Here are some HDACis in clinical trials, I am curious about clinical trials involving trichostatin A but it seems that this natural product was developed further into vorinostat and I'm not sure if it underwent trials itself?
Ioannis Koutsounas, Constantinos Giaginis, and Stamatios Theocharis
"Hydroxamic acids
SAHA (N-hydroxy-N’-phenyl-octanediamide, vorinostat) is a synthetic hydroxamic acid, which is structurally related to the natural product, [trichostatin A] TSA (7-[4-(dimethylamino)phenyl]-N-hydroxyl-4,6-dimethyl-7-oxo-(2E,4E,6R)-2,4-heptadienamide), produced by selected strains of Streptomyces platensis, Streptomyces hygroscopicus Y-50 or Streptomyces sioyaensis. Hydroxamic acids have a high affinity to biometals, including Fe3+, Ni2+ and Zn2+. The synthesis of SAHA and its potency to induce differentiation of murine erythroleukemia (MEL) cells was first reported in 1996. SAHA and TSA comprise a hydroxamic-acid-based metal-binding domain that coordinates the catalytic Zn2 +in the HDAC active site, a 5 (TSA) or 6 (SAHA)-membered carbon-based linker that mimics the Cα functional group of lysine, and a hydrophobic motif that interacts with the periphery of the HDAC binding pocket[28].
SAHA:SAHA (vorinostat) is now undergoing several clinical trials. One current phase I trial is studying the side effects and best dose of SAHA given together with flavopiridol in treating patients with advanced solid tumors. Another trial is studying SAHA in patients with metastatic or unresectable solid tumors or lymphoma and liver dysfunction. Combination with doxorubicin is also under survey for solid tumors, as well as that with bortezomib, vinorelbine, gemcitabine and other agents like paclitaxel and carboplatin, fluorouracil/leucovorin and oxaliplatin. A phase I /II trial is studying the highest tolerable dose of SAHA that can be given in combination with radiotherapy to patients with locally advanced pancreatic cancer, as well the efficacy of combined therapy. Another phase I clinical trial is now examining the safety, pharmacokinetics, pharmacodynamics and efficacy of iv proteasome inhibitor NPI-0052 in combination with oral SAHA in patients with non-small cell lung cancer, pancreatic cancer, melanoma or lymphoma. A phase I /II study of SAHA in combination with radiotherapy and infusional 5-FU in patients with locally advanced adenocarcinoma of the pancreas is under way. Finally, SAHA in combination with capecitabine plus radiotherapy is also being evaluated in patients with non-metastatic pancreatic cancer. The above studies are recruiting for participants and possible patients suffering from pancreatic cancer remain to determine the efficiency of these therapies[29].
Cyclic peptides
FK228 (FR901228, depsipeptide, romidepsin): Depsipeptide (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis (1-methyletheyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone, is a bicyclic peptide isolated from Chromobacterium violaceum and has demonstrated potent in vitro cytotoxic activity against human tumor cell lines and in vivo efficacy against human tumor xenografts. Upon entering cells, FK228 is reduced to an active compound, capable of preferentially interacting with the zinc in the active site of the HDAC class I enzymes, however, it is still generally classified as a broad-spectrum inhibitor as it does inhibit class II enzymes. It was approved by the United States Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma (CTCL)[30].
Among other current clinical trials for patients with advanced solid tumors, FK228 is being studied in combination with gemcitabine in patients with pancreatic cancer. This phase I/II dose escalation trial is designed to determine the maximum tolerated dose for the combination, as well as evaluate toxicities and objective disease responses. Furthermore, another phase II trial is studying the effectiveness of FK228 in patients who have locally advanced or metastatic neuroendocrine tumors; among them pancreatic islet tumors[29].
Short-chain fatty acids
Valproic acid: Valproic acid (VPA) is now an established antiepileptic drug, by affecting the function of the neurotransmitter GABA. The finding that VPA was an effective inhibitor of HDACs arose from the observations that VPA was able to relieve transcriptional repression of a peroxisomal proliferation and activation of a glucocorticoid receptor (GR)-PPAR epsilon hybrid receptor, suggesting that it acts on a common mechanism in gene regulation, such as histone deacetylation, rather than on individual transcription factors or receptors. Consistent with this finding, it was shown that VPA causes hyperacetylation of the N-terminal tails of histones H3 and H4 in vitro and in vivo, and was found to inhibit HDAC enzymatic activity at a concentration of 0.5 mmol/L[31]. VPA has shown potent antitumor effects in a variety of in vitro and in vivo systems, by modulating multiple pathways including cell cycle arrest, apoptosis, angiogenesis, metastasis, differentiation and senescence. Most preclinical and clinical data on the anticancer effects of VPA have been generated for malignant hematological diseases[32].
A phase I clinical trial investigated the safety, toxicity and maximum-tolerated dose of VPA and the topoisomerase II inhibitor epirubicin in solid tumors. Forty-eight patients with different malignancies were enrolled; one with pancreatic cancer. The patient suffering from pancreatic cancer experienced a partial response at 100 mg/kg VPA and 100 mg/m2 on day 3 of the cycle, while no dose-limiting toxicities occurred. All patients with a partial response had at least a twofold increase in histone acetylation[33].
Phase I clinical trials are currently testing VPA in combination with other agents such as erlotinib, 5-FU, cyclophosphamide, bevacizumab, and azacytidine, as well as epirubicin to determine safety, tolerability and effectiveness in treating patients with advanced solid tumors. In addition, another phase II trial is studying VPA combined with the hypomethylating factor hydralazine. A phase I clinical trial is undertaking recruitment to determine maximum tolerated doses of VPA in combination with sunitinib, sorafenib, dasatinib, erlotinib, lapatinib, or lenalidomide for the treatment of patients with advanced solid tumors, as well as to estimate the safety and treatment response[29].
4-PB:
4-PB is a short-chain fatty acid known to inhibit reversibly class I and II HDACs. It is considered as an HDAC inhibitor of the first generation, as the HDAC inhibitory effect is not specific. Working concentrations are rather high, in the millimolar range, and the effects are pleiotropic. 4-PB is known to exert multiple effects in the cell, including the modulation of protein isoprenylation, which importantly regulates the ras proto-oncoprotein, and activation of the nuclear steroid PPAR[34]. 4-PB exerts a potent antitumor effect in vitro and has been shown to cause growth inhibition and differentiation in various human cancer cell lines[35].
A phase I dose escalating trial to evaluate twice daily iv 4-PB infusion has been undertaken. 4-PB was administered for five consecutive days for a total of 20 doses over two consecutive weeks from 60 to 360 mg/kg per day. Twenty-one patients with different malignancies, including one with pancreatic carcinoma, participated in the trial. Dose limiting toxicities were fatigue and headache, while no significant myelosuppression was seen. Three patients with brain malignancies remained stable for an average of 6 mo[36].
A current phase I clinical trial is investigating oral phenylbutyrate three times daily in patients with refractory solid tumors. Combination with azacytidine is also being studied to determine effectiveness and maximum dose in patients with advanced or metastatic solid tumors[29].
NaBu:
NaBu has multiple effects on cultured mammalian cells that include inhibition of proliferation, induction of differentiation and induction or repression of gene expression. Sodium butyrate inhibits most HDACs except class III HDAC and class II HDAC6 and-10. Promoters of butyrate-responsive genes have butyrate response elements, and the action of butyrate is often mediated through Sp1/Sp3 binding sites[37].
In a recruiting phase I clinical trial, the butyrate prodrug tributyrin is being studied in patients with various advanced solid tumors[29].
Benzamides
MS-275: This synthetic benzamide derivative (3-pyridylmethyl-N-{4-[(2-aminophenyl)carbamoyl]benzyl}carbamate) has been shown to inhibit HDACs, and has antitumor activity in many preclinical models. The first clinical trial with this agent in 2005 included patients with advanced solid tumors or lymphoma. At high concentrations of MS-275, there is a marked induction of reactive oxygen species, mitochondrial damage, caspase activation and apoptosis. Treatment of sensitive tumor cell lines with MS-275 induces gelsolin, a maturation marker, and produces a change in the cell cycle distribution with a decrease in S phase and an accumulation of cells in G1. The in vivo therapeutic efficacy of MS-275 has been shown in a variety of human tumor xenograft models[38].
A phase I study determined the maximum tolerated dose, the dose limiting toxicity and the pharmacokinetic or pharmacodynamic profile of MS-275 in combination with 13-cis-retinoic acid. Patients with advanced solid tumors were treated with MS-275 orally, once weekly, and 13-cis-retinoic acid orally, 1 mg/kg twice daily, for 3 wk every 4 wk. One patient suffering from pancreatic cancer remained on treatment for 6 mo and a patient with renal cell carcinoma showed a partial response in the lungs. Side effects included hyponatremia, neutropenia, anemia and fatigue[39].
Another phase I study evaluated the toxicity and pharmacokinetic profiles of MS-275 in patients with refractory solid tumors and lymphomas, including one patient suffering from metastatic pancreatic cancer, on three different schedules. The patient with metastatic pancreatic cancer developed grade 3 hypophosphatemia, thus meeting criteria for dose limiting toxicity, and was finally removed from study due to disease progression after cycle 2. Objective responses were only observed in patients receiving the every-other-week dosing schedule, but the numbers of patients enrolled were too small to determine whether this dosing regimen was truly more efficacious[40].
CI-994:
CI-994 or N-acetyldinaline [4-(acetylamino)-N-(2-amino-phenyl) benzamide] is a novel oral compound with a wide spectrum of antitumor activity in preclinical models. The mechanism of action may involve inhibition of histone deacetylation and cell cycle arrest. CI-994 is currently undergoing clinical trials. Although several changes in cellular metabolism induced by the drug have been characterized, the primary molecular mechanism of its antitumor activity remains unknown[41].
A phase II trial of CI-994 in patients with advanced pancreatic cancer evaluated the antitumor activity and safety of CI-994. CI-994 was administered orally at 8 mg/m2 per day. Seventeen patients were enrolled, including 15 with metastatic disease. Among patients evaluable for response, stable disease for 8 wk occurred in two patients (12%). Overall, median time to progressive disease was 6 wk and median survival was 10 wk, with one patient alive at 41 wk. Grade 3 thrombocytopenia occurred in eight patients but grade 4 in none. Most common non-hematological toxicities were generally grade 1 or 2 and included fatigue, anorexia, nausea, vomiting and bruising. According to this study, CI-994 was well tolerated but resulted in no objective responses in patients with advanced pancreatic cancer[42].
A phase 1 study in patients with solid tumors was carried out to determine the maximum tolerated daily oral dose for CI-994 administered on a chronic basis. Fifty-three patients, most of them suffering from colorectal, lung and renal malignancies, including one with pancreatic cancer, received CI-994 daily for treatment durations ranging from 2 to 10 wk. Antitumor effects were documented in four patients, including a durable partial response in one pretreated non-small cell lung cancer patient and stable disease in three patients with non-small cell lung, colon and renal cancers[43].
Another study investigated the toxicity profile, maximum tolerated dose and pharmacokinetics of CI-994 in combination with capecitabine. Fifty-four patients were treated according to three different dosing schemes in which the capecitabine dose was fixed and the CI-994 dose was escalated. In schedule C, 22 patients, including four with pancreatic cancer, were treated with capecitabine 2000 mg/m2 per day and CI-994 for 2 of 3 wk. One partial response was achieved at the 4 mg/m2 dose level of schedule A in a patient with colorectal cancer. Disease stabilization was seen in adenocarcinoma of unknown primary origin, appendiceal cancer, breast cancer, colorectal cancer and mesothelioma[44].
A phase I study of oral CI-994 in combination with carboplatin and paclitaxel in patients with advanced solid tumors was carried out. A total of 30 patients were entered into five treatment cohorts, including two suffering from pancreatic cancer. Five patients achieved a partial response (non-small cell lung, colon, unknown primary origin) and two patients achieved a complete response (esophageal and bladder cancer). It was observed that patients whose histone H3 acetylation in peripheral blood lymphocytes was at least 1.5-fold greater after treatment had an objective clinical response or stable disease[45].
A randomized, double-blind, placebo-controlled, multicenter study compared whether CI-994 plus gemcitabine improved OS, duration of response, time to treatment failure, and quality of life compared to gemcitabine alone. Patients had diagnosis of advanced or metastatic adenocarcinoma of the exocrine pancreas and were not considered surgical candidates. A total of 174 patients received CI-994 6 mg/m2 per d orally on days 1-21 plus gemcitabine 1000 mg/m2 on days 1, 8 and 15 or placebo plus gemcitabine 1000 mg/m2 on days 1, 8 and 15 of each 28-d cycle. There was no observed difference in survival time between the two cases. The estimated median survival was 194 and 214 d and objective response rates based on investigator assessments were 12% and 14%, respectively. In addition, pain responses did not differ significantly. Treatment with CI-994 was associated with more cases of grade 3/4 thrombocytopenia, anemia and leukopenia than with placebo, while non-hematological toxicities such as nausea, vomiting, anorexia and diarrhea were identical with both treatments. Consequently, in this study, CI-994 in combination with gemcitabine did not appear to offer any benefit compared to gemcitabine as a single agent for the treatment of pancreatic cancer[46].
A randomized phase II trial comparing the effectiveness of gemcitabine with or without CI-994 in patients with advanced pancreatic cancer is still ongoing[29].
MGCD0103:
MGCD0103 is an isotype-specific aminophenylbenzamide that inhibits HDAC classes I and IV, with almost no class II effect. MGCD0103 is well tolerated and exhibits favorable pharmacokinetic and pharmacodynamic profiles, demonstrating target inhibition and clinical responses. It induces cell death and autophagy, synergizes with proteasomal inhibitors and affects non-histone targets, such as microtubules[47].
In a phase I study MGCD0103 was given three times weekly orally to patients with advanced solid tumors to determine safety, tolerability and pharmacokinetics. Thirty-eight patients were enrolled and completed a total of 99 cycles of MGCD0103, including two with pancreatic cancer. No objective tumor responses were observed. Five patients with previously progressive colorectal, renal cell and lung cancers had stable disease for four or more cycles. Furthermore, MGCD0103 exerted dose-dependent HDAC inhibitory activity and was able to induce histone acetylation in peripheral leukocytes[48].
Oral MGCD0103 three times weekly is currently being studied in combination with gemcitabine, in patients with advanced solid tumors. In this phase I/II study, patients with locally advanced or metastatic pancreatic cancer can participate. Maximum tolerated dose of MGCD0103 and objective response of patients remain to be determined[29,49].
Other HDACIs
A phase I study of LAQ824 has determined the safety, maximum tolerated dose, and pharmacokinetic-pharmacodynamic profile in patients with advanced solid tumors. Thirty-nine patients were recruited and were eligible for assessment of toxicity, including three with pancreatic cancer. At 100 mg/m2, one patient who had advanced pancreatic cancer, developed grade 4 hyperbilirubinemia associated with febrile neutropenia on day 3. The patient finally died after an episode of atrial fibrillation and acute renal failure 18 d after the first infusion. All patients treated with LAQ824 at 12 mg/m2 or above showed increase in histone acetylation. No objective responses were documented. One patient with hepatocellular carcinoma and two with fibrosarcoma and papillary carcinoma of the thyroid showed disease stabilization[50].
A phase I study is investigating safety, pharmacodynamic, antitumor activity, and pharmacokinetics of PXD101 (belinostat) alone and in combination with 5-FU in patients with advanced solid tumors or lymphoma[51]. Another recruiting phase I trial is studying the safety, tolerability and pharmacokinetics of orally administered PXD101 in combination with carboplatin and/or paclitaxel in patients with advanced solid tumors or lymphoma[52].
A recruiting phase I study is evaluating the pharmacokinetics and safety of oral LBH589 (panobinostat) in patients with advanced solid tumors and varying degrees of renal function. Another phase II trial will determine tumor response, toxicity and tolerability of LBH589 in patients with gastrointestinal neuroendocrine tumors. A phase IA, dose-escalating study of iv LBH589 in adult patients with advanced solid tumors is ongoing. Another phase I study will evaluate the safety and tolerability of the combination of LBH589 and paclitaxel/carboplatin in patients with metastatic or locally advanced solid tumors. Finally, a phase I dose escalation trial of LBH589 and gemcitabine in patients with solid malignancies has been temporarily suspended[53,54].
Other HDACIs, such as CHR-3996, CRA-024781, SB939 and R306465, are under phase I trials for the treatment of patients with advanced solid tumors[29]."
Edited by Phoenicis, 13 May 2014 - 06:47 AM.
