Phase I study of panobinostat and imatinib in patients with treatment-refractory metastatic gastrointestinal stromal tumors.

Abstract

BACKGROUND:

Panobinostat, a pan-deacetylase inhibitor, overcomes imatinib resistance in preclinical models of gastrointestinal stromal tumours (GIST). Here we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of panobinostat in combination with imatinib (IM) for treatment of patients with refractory GIST.

METHODS:

Following a 7-day run-in phase of IM (400 mg per day), escalating doses of panobinostat were added following a '3 plus 3' design. Twelve heavily pretreated GIST patients were enrolled in two dose levels.

RESULTS:

Most common adverse events were thrombocytopenia, anaemia, fatigue, creatinine elevation, nausea, emesis and diarrhoea. Twenty micrograms of panobinostat and 400 mg IM were declared the MTD. Pharmacologically active concentrations of panobinostat and IM were achieved as evidenced by histone H3 acetylation in blood mononuclear cells in vivo and inhibition of the IM-resistant KIT (D816) mutation in vitro. In FDG-PET-CT scans after IM run-in and following 3 weeks panobinostat treatment, 1 out of 11 evaluable patients showed a metabolic partial response, 7 patients were metabolically stable and 3 patients progressed. Longest treatment duration was 17 weeks (median 6).

CONCLUSION:

Panobinostat and IM can be administered at doses achieving target inhibition in vivo. Further clinical exploration of patients with treatment-refractory GIST is warranted. Correlative studies in this trial may help to optimise dosing schedules in GIST.

• Authors: S Bauer, R A Hilger, T Mühlenberg, F Grabellus, J Nagarajah, M Hoiczyk, A Reichardt, M Ahrens, P Reichardt, S Grunewald, M E Scheulen, A Pustowka, E Bock, M Schuler, D Pink
• Journal: British journal of cancer (Br J Cancer) Vol. 110 Issue 5 Pg. 1155-62 (Mar 04 2014) ISSN: 1532-1827 [Electronic] England
• PMID: 24434430 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Indoles
• Piperazines
• Pyrimidines
• Imatinib Mesylate
• Panobinostat

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Benzamides (administration & dosage, adverse effects)
• Female
• Gastrointestinal Neoplasms (drug therapy)
• Gastrointestinal Stromal Tumors (drug therapy)
• Histone Deacetylase Inhibitors (administration & dosage, adverse effects)
• Humans
• Hydroxamic Acids (administration & dosage, adverse effects)
• Imatinib Mesylate
• Indoles (administration & dosage, adverse effects)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Panobinostat
• Piperazines (administration & dosage, adverse effects)
• Pyrimidines (administration & dosage, adverse effects)