Patient population Individuals were required to have histologically confirmed recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, and had to have received at least one prior platinum-based chemotherapy regimen for management of primary disease

Patient population Individuals were required to have histologically confirmed recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, and had to have received at least one prior platinum-based chemotherapy regimen for management of primary disease. to aggresomes and promoting fusion of autophagosomes and lysosomes. Therefore, HDAC6 inhibition in a tumor cell already predisposed to producing large amounts of abnormal proteins may amplify cellular stress and induce cell death (Boyault et al., 2007). HDAC6 additionally impairs the chaperone activity of HSP90 and alters the function of p53, further suggesting a role in oncogenesis and a therapeutic role for HDAC6 inhibition (Seidel et al., 2016; Bali et al., 2005). HDAC6 also modulates microtubule Triptolide (PG490) dynamics via deacetylation of -tubulin (Hubbert et al., 2002). HDAC inhibitors have potential as an oncologic therapy, with largest effect in synergistic combinations, such as with proteasome inhibitors in lymphoma (Amengual et al., 2015) and multiple myeloma (Qi et al., 2017) and various chemotherapeutic agents in preclinical evaluations of solid tumors, including ovarian and uterine cancer (Singh et al., 2011; Chobanian et al., 2004; Budman et al., 2011). In ovarian cancer cell lines, HDAC inhibition led to G1 or G2 cell cycle arrest and apoptosis. In unreported internal data, ricolinostat (ACY1215, ACY63, ACY161-63), an orally active, small molecule, selective inhibitor of HDAC6 was tested in combination with paclitaxel in preclinical ovarian cancer xenotransplant models and showed synergy in tumor suppression compared to either agent alone. The effect of HDAC6 on -tubulin led to the hypothesis that HDAC6 inhibition may reverse axonal transport defects, such as those seen in chemotherapy-induced peripheral neuropathy, and potentially ameliorate this dose-limiting aspect of treatment. HDAC6-specific inhibition by ricolinostat and another experimental agent has prevented and reversed cisplatin-mediated allodynia, pain, and numbness in murine models (Krukowski et al., 2017). HDAC6 inhibition in a vincristine-based murine model both prevented peripheral neuropathy and reduced tumor progression (Van Helleputte et al., 2018). Therefore, the rationale behind and potential benefit of a combination of ricolinostat and paclitaxel in women with ovarian cancer was two-fold: first, to capture synergistic anti-tumor effects, and second, to utilize ricolinostat’s microtubule effects to attenuate taxane-induced neurotoxicity. 2.?Patients & methods We designed and conducted an open-label Phase Ib study of weekly paclitaxel and daily oral ricolinostat for patients with recurrent ovarian, peritoneal, or fallopian tube cancer at Dana-Farber Cancer Institute from March 2016 to January 2017. The primary objective of this study was to establish a maximally tolerated dose (MTD) of oral daily ricolinostat in combination with paclitaxel. Secondary endpoints included safety and tolerability, objective response rate (ORR), duration of response (DOR), and progression free survival (PFS). Institutional review board approval was obtained. Each patient provided signed informed consent before study enrollment. 2.1. Patient population Participants were required to have histologically confirmed recurrent Triptolide (PG490) or persistent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, and had to have received at least one prior platinum-based chemotherapy regimen for management of primary disease. Triptolide (PG490) Additional eligibility included recurrence within 12?months of the last platinum-containing regimen, ECOG performance status of 0 or 1, and measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. There was no limitation on number of prior therapies. Prior paclitaxel was allowed, unless recurrence or progression occurred on or within 8?weeks of the last dose of paclitaxel. Prior use of an HDAC inhibitor was exclusionary. Participants were required to recover from prior treatment-related toxicities to grade 1 or better, and needed to demonstrate adequate bone marrow and organ function, including leukocyte count 3000/mcL, ANC 1500/mcL, and platelets 100,000/mcL. Exclusion criteria included the use of chemotherapy, radiation, or small molecule kinase inhibitors within four weeks of study entry, hormonal therapy within one week of study treatment initiation, or radiation to 25% of the marrow. Additionally, patients were excluded if they had severe or uncontrolled comorbidities or evidence of other malignancies within the preceding three years, excepting non-melanoma skin cancers, carcinoma-in-situ of the breast or cervix, or primary endometrial cancer with stage not greater than IA, grade 1 or 2 2, no lymphovascular invasion, and no more than superficial myometrial invasion. 2.2. Treatment plan & safety assessment At the starting dose (dose level 1), ricolinostat was given orally at 80?mg daily on days 1C21 of a 28?day?cycle. Paclitaxel was given weekly on days 1, 8, and 15 on a 28?day?cycle, at a dose of 80?mg/m2. Additional dose escalation levels included ricolinostat given orally IL8 at 120?mg daily, 180?mg daily, or 240?mg daily on days 1C21 of a 28-day?cycle, in combination with paclitaxel as above. Patients were treated on an outpatient basis and remained on study until disease progression, voluntary withdrawal, or drug-related toxicity. All patients followed for up to 30?days after removal from protocol therapy or until death. The primary endpoint was determination.