In our study, the MTD and recommended phase II dose of obatoclax as a 3-h infusion, in combination with etoposide and carboplatin, were determined to be 30
mg daily for 3 days. As expected, the observed DLTs consisted of CNS AEs previously described with single-agent obatoclax infusions. Somnolence, euphoric mood, and disorientation defined the MTD for the 3-h infusion schedule. The majority of these AEs occurred during obatoclax infusion and resolved shortly after the infusion ended, and did not require any special intervention, except for the standard observation planned in the protocol during and after the drug infusion. There was no MTD defined for the 24-h obatoclax infusion, and only one patient was enrolled at the highest dose level of 60
mg (as the available information was already considered to be adequate to choose between the two schedules).
We observed marked differences in the incidence of somnolence in the 3-h infusion arm (75%) versus the 24-h infusion arm (0%), and in the incidence of euphoric mood in the 3-h infusion arm (44%) versus the 24-h infusion arm (11%). These findings agree with those of previous studies of single-agent obatoclax in which CNS AEs were more frequent and of higher toxicity grade with shorter infusions of obatoclax (Schimmer et al, 2008
; Hwang et al, 2010
). Although no direct correlation has been shown between the intensity of CNS symptoms and Cmax
or area under the curve, these symptoms appear to be related to the level of obatoclax exposure. Furthermore, the presence of these symptoms indicates that the drug is able to cross the blood–brain barrier; indeed, the CNS toxicity may be an on-target effect resulting from inhibition of BCL-XL expressed in neurons.
Comparison of the incidence of non-CNS AEs between the two infusion schedules did not indicate major differences or patterns suggestive of specific organ system toxicity. However, increased neutropenia was observed in patients previously treated with chemotherapy. This was likely due to the effects on the bone marrow of prior cytotoxic therapy and not likely due to a direct obatoclax effect, as the overall incidence of neutropenia observed in our trial appears similar to that reported for etoposide and carboplatin in comparable patient populations (Lara et al, 2009
; Socinski et al, 2009
Navitoclax is another agent in development that inhibits BCL-2 family members BCL-2, BCL-XL, and BCL-W. Phase I evaluation of single-agent navitoclax demonstrated that thrombocytopenia was the dose-limiting AE (Gandhi et al, 2011
), which is consistent with the role shown for BCL-XL in platelet regulation (Zhang et al, 2007
). Thrombocytopenia has not been a prominent finding in single-agent phase I trials of obatoclax administered as a 3-h (O'Brien et al, 2009
) or a 24-h infusion (Schimmer et al, 2008
). Instead, two patients with myelodysplastic syndrome had marked increases in platelets and became platelet transfusion-independent when treated with single-agent obatoclax (Schimmer et al, 2008
In this trial, grade 3 or 4 thrombocytopenia occurred in 33% of the chemotherapy-naïve patients. This may be a higher rate of grade 3 or 4 thrombocytopenia than the rate of 10% reported in the carboplatin and etoposide control arm of a recent SCLC trial (Socinski et al, 2009
); however, without a controlled trial, any conclusions in this regard are tentative. Nevertheless, the degree of thrombocytopenia seen with obatoclax in multiple studies appears less than that seen with navitoclax. As plasma exposures of navitoclax in patients treated with this agent (Gandhi et al, 2011
) are considerably higher than those achieved with obatoclax (O'Brien et al, 2009
) due to CNS-limiting events, one explanation for the low rate of thrombocytopenia seen with obatoclax may be that obatoclax does not achieve the concentrations in platelets necessary to completely inhibit BCL-XL. Alternatively, it is possible that obatoclax may not inhibit BCL-2 to the same degree as navitoclax.
In this study, it was initially recommended that diphenhydramine and an H2-blocking agent be administered before obatoclax infusion to prevent cytokine release syndrome. Diphenhydramine was recognised to worsen somnolence, and the recommendation was changed to utilise prophylaxis with only an H2-blocking agent. Thus, prophylactic treatment with diphenhydramine is no longer recommended.
Although the study was not powered to compare the efficacy of the two infusion schedules, the overall response rate was higher in patients receiving the 3-h infusion compared with patients receiving the 24-h infusion (81 vs 44%), and overall survival was longer in the 3-h infusion cohorts. These data indicate that the 3-h infusion schedule demonstrates promising activity and supports utilising this schedule in future studies.
Data from an earlier study in older patients with previously untreated acute myeloid leukemia also support the conclusion that efficacy with the 3-h infusion of obatoclax may be increased when compared with efficacy with the 24-h infusion (Raza et al, 2009
). In this study, 13 patients received single-agent obatoclax utilising a 3-h infusion (3 at 20
and 10 at 30
) and 5 received obatoclax utilising a 24-h infusion (all at 60
), with obatoclax administered on days 1–3 of a 14-day cycle. Efficacy data after cycle 2 indicated that four patients receiving a 3-h infusion of obatoclax had a
50% decrease in bone marrow blasts, compared with none of the patients on the 24-h schedule of obatoclax infusion.
Analysis of pharmacodynamic endpoints in the patients in this trial was performed as a measure of cell death and has been reported elsewhere (Dean et al, 2011
). These data indicate that patients with radiologic, unconfirmed complete or partial responses after two cycles of treatment (‘responders') had a significant increase in circulating cell death biomarkers (cleaved cytokeratin 18 and oligonucleosomal DNA) by day 3 with both infusion schedules, whereas nonresponders did not.
There were practical issues seen in the outpatient setting with patients on the 24-h obatoclax infusions that were not seen with the shorter 3-h infusions administered in the infusion suite. Pump malfunctions at home led to the administration of less than full doses for those patients. This difficulty provided an additional reason to favour the 3-h obatoclax infusion schedule in future studies.
Study limitations included the uncontrolled study design, making it difficult to distinguish toxicity related to obatoclax from that related to chemotherapy, and the small number of patients enrolled. Furthermore, pharmacokinetic analyses were not performed in this trial, so precise exposure levels at the different dosages are not available.
Obatoclax administered as a 3-h infusion in combination with carboplatin and etoposide was generally well tolerated at doses of up to 30
mg per day. Although the 3-h infusion was associated with a higher incidence of some (particularly CNS) AEs than the 24-h infusion, preliminary data indicate it may also be associated with improved efficacy compared with obatoclax as a 24-h infusion. In consideration of these preliminary efficacy findings, as well as practical issues with the 24-h infusion arm, 3-h infusions of obatoclax with carboplatin and etoposide are recommended for use in future clinical trials in patients with SCLC.