Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia

Abstract

BackgroundUntil today, adult and pediatric clinical trials investigating single-agent or combinatorial HDAC inhibitors including vorinostat in solid tumors have largely failed to demonstrate efficacy. These results may in part be explained by data from preclinical models showing significant activity only at higher concentrations compared to those achieved with current dosing regimens. In the current pediatric trial, we applied an intra-patient dose escalation design.The purpose of this trial was to determine a safe dose recommendation (SDR) of single-agent vorinostat for intra-patient dose escalation, pharmacokinetic analyses (PK), and activity evaluation in children (3–18 years) with relapsed or therapy-refractory malignancies.ResultsA phase I intra-patient dose (de)escalation was performed until individual maximum tolerated dose (MTD). The starting dose was 180 mg/m2/day with weekly dose escalations of 50 mg/m2 until DLT/maximum dose. After MTD determination, patients seamlessly continued in phase II with disease assessments every 3 months. PK and plasma cytokine profiles were determined. Fifty of 52 patients received treatment. n = 27/50 (54%) completed the intra-patient (de)escalation and entered phase II. An SDR of 130 mg/m2/day was determined (maximum, 580 mg/m2/day). n = 46/50 (92%) patients experienced treatment-related AEs which were mostly reversible and included thrombocytopenia, fatigue, nausea, diarrhea, anemia, and vomiting. n = 6/50 (12%) had treatment-related SAEs. No treatment-related deaths occurred. Higher dose levels resulted in higher Cmax. Five patients achieved prolonged disease control (> 12 months) and showed a higher Cmax (> 270 ng/mL) and MTDs. Best overall response (combining PR and SD, no CR observed) rate in phase II was 6/27 (22%) with a median PFS and OS of 5.3 and 22.4 months. Low levels of baseline cytokine expression were significantly correlated with favorable outcome.ConclusionAn SDR of 130 mg/m2/day for individual dose escalation was determined. Higher drug exposure was associated with responses and long-term disease stabilization with manageable toxicity. Patients with low expression of plasma cytokine levels at baseline were able to tolerate higher doses of vorinostat and benefited from treatment. Baseline cytokine profile is a promising potential predictive biomarker.Trial registrationClinicalTrials.gov, NCT01422499. Registered 24 August 2011,

Clinically aggressive pediatric spinal ependymoma with novel MYC amplification demonstrates molecular and histopathologic similarity to newly described MYCN-amplified spinal ependymomas

“…Additionally, histone deacetylase (HDAC) inhibitors have been shown to impede MYC -amplified Group 3 medulloblastoma tumor growth in vitro [ 14 , 15 , 39 , 44 ]. Due to the focal MYC amplification, our patient received single-agent vorinostat, an oral HDAC inhibitor that is well tolerated in children with relapsed CNS tumors [ 19 , 24 , 31 , 50 ], following his first relapse. However, he presented with progressive disease after seven months.…”

Challenges and Opportunities of Therapies Targeting Early Life Immunity for Pediatric HIV Cure

“…Many anti-tumor drugs approved for use in adults and children are currently under evaluation for their potential to act as LRAs in adults with HIV ( Table 3 ). Existing anti-tumor drugs are easily translatable to LRA discovery because of the shared strategy to induce epigenetic changes that promote cell cycle arrest, apoptosis, autophagy, and cell death of cancer-infected cells ( 163 ). Several LRAs have undergone testing in adult clinical trials including the histone deacetylase inhibitors, such as vorinostat, panobinostat, belinostat, and romidepsin, as well as immunomodulatory compound such as IL-15 receptor superagonist complex (N-803).…”

The Current Landscape of Targeted Clinical Trials in Non-WNT/Non-SHH Medulloblastoma

“…A recent study demonstrated that HDAC inhibitors stabilize the MYC protein and thus lead to reduced DNA binding and ultimately lower expression of MYC target genes [63]. Furthermore, a combined phase I/II dose escalation trial showed overall manageable toxicity and partial responses in a fraction of patients (including eight MB patients) for the HDAC inhibitor Vorinostat [68]. This is in line with another study that showed a good safety profile for the combination of Vorinostat and Temozolomide in a small cohort of children with relapsed CNS malignancies, including two MB patients (NCT01076530) [69].…”