Pomalidomide (CC-4047)

Pomalidomide, previously known as CC-4047 or actimid, is a potent immunomodulatory molecule that exhibits antineoplastic activity for the treatment of hematological malignancies, especially relapsed and refractory multiple myeloma (MM). As a derivative of thalidomide, pomalidomide has a similar chemical structure as thalidomide except for the addition of two oxo groups in the phthaloyl ring and an amino group at the fourth position. Generally, as an immunomodulatory molecule, pomalidomide demonstrates antitumor activity through a mechanism of blocking the tumor microenvironment by modulation of tumor-supporting cytokines (TNF-α, IL-6, IL-8 and VEGF), directly down-regulating key functions of tumor cells, and engaging support from non-immune host cells.

Reference

AA Chanan-Khan, A Swaika, A Paulus, SK Kumar, JR Mikhael, SV Rajkumar, A Dispenzieri, and MQ Lacy. Pomalidomide: the new immunomodulatory agent for the treatment of multiple myeloma. Blood Cancer Journal (2013) 3, el43

Evangelos Terpos, Nikolaos Kanellias, Dimitrios Christoulas, Efstathios Kastritis, and Meletios A Dimopoulos. Pomalidomide: a novel drug to treat relapsed and refractory multiple myeloma. Onco Targets Ther 2013; 6: 531-538

A phase I, dose-escalation study of pomalidomide (CC-4047) in combination with gemcitabine in metastatic pancreas cancer.[Pubmed:21051221]

Eur J Cancer. 2011 Jan;47(2):199-205.

INTRODUCTION: Pomalidomide is an investigational immunomodulating drug (IMiD) that also inhibits angiogenesis and has direct anti-tumour effects. This phase I study was performed to identify the optimal dose of pomalidomide to be used in combination with gemcitabine in the treatment of patients with metastatic pancreatic cancer. METHODS: Eligible patients had histologically documented metastatic adenocarcinoma of the pancreas. No prior gemcitabine for metastatic disease or for primary treatment of locally advanced disease was allowed although prior radiation therapy with 5-flourouracil (5-FU) or gemcitabine as a radiosensitizer was allowed. All patients received gemcitabine 1000 mg/m(2) IV on days 1, 8 and 15 of a 28 day cycle. Pomalidomide was administered orally on days 1-21 at doses escalated from 2 to 10mg daily. Patients were re-evaluated every 8 weeks; treatment continued until disease progression or intolerable toxicity occurred. RESULTS: Twenty-three patients were enrolled with a median age of 62 and Eastern Cooperative Oncology Group (ECOG) performance status 0 (87%) and 1 (13%). The maximum tolerated dose (MTD) was 10mg/day on days 1-21. Neutropaenia was the most common grade 3/4 toxicity (38%); other grade 3/4 toxicity included deep vein thrombosis (DVT) (22%) and anaemia (9%). While efficacy was not a primary end-point of this study, 3 of 20 evaluable patients (15%) had partial responses and 10 patients (50%) had >50% decrease in CA 19-9 levels. CONCLUSIONS: The combination of pomalidomide and gemcitabine was feasible and safe in most patients receiving first-line chemotherapy for metastatic pancreatic cancer. Neutropaenia, the dose-limiting toxicity, was brief and reversible. Intermittent dosing of pomalidomide allowed substantially higher doses than were previously reported with a continuous schedule. This combination merits further evaluation in the treatment of metastatic pancreatic cancer.

A phase I study of pomalidomide (CC-4047) in combination with cisplatin and etoposide in patients with extensive-stage small-cell lung cancer.[Pubmed:23370364]

J Thorac Oncol. 2013 Apr;8(4):423-8.

INTRODUCTION: This phase I/IIA study evaluated the maximum-tolerated dose (MTD), safety, and clinical benefit of pomalidomide, an immunomodulatory drug (IMiD), combined with cisplatin+etoposide chemotherapy, in treatment-naive patients with extensive-stage (ES) small-cell lung cancer (SCLC). METHODS: In this multicenter, open-label, dose-escalation study, patients received 21-day cycles of oral pomalidomide (1, 3, 5, and 4 mg/day) on days 1 to 14, plus cisplatin 25 mg/m and etoposide 100 mg/m administered intravenously on days 1 to 3; the MTD was determined during cycle 1 (standard 3+3 dose-escalation design), followed by a five-cycle extension phase. RESULTS: Twenty-two patients with ES SCLC, with a median age of 64.5 years received one or more doses of the study medication. Dose-limiting toxicities included grade 4 cerebral ischemia and grade 5 sepsis (1-mg cohort), grade 4 transient ischemic attack (5-mg cohort), and grade 5 neutropenic infection (5-mg cohort). The MTD for pomalidomide was 4 mg/day. In the MTD phase, the most common pomalidomide-related adverse events (AEs) were fatigue (72.7%), nausea (45.5%), and neutropenia (40.9%); 31.8% of patients experienced pomalidomide-related serious AEs and 40.9% cisplatin/etoposide-related serious AEs. Overall response rate was 31.8% (7 of 22); these were partial responses. Stable disease and progressive disease occurred in four patients (18.2%) each. The median response duration was 12.4 weeks. Median overall survival was 49.6 weeks. CONCLUSIONS: Pomalidomide at the MTD of 4 mg/day plus standard cisplatin+etoposide seems safe in treatment-naive patients with ES SCLC. However, addition of pomalidomide does not seem to improve the therapeutic index of chemotherapy alone.

Pomalidomide is the third-generation immunomodulatory agent, functions through interacting with the E3 ligase cereblon and induces degradation of essential Ikaros transcription factors.

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