To the editor:
Bcl-2 overexpression is frequently observed in classic Hodgkin lymphoma (cHL)1 and may confer poor prognosis.2,3 Obatoclax mesylate (GX15-070) is a small-molecule antagonist of the Bcl-2 family of proteins, which activates apoptosis in vitro and exhibits anti-tumor activity in animal models.4–6 The safety has been tested in human.7,8 We report the result of a phase 2 study of obatoclax in patients with relapsed or refractory cHL.
This study was supported by GeminX, registered at clinicaltrials.gov (NCT00359892) and approved by the institutional review board. Patients were eligible if they had relapsed or refractory cHL with a bidimensionally measurable disease, had received a minimal of 1 prior treatment and had progression of disease after stem cell transplant or were not a transplant candidate. They were required to have adequate major organ functions. Single-agent obatoclax was administered intravenously at 60 mg over 24 hours every 2 weeks. Response was evaluated by CT9 after 4 cycles of treatment.
Simon's 2-stage model was used to evaluate the success rate (no progressive disease9 in 8 weeks) with α of 0.05 and a power of 0.8. We considered success rate ≥ 20% to be meaningful and ≤ 5% to be of no interest. If success was seen in ≥ 1 of first 10 patients, accrual was to continue to 29 patients.
Thirteen eligible patients received at least 1 dose of obatoclax (Table 1). Although the study met its first step end point, the lack of significant response decreased enthusiasm for continuing enrollment. The median number of prior treatment regimens was 6 (range 3-11). A total of 80 cycles of obatoclax was administered, with the median 4 cycles per patient (range 1-24). One patient withdrew consent after one treatment. Two patients were hospitalized for the management of fever with intravenous antibiotics before response evaluation and were taken off study. Otherwise the treatment was generally well tolerated. Toxicities that were considered to be definitely or probably related to the study drugs were dizziness (n = 5), euphoria (n = 3) and hypotension (n = 1), which were all grade 1.
Summary of obatoclax clinical activity in 13 patients with relapsed classical Hodgkin lymphoma
| Patient no. . | Age, y . | Sex . | No. of prior regimen . | Prior transplantation . | Treatment duration, wk . | Best response . |
|---|---|---|---|---|---|---|
| 1 | 37 | male | 7 | yes | 24 | stable disease |
| 2 | 25 | female | 5 | yes | 8 | stable disease |
| 3 | 33 | female | 8 | yes | 7 | progression |
| 4 | 51 | male | 4 | yes | 98 | stable disease |
| 5 | 58 | male | 3 | no | 8 | not evaluated |
| 6 | 37 | male | 5 | yes | 5 | progression |
| 7 | 42 | male | 11 | yes | 7 | progression |
| 8 | 60 | male | 7 | yes | 16 | stable disease |
| 9 | 39 | female | 7 | yes | 4 | not evaluated |
| 10 | 50 | male | 5 | yes | 8 | progression |
| 11 | 25 | male | 6 | yes | 16 | stable disease |
| 12 | 27 | male | 5 | no | 8 | progression |
| 13 | 34 | male | 8 | no | 3 | not evaluated |
| Patient no. . | Age, y . | Sex . | No. of prior regimen . | Prior transplantation . | Treatment duration, wk . | Best response . |
|---|---|---|---|---|---|---|
| 1 | 37 | male | 7 | yes | 24 | stable disease |
| 2 | 25 | female | 5 | yes | 8 | stable disease |
| 3 | 33 | female | 8 | yes | 7 | progression |
| 4 | 51 | male | 4 | yes | 98 | stable disease |
| 5 | 58 | male | 3 | no | 8 | not evaluated |
| 6 | 37 | male | 5 | yes | 5 | progression |
| 7 | 42 | male | 11 | yes | 7 | progression |
| 8 | 60 | male | 7 | yes | 16 | stable disease |
| 9 | 39 | female | 7 | yes | 4 | not evaluated |
| 10 | 50 | male | 5 | yes | 8 | progression |
| 11 | 25 | male | 6 | yes | 16 | stable disease |
| 12 | 27 | male | 5 | no | 8 | progression |
| 13 | 34 | male | 8 | no | 3 | not evaluated |
There was no objective response observed. Five patients experienced a progression of disease within 8 weeks after initiation of treatment. Five patients had stable disease (38%) on evaluation after 8 weeks. One of them was taken off study at treating physicians discretion, because of lack of clinical benefit, and in other 4 patients with stable disease, the event free survival was 16, 16, 24, and 98 weeks.
Plasma concentrations of obatoclax were evaluated at 3, 23 and 25 hours after the first cycle of therapy in 11 patients. The median concentrations ± SEM were 6.25 ± 1.04 ng/mL, 4.96 ± 1.15 ng/mL, and 2.65 ± 0.44 ng/mL, respectively, consistent with a previous report.10
In our study, obatoclax mesylate, a small-molecule BCL-2 antagonist, showed limited clinical activity in heavily pretreated patients with cHL. Future studies should investigate more potent Bcl-2 family inhibitors with pharmacodynamic studies to ensure target inhibition and biomarker analysis for possible patient selection.
Authorship
Conflict-of-interest disclosure: M.F. received research funding from Seattle Genetics, Novartis, Medimmunne, Millennium, Genentech, and Onyx, received honoraria from Seattle Genetics and Novartis, and served on the advisory board for Seattle Genetics: J.R. received research funding from Millennium and Celgene. A.Y. received research funding from Genentech, Novartis, SBIO, Seattle Genetics, Syndax, and Sanofi-Aventis, and received honoraria from Novartis, Seattle Genetics, and Sanofi-Aventis. The remaining authors declare no competing financial interests.
Contribution: Y.O. collected and analyzed data and wrote the paper; A.C. collected and analyzed data and reviewed the paper; F.H. provided patient care and reviewed the paper; L.E.F. and M.F. provided patient care; J.R. provided patient care and edited paper; and A.Y. designed and supervised the clinical trial, provided patient care, analyzed data, and wrote the paper.
Correspondence: Anas Younes, MD, Department of Lymphoma/Myeloma, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 429, Houston, TX 77030; e-mail: ayounes@mdanderson.org.
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