Phase I/II study of mocetinostat in combination with gemcitabine for patients with advanced pancreatic cancer and other advanced solid tumors

Chan, Emily; Chiorean, E. Gabriela; O’Dwyer, Peter J.; Gabrail, Nashat; Alcindor, Thierry; Potvin, Diane; Chao, Richard C.; Hurwitz, Herbert I.

doi:10.1007/s00280-017-3494-3

Cited by 39 publications

(32 citation statements)

References 41 publications

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“…32 However, since mocenostat in combination with gemcitabine was related to non-negligible toxicities on individuals with advanced PDAC, the trial was terminated. 33 In our study, the molecular and clinical findings demonstrate that KDM6A deficiency is characteristics of the malignant subtype of PDAC and contributes to epigenetic inactivation of CDKN1A through the modulation of histone acetylation, and that HDAC inhibitors can specifically eliminate KDM6A-deficient PDAC by the restoration of CDKN1A expression ( Fig. 6e).…”

Section: Discussionsupporting

confidence: 57%

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Loss of KDM6A characterizes a poor prognostic subtype of human pancreatic cancer and potentiates HDAC inhibitor lethality

Watanabe

Shimada

Akiyama

et al. 2018

Intl Journal of Cancer

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Although genomic analysis have recently discovered the malignant subtype of human pancreatic ductal adenocarcinoma (PDAC) characterized by frequent mutations of histone demethylase KDM6A, the biological and molecular roles still remain obscure. We herein elucidated the clinical and biological impacts of KDM6A deficiency on human PDAC and identified the therapeutic potential by pathological and molecular evaluation. Immunohistochemical analysis suggested that loss of KDM6A in cancerous tissues was an independent prognostic factor for both recurrence‐free and overall survival in the 103 tumor specimens surgically resected from patients with PDAC. We established KDM6A knocked out cells by using the CRISPR/Cas9 system and KDM6A‐expressed cells by doxycycline‐inducible system from each two human PDAC cell lines, respectively. KDM6A knockout enhanced aggressive traits of human PDAC cell lines, whereas KDM6A overexpression suppressed them. Microarray analysis revealed reduced expression of 22 genes including five well‐known tumor suppressors, such as CDKN1A, and ChIP‐PCR analysis displayed depleted enrichment of histone H3 lysine 27 acetylation (H3K27ac) at the promoter regions of the five candidates. The epigenetic alterations were induced by the impaired recruitment of histone acetyltransferase p300, which cooperatively interacted with KDM6A. Consistent with these results, the KDM6A knockout cells demonstrated higher vulnerability to histone deacetylase (HDAC) inhibitors through the reactivation of CDKN1A in vitro and in vivo than the KDM6A wild‐type. In conclusion, KDM6A exhibited essential roles in human PDAC as a tumor suppressor and KDM6A deficiency could be a promising biomarker for unfavorable outcome in PDAC patients and a potential surrogate marker for response to HDAC inhibitors.

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Section: Discussionsupporting

confidence: 57%

“…The combination of vorinostat and conventional chemoradiation with capecitabine was well‐tolerated with encouraging median overall survival in PDAC patients . However, since mocenostat in combination with gemcitabine was related to non‐negligible toxicities on individuals with advanced PDAC, the trial was terminated …”

Section: Discussionmentioning

confidence: 99%

Loss of KDM6A characterizes a poor prognostic subtype of human pancreatic cancer and potentiates HDAC inhibitor lethality

Watanabe

Shimada

Akiyama

et al. 2018

Intl Journal of Cancer

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“…The ORR of 11% and the finding that of 9 evaluable patients, only 1 patient (with lymph nodeonly disease and multiple genomic alterations) was alive and free of disease progression for 4 months was not consistent with meaningful clinical activity. Although mocetinostat-related AEs, including gastrointestinal events and fatigue, were consistent with the safety profiles reported in other settings, 11,12,21 frequent dose interruptions and reductions were required. Mocetinostat exposure (mean dose-normalized C max of 0.2 ng/mL/mg) was lower than in prior trials of mocetinostat TIW (range, 0.8-1.6 ng/mL/mg).…”

Section: Discussionsupporting

confidence: 72%

Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes

Grivas

Mortazavi

Picus

et al. 2018

Cancer

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Background The authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [ CREBBP ] and/or E1A binding protein p300 [ EP300 ] histone acetyltransferase genes in a single‐arm, open‐label phase 2 study. Methods Eligible patients with platinum‐treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28‐day cycles in a 3‐stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate. Results Genomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intent‐to‐treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of ≤15%). All patients experienced ≥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (dose‐normalized maximum serum concentration [C max ] after TIW dosing of 0.2 ng/mL/mg). Conclusions To the authors’ knowledge, the current study represents the first clinical trial using genomic‐based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting.

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“…We chose mocetinostat as our model HDAC inhibitor because prior preclinical studies have shown synergy with gemcitabine [ 52 ] as measured by in vitro growth inhibition and apoptosis of PANC1 and BxPC3 pancreatic cancer cells. In a phase I/II study of mocetinostat and gemcitabine in patients with refractory solid tumors [ 67 ], the maximum tolerated dose of mocetinostat was 90 mg per dose, three doses per week, when administered with 1000 mg/m 2 gemcitabine, given weekly for three weeks in every 28-day cycles. DLTs included fatigue, abdominal pain, deep vein thrombosis, diarrhea, nausea, mental status change, thrombocytopenia, and vomiting.…”

Section: Discussionmentioning

confidence: 99%

SARC018_SPORE02: Phase II Study of Mocetinostat Administered with Gemcitabine for Patients with Metastatic Leiomyosarcoma with Progression or Relapse following Prior Treatment with Gemcitabine-Containing Therapy

Choy

Ballman

Chen

et al. 2018

Sarcoma

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Histone deacetylase inhibitors (HDACi) can reverse chemoresistance, enhance chemotherapy-induced cytotoxicity, and reduce sarcoma proliferation in cell lines and animal models. We sought to determine the safety and toxicity of mocetinostat and its ability to reverse chemoresistance when administered with gemcitabine in patients with metastatic leiomyosarcoma resistant to prior gemcitabine-containing therapy. Participants with metastatic leiomyosarcoma received mocetinostat orally, 70 mg per day, three days per week, increasing to 90 mg after three weeks if well tolerated. Gemcitabine was administered at 1,000 mg/m2 intravenously at 10 mg/m2/minute on days five and 12 of every 21-day cycle. Disease response was evaluated with CT or MRI. Twenty participants with leiomyosarcoma were evaluated for toxicity. Median time to disease progression was 2.0 months (95% CI 1.54–3.12). Eighteen participants were evaluated for radiologic response by RECIST 1.1. Best responses included one PR and 12 SD. Tumor size reduced in 3 patients. Most common toxicities were fatigue, thrombocytopenia, anemia, nausea, and anorexia. One patient experienced a significant pericardial adverse event. No study-related deaths were observed. Rechallenging with gemcitabine by adding mocetinostat was feasible and demonstrated modest activity in patients with leiomyosarcoma. Further studies are needed to better define the role of HDAC inhibitors in patients with metastatic leiomyosarcoma.

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Phase I/II study of mocetinostat in combination with gemcitabine for patients with advanced pancreatic cancer and other advanced solid tumors

Abstract: Mocetinostat TIW in combination with gemcitabine was associated with significant toxicities in patients with advanced pancreatic cancer. The level of clinical activity of this treatment combination was not considered high enough to merit further testing in this setting.

Cited by 39 publications

References 41 publications

Loss of KDM6A characterizes a poor prognostic subtype of human pancreatic cancer and potentiates HDAC inhibitor lethality

Loss of KDM6A characterizes a poor prognostic subtype of human pancreatic cancer and potentiates HDAC inhibitor lethality

Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes

SARC018_SPORE02: Phase II Study of Mocetinostat Administered with Gemcitabine for Patients with Metastatic Leiomyosarcoma with Progression or Relapse following Prior Treatment with Gemcitabine-Containing Therapy

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