Abstract
Introduction
The proapoptotic small-molecule pan–Bcl-2 inhibitor obatoclax mesylate (GX15-070) may enhance the cytotoxicity of chemotherapy in relapsed/refractory non–small-cell lung cancer (NSCLC).
Methods
Obatoclax was administered with docetaxel in patients with relapsed or refractory NSCLC—docetaxel as a 1-hour infusion on day 1 and obatoclax as a 24-hour infusion on days 1 and 2—every 3 weeks for up to eight cycles. Four dose levels were evaluated in phase 1 (level 1: docetaxel 55 mg/m2 × 1 and obatoclax 30 mg × 2; levels 2–4: docetaxel 75 mg/m2 and obatoclax 30 mg, 45 mg, or 60 mg × 2) to identify dose-limiting toxicity and a phase 2 dose. In phase 2, response and tolerability were evaluated.
Results
Eighteen patients were included in phase 1. Two dose-limiting toxicities occurred during cycle 1: one febrile neutropenia each at dose levels 3 and 4. Maximum tolerated dose was not reached; 32 patients (including 3 from phase 1) were treated in phase 2 with docetaxel 75 mg/m2 and obatoclax 60 mg (median 2 cycles). Three patients (11%) had partial responses in phase 2; two demonstrated stable disease lasting 12 weeks or more. Median duration of response was 4.8 months. Overall, median progression-free survival was 1.4 months. Neutropenia (31%), febrile neutropenia (16%), and dyspnea (19%) were the most common grade 3/4 adverse events observed.
Conclusions
Combined obatoclax mesylate plus docetaxel is tolerable in patients with NSCLC, but response was minimal and neutropenia was a common adverse event.
Keywords: Non–small-cell lung cancer, Apoptosis, Maximum tolerated dose, Efficacy
Few effective treatments exist for patients with advanced non–small-cell lung cancer (NSCLC) who have progressed during or relapsed after first-line platinum-based chemotherapy. Docetaxel is standard in the second-line NSCLC setting,1 but the objective response rate in patients with relapsed/refractory disease is lower than 10% and median time to progression is approximately 3 months.1,2 Thus, novel agents that may enhance the sensitivity of NSCLC cells to taxanes are needed.
The Bcl-2 family of antiapoptotic proteins, frequently expressed in NSCLC cells,3 is an attractive target for inhibiting tumor growth. Obatoclax mesylate modulates the Bcl-2 protein family with antagonistic activity to Bcl-2, Bcl-xL, Bcl-W, and Mcl-1.4 Obatoclax has been investigated in combination with standard chemotherapy in patients with advanced solid tumors (including small-cell lung cancer).5–7 We evaluated the safety and tolerability of obatoclax in combination with docetaxel in patients with advanced NSCLC who progressed after prior chemotherapy.
PATIENTS AND METHODS
An open-label, phase 1/2 study was conducted in advanced NSCLC patients who progressed after platinum-based chemotherapy between November 2006 and November 2008 at seven U.S. sites (clinicaltrials.gov NCT00405951). Patients were aged 18 years or more, with pathological confirmation of NSCLC including measurable disease using Response Evaluation Criteria in Solid Tumors v1.0.8 In phase 1, patients progressing after one or more platinum-based regimen or paclitaxel were enrolled. In phase 2, patients were permitted only one prior platinum-based regimen for advanced or metastatic disease; prior paclitaxel, erlotinib, or gefitinib was permitted. In both phases, prior treatment must have been stopped 14 days or more before enrollment, and associated adverse effects resolved to grade 1 or lower. Other inclusion criteria were absolute neutrophil count 1500/mm3 or more, platelet count 100,000/mm3 or more, adequate liver and renal function, and Eastern Cooperative Oncology Group performance status of 0 or 1.
Phase 1 evaluated the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of obatoclax plus docetaxel. Four dose levels were planned (Table 1). If no DLT occurred at the highest planned dose level and MTD was not determined, that dose was used in phase 2. DLTs were defined as grade 3 or higher neurologic adverse event (AE), grade 4 febrile neutropenia or thrombocytopenia, grade 4 neutropenia for 7 days or more, and other grade 3/4 nonhematologic toxicity not ameliorated by symptom-directed therapy. If DLTs occurred, treatment was modified. Once the DLTs were resolved to grade 2 or lower, the patient resumed treatment with appropriate dose reductions. Docetaxel was discontinued in patients who developed grade 2 or higher peripheral neuropathy. Docetaxel dose was reduced for DLTs attributed to myelosuppression; for all other DLTs, the obatoclax dose was reduced to the next lowest dose level. Treatment was discontinued if toxicity occurred at the lowest dose level, recurred after dose reduction, or if treatment was delayed for more than 28 days.
TABLE 1.
Phase 1 Dose Escalation, Drug Exposure, and Summary of Dose-Limiting Toxicities (N = 18)
| Dose Level | Docetaxela | Obatoclaxb | n | Dose-Limiting Toxicities | Median Number of Cyclesc Administered (Range) | Median Number of Treatment Days (Range) |
|---|---|---|---|---|---|---|
| 1 | 55 mg/m2d | 30 mg × 2 days | 3 | Nonee | 3 (2–8) | 59 (23–151) |
| 2 | 75 mg/m2 | 30 mg × 2 days | 3 | Nonee | 4 (2–6) | 80 (24–108) |
| 3 | 75 mg/m2 | 45 mg × 2 days | 6f | 1 febrile neutropenia | 5 (2–8) | 87 (24–150) |
| 4 | 75 mg/m2 | 60 mg × 2 days | 6f | 1 febrile neutropenia | 3 (2–10) | 46 (3–199) |
Intravenous infusion over 1 hour on day 1.
Intravenous infusion over 48 hours on days 1 and 2.
A cycle constituted 21 days.
Initial dose of docetaxel was 55 mg/m2 because obatoclax may inhibit the CYP3A4 isoform responsible for docetaxel metabolism.
Reported during cycle 1.
Group was expanded to six patients because of dose-limiting toxicities reported in first group of three.
Phase 2 assessed the efficacy, safety, and pharmacokinetic properties of obatoclax in combination with docetaxel. Patients received obatoclax plus docetaxel until disease progression, unacceptable toxicity, or investigator/patient decision to stop treatment. A two-stage design was used to detect an objective response rate of 20% or more at 80% power and an α level of 0.05. Efficacy was evaluated per investigator review by using Response Evaluation Criteria in Solid Tumors v1.0.8 AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0.9
Obatoclax plasma concentrations were assessed during cycle 1 of each dose level. Samples were drawn at 1, 3, 24, 47, and 49 hours, timed from the start of the obatoclax infusion. Peak serum concentration (Cmax) and area under the plasma concentration-time curve (AUC0–49h) were determined for each dose level.
The safety population included all patients receiving obatoclax. The efficacy population included patients who received the phase 2 recommended dose, had at least one post-baseline assessment, and received no more than one platinum-containing regimen. Time-to-event data were estimated using Kaplan–Meier methods with associated two-sided 95% confidence intervals (CIs).
The study was conducted in accordance with the Declaration of Helsinki and complied with local, state, and federal regulations. An institutional review board or independent ethics committee reviewed and approved the protocol and all patients provided written informed consent.
RESULTS
Phase 1 Study
Eighteen patients were enrolled (Fig. 1A). All patients received prior therapy for NSCLC (Supplementary Table 1, Supplementary Digital Content 1, http://links.lww.com/JTO/A488). No DLTs were observed at dose levels 1 and 2 (Table 1). At both dose levels 3 and 4, one patient each experienced grade 4 febrile neutropenia in cycle 1; these groups were expanded and no further DLTs were reported. The MTD was not reached; consequently, dose level 4 was selected for phase 2 evaluation.
FIGURE 1.
Patient enrollment and disposition in phase 1 (A) and phase 2 (B). D, docetaxel; O, obatoclax: PR, partial response.
Among phase 1 patients, one patient at dose level 1 and two patients at dose level 4 achieved partial response (PR); stable disease was best response in 11 of 18 patients. Neutropenia was the most common grade 3/4 AE observed (56%); three patients (17%) had febrile neutropenia (Table 3). Twelve patients (67%) experienced one or more psychiatric event, all grade of 2 or lower. Six patients experienced treatment-related serious AEs, including febrile neutropenia (n=3), grade 3 vomiting (n=1) leading to discontinuation, grade 4 neutropenia with grade 2 anemia (n=1), and grade 1 confusional state (n=1).
TABLE 3.
Adverse Events Occurring in ≥10% of Patients Treated with Obatoclax and Docetaxel in Phase 1 and Phase 2
| Treatment-Emergent Adverse Events, n (%) | Phase 1 N = 18 |
Phase 2 N = 32 |
||
|---|---|---|---|---|
| All Grades | Grade 3 or 4 | All Grades | Grade 3 or 4 | |
| ≥1 Event | 18 (100.0) | 15 (83.3) | 32 (100.0) | 20 (62.5) |
| Hematologic | ||||
| Anemia | 10 (55.6) | — | 15 (46.9) | 2 (6.3) |
| Neutropenia | 10 (55.6) | 10 (55.6) | 12 (37.5) | 10 (31.3) |
| Febrile neutropenia | 3 (16.7) | 3 (16.7) | 5 (15.6) | 5 (15.7) |
| Nonhematologic | ||||
| Fatigue | 9 (50) | — | 19 (59) | 2 (6) |
| Nausea | 7 (38.9) | — | 17 (53) | — |
| Dyspnea | 3 (16.7) | 2 (11.1) | 16 (50) | 6 (19) |
| Alopecia | 11 (61.1) | — | 14 (44) | — |
| Anorexia | 5 (27.8) | — | 13 (41) | — |
| Dizziness | 2 (11.1) | — | 11 (34) | — |
| Cough | 2 (11.1) | — | 9 (28) | 1 (3) |
| Constipation | 3 (16.7) | — | 8 (25) | — |
| Insomnia | — | — | 8 (25) | — |
| Diarrhea | 3 (16.7) | — | 7 (22) | — |
| Vomiting | 3 (16.7) | 1 (5.6) | 7 (22) | 1 (3) |
| Mucosal inflammation | — | — | 7 (22) | 1 (3) |
| Flushing | 2 (11.1) | — | 7 (22) | — |
| Ataxia | 3 (16.7) | — | 6 (19) | — |
| Pharyngolaryngeal pain | 7 (38.9) | — | 6 (19) | — |
| Dehydration | 5 (27.8) | — | 6 (19) | — |
| Peripheral edema | — | — | 5 (16) | — |
| Dysgeusia | 2 (11.1) | — | 5 (16) | — |
| Headache | 2 (11.1) | — | 5 (16) | — |
| Peripheral neuropathy | — | — | 5 (16) | — |
| Somnolence | — | — | 5 (16) | — |
| Confusional state | 4 (22.2) | — | 5 (16) | — |
| Euphoric mood | 4 (22.2) | — | 5 (16) | — |
| Back pain | 3 (16.7) | 1 (5.6) | 5 (16) | 2 (6) |
| Chills | 2 (11.1) | — | 4 (13) | — |
| Pyrexia | 3 (16.7) | — | 4 (13) | — |
| Anxiety | — | — | 4 (13) | — |
| Hallucinations | — | — | 4 (13) | 2 (6) |
Phase 2 Study
Thirty-two patients were enrolled, including three patients from phase 1 who met phase 2 enrollment criteria (Fig. 1B). Supplementary Table 1 (Supplementary Digital Content 1, http://links.lww.com/JTO/A488) presents demographics and baseline characteristics. Patients received a median of two treatment cycles (range, 1–12); median dose/cycle of obatoclax was 120 mg (range, 18.7–120 mg) and of docetaxel was 75 mg/m2 (range, 55–75 mg/m2).
The efficacy population included 27 patients (Fig. 1B). Table 2 summarizes best responses to treatment. In the first stage, one patient (9%) included from phase 1 had a PR and the trial proceeded to stage 2. In stage 2, two additional patients (13%) achieved PR, and overall response rate was 11% (95% CI 2.35–29.16). No complete responses were reported. All patients with PR had stage IV disease. Median duration of response was 4.8 months (95% CI 4.4–5.2) in patients with PR (n=3) and 5.3 months (95% CI 4.1–7.1) in patients with PR or stable disease (n=5). Overall, median progression-free survival (PFS) was 1.4 months (95% CI 1.2–3.4).
TABLE 2.
Best Response to Treatment with Obatoclax Plus Docetaxel (Phase 2)
| Obatoclax 60 mg × 2 days + Docetaxel 75 mg/m2
|
|||
|---|---|---|---|
| Stage 1a n = 11 | Stage 2 n = 16 | Total N = 27 | |
| Best response, n (%) | |||
| Complete response | 0 | 0 | 0 |
| Partial response | 1 (9.1) | 2 (12.5) | 3 (11.1) |
| Stable disease ≥12 weeks | 1 (9.1) | 1 (6.3) | 2 (7.4) |
| Stable disease <12 weeks | 2 (18.2) | 5 (31.3) | 7 (25.9) |
| Progressive disease | 7 (63.6) | 8 (50.0) | 15 (55.6) |
| Overall response, n (%) | 1 (9.1) | 2 (12.5) | 3 (11.1) |
Includes one phase 1 patient with partial response.
Twenty-eight patients (88%) experienced one or more nervous system disorder or psychiatric disorder related adverse events (Table 3), most of which were of grade 2 or lesser. One patient each discontinued treatment because of grade 4 cerebral ischemia, grade 3 agitation and hallucination, and grade 3 hallucination; patients with hallucinations had either prior or current secondary brain metastases. Treatment delays occurred in three patients because of grade 3 cough and dyspnea, grade 3 anasarca, and grade 1 pulmonary infiltrate. Docetaxel dose was reduced (75 mg/m2 to 55 mg/m2) in five patients because of grade 3/4 neutropenia or febrile neutropenia.
Six patients experienced treatment-related serious AEs, including febrile neutropenia (n=4), grade 3 leukopenia (n=1), and grade 3 hallucination (n=1). Three patients experiencing febrile neutropenia were treated with filgrastim; recovery from neutropenia occurred at a median of 4 days (range, 2–6 days). Leukopenia resolved without intervention or dose adjustment. Study treatment was stopped in the patient experiencing hallucinations, which resolved without further intervention.
As of the last follow-up assessment, 11 of 32 patients (34%) had died. Two deaths, attributed to AEs (1 broncho-pneumonia, 1 pneumonia), occurred more than 30 days after the last dose of study treatment and were not considered treatment-related. Seven deaths were attributed to disease progression or lung cancer, and causes of death for two patients were unknown.
Pharmacokinetics
Samples from 17 phase 1 patients (across all dose levels) and 30 phase 2 patients were analyzed. Supplementary Table 2 (Supplementary Digital Content 2, http://links.lww.com/JTO/A489) summarizes pharmacokinetic parameters for obatoclax.
DISCUSSION
We evaluated the MTD, safety, pharmacokinetics, and efficacy of the pan–Bcl-2 inhibitor obatoclax in combination with docetaxel in patients with relapsed or refractory NSCLC. AEs were consistent with those previously reported; myelo-suppression was frequent but expected with docetaxel and was manageable with dose reduction of docetaxel. No hematologic AEs led to dose delay or discontinuation of obatoclax or docetaxel.
Transient neurologic toxicities, including dizziness, somnolence, ataxia, and euphoric mood, were observed and anticipated based on previous studies of obatoclax.5–7,10–14 They were considered tolerable in this study. Grade 3 hallucinations leading to treatment discontinuation in two patients (1 patient had brain metastasis) were resolved the following day without treatment in one patient and on the day of onset with haloperidol treatment in the second patient.
Limited efficacy in patients with recurrent NSCLC was observed at the dose selected for phase 2 evaluation (obatoclax 60 mg×2 days plus docetaxel 75 mg/m2) compared with the response rate in phase 1. It should be noted that patients in the 2 phases had different baseline characteristics (e.g., Eastern Cooperative Oncology Group performance status) that may affect treatment exposure. The efficacy of this regimen was similar in terms of response rate but inferior to previously reported results for single-agent docetaxel except with regard to PFS and duration of response.2,15 The MTD for this combination was not reached; efficacy may increase at higher dose levels and by extending treatment exposure, as all patients with PR had received six or more cycles.
Supplementary Material
Acknowledgments
This study was supported by Gemin X Pharmaceuticals, an indirect wholly owned subsidiary of Teva Branded Pharmaceutical Products R&D, Inc. Financial support for medical editorial assistance was provided by Teva Branded Pharmaceutical Products R&D, Inc. The authors acknowledge the medical writing and editorial support provided by Powered 4 Significance LLC.
Footnotes
Disclosure: Dr. Chiappori is on the speaker’s bureau for Genentech, Pfizer, and Celgene. Dr. Rosen has received remuneration for patient enrollment in clinical trials from the Tower Cancer Research Foundation. Dr. Berger was employed by Gemin X Pharmaceuticals from 2007 to 2011, when that company was acquired by Cephalon, which was then acquired by Teva; he held stock options in Gemin X at the time of its acquisition. The remaining authors declare no conflict of interest.
In conclusion, combined administration of the pan–Bcl-2 antagonist obatoclax and docetaxel is tolerable. However, the combination was not associated with encouraging response rates or PFS at the doses studied. These results do not justify continued evaluation of docetaxel and obatoclax at this dosage and schedule in patients with locally advanced/metastatic NSCLC who have progressed after first-line combination platinum therapy.
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