The Novartis oral investigational drug LBH589 (panobinostat) demonstrated substantial disease control and tumour reduction in extensively pre-treated Hodgkin lymphoma patients who had relapsed or had become refractory after an autologous stem cell transplant, according to new data from a Phase II clinical trial was presented.

In this pivotal single-arm study, one of the largest ever conducted in this patient population, 82% (n=106) of patients, most in their fifth line of therapy or beyond, achieved disease control (defined as stable disease or better) and 74% (n=96) achieved tumour reduction at a median follow-up of 9.6 months, demonstrating the sustained anticancer activity of LBH589. Partial and complete responses to treatment, the primary endpoint, were observed in 27% of patients (n=35), with a median duration of response of 6.9 months and a median progression-free survival measured at 10.5 months among those 35 patients.

These data were presented at the 52nd Annual Meeting and Exposition of the American Society of Hematology (ASH) in Orlando, Florida. Worldwide regulatory filings are planned based on the study results.

Currently, up to 35% of patients with Hodgkin lymphoma relapse or become refractory after initial treatment, which typically involves at least two regimens of combination chemotherapy along with high-dose chemotherapy and stem cell transplant. Most patients enrolled in this study had received nearly all of the chemotherapy drugs known to be active in this disease, and 79% had failed an additional round of chemotherapy after a stem cell transplant. In addition, 10% of patients had also received prior allogeneic stem cell transplantations (stem cells from another person) in addition to an autologous transplant (stem cells from the patient). Palliative care is currently the only option remaining for these patients.

“It's impressive to see this response to LBH589 in patients, many of whom have received multiple courses of chemotherapy,” said Anna Sureda, MD, Clinical Hematology Division, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. “The responses suggest LBH589, which has a very different mechanism of action than chemotherapy, has the potential to become a valuable treatment option for these patients.”

LBH589 is an oral pan-deacetylase (DAC) inhibitor, which targets changes in gene function (also known as epigenetic regulation) that regulate processes in the development of cancer, including proliferation and survival of Hodgkin lymphoma cells in laboratory studies. A Phase III clinical trial (PATH: PAnobinostat Trial in Hodgkin's lymphoma) has begun enrollment, investigating the drug as a maintenance therapy following autologous stem cell transplant in patients with Hodgkin lymphoma who have an increased risk for relapse. The clinical development program for LBH589 also includes an ongoing Phase III clinical trial in multiple myeloma and early-stage trials in acute myeloid leukemia and myelodysplastic syndromes.

“These positive findings for LBH589 are encouraging for many Hodgkin lymphoma patients who currently lack effective treatments,” said Alessandro Riva, Global Head, Oncology Development & Medical Affairs, Novartis Oncology. “Patients who are not cured by autologous stem cell transplant and have stopped responding to chemotherapy have an urgent unmet medical need for novel therapeutic options. We are committed to the rapid development of this promising compound for these patients.”

Hodgkin lymphoma is most commonly diagnosed in teenagers and adults between the ages of 15 and 35 and in adults over 50. It is the third most common cancer in people under the age of 20. Treatment options for Hodgkin lymphoma typically involve an initial round of combination chemotherapy, but standard frontline treatments do not lead to long-term disease-free survival in all patients. When a patient relapses or becomes refractory, treatment options include high-dose chemotherapy, usually followed by stem cell transplantation. The use of transplantation has resulted in improved outcomes in patients with relapsed disease, but still 40% to 50% of these patients subsequently relapse. There is currently no standard of care for patients who relapse or are refractory following these treatments.

This Phase II clinical trial evaluated the efficacy and safety of oral LBH589 in patients with refractory/relapsed classical Hodgkin lymphoma who had received prior treatment with high dose chemotherapy and autologous stem cell transplant.

The primary outcome measure was objective response rate to therapy. Secondary outcome measures included response rate based on central review of CT scan/MRI, time to response, duration of response, progression-free survival rate and safety and tolerability of treatment.

As of the data analysis, 129 patients had been enrolled and treated. Patients had received a median number of four (range 2-7) prior systemic regimens, including combination regimens involving drugs such as gemcitabine, vinca-alkaloids or platinum-based chemotherapies. At a median follow-up of 9.6 months, a reduction in measurable tumour size was observed in 96 (74%) patients; responses were observed in 35 patients (5 complete responses, 30 partial responses; overall response rate 27%). Median progression-free survival was 6.1 months (10.5 months among responders).

Common adverse events (mostly grade 1 or 2) included diarrhoea, nausea, fatigue, vomiting, anorexia, dysguesia, asthenia, constipation, leucopenia and muscle spasms. Common related grade 3/4 adverse events included thrombocytopenia, anaemia and neutropenia. Thrombocytopenia was reversible with dose hold or modification and was manageable long term, with only 5% treatment discontinuation for this reason. The overall rate of discontinuation due to adverse events was 16%.

Because it is an investigational compound, the safety and efficacy profile of LBH589 has not yet been established. Access to this investigational compound is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the potential benefits and risks of the compound. Because of uncertainty of clinical trials, there is no guarantee that LBH589 will ever be commercially available anywhere in the world.

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