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Phase II study of TAS-OX (TAS-102 and oxaliplatin) plus bevacizumab for late-line colorectal cancer [Meeting Abstract]

Hochster, H S; Liu, H; Berim, L D; Spencer, K R; Gulhati, P; DiRubbo, M; Cohen, S D; Lee, P; Leitner, S P; Radovich, D; Misdary, C; Perez, C; Datta, S; Gonzalez, A; Saunders, T; Boland, P M
Background: TAS-102 (trifluridine/tipiracil) is a novel oral antimetabolite for late line metastatic colorectal cancer (CRC) approved in 2018. Many patients are treated early in their course with oxaliplatin (OX), particularly adjuvant, and may benefit from re-treatment. In this trial we combine the typical late line use of TAS with OX (BEV [bevacizumab] added at investigator discretion) with goal of improved response.
Method(s): Eligibility included measurable CRC previously treated with all approved drugs per TAS package insert (irinotecan, oxaliplatin, 5FU, anti-VEGF, anti-EGF) as appropriate, PS = 0-1, labs within usual range, neuropathy < grade 2, ability to take oral meds, appropriate contraception. If no contraindication to BEV, this could be added at patient. TAS was dosed at 35 mg/m2 days 1-5 with OX 85/m2 d1 every 14 days (and BEV 5 mg/kg, if given). All supportive care was allowed including growth factors.
Result(s): 47 patients (pts, median age 55) were enrolled in a Simon mini-max design, including 45% female, 21% black, 11% Asian, 11% Hispanic and 5% mixed. 26 pts received BEV. For the first 40 pts, 385 cycles were given (mean = 7 cycles, median 8) with 18 pts (45%) requiring dose reductions (1 dose reduction = 9 pts, 2 = 6, 3 = 3), and 9 receiving (peg)/filgrastim. Toxicities leading to SAEs included gr 3 heme (2), heart failure, abd pain/n/v (6), sepsis (2), urinary (4); and related gr 3 included one gr 3 vomiting and one gr 3 neutropenia. Independently reviewed RECIST Response (N = 32) included PR 2(6%), SD 23 (72%), PD 7 (22%). Mean TTP was 4.5 m (median 4, range 1 - 18) with 9 (28%) pts more than 6 months.
Conclusion(s): In patients with late-line CRC and candidates for TAS (trifluridine/tipiracil), treatment with TAS plus OX is both well tolerated and active. RR is higher than single agent and 78% (95% CI, 60-91%) of patients had stable disease or response, with 60% receiving 8 or more cycles. Randomized trials comparing to single agent TAS are warranted in this setting
EMBASE:640368484
ISSN: 1527-7755
CID: 5512342

HCRN GI16-288: A phase II trial of perioperative CV301 vaccination in combination with nivolumab and systemic chemotherapy for resectable hepatic-limited metastatic colorectal cancer-Preliminary efficacy and correlative results [Meeting Abstract]

Spencer, K R; Hochster, H S; Boland, P M; Berim, L D; Kennedy, T; Grandhi, M; Langan, R C; Moore, D F; Kane, M P; Krishnamurthi, S S; Mayo, S C; Kasi, A; Pimentel, A; Carpizo, D R
Background: Novel strategies to improve the efficacy of immune checkpoint inhibitors in microsatellite stable (MSS) mCRC are needed. CV301 is a vector-based vaccine that expresses carcinoembryonic antigen (CEA) and mucin 1 (MUC1), and in a phase II study in resected hepatic limited mCRC significantly improved OS compared with unvaccinated contemporary controls.
Method(s): In this multicenter randomized phase II study, patients with previously untreated resectable hepatic-limited mCRC were randomized to perioperative nivolumab + mFOLFOX +/- CV301 (Arm B) with a primary endpoint of 3-year OS. Treatment included mFOLFOX-nivo (+/- CV) x 4 cycles followed by resection, then 8 more cycles of mFOLFOX-nivo followed by maintenance nivo monthly for two years in both arms, and CV boosters concurrently with mFOLFOX, and then every 3 months for two years in arm B. Secondary endpoints of ORR (following induction pre-resection), PRR, and safety were determined. Correlative analyses included immune cell quantification using Immunoscore and T-cell clonality.
Result(s): 17 patients were enrolled prior to premature closure for slow accrual (8 arm A, 9 arm B). At the time of data cutoff, 5 patients remained on treatment and no deaths had occurred. One patient was removed from study due to protocol non-compliance. The median age was 61, majority were male (59% vs 41%), and ECOG PS 0-1 (71% 0, 17% 1). All patients had complete surgical resection. Four patients (24%) experienced a SAE related to drug. The TRAE rate was 40.3%,. No AEs delayed/prevented surgical resection. The ORR in arm A was 50% (including 4 CR) and 87.5% in arm B (including 7 CR) (p=0.129, NS). There was no significant difference in pathologic response (p=0.9047). Correlative analyses demonstrated the Immunoscore CD3/CD8 predicted response to mFOLFOX + nivolumab, but did not correlate with response to CV301, though CV301 may induce a shift to predominantly cytotoxic CD8+ T cells. While there was no significant difference in T cell repertoire, clonality, fraction (TCFr) or richness, patients in arm B had significant decreases in blood TCFr and increase in tumor TCFr with treatment; those with CR had higher TCFr and clonality.
Conclusion(s): The addition of CV301 to perioperative nivolumab and mFOLFOX was safe, did not delay or prevent surgical resection, and gave a higher response (p=ns due to sample size). Changes in T cells suggest a vaccine response. (Table Presented)
EMBASE:640367866
ISSN: 1527-7755
CID: 5512392

Treating Biliary Tract Cancers: New Targets and Therapies

Ho, Joseph; Fiocco, Constance; Spencer, Kristen
Biliary tract cancers (BTCs) are rare and aggressive tumors that typically present at an advanced stage when surgical resection is no longer considered a therapeutic option. While gemcitabine and cisplatin have been the mainstay of treatment, unique chemotherapy combination strategies, targeted therapies, and immunotherapies have had some clinical efficacy and remain promising areas for clinical research. The use of molecular profiling of BTCs has facilitated the development and subsequent clinical application of novel targeted therapy compounds. Among the many genomic alterations identified in BTCs, molecular abnormalities in the fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), human epidermal growth factor receptor 2 (HER2), and BRAF have been successfully targeted therapeutically in clinical trials. Furthermore, the expanded use of new chemotherapy combinations, targeted therapies, and immunotherapies into alternate clinical settings such as in the neoadjuvant and adjuvant spaces is an area of active investigation. The management of BTCs is rapidly evolving. In this article, we review the emerging targets and therapies in BTC.
PMID: 36441502
ISSN: 1179-1950
CID: 5373872

First-in-human phase I/II, open-label study of the anti-OX40 agonist INCAGN01949 in patients with advanced solid tumors

Davis, Elizabeth J; Martin-Liberal, Juan; Kristeleit, Rebecca; Cho, Daniel C; Blagden, Sarah P; Berthold, Dominik; Cardin, Dana B; Vieito, Maria; Miller, Rowan E; Hari Dass, Prashanth; Orcurto, Angela; Spencer, Kristen; Janik, John E; Clark, Jason; Condamine, Thomas; Pulini, Jennifer; Chen, Xuejun; Mehnert, Janice M
BACKGROUND:OX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed to promote tumor-specific immunity by effector T-cell activation and Fcγ receptor-mediated Treg depletion. This first-in-human study was conducted to determine the safety, tolerability, and preliminary efficacy of INCAGN01949. METHODS:Phase I/II, open-label, non-randomized, dose-escalation and dose-expansion study conducted in patients with advanced or metastatic solid tumors. Patients received INCAGN01949 monotherapy (7-1400 mg) in 14-day cycles while deriving benefit. Safety measures, clinical activity, pharmacokinetics, and pharmacodynamic effects were assessed and summarized with descriptive statistics. RESULTS:Eighty-seven patients were enrolled; most common tumor types were colorectal (17.2%), ovarian (8.0%), and non-small cell lung (6.9%) cancers. Patients received a median three (range 1-9) prior therapies, including immunotherapy in 24 patients (27.6%). Maximum tolerated dose was not reached; one patient (1.1%) receiving 350 mg dose reported dose-limiting toxicity of grade 3 colitis. Treatment-related adverse events were reported in 45 patients (51.7%), with fatigue (16 (18.4%)), rash (6 (6.9%)), and diarrhea (6 (6.9%)) being most frequent. One patient (1.1%) with metastatic gallbladder cancer achieved a partial response (duration of 6.3 months), and 23 patients (26.4%) achieved stable disease (lasting &gt;6 months in one patient). OX40 receptor occupancy was maintained over 90% among all patients receiving doses of ≥200 mg, while no treatment-emergent antidrug antibodies were detected across all dose levels. Pharmacodynamic results demonstrated that treatment with INCAGN01949 did not enhance proliferation or activation of T cells in peripheral blood or reduce circulating Tregs, and analyses of tumor biopsies did not demonstrate any consistent increase in effector T-cell infiltration or function, or decrease in infiltrating Tregs. CONCLUSION:No safety concerns were observed with INCAGN01949 monotherapy in patients with metastatic or advanced solid tumors. However, tumor responses and pharmacodynamic effects on T cells in peripheral blood and post-therapy tumor biopsies were limited. Studies evaluating INCAGN01949 in combination with other therapies are needed to further evaluate the potential of OX40 agonism as a therapeutic approach in patients with advanced solid tumors. TRIAL REGISTRATION NUMBER:NCT02923349.
PMCID:9628691
PMID: 36316061
ISSN: 2051-1426
CID: 5358222

A phase Ib dose-escalation study of troriluzole (BHV-4157), an oral glutamatergic signaling modulator, in combination with nivolumab in patients with advanced solid tumors

Silk, Ann W; Saraiya, Biren; Groisberg, Roman; Chan, Nancy; Spencer, Kristen; Girda, Eugenia; Shih, Weichung; Palmeri, Marisa; Saunders, Tracie; Berman, Robert M; Coric, Vlad; Chen, Suzie; Zloza, Andrew; Vieth, Joshua; Mehnert, Janice M; Malhotra, Jyoti
BACKGROUND:Glutamate signaling activates MAPK and PI3K/AKT pathways in tumor cells. Treatment with riluzole, a glutamate release inhibitor, has been previously shown to be safe in melanoma patients and produced biologic effects, but did not lead to radiographic responses, possibly due to poor pharmacokinetic properties. Therefore, we conducted a phase Ib trial to determine the safety and tolerability of the combination of the riluzole prodrug troriluzole (BHV-4157, trigriluzole) and the PD-1 antibody nivolumab in patients with advanced solid tumors. METHODS:Patients with advanced or refractory solid tumors and measurable disease per RECIST 1.1 were treated with increasing doses of troriluzole using a semi-Bayesian modified toxicity probability interval dose escalation procedure. Troriluzole monotherapy was orally self-administered for a 14-day lead-in period followed by continuation of troriluzole in combination with nivolumab 240 mg IV every 2 weeks. Endpoints included safety, pharmacokinetics (PK) and efficacy. RESULTS:We enrolled 14 patients with advanced solid tumors (melanoma = 3, NSCLC = 3, renal cell carcinoma = 2, bladder/urothelial = 2, ovarian cancer = 1, adenoid cystic carcinoma = 1, pleural mesothelial = 1, head and neck cancer = 1). Eleven patients had cancer progression on prior therapy with PD-1 or PD-L1 agent. Patients received troriluzole total daily doses from 140 to 560 mg (divided). The most common treatment-related adverse events (TRAE) occurring in ≥ 5 patients (> 35%) were transaminitis and increased lipase. DLT (dose-limiting toxicity) occurred in 3 patients: (1) grade 3 anorexia, (2) grade 3 fatigue and, (3) grade 3 atrial fibrillation. Six patients were treated at the MTD (maximum tolerated dose). No subjects discontinued treatment due to AEs. One response occurred (7%), which was a partial response in a subject who had PD-1 refractory disease. The 6-month PFS rate was 21%. PK data showed that the prodrug troriluzole was efficiently cleaved into riluzole by 2-h post-dosing in all dose cohorts tested. CONCLUSION/CONCLUSIONS:The combination of troriluzole and nivolumab was safe and well-tolerated. The MTD of troriluzole was determined to be 420 mg total daily dose. The observed antitumor activity, primarily disease stabilization, is of interest in patients with PD-1 resistant tumors. Trial Registration ClinicalTrials.gov Identifier NCT03229278.
PMCID:9250196
PMID: 35780243
ISSN: 2047-783x
CID: 5278302

Abstract CT170: A phase 1/2 study of olaparib in combination with ramucirumab in metastatic gastric and gastroesophageal junction adenocarcinoma (GEJ)

Cecchini, Michael; Chao, Joseph; Shyr, Yu; Cleary, James; Uboha, Nataliya; Cho, May; Shields, Anthony;Pant, Shubham; Goff, Laura; Spencer, Kristin; Kim, Edward; Hsu, Chih-Yuan; Stein, Stacey; Thumar, Jaykumar, Kortmansky, Jeremy; Kunstman, John; LoRusso, Patricia; Ivy, Percy; Lacy, Jill
ORIGINAL:0017031
ISSN: 0008-5472
CID: 5569032

Pembrolizumab (pembro) plus binimetinib (bini) with or without chemotherapy (chemo) for metastatic colorectal cancer (mCRC): Results from KEYNOTE-651 cohorts A, C, and E

Chen, Eric Xueyu; Kavan, Petr; Tehfe, Mustapha; Kortmansky, Jeremy S; Sawyer, Michael B; Chiorean, E. Gabriela; Lieu, Christopher Hanyoung; Polite, Blase N; Wong, Lucas; Fakih, Marwan; Spencer, Kristen Renee; Chaves, Jorge; Li, Chenxiang; Carpenter, David; Leconte, Pierre; Kim, Richard D
ORIGINAL:0017039
ISSN: 0732-183x
CID: 5569112

High-risk MSI-H stage II colon cancer: Treatment patterns and outcomes [Meeting Abstract]

Fleming, Patrick; Chen, Chunxia; Moore, Dirk F; Hochster, Howard S; Jabbour, Salma K; Berim, Lyudmyla Derby; Spencer, Kristen Renee; Gulhati, Pat; Donohue, Kristen; Maloney Patel, Nell; Boland, Patrick M
ORIGINAL:0017032
ISSN: 0732-183x
CID: 5569042

Pembrolizumab (pembro) plus mFOLFOX7 or FOLFIRI for metastatic colorectal cancer (CRC) in KEYNOTE-651: Long-term follow-up of cohorts B and D

Kim, Richard D; Tehfe, Mustapha; Kavan, Petr; Chaves, Jorge; Kortmansky, Jeremy S; Chen, Eric Xueyu; Lieu, Christopher Hanyoung; Wong, Lucas; Fakih, Marwan; Spencer, Kristen Renee; Zhao, Qing; Predoiu, Raluca; Li, Chenxiang; Carpenter, David; Leconte, Pierre; Chiorean, E. Gabriela
ORIGINAL:0017033
ISSN: 0732-183x
CID: 5569052

Making National Cancer Institute-Designated Comprehensive Cancer Center Knowledge Accessible to Community Oncologists via an Online Tumor Board: Longitudinal Observational Study

Kalra, Maitri; Henry, Elizabeth; McCann, Kelly; Karuturi, Meghan S; Bustamante Alvarez, Jean G; Parkes, Amanda; Wesolowski, Robert; Wei, Mei; Mougalian, Sarah S; Durm, Gregory; Qin, Angel; Schonewolf, Caitlin; Trivedi, Meghna; Armaghani, Avan J; Wilson, Frederick H; Iams, Wade T; Turk, Anita A; Vikas, Praveen; Cecchini, Michael; Lubner, Sam; Pathak, Priyadarshini; Spencer, Kristen; Koshkin, Vadim S; Labriola, Matthew K; Marshall, Catherine H; Beckermann, Katy E; Sharifi, Marina N; Bejjani, Anthony C; Hotchandani, Varsha; Housri, Samir; Housri, Nadine
BACKGROUND:Expert knowledge is often shared among multidisciplinary academic teams at tumor boards (TBs) across the country, but these conversations exist in silos and do not reach the wider oncology community. OBJECTIVE:Using an oncologist-only question and answer (Q&A) website, we sought to document expert insights from TBs at National Cancer Institute-designated Comprehensive Cancer Centers (NCI-CCCs) to provide educational benefits to the oncology community. METHODS:We designed a process with the NCI-CCCs to document and share discussions from the TBs focused on areas of practice variation on theMednet, an interactive Q&A website of over 13,000 US oncologists. The faculty translated the TB discussions into concise, non-case-based Q&As on theMednet. Answers were peer reviewed and disseminated in email newsletters to registered oncologists. Reach and engagement were measured. Following each Q&A, a survey question asked how the TB Q&As impacted the readers' practice. RESULTS:A total of 23 breast, thoracic, gastrointestinal, and genitourinary programs from 16 NCI-CCC sites participated. Between December 2016 and July 2021, the faculty highlighted 368 questions from their TBs. Q&As were viewed 147,661 times by 7381 oncologists at 3515 institutions from all 50 states. A total of 277 (75%) Q&As were viewed every month. Of the 1063 responses to a survey question on how the Q&A affected clinicians' practices, 646 (61%) reported that it confirmed their current practice, 163 (20%) indicated that a Q&A would change their future practice, and 214 (15%) reported learning something new. CONCLUSIONS:Through an online Q&A platform, academics at the NCI-CCCs share knowledge outside the walls of academia with oncologists across the United States. Access to up-to-date expert knowledge can reassure clinicians' practices, significantly impact patient care in community practices, and be a source of new knowledge and education.
PMCID:9164098
PMID: 35588361
ISSN: 2369-1999
CID: 5523062