Entinostat, nivolumab and ipilimumab for women with advanced HER2-negative breast cancer: a phase Ib trial.

We report the results of 24 women, 50% (N = 12) with hormone receptor-positive breast cancer and 50% (N = 12) with advanced triple-negative breast cancer, treated with entinostat + nivolumab + ipilimumab from the dose escalation (N = 6) and expansion cohort (N = 18) of ETCTN-9844 ( NCT02453620 ). The primary endpoint was safety. Secondary endpoints were overall response rate, clinical benefit rate, progression-free survival and change in tumor CD8:FoxP3 ratio. There were no dose-limiting toxicities. Among evaluable participants (N = 20), the overall response rate was 25% (N = 5), with 40% (N = 4) in triple-negative breast cancer and 10% (N = 1) in hormone receptor-positive breast cancer. The clinical benefit rate was 40% (N = 8), and progression-free survival at 6 months was 50%. Exploratory analyses revealed that changes in myeloid cells may contribute to responses; however, no correlation was noted between changes in CD8:FoxP3 ratio, PD-L1 status and tumor mutational burden and response. These findings support further investigation of this treatment in a phase II trial.

Phase I Study of Entinostat and Nivolumab with or without Ipilimumab in Advanced Solid Tumors (ETCTN-9844).

PURPOSE: Epigenetic modulators improve immune checkpoint inhibitor (ICI) efficacy and increase CD8+ effector:FoxP3+ regulatory T cell ratios in preclinical models. We conducted a multicenter phase I clinical trial combining the histone deacetylase inhibitor entinostat with nivolumab ± ipilimumab in advanced solid tumors. PATIENTS AND METHODS: Patients received an entinostat run-in (5 mg, weekly × 2) prior to the addition of ICIs. Dose escalation followed a modified 3+3 design [dose level (DL)1/2: entinostat + nivolumab; DL 3/4: entinostat + nivolumab + ipilimumab]. Blood and tissue samples were collected at baseline, after entinostat run-in, and after 8 weeks of combination therapy. Primary endpoints included safety and tolerability, and the recommended phase II dose (RP2D). Secondary endpoints included antitumor activity and change in tumor CD8/FoxP3 ratio pre- and post-therapy. RESULTS: Thirty-three patients were treated across four dose levels. Treatment-related adverse events (AE) included fatigue (65%), nausea (41%), anemia (38%), diarrhea (26%), and anorexia (26%). Grade 3/4 AEs included fatigue (n = 7, 21%), anemia (n = 9, 27%), and neutropenia (n = 4, 12%). The RP2D was 3 mg entinostat weekly, 3 mg/kg every 2 weeks nivolumab, and 1 mg/kg every 6 weeks ipilimumab (max four doses). The objective response rate by RECIST 1.1 was 16%, including a complete response in triple-negative breast cancer. A statistically significant increase in CD8/FoxP3 ratio was seen following the addition of ICIs to entinostat, but not post-entinostat alone. CONCLUSIONS: The combination of entinostat with nivolumab ± ipilimumab was safe and tolerable with expected rates of immune-related AEs. Preliminary evidence of both clinical efficacy and immune modulation supports further investigation.

Phase I and Pharmacokinetic Study of Romidepsin in Patients with Cancer and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study.

PURPOSE: Romidepsin dosing recommendations for patients with malignancy and varying degrees of hepatic dysfunction was lacking at the time of regulatory approval for T-cell lymphoma. We conducted a multicenter phase I clinical trial (ETCTN-9008) via the NCI Organ Dysfunction Working Group to investigate safety, first cycle MTD, and pharmacokinetic profile of romidepsin in this setting. PATIENTS AND METHODS: Patients with select advanced solid tumors or hematologic malignancies were stratified according to hepatic function. Romidepsin was administered intravenously on days 1, 8, and 15 of a 28-day cycle and escalation followed a 3 + 3 design in moderate and severe impairment cohorts. Blood samples for detailed pharmacokinetic analyses were collected after the first dose. RESULTS: Thirty-one patients received one dose of romidepsin and were evaluable for pharmacokinetic analyses in normal (n = 12), mild (n = 8), moderate (n = 5), and severe (n = 6) cohorts. Adverse events across cohorts were similar, and dose-limiting toxicity occurred in two patients (mild and severe impairment cohorts). The MTD was not determined because the geometric mean AUC values of romidepsin in moderate (7 mg/m2) and severe (5 mg/m2) impairment cohort were 114% and 116% of the normal cohort (14 mg/m2). CONCLUSIONS: Data from the ETCTN-9008 trial led to changes in the romidepsin labeling to reflect starting dose adjustment for patients with cancer and moderate and severe hepatic impairment, with no adjustment for mild hepatic impairment.

A phase 1 trial of the oral DNA methyltransferase inhibitor CC-486 and the histone deacetylase inhibitor romidepsin in advanced solid tumors.

BACKGROUND: Epigenetic abnormalities are manifold in all solid tumors and include changes in chromatin configuration and DNA methylation. The authors designed a phase 1 study to evaluate the oral DNA methyltransferase inhibitor CC-486 combined with the histone deacetylase inhibitor romidepsin in advanced solid tumors with dose expansion to further evaluate pharmacodynamics and possible clinical benefit of the recommended phase 2 dose (RP2D). METHODS: This was a phase 1 study with a 3 + 3 dose-escalation design and an expansion phase for patients with virally mediated cancers. The disease control rate (DCR) was the primary outcome for the expansion cohort. Correlative studies included long interspersed nucleotide element 1 (LINE-1) methylation and drug exposure in blood samples (clinicaltrials.gov identifier NCT01537744). RESULTS: Fourteen patients were enrolled in the dose-escalation portion at 3 dose levels. Three patients experienced dose-limiting toxicities; the RP2D was oral CC-486 300 mg daily on days 1 through 14 and romidepsin 8 mg/m2 on days 8 and 15. Because of slow accrual into the expansion phase, the trial was closed after 4 patients enrolled. Common toxicities of the combination included nausea (83.3%), anorexia (72.2%), fatigue (61.1%), and constipation (55.6%). There were 12 patients evaluable for response, 5 with stable disease, of whom 2 received >4 cycles; there were no responses. Exposure to CC-486 and romidepsin was consistent with prior data. LINE-1 methylation on C1D8 was significantly reduced (mean, -6.23; 95% CI, -12.23, -0.24; P = .04). CONCLUSIONS: Although, at the RP2D, the combination of CC-486 and romidepsin was tolerable, no significant anticancer activity was observed. Significant demethylation in post-treatment circulating tumor DNA and biopsies provided proof of target acquisition.