Efficacy and safety of liposomal irinotecan plus fluorouracil/leucovorin after progression on conventional irinotecan-containing chemotherapy for metastatic pancreatic adenocarcinoma.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 382-382
Author(s):  
Kyunghye Bang ◽  
Jaekyung Cheon ◽  
Jae Ho Jeong ◽  
Hyeon-Su Im ◽  
Kyu-Pyo Kim ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Cumulative Dose ◽  
Negative Correlation ◽  
Objective Response ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Common Grade ◽  
Previously Treated ◽  
Liposomal Irinotecan ◽  
Grade 3 ◽  
Median Cumulative Dose

382 Background: Liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (5-FU/LV) has demonstrated its clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPAC) who progressed on prior gemcitabine-based chemotherapy. However, its role in patients who previously treated with conventional irinotecan has not been investigated. We analyzed clinical outcomes of nal-IRI + 5-FU/LV in mPAC patients after progression on conventional irinotecan-containing chemotherapy. Methods: In this multicenter retrospective analysis, a total of 35 patients with mPAC who received nal-IRI + 5-FU/LV after progression on irinotecan-containing regimen, between January 2017 and March 2020, were included. The ratio of time-to-progression (TTP) with nal-IRI + 5-FU/LV to TTP with conventional irinotecan (TTPr) was correlated with duration and cumulative dose of prior conventional irinotecan. Results: The median age was 58 years (range, 35-73) and 16 patients (46%) were male. All patients received prior irinotecan as the component of FOLFIRINOX. The median duration of prior irinotecan was 4.6 months (range, 0.5-16.8) and median cumulative dose of prior irinotecan was 1230 mg (range, 150-4650). Objective response rate of nal-IRI + 5-FU/LV was 2.9% (1 partial response) and stable disease was achieved in 31.4% (n = 11). With median follow-up duration of 9.2 months [95% CI, 7.8-10.5], the median PFS and OS were 2.0 months [95% CI, 1.4-2.6] and 4.4 months [95% CI, 3.6-5.7], respectively. 6-month PFS rate was 16.3% and OS rate was 37.5%. The median TTPr was 0.41 (range 0.07-2.07) and this showed negative correlation between cumulative dose of prior irinotecan (R = -0.37, p = 0.041). There was a tendency for the negative correlation between TTPr and duration of prior irinotecan (R = -0.35, p = 0.062). Most common grade 3-4 toxicities were neutropenia (20%) and fatigue (8.6%). Conclusions: Nal-IRI + 5-FU/LV showed only modest efficacy for mPAC patients who progressed on conventional irinotecan-containing chemotherapy. Cumulative dose of prior conventional irinotecan may be correlated with the efficacy of nal-IRI + 5-FU/LV.

scholarly journals Clinical outcomes of liposomal irinotecan plus fluorouracil/leucovorin for metastatic pancreatic adenocarcinoma in patients previously treated with conventional irinotecan-containing chemotherapy

2021 ◽  
Vol 13 ◽  
pp. 175883592110030
Author(s):  
Kyunghye Bang ◽  
Jaekyung Cheon ◽  
Jae Ho Jeong ◽  
Hyeon-Su Im ◽  
Kyu-pyo Kim ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Cumulative Dose ◽  
Negative Correlation ◽  
Objective Response ◽  
Progression Free Survival ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Previously Treated ◽  
Liposomal Irinotecan ◽  
Grade 3 ◽  
Median Cumulative Dose

Introduction: Liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (5-FU/LV) has shown clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPAC) who progressed on gemcitabine-based chemotherapy. However, its role in patients with mPAC previously treated with conventional irinotecan-containing chemotherapy has not been appropriately investigated. Methods: In this retrospective analysis, patients with mPAC who received nal-IRI plus 5-FU/LV after conventional irinotecan-containing regimen between January 2017 and March 2020, were identified from two referral cancer centers in South Korea. The ratio of time to progression (TTP) with nal-IRI plus 5-FU/LV to TTP with conventional irinotecan (TTPr) was analyzed with respect to the duration and cumulative dose of conventional irinotecan treatment. Results: In total, 35 patients treated with nal-IRI plus 5-FU/LV after the irinotecan-containing regimen were analyzed. The median age was 58 years and 16 (46%) patients were male. The median duration of conventional irinotecan therapy was 4.6 months at a median cumulative dose of 1230 mg. The objective response rate of nal-IRI plus 5-FU/LV was 2.9%, and stable disease was achieved in 11 (31.4%) patients. During the median follow-up of 9.2 [95% confidence interval (CI): 7.8–10.5] months, the median progression-free survival (PFS) and overall survival (OS) were 2.0 (95% CI: 1.4–2.6) months and 4.4 (95% CI: 3.6–5.7) months, respectively. The 6-month PFS and OS rates were 16.3% and 37.5%, respectively. The median TTPr was 0.41 (range, 0.07–2.07), showing a negative correlation with the cumulative dose of prior irinotecan therapy (R = −0.37, p = 0.041). A tentative negative correlation between TTPr and duration of prior irinotecan therapy was observed ( R = −0.35, p = 0.062). The most common grade 3–4 toxicities were neutropenia (20%) and fatigue (8.6%). Conclusion: Nal-IRI plus 5-FU/LV showed modest effectiveness and manageable toxicities for patients with mPAC previously treated with conventional irinotecan-containing chemotherapy. The cumulative dose of prior conventional irinotecan therapy may be inversely correlated with the effectiveness of nal-IRI plus 5-FU/LV.

scholarly journals Real-world efficacy and safety of liposomal irinotecan plus fluorouracil/leucovorin in patients with metastatic pancreatic adenocarcinoma: a study by the Korean Cancer Study Group

2019 ◽  
Vol 11 ◽  
pp. 175883591987112 ◽  
Author(s):  
Changhoon Yoo ◽  
Hyeon-Su Im ◽  
Kyu-pyo Kim ◽  
Do-Youn Oh ◽  
Kyung-Hun Lee ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Real World ◽  
Performance Status ◽  
Objective Response ◽  
Real Life ◽  
Progression Free Survival ◽  
Real World Data ◽  
Ecog Performance Status ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Liposomal Irinotecan

Background: Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) was effective and well-tolerated in patients with metastatic pancreatic adenocarcinoma (mPAC) that progressed on gemcitabine-based therapy in the global NAPOLI-1 trial. Real-world data may further clarify the outcomes and safety profile of nal-IRI + 5-FU/LV in clinical practice. Methods: This retrospective analysis included patients with mPAC who received nal-IRI + 5-FU/LV following gemcitabine-based therapy under a Managed Access Program in Korea. Results: From January 2017 to April 2018, 86 patients across 10 institutions received nal-IRI + 5-FU/LV (median age, 61 years; 60% male; ECOG performance status, 0–1). A total of 35 (41%) and 51 (59%) patients had received less than two and two or more lines of chemotherapy before inclusion, respectively. At a median follow up of 6.4 months, median overall survival (OS) was 9.4 months (95% confidence interval [CI] 7.4–11.4) and median progression-free survival (PFS) was 3.5 months (95% CI 1.3–5.7). Six-month OS and PFS rates were 65.1% and 37.5%, respectively. Objective response and disease control rates were 10% and 55%, respectively. Most common grade 3–4 toxicities were neutropenia (37.2%), nausea (10.5%), vomiting (9.3%), anorexia (8.1%) and diarrhoea (4.7%). Conclusion: Real-life data for Korean patients indicate that, consistent with NAPOLI-1, nal-IRI + 5-FU/LV is effective and well-tolerated in patients with mPAC that progressed on gemcitabine-based therapy.

LOTUS (NCT02162719): A double-blind placebo (PBO)-controlled randomized phase II trial of first-line ipatasertib (IPAT) + paclitaxel (P) for metastatic triple-negative breast cancer (TNBC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1009-1009 ◽  
Author(s):  
Rebecca Alexandra Dent ◽  
Sung-Bae Kim ◽  
Seock-Ah Im ◽  
Marc Espie ◽  
Sibel Blau ◽  
...  
Keyword(s):  
Objective Response ◽  
Locally Advanced ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Akt Inhibitor ◽  
Double Blind ◽  
Common Grade ◽  
Duration Of Response ◽  
Grade 3 ◽  
Median Cumulative Dose

1009 Background: The oral Akt inhibitor IPAT is being evaluated in cancers with a high prevalence of PI3K/Akt pathway activation, including TNBC. Methods: Eligible patients (pts) had measurable inoperable locally advanced/metastatic TNBC previously untreated with systemic therapy. Pts were stratified by prior (neo)adjuvant therapy, chemotherapy-free interval and tumor PTEN status, and randomized 1:1 to P 80 mg/m2 (d1, 8 & 15) with either IPAT 400 mg or PBO (d1–21) q28d until progression or unacceptable toxicity. Co-primary endpoints were progression-free survival (PFS) in the ITT population and pts with PTEN-low tumors by IHC. Secondary endpoints included objective response rate (ORR), duration of response (DoR) and overall survival in the ITT and IHC PTEN-low populations, efficacy in pts with PIK3CA/AKT1/PTEN-altered tumors by next-generation sequencing (NGS), and safety. Results: Baseline characteristics were generally balanced between arms. Efficacy is shown below. The most common grade ≥3 AEs (grouped terms) were diarrhea (23% IPAT+P vs 0% PBO+P; no grade 4 or colitis in either arm), neutropenia (18% vs 8%), asthenia (5% vs 6%), peripheral neuropathy (5% vs 5%) and pneumonia (5% vs 0%). More pts receiving IPAT+P than PBO+P had an AE leading to dose reduction of IPAT/PBO (21% vs 6%) or P (38% vs 11%) but median cumulative dose intensity was similar (IPAT/PBO: 99% vs 100%; P: 100% vs 100%). AEs led to IPAT/PBO discontinuation in 13% vs 11% of pts, respectively; 2 pts (3%) discontinued IPAT for grade 3 diarrhea. Conclusions: Adding IPAT to P for TNBC modestly improved PFS in the ITT pts. The effect was more pronounced in the prespecified subgroup with PIK3CA/AKT1/PTEN alterations, warranting further evaluation of IPAT in these pts. AEs were manageable. Clinical trial information: NCT02162719. [Table: see text]

Modified FOLFIRINOX for metastatic pancreatic adenocarcinoma after failure of nab-paclitaxel plus gemcitabine.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 467-467
Author(s):  
Masato Ozaka ◽  
Takashi Sasaki ◽  
Seita Kataoka ◽  
Ryo Kanata ◽  
Kazunaga Ishigaki ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Objective Response ◽  
Kidney Injury ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Start Date ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Head Of The Pancreas ◽  
Grade 3

467 Background: Both FOLFIRINOX and Nab-paclitaxel plus Gemcitabine standard treatment in first-line treatment of metastatic pancreatic adenocarcinoma (MPA). It could be of interest to use them consecutively, knowing that there is currently no standard for 2nd line treatments for MPA. The aim of this study was to evaluate the efficacy and tolerability of modified FOLFIRINOX after gemcitabine plus Nab-paclitaxel failure in MPA. Methods: From January 2015 to March 2016, medical records were retrospectively reviewed for consecutive patients receiving modified FOLFIRINOX for a histologically proven MPA after failure of Nab-paclitaxel plus Gemcitabine. Patients were treated with modified FOLFIRINOX every 2 weeks as follows: intravenous oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, 5-FU infusion 2,400 mg/m2 over 46 h, no bolus 5-FU, until disease progression, patient refusal or unacceptable toxicity. Results: Modified FOLFIRINOX was administered to 23 pts. Among these patients, median age was 64 years (range 42.4 - 74.2). 83% of the patients had a PS 0, the primary site of the tumor was the head of the pancreas in 39% of patients, and 26% of patients experienced recurrence after resection. Disease control rate was 66.7% (n = 17) with a 23.8 % (n = 17) objective response rate (RECIST). Within the whole cohort, median PFS was 4.3 months (95% CI: 3.1-5.3) and median overall survival (OS) was 9.3 months (95% CI: 3.8-14.8). Since the start date of first line chemotherapy with Nab-paclitaxel plus Gemcitabine, median OS was 18.8 months (95% CI: 9.6-27.9). No toxic death occured. Grade 3-4 toxicities were reported in 30% of patients and were neutropenia (17%), anemia (8%), cholangitis (8%) and acute kidney injury (4%). Conclusions: Modified FOLFIRINOX seems promising with a manageable toxicity profile after Nab-paclitaxel plus Gemcitabine failure, in selected patients able to receive second line treatment for a MPA. These promising results have now to be confirmed in a phase III randomized trial.

Phase I trial of biweekly S-1, leucovorin, oxaliplatin, and gemcitabine (the SLOG regimen) in metastatic pancreatic adenocarcinoma (mPDAC).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 369-369
Author(s):  
Nai-Jung Chiang ◽  
Kelvin K. Tsai ◽  
Jen-Shi Chen ◽  
Shih-Hung Yang ◽  
Chiun Hsu ◽  
...  
Keyword(s):  
Dose Level ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Common Grade ◽  
Frontline Treatment ◽  
Fixed Dose Rate Infusion ◽  
Grade 3

369 Background: Gemcitabine and S-1 had been approved as the frontline treatment for mPDAC in Taiwan and Japan. Our previous study showed biweekly gemcitabine plus modified FOLFOX4 (the GOFL regimen) was a moderate active and well-tolerated regimen in mPDAC. To explore whether oral S-1/LV can be a substitute for infusion 5-FU/LV in combination with gemcitabine and oxaliplatin as “the SLOG regimen” to improve treatment efficacy and convenience. To define the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and preliminary anti-tumor efficacy of SLOG in patients with chemo-naïve mPDAC. Methods: Enrolled patients would receive intravenous infusion of 800 mg/m2 gemcitabine (fixed-dose rate infusion, 10 mg/m2/min) followed by 85mg/m2 oxaliplatin (2 hours) on D1 and escalating dose of oral S-1 and 20 mg/m2 leucovorin, twice daily D1-D7, every 14 days. DLTs were evaluated during the first 2 cycles of treatment. The treatment was continued until disease progression, unacceptable toxicity or withdrawal of informed consent. Results: 19 patients were enrolled into four dose levels of S-1, 20 mg/m2 (three), 30 mg/m2 (seven), 35 mg/m2 (six) and 40 mg/m2 (three). At 30 mg/m2 dose level, one patient who withdrew consent after one cycle treatment was replaced with another one. DLTs were observed in three patients, one at 30 mg/m2 (grade 3 diarrhea) and two at 40 mg/m2 (grade 3 hypersensitivity reaction and diarrhea in one each). MTD of S-1 was determined as 35 mg/m2. The median treatment duration was 8 cycles (ranged, 1-26). Of the 16 evaluable patients, the objective response rate and disease control rate were 37.5% (6 partial response, PR) and 81.3% (6 PR + 7 stable disease, SD), respectively. The median progression-free survival (PFS) was 4.6 months. At MTD dose level, there were 4 PR and 2 SD, with 6.7 months of PFS. The most common grade 3-4 adverse events included neutropenia (26.4%), diarrhea (15.8%), ALT increased (10.5%) and anemia (10.5%). Conclusions: The MTD of S-1 was 35 mg/m2 in the SLOG regimen. Extension phase II study in mPDAC is ongoing. Clinical trial information: NCT 01415713.

scholarly journals A Phase 2 Study of Oxaliplatin Combined With Continuous Infusion Topotecan for Patients With Previously Treated Ovarian Cancer

2013 ◽  
Vol 23 (9) ◽  
pp. 1577-1582 ◽  
Author(s):  
Stacey M. Stein ◽  
Amy Tiersten ◽  
Howard S. Hochster ◽  
Stephanie V. Blank ◽  
Bhavana Pothuri ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Objective Response ◽  
Primary Objective ◽  
Phase 2 ◽  
Topoisomerase 1 ◽  
Platinum Sensitive ◽  
Resistant Disease ◽  
Common Grade ◽  
Previously Treated ◽  
Grade 3

BackgroundPhase 2 trials suggest that prolonged intravenous (IV) infusion of the topoisomerase 1 inhibitor topotecan may be less toxic than when given by standard IV bolus 5-day administration. Oxaliplatin exhibits efficacy in platinum-pretreated disease and shows preclinical synergy with topoisomerase 1 inhibitors. We sought to determine the efficacy and safety of oxaliplatin plus infusion topotecan in recurrent platinum-pretreated ovarian cancer.MethodsPatients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers previously treated with 1 to 2 prior regimens including platinum and taxane received oxaliplatin (85 mg/m2day 1 and day 15) and topotecan (0.4 mg/m2per day) by continuous IV infusion over 14 days every 4 weeks. The primary objective of the trial was to estimate the objective response rate in platinum-resistant disease (stratum 1) and in platinum-sensitive disease (stratum 2). Toxicities were assessed in all patients.ResultsThirty-eight patients received 144 cycles of therapy (median, 4; range, 1–6). The most common grade 3 and grade 4 toxicities included thrombocytopenia (grade 3, 37%; and grade 4, 19%), neutropenia (grade 3, 37%; grade 4, 11%), and anemia (grade 3, 15%). Response occurred in 4 of 19 patients in stratum I (21%; 95% confidence intervals, 6%–46%) and 9 of 19 patients in stratum 2 (47%; 95% CI, 24%–71%). Three in each stratum had lengthy complete responses.ConclusionsBiweekly oxaliplatin plus a 14-day continuous IV infusion of topotecan, given monthly, is an active regimen in platinum-pretreated ovarian cancer and merits additional evaluation.

scholarly journals A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 342-342
Author(s):  
Aaron James Scott ◽  
Bert H. O'Neil ◽  
Christina Gomes ◽  
Joaquina Celebre Baranda ◽  
Steven J. Cohen ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Randomized Study ◽  
Gene Mutations ◽  
Mutational Status ◽  
Best Response ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Common Grade ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Phosphoinositide 3 Kinase

342 Background: Rigosertib (ON 01910.Na), a dual non-ATP inhibitor of polo-like kinase 1 (Plk1) and phosphoinositide 3-kinase (PI3K) pathways, was assessed in patients with treatment-naïve metastatic pancreatic adenocarcinoma. Methods: Patients with metastatic adenocarcinoma of the pancreas were randomized in a 2:1 fashion to gemcitabine 1000 mg/m2 weekly for 3 weeks of a 4-week cycle plus rigosertib 1800mg/m2 via 2-hr CIV infusions given twice weekly for 3 weeks of a 4-week cycle versus gemcitabine 1000mg/m2 weekly for 3 weeks in a 4-week cycle. Results: A total of 160 patients were enrolled globally and randomly assigned to rigosertib plus gemcitabine (106 patients) or gemcitabine (54). The most common grade 3 or higher adverse events were neutropenia (8% in the rigosertib plus gemcitabine group vs. 6% in the gemcitabine group), hyponatremia (17% vs. 4%), and anemia (8% vs. 4%). The primary outcome of the study, median OS, was 6.1 months in the gemcitabine plus rigosertib arm versus 6.4 months with gemcitabine alone (hazard ratio (HR), 1.24; 95% confidence interval [CI], 0.85-1.81). The median PFS was 3.4 months for both groups (HR, 0.96; 95% CI, 0.68-1.36). The overall best response between arms were partial response rates of 19% versus 13% and stable disease in 50% versus 56% in the gemcitabine plus rigosertib versus gemcitabine alone, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40/47, 85%), which included c.35G>T, p.G12V (12 cases), c.35G>A, p.G12D (21 cases), c.34G>C, p.G12R (4 cases), c.34G>T, p.G12C (1 case) and c.183C>A, p.Q61H (2 cases). Other mutations detected included TP53 (13 cases) and PIK3CA(1 case). No correlation between mutational status and efficacy was detected. Conclusions: The combination of rigosertib plus gemcitabine failed to demonstrate an improvement in survival or response compared to gemcitabine alone in metastatic pancreatic adenocarcinoma. Clinical trial information: NCT01360853.

Endometriumkarzinom: Kombination aus Lenvatinib und Pembrolizumab zeigt Wirksamkeit unabhängig vom Mikrosatellitenstatus

2021 ◽  
pp. 1-2
Author(s):  
Sarah Matz
Keyword(s):  
Endometrial Carcinoma ◽  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Efficacy Analysis ◽  
Duration Of Response ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Prior Systemic Therapy ◽  
Grade 3

<b>Purpose:</b> Patients with advanced endometrial carcinoma have limited treatment options. We report final primary efficacy analysis results for a patient cohort with advanced endometrial carcinoma receiving lenvatinib plus pembrolizumab in an ongoing phase Ib/II study of selected solid tumors. <b>Methods:</b> Patients took lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks, in 3-week cycles. The primary end point was objective response rate (ORR) at 24 weeks (ORRWk24); secondary efficacy end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Tumor assessments were evaluated by investigators per immune-related RECIST. <b>Results:</b> At data cutoff, 108 patients with previously treated endometrial carcinoma were enrolled, with a median follow-up of 18.7 months. The ORRWk24 was 38.0% (95% CI, 28.8% to 47.8%). Among subgroups, the ORRWk24 (95% CI) was 63.6% (30.8% to 89.1%) in patients with microsatellite instability (MSI)-high tumors (n = 11) and 36.2% (26.5% to 46.7%) in patients with microsatellite-stable tumors (n = 94). For previously treated patients, regardless of tumor MSI status, the median DOR was 21.2 months (95% CI, 7.6 months to not estimable), median PFS was 7.4 months (95% CI, 5.3 to 8.7 months), and median OS was 16.7 months (15.0 months to not estimable). Grade 3 or 4 treatment-related adverse events occurred in 83/124 (66.9%) patients. <b>Conclusion:</b> Lenvatinib plus pembrolizumab showed promising antitumor activity in patients with advanced endometrial carcinoma who have experienced disease progression after prior systemic therapy, regardless of tumor MSI status. The combination therapy had a manageable toxicity profile. <b>Trial registration:</b> ClinicalTrials.gov NCT02501096.

Romidepsin (HDACi) plus cisplatin and nivolumab triplet combination in patients with metastatic triple negative breast cancer (mTNBC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1076-1076
Author(s):  
Priyanka Sharma ◽  
Vandana G Abramson ◽  
Anne O'Dea ◽  
Lauren Elizabeth Nye ◽  
Ingrid A. Mayer ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Phase I ◽  
Phase Ii ◽  
Histone Deacetylase Inhibitors ◽  
Objective Response ◽  
Common Grade ◽  
Group 2 ◽  
Grade 3 ◽  
Recognition And Response ◽  
Minimax Design

1076 Background: Histone deacetylase inhibitors (HDACi) upregulate genes involved in antigen presentation machinery and increase expression of natural killer group 2, member D ligands (NKG2DL), thus resulting in enhanced tumor cell recognition and response to PD-1/CTLA-4 blockade. Cisplatin and HDACi combination synergistically induces cytotoxicity, apoptosis, and DNA damage. This phase I-II trial investigated combination of romidepsin (HDACi) plus cisplatin and nivolumab (PD-1 inhibitor) in mTNBC. Patients and Methods: Eligible patients had mTNBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of romidepsin (8, 10, 12mg/m2, D2, 9) plus cisplatin 75mg/m2 D 1 every 21 days. Phase II treatment included romidepsin plus cisplatin plus nivolumab 360mg every 21 days and was designed according to Simon’s two stage minimax design. Primary endpoints were recommended phase 2 dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, PFS, and pharmacokinetics. Results: 51 patients were enrolled (N=13 phase I, N=38 phase II) between 2015-2020. 69% had received ≥1 prior metastatic chemotherapy, 47% had prior platinum, 53% had liver metastasis, 12% had BRCA1/2 mutation, and 11% had PD-L1 positive disease. There were no dose limiting toxicities in phase I. The RP2D was romidepsin 12mg/m2 D2,9 + cisplatin 75mg/m2 D1 + nivolumab 360mg D1 every 21 days. Thrombocytopenia (G3:27%, G4:0%), neutropenia (G3:25%, G4:0%), anemia (G3:22%, G4:0%), nausea (G3:22%, G4:0%), and vomiting (G3:20%, G4:0%) were the most common grade 3/4 adverse events. 21% of patients had immune AEs (G3-4:8%). Among 34 evaluable phase II patients, ORR was 44% (Table), median PFS was 4.4 months, and 1-year PFS was 23%. Median OS was 10.3 months and 1-year OS was 43%. No pharmacokinetic interactions were detected with co-administration of romidepsin-cisplatin-nivolumab. Conclusions: The triplet combination of romidepsin plus cisplatin and nivolumab was well tolerated and shows encouraging efficacy in pretreated mTNBC, including in patients with PD-L1 negative disease and in those with liver metastasis. Correlative biomarker work is ongoing. This combination warrants further evaluation in larger studies. Clinical trial information: NCT02393794 .[Table: see text]

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