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Journal of Clinical Oncology, Vol 25, No 12 (April 20), 2007: pp. 1512-1518 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.5125 Phase I Trial of G3139, a bcl-2 Antisense Oligonucleotide, Combined With Doxorubicin and Cyclophosphamide in Children With Relapsed Solid Tumors: A Children's Oncology Group Study
From the Children's Hospital of Philadelphia, Philadelphia, PA; Texas Children's Cancer Center at Baylor College of Medicine, Houston, TX; Investigational Drug Branch, Cancer Therapy Evaluation Program, Bethesda, MD; Genta Inc, Berkeley Heights, NJ; Children's Oncology Group, Arcadia; and University of Southern California Keck School of Medicine, Los Angeles, CA Address reprint requests to Peter C. Adamson, MD, Division of Clinical Pharmacology & Therapeutics, The Children's Hospital of Philadelphia, ARC 916, 34th St & Civic Center Blvd, Philadelphia, PA 19104; e-mail: adamsonp{at}mail.med.upenn.edu
Purpose To determine the maximum-tolerated dose, toxicity, pharmacokinetics, and biologic effects of G3139 when administered with doxorubicin and cyclophosphamide to children with relapsed solid tumors. Patients and Methods Patients received a 7-day continuous infusion of 3, 5, or 7 mg/kg/d of G3139 every 21 days. Doxorubicin, cyclophosphamide, and dexrazoxane were administered on days 5 and 6 of the infusion. Pharmacokinetics and biology studies were performed during the first course. Results Thirty-seven patients, median age 14 years (range, 1 to 19 years), were enrolled, of whom 29 were fully assessable for toxicity. Because of dose-limiting neutropenia, doses of doxorubicin 30 mg/m2/d for 2 days, dexrazoxane 300 mg/m2/d for 2 days, and cyclophosphamide 500 mg/m2/d for 2 days were reduced initially, but with the addition of granulocyte colony-stimulating factor (GCSF), could be re-escalated to starting doses. At the 7 mg/kg/d dose level, only one of six patients experienced DLT (neutropenia > 7 days). At this dose, the average (± standard deviation) steady-state G3139 concentration was 2.04 ± 1 µg/mL, a concentration associated with biologic activity. Eleven of 15 patients had reduced bcl-2 expression in peripheral-blood mononuclear cells at the first assessable time point of G3139 exposure, and in eight of 14 patients with serial specimens this reduction persisted through day 6. Conclusion The recommended phase II dose of G3139 is 7 mg/kg/d as a 7-day continuous infusion, with cyclophosphamide 500 mg/m2/d and doxorubicin 30 mg/m2/d on days 5 and 6, followed by GCSF. G3139 may accentuate the myelosuppressive effects of doxorubicin and cyclophosphamide. Evidence for biologic effects of G3139 was demonstrated.
G3139 (oblimersen sodium, bcl-2 antisense, Genasense; Genta Inc, Berkeley Heights, NJ) is an 18-mer phosphorothioate oligodeoxynucleotide antisense (5'-TCTCCCAGCGTGCGCCAT-3') designed to bind to the first six codons of the human bcl-2 mRNA. The members of the bcl-2 family of proteins are key regulators of the intrinsic or mitochondrial apoptosis pathway mediating cytochrome c release and effector caspase activation.1 Bcl-2, an antiapoptotic family member, contributes to neoplastic progression by enhancing cell survival through repression of mitochondrial death signaling.2-4 Overexpression of bcl-2 results in a resistance to apoptosis-inducing agents including radiation and chemotherapy, and has been associated with poor clinical response and shorter survival.4-6 Targeted downregulation of bcl-2 expression by G3139 may result in apoptosis of tumor cells, especially when coadministered with cytotoxic drugs.5,6 A spectrum of pediatric solid tumor cell lines, including neuroblastoma,7,8 Ewing sarcoma,9,10 Wilms' tumor,11,12 and synovial sarcoma,13 overexpress bcl-2. In neuroblastoma cell lines, the expression of bcl-2 is associated with inhibition of chemotherapy-induced apoptosis,8,14,15 and cell lines expressing high levels of bcl-2 demonstrate broad chemotherapy resistance. High bcl-2 expression has been associated with unfavorable histology and MYCN gene amplification, suggesting an association with poor prognosis.14-16 Finally, bcl-2 expression is increased in histologically differentiated neuroblastoma, suggesting that downregulation of bcl-2 may be correlated with terminal differentiation.17-20 In adult trials, G3139 in doses up to 7 mg/kg/d for 5 to 7 days is well tolerated, with reduction of bcl-2 expression in peripheral-blood mononuclear cells (PBMCs) occurring within 3 to 4 days of initiation of the infusion.21,22 Clinical trials have combined G3139 with a number of different chemotherapeutic agents, including dacarbazine,23 mitoxantrone,24 docetaxel,22,25 paclitaxel,26 cytarabine,27 fludarabine,27 and daunorubicin.28 In general, G3139 toxicity has not been dose limiting, and dose escalation was stopped when steady-state concentrations of G3139 exceeded target concentrations. Non–dose-limiting G3139 toxicities when administered in combination with cytotoxic chemotherapy include neutropenia, anemia, thrombocytopenia, lymphopenia, leukopenia, fatigue, mucositis, fever, nausea, arthralgias, myalgias, and transient elevations in serum creatinine, hepatic aminotransferases, and glucose.21,22,24-26 Anthracyclines and alkylating agents have significant activity in a broad range of childhood cancers. Doxorubicin and cyclophosphamide are used in both first-line and relapse chemotherapy protocols for children with solid tumors, including neuroblastoma, Wilms' tumor, Ewing sarcoma, and other soft tissue sarcomas. Both drugs are capable of initiating the apoptosis cascade through the generation of genotoxic stress and activation of cellular DNA damage response pathways. Thus, pharmacologic downregulation of bcl-2 by G3139 may potentially enhance chemotherapy responsiveness of tumor cells to these drugs. We conducted a pediatric phase I trial of G3139 in combination with doxorubicin and cyclophosphamide. The primary aims of this study were to determine the maximum-tolerated dose (MTD) or recommended phase II dose, describe the dose-limiting toxicities (DLTs), and define the pharmacokinetics (PK) of G3139 administered as a 7-day continuous intravenous infusion (CI) in children with relapsed and refractory solid tumors. Secondary aims included assessing the biologic activity of G3139 in PBMCs and preliminarily defining the antitumor activity of this combination.
Eligibility Criteria Eligibility criteria included age older than 1 year and younger than 22 years; a diagnosis of a malignant solid tumor (excluding lymphoma and CNS tumors) refractory to conventional therapy; Karnofsky (children older than 10 years) or Lansky (children  10 years) score  50; life expectancy 8 weeks; recovery from prior therapy; no chemotherapy within 2 weeks (6 weeks for prior nitrosourea therapy) and no biologic agent or growth factor therapy within 1 week of study entry; no substantial radiotherapy to the bone marrow within 6 weeks of study entry; no allogeneic stem-cell transplantation within 6 months of study entry and no active graft-versus-host disease; normal age-adjusted serum creatinine or glomerular filtration rate 70 mL/min/1.73 m2; serum bilirubin concentration 1.5x and serum ALT 3x the upper limit of the normal for age; and a cardiac shortening fraction 28% or an ejection fraction 45%.
Initially, patients were allowed to enroll onto the study with the following hematologic requirements: an absolute neutrophil count
Institutional review boards at participating institutions approved the study. Informed consent was obtained from patients age
Trial Design Patients who exceeded a lifetime dose of 750 mg/m2 of doxorubicin could continue therapy with G3139 and cyclophosphamide only. Patients who experienced a DLT that resolved could continue treatment with 25% reduction of the cytotoxic drug dosing. Protocol therapy stopped due to disease progression, patient choice, or when an irreversible DLT occurred. At least three patients were studied at each dose level. If none of these three patients experienced a DLT, the subsequent three patients were enrolled at the next higher dose level. If one of three patients at a given dose level experienced a DLT, then up to three more patients were treated at the same level. When DLT was observed in at least two patients in a cohort of three to six, the MTD was exceeded and an additional three patients were treated at the next lower dose level provided only three assessable patients had been enrolled previously at that level. The MTD was defined as the dose level at which zero of six or one of six patients experienced DLT with at least two of three or two of six patients encountering DLT at the next higher dose.
Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. Dose-limiting hematologic toxicity was defined as any grade 4 neutropenia or thrombocytopenia lasting more than 7 days. Hematologic toxicity that caused a delay of
Dosage and Drug Administration
Pharmacokinetics
Biologic Studies
A total of 37 patients were enrolled onto Children's Oncology Group trial ADVL 0211 (Table 1). All patients were eligible, but eight were not fully assessable for toxicity: two never started drug therapy, one never completed the G3139 infusion due to family preference, one was diagnosed with myelodysplastic syndrome [t(3,8) translocation] within 2 weeks of enrolling onto the study, three did not have scheduled laboratory evaluations to accurately determine duration of neutropenia, and one did not receive a proper dose of drug due to pump malfunction (PK results for this patient, who received 4.25 mg/kg/d of G3139, are included in Table 2). Patients received a median of two courses (range, two to 12 courses).
Toxicity Overall, the G3139 infusion was well tolerated and the primary toxicities of the combination were hematologic. Two strategies were used when myelosuppression was found to be the DLT at the initial dose level. First, doses of the cytotoxic drugs were reduced to doxorubicin 22.5 mg/m2/d for 2 days (dexrazoxane 225 mg/m2/d for 2 days) and cyclophosphamide 400 mg/m2/d for 2 days. When only isolated neutropenia remained as the DLT, granulocyte colony-stimulating factor (GCSF) was administered at 5 µg/kg/d starting day 8 until the postnadir absolute neutrophil count was more than 1,500/µL. These changes allowed for subsequent G3139 escalation to 5 and 7 mg/kg/d. Once 7 mg/kg/d was tolerated in a cohort of patients, the doses of cytotoxics were successfully re-escalated to their initial dose; however, additional increase in cytotoxics was not tolerated (Table 3). Therefore, the MTDs for this regimen were G3139 7 mg/kg/d as a 7-day CI, cyclophosphamide 500 mg/m2/d and doxorubicin 30 mg/m2/d on days 5 and 6, followed by GCSF.
There was one nonhematologic DLT. The patient, who also received gentamicin and had undergone a computed tomography scan with intravenous contrast within 24 hours of starting 3 mg/kg/d G3139, developed a grade 3 elevation in serum creatinine (maximum, 4.1 g/dL) on day 3 of his infusion. His serum creatinine returned to baseline within 2 weeks of drug discontinuation. Other grade 1 nonhematologic non-DLTs that occurred in more than 10% of patients are listed in Table 4. Nonhematologic toxicities did not appear to be correlated to dose level of drug.
Disease Response One patient with Ewing sarcoma had a partial response to therapy, and eight patients (synovial sarcoma, n = 2; neuroblastoma, n = 2; osteosarcoma, n = 2; renal cell carcinoma, n = 1; thymoma, n = 1) had prolonged stable disease, receiving a median of seven courses (range, four to 12 courses).
PK Studies
Biology Studies The pretreatment normalized PBMC bcl-2 expression ratio for the 15 patients ranged from 0.3 to 70.9 (mean, 8.3 ± 19.0; median, 2.1), predominantly reflecting interpatient variability in PBMC actin isoform abundance. Marked interpatient variability in bcl-2 bioresponse in PBMCs was apparent (Fig 1). Eleven (73%) of 15 patients demonstrated a reduction in PBMC bcl-2, defined by a reduction in bcl-2/actin ratio at the earliest assessed time point (day 5, n = 6; or day 6, n = 5; Fig 2). Eight (57%) of 14 patients with serial samples demonstrated a decrease in bcl-2 expression across all assessable time points. In these eight patients, the median maximal bcl-2 reduction was 71% (range, 20% to 86%). After cytotoxic chemotherapy, the relative bcl-2 levels obtained on day 8 were more variable (data not shown). In the seven patients who had both PK and biologic assays performed, there was no correlation between Css and decrease in bcl-2 expression.
In this phase I trial, we evaluated the toxicities of G3139 administered by CI for 7 days in 21-day cycles with concomitant cytotoxic chemotherapy on days 5 and 6 of a cycle. Cyclophosphamide and doxorubicin were selected based on their known activity in the treatment of a spectrum of pediatric solid tumors. The median plasma G3139 clearance of 0.14 L/kg/h in children seems to be greater than the plasma G3139 clearance of 0.09 L/kg/h reported in an adult study that used the same bioanalytical methodology.31 A range of plasma drug clearances, however, has been observed in adult patients,28,30,32-35 but methodologies have differed, making direct comparisons more difficult. The interpatient variability in drug clearance in both adult and pediatric patients is high, and thus additional studies will be needed to determine whether a true difference in drug disposition exists. Importantly, the children treated at the 7 mg/kg/d dose level achieved drug exposures that have been associated with targeted effects in animal models. We found significant interpatient variability in PBMC bcl-2 levels after exposure to G3139, both in direction and magnitude of responses. Similar to previous reports,33 bcl-2 protein expression in surrogate tissues decreased after antisense exposure in the majority of patients (11 of 15), supporting a targeted biologic effect. Six of these patients had reductions in PBMC bcl-2 to less than 50% of pretreatment levels. Day 8 bcl-2 levels tended to be higher than levels on days 5 or 6, possibly reflecting effects of cytotoxic drugs on PBMC composition and/or protein content. No correlation was found between bcl-2 protein change and G3139 dose level or Css. There was no correlation between PBMC bcl-2 reduction and disease response. Antisense oligonucleotide effects reflect a series of complex stoichiometric interactions: cellular exposure, oligonucleotide uptake, antisense-hybridization and mRNA degradation (via passive and active mechanisms), and diminished protein synthesis that fails to sustain protein abundance in the setting of normal degradation. In prior adult phase I and II G3139 trials, bcl-2 knockdown has not correlated with either drug dose or plasma Css.24,33,34,36-39 Various assays have been used to assess bioresponse, including bcl-2 mRNA or bcl-2 protein assessment, with generally similar results.24,38 Recent studies have demonstrated that intracellular G3139 concentration is more closely correlated to biologic activity (bcl-2 mRNA or protein reduction) than plasma G3139 concentration. Furthermore, although intracellular G3139 levels increased over time of exposure in all patients, there was marked interpatient variability, whereas plasma concentrations were largely invariant36,37 and did not correlate with the intracellular concentration achieved or bioresponse. Thus, the lack of correlation in our study between steady-state plasma G3139 concentrations and surrogate biologic effect may reflect inherent interpatient differences in cellular uptake of G3139. In summary, G3139 administered as a 7-day CI with cytotoxic chemotherapy to children with relapsed or refractory solid tumors was generally well tolerated, and at a dose of 7 mg/kg/d, was associated with biologic activity. G3139 may have accentuated the myelosuppressive effects of doxorubicin and cyclophosphamide in heavily pretreated pediatric patients, but cytotoxic doses of these drugs were delivered with an acceptable degree of myelosuppression. When combined with G3139, the recommended phase II doses for children with relapsed solid tumors are cyclophosphamide 500 mg/m2/d for 2 days, dexrazoxane 300 mg/m2/d for 2 days, and doxorubicin 30 mg/m2/d for 2 days, followed by GCSF. In future studies, bcl-2 target knockdown studies in leukemia cells or surrogate PBMCs should also assess intracellular G3139 concentrations associated with this effect.
Although all authors completed the disclosure declaration, the following author or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: Reddy Chandula, Genta Inc Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A
Conception and design: Susan R. Rheingold, Michael D. Hogarty, Susan M. Blaney, Mark D. Krailo, Peter C. Adamson Administrative support: Susan M. Blaney, Peter C. Adamson Provision of study materials or patients: Susan R. Rheingold, Susan M. Blaney, Peter C. Adamson Collection and assembly of data: Susan R. Rheingold, Michael D. Hogarty, Calies Sauk-Schubert, Reddy Chandula Data analysis and interpretation: Susan R. Rheingold, Michael D. Hogarty, Susan M. Blaney, James A. Zwiebel, Calies Sauk-Schubert, Reddy Chandula, Mark D. Krailo, Peter C. Adamson Manuscript writing: Susan R. Rheingold, Michael D. Hogarty, Reddy Chandula, Mark D. Krailo, Peter C. Adamson Final approval of manuscript: Susan R. Rheingold, Michael D. Hogarty, James A. Zwiebel, Peter C. Adamson
Supported by National Cancer Institute Grants No. U01 CA97452, M01 RR00188, M01 RR00084, M01 RR000037, M01 RR00585, and MO1 RR02172. A complete listing of grant support for research conducted by CCG and POG before initiation of the COG grant in 2003 is available online at: http://www.childrensoncologygroup.org/admin/grantinfo.htm. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Tolcher AW, Kuhn J, Schwartz G, et al: A phase I pharmacokinetic and biological correlative study of oblimersen sodium (genasense, g3139), an antisense oligonucleotide to the bcl-2 mRNA, and of docetaxel in patients with hormone-refractory prostate cancer. Clin Cancer Res 10:5048-5057, 2004 35. Waters JS, Webb A, Cunningham D, et al: Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin's lymphoma. J Clin Oncol 18:1812-1823, 2000 36. Dai G, Chan KK, Liu S, et al: Cellular uptake and intracellular levels of the bcl-2 antisense g3139 in cultured cells and treated patients with acute myeloid leukemia. Clin Cancer Res 11:2998-3008, 2005 37. Dai S, Wan T, Wang B, et al: More efficient induction of HLA-A*0201-restricted and carcinoembryonic antigen (CEA)-specific CTL response by immunization with exosomes prepared from heat-stressed CEA-positive tumor cells. Clin Cancer Res 11:7554-7563, 2005 38. 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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
