Obatoclax is a small molecule inhibitor of all members of the bcl-2 family of prosurvival proteins which mimics the BH3-only pro-apoptotic proteins of the bcl-2 family. By binding to a hydrophobic groove on the prosurvival bcl-2 proteins (such as bcl-2 and mcl-1), obatoclax releases bax and bak and induces apoptosis. Obatoclax has clinical activity in CLL (O’Brien et al, ASH 2005) with a recommended phase II dose of 28 mg/m2 given over 3 h every 3 weeks with DLT of grade 3 infusional CNS toxicities. Similar toxicities with weekly dosing led to an MTD of 20 mg/m2 weekly (
Firozvi et al, ASCO 2006
). Bortezomib has been shown to be an effective agent in patients with relapsed mantle cell lymphoma (MCL) but increases levels of mcl-1, a bcl-2 prosurvival family member. Obatoclax inhibits mcl-1, and in vitro data indicate synergy between obatoclax and bortezomib in MCL cell lines and patient samples (Blood 109:4441, 2007
). We have completed an ascending dose study evaluating the combination of obatoclax (3 hour IV infusion) and bortezomib (IV push) in patients with MCL. Both obatoclax and bortezomib were administered on days 1, 4, 8, & 11 of 21 day cycles, and up to 8 cycles were administered. Three patients received 30 mg of obatoclax and 1.0 mg/m2 of bortezomib, 3 received 30 mg of obatoclax and 1.3 mg/m2 of bortezomib, and 6 received 45 mg of obatoclax and 1.3 mg/m2 of bortezomib, which was the highest dose evaluated. Efficacy evaluation was performed every 2 cycles, approximately every 6 weeks. Median age was 67 (range 44 – 81), with 7 males. All patients had prior anthracyclines and rituximab, and 5 had previously received bortezomib. In preliminary data on the first 9 patients, adverse events with an overall incidence of ≥25% were thrombocytopenia, abdominal distension, abdominal pain, constipation, diarrhea, nausea, fatigue, weight loss, dehydration, neuropathy, somnolence, euphoric mood, cough, and rash. The most common grade 3 and grade 4 adverse event was thrombocytopenia (22.2%). Somnolence and euphoric mood resolved soon after the infusion ended. There were no grade 3 or 4 infusional CNS toxicities. Obatoclax 45 mg and bortezomib 1.3 mg/m2 was determined to be the combination dosage to be used for further evaluation. Using Investigator Reported assessments confirmed by evaluation after 2 additional cycles of treatment, 2 patients in the obatoclax 30 mg/bortezomib 1.0 mg/m2 dosage group and 1 patient in the obatoclax 30 mg/bortezomib 1.3 mg/m2 dosage group achieved a CR/CRu. Two of these patients had prior high dose therapy with autologous stem cell transplants, and the third had prior bortezomib.Conclusions: Obatoclax and bortezomib (45 mg and 1.3 mg/m2, respectively) administered on days 1, 4, 8, & 11 of a 21 day cycle was found to have acceptable tolerability. Building on pre-clinical data indicating synergy, this study supports a novel twice-weekly administration schedule for obatoclax with bortezomib, and demonstrates initial evidence of efficacy of the combination in heavily-pretreated patients with relapsed mantle cell lymphoma.
Prior Treatment and Response by Dosage Group
| Dosage Group*
. | Mean # Regimens
. | Prior Bortezomib
. | CR/CRu
. | SD
. | PD
. | Unk^
. | Total
. |
|---|
| * Obatoclax mg/bortezomib mg/m2 ^ Follow-up ongoing |
| 30/1.0 | 2 (1–3) | 1 | 2 | 1 | 0 | 0 | 3 |
| 30/1.3 | 3 (1–7) | 1 | 1 | 1 | 1 | 0 | 3 |
| 45/1.3 | 2 (1–4) | 3 | 0 | 2 | 3 | 1 | 6 |
| Dosage Group*
. | Mean # Regimens
. | Prior Bortezomib
. | CR/CRu
. | SD
. | PD
. | Unk^
. | Total
. |
|---|
| * Obatoclax mg/bortezomib mg/m2 ^ Follow-up ongoing |
| 30/1.0 | 2 (1–3) | 1 | 2 | 1 | 0 | 0 | 3 |
| 30/1.3 | 3 (1–7) | 1 | 1 | 1 | 1 | 0 | 3 |
| 45/1.3 | 2 (1–4) | 3 | 0 | 2 | 3 | 1 | 6 |
