce or augment immunogenic tumor cell death will be assessed and reported.

TPS2609 Background: The DNA damage response (DDR) pathway is a key element of cellular integrity. Platinum compounds form covalent bonds with purine bases causing DNA cross-links that stall replication forks halting transcription. Poly (ADP-ribose)polymerase-1 (PARP-1) plays a pivotal role in DDR and base-excision repair. Ataxia-telangiectasia-related (ATR) protein kinase is also central to DDR and homologous recombination, activating a series of phosphorylation cascades culminating in cell cycle arrest to allow time for DNA repair. Veliparib (ABT-888) is a PARP 1/2 inhibitor (PARPi) with clinical evidence of antitumor activity in combination with cisplatin in BRCA mutation carriers (Rodler et al, Cancer Res. 2011). VX-970 is a potent ATR inhibitor, with antitumor activity across a range of cell lines in combination with DNA damaging agents, including cisplatin (Huntoon et al, Cancer Res. 2013). In this trial, we will evaluate whether the combination of veliparib + VX-970 impairs DNA repair, inducing a “BRCA null”-like phenotype leading to potentiation of the antitumor activity of cisplatin. Methods: Open label phase I trial of the veliparib+VX-970+cisplatin combination, following a 3+3 design, with dose limiting toxicities defined during cycle 1. Estimated enrollment: 24 patients (pts); Dana Farber and MD Anderson planned as additional sites. Drug administration over a 21-day cycle: VX- intravenously (IV) on Days 2 and 9; Veliparib orally twice daily (q12 hours ± 1 hour) Days 1-3 and 8-10; cisplatin 40 mg/m2 IV Day 1 (with Day 8 added from DL3 onwards). Pts must be ≥ 18 years of age; have histologically confirmed solid tumors that have progressed on standard of care therapy known to prolong survival or without known standard, ECOG PS ≤2, and life expectancy ≥3 months. Pts with treated brain metastasis with stable disease ≥4 weeks without requiring steroids or anti-seizure medication are eligible. Exclusion criteria include a prolonged QTc interval, and sensory/motor neuropathy ≥grade 2 by CTCAE v.4. At this time, cohort 3 has enrolled 1 of 3 planned pts. Assessment of DDR and apoptosis biomarkers at the maximally tolerated dose using a validated and quantitative immunofluorescence assay is planned. Clinical trial information: NCT02723864.

88 Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Radiofrequency ablation (RFA) has been shown to induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment. Methods: Patients with refractory BTC were enrolled in a study of monthly Tremelimumab (10mg/kg, 6 doses) combined with RFA (to one lesion) performed on week 6. Tumor biopsies were performed at time of RFA with regular PBMC collection for intensive immunemontoring. Results: 17 pts enrolled. Characteristics: M:F 8:9; Median age 57(range 36-67); BTC subtype - intrahepatic/exrahepatic: 12/5. 13/17 had metastatic disease. All pts were chemorefractory with 12/17 having received at least 2 regimens. While on study, 6 pts had early PD within 6 weeks; 11 were able to undergo RFA. No DLT encountered. Most common toxicity was pruritus. There were no objective responses. Of evaluable pts N = 6 (55%) had stable disease as a best response. Conclusions: Tremelimumab in combination with subtotal RFA in patients with advanced BTC is safe and feasible. No objective responses have so far been seen in this predominantly primary intrahepatic BTC population. Full efficacy and immune monitoring data will be presented. Clinical trial information: NCT01853618.

TPS470 Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and causes inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. MEDI4736 is a human monoclonal antibody directed against PD-L1. Blockage of ligation between PD-L1 and PD1 induces local immune activation and prevents anergy and exhaustion of effector T-cells. Several studies have documented an increase in peripheral antitumor immunity following radiation. This effect is evidently too weak to be clinically relevant, but has the potential to be boosted by immune modulation. The underlying hypothesis of this study is that the effect of immune checkpoint inhibition (accomplished via tremelimumab and/or MEDI4736) treatment can be enhanced by radiation in patients with advanced pancreatic carcinoma. Whilst radiation treatment in pancreas cancer is commonly employed in limited or early stage disease, if radiation can enhance the effect of immune checkpoint inhibition to produce systemic anti-tumor effects the combination could become an effective treatment modality for patients with advanced disease. Methods: Patients with histologically confirmed metastatic pancreatic cancer with primary in-situ (or locally-recurrent) disease are being enrolled to this pilot study. The primary objectives are to determine the safety, tolerability and feasibility of immune checkpoint inhibition [comprising either MEDI4736 alone (Cohort A), Tremelimumab (Cohort B) or combined MEDI4736 and Tremelimumab (Cohort C)] in combination with stereotactic body radiation therapy (SBRT) in patients with unresectable pancreatic cancer. Select eligibility criteria are as follows: at least 1 measurable metastatic lesion by RECIST 1.1 criteria and accessible for biopsy. No prior radiation therapy to the pancreas allowed. There is no limit to the number of prior chemotherapy regimens received; ECOG ≤ 1; Life expectancy of greater than 3 months. Acceptable organ and bone marrow function. No active or prior documented autoimmune or inflammatory disorders. Clinical trial information: NCT02311361.

270 Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA) and cryoablation (CA) have been shown to induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced HCC. Methods: Patients with HCC [Childs Pugh A/B7; BCLC B/C; ECOG 0/1; post-sorafenib (BCLC stage C only)] or refractory BTC were enrolled in a study of Tremelimumab combined with subtotal TACE, RFA or CA performed on week 6. All BTC patients received RFA as the immune-stimulant in combination with tremelimumab. Tumor biopsies were performed at baseline and at time of RF/TACE. Results: 34 pts enrolled (28 HCC, 6 BTC). Characteristics: M:F 26:8; Median age 54(range 42-76); In HCC pts cirrhosis present in 17pts, BCLC Stage B/C: 9/19; Hepatitis B/C/neg: 4/15/9. 13 pts received TACE, 16 underwent RFA (inc 6 BTC pts), 3 CA during week 6 of tremelimumab therapy. 2 pts did not receive an ablative procedure. No DLT encountered. Most common toxicity was pruritus. One patient developed pulmonitis and was taken off study but remained disease-free at 16m. Of N = 17 pts evaluable for response outside of TACE/RFA-treated lesion 4 (23.5%) achieved confirmed partial responses. 8 of 9 pts with quantifiable HCV experienced a marked reduction in viral load. 6-week tumor biopsies showed immune cell infiltration on all evaluable patients. Median PFS for the evaluable HCC population (N = 25) was 5.7m. Conclusions: Tremelimumab in combination with subtotal TACE, RFA or CA in patients with advanced HCC and BTC is safe and feasible. Obtaining tumor biopsies at baseline and at the time of RFA/TACE is safe. Evidence of immune cell infiltration was seen on evaluable patients. Encouraging clinical activity seen with objective confirmed responses, PFS 5.7m and possibly surrogate reductions in HCV viral load. Clinical trial information: NCT01853618.