PCI-24781: Pan-HDAC Inhibitor for Oncology
PCI-24781 (abexinostat hydrochloride) is an oral inhibitor of HDAC enzymes that shows anti-tumor activity in vitro and in vivo (Buggy et al. Mol Cancer Ther 2006). PCI-24781 treatment effectively synergizes with DNA-damaging agents such as radiation and chemotherapy for combination treatment in tumor cells (Adimoolam et al. PNAS 2007; Lopez et al. Clin Cancer Res 2009), through mechanisms involving inhibition of DNA repair. Synergy has also been demonstrated with proteasome inhibitors such as bortezomib in lymphomas (Bhalla et al., Clin Cancer Res 2009), likely due to increased oxidative stress and attenuation of antioxidant and proteasome gene expression in tumor cells.
Preclinical Experience
In preclinical studies, PCI-24781 shows activity against primary human tumor cells taken from patients with colon, ovarian, lung and many hematological cancers.
Clinical Development
In Solid Tumors
Phase 1 in solid tumors
Clinical development assessed intravenous (IV) administration of investigational, single-agent PCI-24781 in a Phase I study (PCYC-0401) of patients with advanced solid tumors. A second Phase I study (PCYC-0402) assessed oral administration of single-agent PCI-24781 in a dose-finding study of patients with solid tumors.
Phase I/II in sarcoma
A Phase I/II trial testing PCI-24781 in combination with doxorubicin for patients with soft tissue sarcoma is currently ongoing.
Sarcoma
Sarcoma is a cancer type that falls into two main types depending on whether it develops from bone (osteosarcoma) or soft tissues such as muscle, nerves, fibrous tissues, vessels, or skin tissues (soft tissue sarcoma). Annually, there are around 10,000 new patient diagnoses of soft tissue sarcomas in the U.S. (and 3,820 soft tissue sarcoma deaths in U.S. in 2009)
The most common types of soft tissue sarcoma in adults are malignant fibrous histiocytoma, liposarcoma, and leiomyosarcoma, with each type affecting particular regions of the body. Rhabdomyosarcoma is the most common soft tissue sarcoma diagnosed in children. Other types of sarcoma include hemangiosarcoma, Kaposi's sarcoma, synovial sarcoma, fibrosarcomas and malignant peripheral nerve sheath tumors (MPNST)
The average overall 5-year survival of patients diagnosed with soft tissue sarcoma is 50% (NCI statistics). This percentage varies greatly depending on the tumor stage and extent of the disease, and the outlook is poorer for sarcomas that have spread beyond local or regional areas of the body.
Clinical Development
In Hematologic Cancer
Phase I/II in B-cell malignancies
The improved potency and pharmacokinetic aspects of PCI-24781 served as the basis for an ongoing Phase I/II trial in patients with relapsed or refractory lymphoma (PCYC-0403). Please see clinicaltrials.gov for more information.
B-cell Lymphoma
Lymphoma, a cancer arising from the white blood cells (both B-cells and T-cells) of the immune system, is the most common type of blood cancer in the US. Lymphoma affects more than 500,000 individuals in the US, with 74,000 new diagnoses annually. About 95% of lymphomas originate from B-cells, and B-cell lymphomas are classically divided into two categories: Hodgkin's Lymphoma (HL) and non-Hodgkin's Lymphoma (NHL).
NHL includes many different subtypes of B-cell lymphomas, including diffuse large B-cell lymphoma, follicular lymphoma (FL), mantle cell lymphoma and chronic lymphocytic leukemia (CLL). In less aggressive forms of NHL, the disease may exist for many years; however, in more aggressive cases of NHL, the disease can be fatal without appropriate treatment. The standard treatment regimens include a combination of chemotherapy, monoclonal antibodies, immunotherapy, radiation, and hematopoietic stem cell transplantation.
Clinical Development Ex-US
Les Laboratoires Servier ("Servier"), the largest independent French pharmaceutical company, is developing PCI-24781/S 78454 in the European Union and globally ex-US, based on an ex-US collaboration agreement signed in April of 2009. Over the past years Servier has engaged in several exploratory Phase I/II trials in solid tumors and hematologic malignancies. Servier is now focused on its Phase II programs to enable the registration pathway for PCI-24781 / S 78454.
