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A phase I/II study of ivaltinostat combined with gemcitabine and erlotinib in patients with untreated locally advanced or metastatic pancreatic adenocarcinoma.

ABSTRACT: This phase I/II study evaluated the safety and efficacy of a new histone deacetylase (HDAC) inhibitor, ivaltinostat, in combination with gemcitabine and erlotinib for advanced pancreatic ductal adenocarcinoma (PDAC). Patients diagnosed with unresectable, histologically confirmed PDAC who had not undergone previous therapy were eligible. Phase I had a 3 + 3 dose escalation design to determine the maximum tolerable dose (MTD) of ivaltinostat (intravenously on days 1, 8 and 15) with gemcitabine (1000 mg/m² intravenously on days 1, 8 and 15) and erlotinib (100 mg/day, orally) for a 28-day cycle. In phase II, patients received a six-cycle treatment with the MTD of ivaltinostat determined in phase I. The primary endpoint was the objective response rate (ORR). Secondary endpoints included overall survival (OS), disease control rate (DCR) and progression-free survival (PFS). The MTD of ivaltinostat for the phase II trial was determined to be 250 mg/m² . In phase II, 24 patients were enrolled. The median OS and PFS were 8.6 (95% confidence interval [CI]: 5.3-11.2) and 5.3 months (95% CI: 3.7-5.8). Of the 16 patients evaluated for response, ORR and DCR were 25.0% and 93.8% with a median OS/PFS of 10.8 (95% CI: 8.3-16.7)/5.8 (95% CI: 4.6-6.7) months. Correlative studies showed that mutation burden detected by cfDNA and specific blood markers such as TIMP1, pro-MMP10, PECAM1, proMMP-2 and IGFBP1 were associated with clinical outcomes. Although the result of a small study, a combination of ivaltinostat, gemcitabine and erlotinib appeared to be a potential treatment option for advanced PDAC.

SUBMITTER: Jo JH

PROVIDER: S-EPMC9545559 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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A phase I/II study of ivaltinostat combined with gemcitabine and erlotinib in patients with untreated locally advanced or metastatic pancreatic adenocarcinoma.

Jo Jung Hyun JH Jung Dawoon E DE Lee Hee Seung HS Park Soo Been SB Chung Moon Jae MJ Park Jeong Youp JY Bang Seungmin S Park Seung Woo SW Cho Sangsook S Song Si Young SY

International journal of cancer 20220621 9

This phase I/II study evaluated the safety and efficacy of a new histone deacetylase (HDAC) inhibitor, ivaltinostat, in combination with gemcitabine and erlotinib for advanced pancreatic ductal adenocarcinoma (PDAC). Patients diagnosed with unresectable, histologically confirmed PDAC who had not undergone previous therapy were eligible. Phase I had a 3 + 3 dose escalation design to determine the maximum tolerable dose (MTD) of ivaltinostat (intravenously on days 1, 8 and 15) with gemcitabine (10 ...[more]

PMID: 35657348

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Project description:LESSONS LEARNED:Dual epidermal growth factor receptor (EGFR)-directed therapy with erlotinib and panitumumab in combination with gemcitabine was superior to gemcitabine and erlotinib, but the clinical relevance is uncertain given the limited role of gemcitabine monotherapy.A significantly longer overall survival was observed in patients receiving the dual EGFR-directed therapy.The dual EGFR-directed therapy resulted in increased toxicity. BACKGROUND:Gemcitabine is active in patients with advanced pancreatic adenocarcinoma. The combination of erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, and gemcitabine was shown to modestly prolong overall survival when compared with gemcitabine alone. The North Central Cancer Treatment Group (now part of Alliance for Clinical Trials in Oncology) trial N064B compared gemcitabine plus erlotinib versus gemcitabine plus combined EGFR inhibition with erlotinib and panitumumab. METHODS:Eligible patients with metastatic adenocarcinoma of the pancreas were randomized to either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle with erlotinib 100 mg p.o. daily (Arm A) or the same combination with the addition of panitumumab 4 mg/kg on days 1 and 15 of a 28-day cycle (Arm B). The primary endpoint of the trial was overall survival. Secondary endpoints included progression-free survival, the confirmed response rate, and toxicity. Comparison between arms for the primary endpoint was done with a one-sided log-rank test, and a p value less than .20 was considered statistically significant. Response rate comparison was done with Fisher's exact test. All other reported p values are two-sided. RESULTS:A total of 92 patients were randomized, 46 to each arm. The median overall survival was 4.2 months in Arm A and 8.3 months in Arm B (hazard ratio, 0.817; 95% confidence interval [CI], 0.530-1.260; p = .1792). The progression-free survival was 2.0 months in Arm A and 3.6 months in Arm B (hazard ratio, 0.843; 95% CI, 0.555-1.280; p = .4190). A partial confirmed response was seen in 8.7% of patients on Arm A and 6.5% on Arm B (p = .9999). No patients had a complete response. Grade 3 and higher nonhematologic toxicities were more common in patients on Arm B compared with those on Arm A (82.6% vs. 52.2%; p = .0018). CONCLUSION:Dual EGFR-directed therapy resulted in a significant prolongation of overall survival in patients with advanced adenocarcinoma of the pancreas but was associated with substantially increased toxicities. Dual EGFR-directed therapy in combination with gemcitabine alone cannot be recommended for further study, as single-agent gemcitabine is no longer considered an appropriate therapy for otherwise fit patients with metastatic pancreatic cancer.

Project description:BackgroundEpidermal growth factor receptor (EGFR) is overexpressed in pancreatic cancer. EGFR expression plays a potentially important role in modulation of tumor sensitivity to either chemotherapy or radiotherapy. Erlotinib is a receptor tyrosine kinase inhibitor with specificity for EGFR/HER1. A phase II trial was conducted to explore the efficacy of a regimen utilizing erlotinib and proton therapy.MethodsPatients with unresectable or borderline resectable non-metastatic adenocarcinoma of the pancreas were included. Patients received 8-week systemic treatment with gemcitabine 1,000 mg/m2 and erlotinib 100 mg (GE). If there was no evidence of metastatic disease after GE, then patients preceded with proton therapy to 50.4 Gy in 28 fractions with concurrent capecitabine 825 mg/m2 (CPT). This was followed with oxaliplatin 130 mg/m2 and capecitabine 1,000 mg/m2 (CapOx) for 4 cycles. The primary study objective was 1-year overall survival (OS). The benchmark was 43% 1-year survival as demonstrated in RTOG/NRG 98-12. The Kaplan-Meier method was used to estimate the one-year OS and the median OS and progression-free survival (PFS).ResultsThe study enrolled 9 patients ages 47-81 years old (median 62) between January 2013 and March 2016, when the trial was closed due to low patient accrual. The 1-year OS rate was 55.6% (95% CI: 31% to 99%). The median OS was 14.1 months (95% CI: 11.4-NE) and the median PFS was 10.8 months (95% CI: 7.44-NE). A majority of patients completed CPT and GE, but only 33.3% completed the four cycles of CapOx. A third of patients experienced grade 3 toxicities, which were all hepatic along with one patient who also had grade 3 diarrhea. There were no grade 4 or 5 toxicities. Four patients were enrolled with borderline resectable disease, three of which were eligible for pancreaticoduodenectomy after GE and CPT treatment. One of two patients who underwent resection had a negative margin.ConclusionsThis regimen for locally advanced pancreatic cancer (LAPC) exceeded the pre-specified benchmark and was safe and well tolerated. Additional investigations utilizing more current systemic treatment regimens with proton therapy are warranted.Trial registrationClinicalTrials.gov identifier (NCTNCT01683422).

Project description:BackgroundBinding of insulin-like growth factor-I (IGF-1) to its receptor (IGF-1R) initiates downstream signals that activate PI3K/Akt/mTOR and MEK/Erk pathways, which stimulate cancer cell proliferation and induce drug resistance. Cross talk between IGF-1R and epidermal growth factor receptor (EGFR) mediates resistance to anti-EGFR agents. We studied safety, tolerability, and outcomes of MK-0646, IGF-1 monoclonal antibody, in combination with gemcitabine (G) ± erlotinib (E) in metastatic pancreatic cancer.MethodsOur study included a phase I dose escalation and phase II randomization and expansion cohorts. A 3 + 3 dose escalation protocol was used to determine MK-0646 maximum tolerable dose (MTD) in combination with G ± E standard doses. For phase II, patients were randomized to arm A (G + MK), arm B (G + MK + E), or arm C (G + E). Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), disease control rate, toxicity, and correlation between OS and IGF-1 in patients treated with MK-0646.ResultsMK-0646 MTD was 10 mg/kg in combination with G and 5 mg/kg in combination with G + E. In randomization cohort, 15 patients were treated in each arm. Disease control rates were 50, 60, and 40% respectively. PFS was not different between the three arms. OS was significantly different between arm A (10.4 months) and C (5.7 months) (P = 0.02). However, addition of erlotinib in arm B yielded no OS benefit compared to arm A (P = 0.6). Plasma and tissue IGF-1 levels did not correlate with OS (P = 0.64, 0.87). Grade 3-4 toxicity during phase II cohorts were neutropenia (10/arm A, 14/arm B, 5/arm C), leukopenia (5/A, 5/B, 7/C), thrombocytopenia (8/A, 9/B, 2/C), hyponatremia (1/A, 3/B), and hyperglycemia (8/A, 1/B).ConclusionsMK-0646 was tolerable in combination with G and associated with improvement in OS but not PFS as compared with G + E. Tissue and serum IGF-1 did not correlate with clinical outcome.Trial registrationThis trial is registered in ClinicalTrial.gov under the Identifier NCT00769483 and registration date was October 9, 2008.

Dataset Information

A phase I/II study of ivaltinostat combined with gemcitabine and erlotinib in patients with untreated locally advanced or metastatic pancreatic adenocarcinoma.

Publications

A phase I/II study of ivaltinostat combined with gemcitabine and erlotinib in patients with untreated locally advanced or metastatic pancreatic adenocarcinoma.

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