Phase II Trial of Combination of the Histone Deacetylase Inhibitor ITF2357 and Meclorethamine Demonstrates Clinical Activity and Safety in Heavily Pretreated Patients with Relapsed/Refractory Hodgkin Lymphoma (HL)

Introduction: HL patients with refractory disease or relapsing after autologous stem cell transplantation (SCT) have very poor prognosis with currently available salvage chemotherapy. ITF2357 (Italfarmaco S.p.A., Milano, Italy) is an orally bioavailable hydroxamate inhibitor of class I and II histone deacetylases (HDACs) with preclinical and clinical activity as single agent in hematopoietic cancers. Our preclinical data demonstrating a synergistic activity of ITF2357 with the alkylating agent Meclorethamine in HL cell lines, established the rationale for this currently ongoing phase II study aimed to determine activity and safety of the sequential ITF2357 and Meclorethamine treatment.

Methods: Patients with relapsed/refractory HL who have failed second- or subsequent-line salvage chemo-radiotherapy were enrolled. Eligibility criteria included prior treatment with autologous and/or allogeneic SCT, prior treatment with single agent Meclorethamine, at least one target lesion ≥2 cm, ECOG performance status of 0–1, and platelet ≥75,000/μL. ITF2357 (50 mg QID, per os, days 1–3) followed by Meclorethamine (6 mg/sqm, intravenously, day 4) was dosed in 3-week cycles until disease progression or appearance of clinical significant toxicity, but for a maximum of 12 cycles. Tumor responses were determined after cycles 2, 6, 9 and 12 by computed tomography (CT) and positron emission tomography (PET) scan. Serum levels of thymus- and activation-regulated chemokine (TARC) were assessed by ELISA prior to each cycle of therapy.

Results: To date, 19 patients have been enrolled (16 males and 3 females; median age, 33 years; range, 21–61 years), including 8 patients enrolled in a preliminary compassionate use trial, and 11 patients of a planned 23 enrolled in this ongoing phase II trial. Prior to study entry, patients received a median of 5 (range 2–7) lines of treatment with autologous SCT performed in 15 (79%) and an additional allogeneic SCT in 5 (26%) patients. At study entry, 6 patients had relapsed and 13 refractory HL. Seventeen of 19 patients received a median of 3 cycles (range, 1–10) of ITF2357/Meclorethamine and are evaluable for response by CT and PET scans. Best response to therapy included 2 (12%) complete remissions (CR) and 3 (18%) partial remissions (PR), for an overall response rate (ORR) of 30%. In addition, 5 (29%) patients had stable disease (SD) with 4 (23%) patients achieving SD for ≥4 months, while 7 (41%) patients progressed. After the first cycle of therapy, serum TARC levels were decreased by 70±16% (mean±SEM, P ≤0.05) in 5 patients who achieved major clinical responses (PR+CR), and by 16±14% (P = ns) in patients who achieved SD. Overall, therapy was well tolerated without significant adverse events, and no patient required dose reductions for management of toxicities. The most common drug-related non-hematological toxicities were grade 1–2 nausea (12/17) and fatigue (14/17). Four patients experienced infections [pneumonia (n = 1), oral herpes simplex (n = 2), oral candidiasis (n = 1)]. No prolongation of QT/QTc interval has been detected over 70 therapy cycles. Hematological toxicities included grade 1–2 anemia (13/17), neutropenia (7/17), and thrombocytopenia (12/17). Grade 3–4 neutropenia and thrombocytopenia were observed in 7 and 8 patients, respectively. RBC and platelet transfusions were required by 4 and 5 patients, respectively.

Conclusions: Preliminary results from this ongoing trial suggest that ITF2357, in combination with Meclorethamine, demonstrates significant anti-tumor activity in heavily pretreated relapsed/refractory HL and is well tolerated. Preliminary data also suggest that early decrease in serum TARC levels may predict response to therapy.