Isotype-Selective HDAC Inhibitor MGCD0103 Decreases Serum TARC Concentrations and Produces Clinical Responses in Heavily Pretreated Patients with Relapsed Classical Hodgkin Lymphoma (HL).
Authors: Younes Anas , Pro Barbara , Fanale Michelle , McLaughlin Peter , Neelapu Sattva , Fayad Luis , Wedgwood Amanda , Buglio Daniela , Patterson Tracy , Dubay Marja , Li Zuomei , Martell Robert E. , Ward M. Renee , Bociek R. Gregory 
Published: April 2020

Purpose: HL patients (pts) with recurrent refractory disease after stem cell transplant have poor prognosis and are considered not curable with currently available salvage therapy. Novel therapeutic agents are needed for this pt population. MGCD0103 is an oral isotype-selective inhibitor of histone deacetylases (HDACS) with significant biological activity in preclinical models of hematopoietic cancers. Thymus- and activation-regulated chemokine (TARC) which is highly expressed by Reed-Sternberg cells in HL was one of the biomarkers assessed in this study.

Methods: A phase II trial of MGCD0103 is ongoing in pts with relapsed/refractory classical HL. MGCD0103 was dosed at 110 mg 3×/week in 4-week cycles, with dose reductions to 85 and 60 mg in case of toxicities. Eligibility criteria included prior treatment with autologous and/or allogeneic stem cell transplant, at least one target lesion ≥ 2 cm, ECOG performance status of 0–1 and platelet counts of at least 25,000/mL. Tumor responses were determined every 8 weeks. Serum TARC levels were determined by ELISA using blood samples that were obtained prior to starting therapy and 8 days after therapy.

Results: To date, 27 pts of a planned 12–35 have been enrolled (median age, 29 yrs; range, 20–62 yrs). Among 20 evaluable pts, 2 (10%) had CRs and 6 (30%) had PRs, for an OR rate of 40% (median time to response, 2 cycles). In addition, one pt (5%) had SD (&lt;50% reduction) for ≥ 6 m. The rate of disease control (CR + PR + SD ≥ 6 m) was 45%. As assessed by CT scans, 15 pts (75%) exhibited tumor reductions: 12 (60%) had reductions of &gt; 30%, and 8 (40%) had reductions of ≥ 50%. Serum TARC levels were determined in 15 paired samples. After one week of therapy serum TARC levels were decreased by at least 40% in 5 pts, and all achieved major clinical responses (PR+CR). Seventeen of 25 pts required dose reductions for management of toxicities. The most common drug-related non-hematological toxicities were nausea (11/25), fatigue (10/25), vomiting (8/25), diarrhea (7/25), anorexia (4/25), pneumonia (3/25), abdominal pain (3/25) and weight loss (3/25). There were 2 deaths on study, both in heavily pretreated pts, one of unknown cause in a woman with h/o mantle XRT, BMT, suffering from significant GI AEs and the other of neutropenic fever, pneumonia and sepsis in a man with severe marrow compromise at baseline. Six pts experienced grade 3 or 4 toxicity. Of these, only pneumonia occurred in &gt; 1 pt. Dose modification was effective in managing most toxicities. HDAC inhibition was observed in PBMCs from the majority of evaluable pts. By using microarray expression analysis, transcriptional profiles of PBMCs from limited pts with/without clinical response were compared.

Conclusions: Interim results from this ongoing trial suggest that single-agent MGCD0103 demonstrates significant anti-tumor activity in relapsed/refractory classical HL and is well tolerated, with dose modifications used as necessary to manage toxicities. Preliminary data also suggests that early decrease in serum TARC levels may predict response to therapy.