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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0000000000000058
Brief Reports

NCIC CTG IND.190 Phase I Trial of Dalotuzumab (MK-0646) in Combination with Cisplatin and Etoposide in Extensive-Stage Small-Cell Lung Cancer

Ellis, Peter M. MD, PhD*; Shepherd, Frances A. MD; Laurie, Scott A. MD; Goss, Glenwood D. MD; Olivo, Martin MD§; Powers, Jean MSc§; Seymour, Lesley MD§; Bradbury, Penelope A. MD§

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Author Information

*Department of Oncology, McMaster University, Juravinski Cancer Centre, Hamilton Ontario, Canada; Medical Oncology Department, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, Ontario, Canada; and §NCIC CTG Queens University, Kingston, Ontario, Canada.

Disclosure: The authors declare no conflict of interest.

Address for correspondence: Peter Ellis, MD, PhD, Juravinski Cancer Centre, 699 Concession St., Hamilton, ON L8V 5C2, Canada. E-mail: peter.ellis@jcc.hhsc.ca

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Abstract

The insulin-like growth factor receptor is a potential target in small-cell lung cancer. We conducted a phase I study of cisplatin, etoposide plus dalotuzumab. Two dose levels of dalotuzumab (DL1 5mg/kg, DL2 10mg/kg IV weekly) were evaluated in combination with cisplatin (25mg/m2) and etoposide (100mg/m2) IV D1-3, every 21 days, for patients with chemotherapy-naive extensive-stage small-cell lung cancer. Primary outcome was determination of the recommended phase 2 dose. Secondary outcomes included response rate and toxicity. Twelve patients were treated (DL1, 3 and DL2, 9). The median age was 63 years (48–70), with six males and six females. The majority of patients were Eastern Cooperative Oncology Group1 and had four or more sites of disease. No dose-limiting toxicities were observed in DL1 or DL2, although one patient died from neutropenic sepsis in an expanded cohort at DL2. The recommended phase 2 dose of dalotuzumab was 10mg/kg/week. The confirmed objective response rate was 67% (partial response 8, stable disease 2, progressive disease 1, nonevaluable 1). Grade 3 or higher toxicities (any cycle) occurring in more than one patient included: neutropenia (92%); thrombocytopenia (25%); leukopenia (50%); anemia (17%); fatigue (33%); joint pain (17%); thrombosis (25%). Grade 2 or 3 hyperglycemia was observed in one of three (DL1) and five of nine (DL2) patients. Eight serious adverse events (thrombosis, febrile neutropenia, infection, syncope, fatigue [2], dyspnea, back pain) were observed in three patients. Dalotuzumab can be combined at full dose with standard doses of cisplatin and etoposide. The observed toxicities are consistent with that expected from cisplatin and etoposide except for hyperglycemia, which seems to be dose dependent.

Small-cell lung cancer (SCLC) represents approximately 15% of all lung cancers, representing 34,000 cases and 29,000 deaths annually in the United States.1 Although recent recommendations from the International Association for the Study of Lung Cancer suggest Tumor Node Metastasis staging provides better prognostic information,2 a simplified approach to staging, based on the presence (extensive-stage [ES]) or absence (limited-stage) of disease outside of the thorax, is still commonly used. Little progress has been made though, in systemic treatment and outcomes for ES SCLC.3 A variety of strategies have been evaluated over the last 15 years including the use of non–cross-resistant chemotherapy,4 intense weekly chemotherapy,5 maintenance chemotherapy6 and high-dose chemotherapy with transplantation.7 However, none of these strategies have resulted in clear improvements in survival for patients with SCLC.

Additional research has focused on targeted approaches, since multiple molecular abnormalities have been documented in SCLC tumors.8 However, the evaluation of targeted therapies in this malignancy has, to date, been unrewarding. Trials evaluating antiangiogenic agents, matrix metalloproteinase inhibitors, inhibition of c-myc with imatinib, B cell lymphoma 2 (BCL-2) antisense therapy, and proteosome inhibition with bortezomib have all proven ineffective.8

One promising research target for SCLC is the insulin-like growth factor receptor (IGF-R) pathway. In vitro and in vivo data support a role for serum IGF,9 as well as IGF-1 and IGF-2 gene expression in SCLC.10 Dalotuzumab (MK-0646; Merck, Whitehouse Station, NJ) is a recombinant IgG1 monoclonal antibody against the IGF-1R, with potential for antibody-directed cell-mediated cytotoxicity.11 Single-agent phase I studies have shown dalotuzumab to be safe and well tolerated. The recommended phase II dose was determined to be 10mg/kg once weekly by intravenous (IV) infusion. Given the preclinical rationale, we conducted a phase I trial of dalotuzumab in combination with cisplatin and etoposide in patients with ES SCLC.

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PATIENTS AND METHODS

Eligible patients had ES SCLC, amenable to platinum-based chemotherapy, measurable disease, no prior chemotherapy, Eastern Cooperative Oncology Group performance status 0 to 2, adequate hematological and biochemical parameters. Treated brain metastases were allowed. The study (NCT00869752) was approved by the Ontario Cancer Research Ethics Board, and all patients provided written informed consent. A standard phase I design was used to define the recommended phase-two dose (RP2D) of dalotuzumab in combination with cisplatin (25mg/m2) and etoposide (100mg/m2) administered intravenously on days 1 to 3 every 21 days. Two dose levels of dalotuzumab were planned (5mg/kg and 10mg/kg intravenously administered weekly). Dose-limiting toxicities (DLT) were defined as any of the following occurring during cycle 1 of therapy: unexpected febrile neutropenia or grade 4 neutropenia lasting more than 7 days; grade 4 thrombocytopenia; grade 3 or 4 nonhematological toxicities not usually observed with cisplatin and etoposide therapy (excluding alopecia, fatigue, grade 3 nausea, vomiting, diarrhea, or hyperglycemia); inability to administer cycle 2 within 14 days of planned treatment. A minimum of three evaluable patients were planned at each dose level. If two or more DLTs were observed in the initial cohort, the dose of dalotuzumab could be de-escalated to 2.5mg/kg weekly. If one DLT was observed in the initial three patients, the cohort would be expanded to six evaluable patients. There were no plans to escalate the dose of dalotuzumab beyond the single-agent RP2D of 10mg/kg weekly. Up to six additional patients were to be treated at the RP2D. The trial protocol initially included a phase 2 component at the RP2D of dalotuzumab, but this did not proceed because of a decision by Merck Frost to halt development of dalotuzumab in this setting.

Patients were treated with cisplatin, etoposide, and dalotuzumab for a maximum of four to six cycles, with weekly dalotuzumab continued beyond this, until disease progression, unacceptable toxicity, or patient request to withdraw. Prophylactic cranial irradiation was allowed if indicated and dalotuzumab administration was interrupted during prophylactic cranial irradiation. Disease status was determined after every second cycle of therapy and response to therapy determined by the investigator according to Response Evaluation Criteria in Solid Tumors 1.1. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria version 3.0. Serum to measure human-antihumanized antibody response to MK-0646 was collected at baseline and multiple time points in the study.

The primary outcome was determination of the RP2D. Secondary outcomes included assessment of objective response rate and toxicity. As there were only two planned dose levels, it was estimated that nine to 15 patients would be accrued to the phase I trial.

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RESULTS

Twelve patients were enrolled in this phase I study (DL1-3, DL2-9). Demographic characteristics are summarized in Table 1. Two patients had small asymptomatic brain metastases at study entry. There were no DLTs observed during cycle 1 in either dose-escalation cohort. Therefore the RP2D of dalotuzumab was determined to be 10mg/kg weekly when combined with standard doses of cisplatin and etoposide. After determination of the RP2D, one DLT during cycle 1 (grade 5 neutropenic sepsis) was observed in the expanded cohort at dose level 2. A second patient enrolled in the expanded dose level 2 cohort had a grade 3 syncopal event that was considered to be secondary to dehydration from the cisplatin chemotherapy. The objective response rate for the combination of cisplatin, etoposide, and dalotuzumab was 67% (8 partial response [PR], 2 stable disease [SD], 1 progressive disease [PD], and 1 nonevaluable). Responses are summarized in a waterfall plot in Figure 1.

Table 1
Table 1
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Figure 1
Figure 1
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The addition of dalotuzumab to cisplatin and etoposide did not seem to affect the administered dose of chemotherapy. The median number of cycles of chemotherapy was four (range, 3–6) in dose level 1 and five (range, 1–6) in dose level 2, and the median number of cycles of dalotuzumab was six (range, 1–10) in both dose levels. There was no evidence of lower-dose intensity of cisplatin and etoposide with the higher-dose level of dalotuzumab (Table 2). The majority of patients (DL1, 2 and DL2, 7) experienced at least one dose delay of either chemotherapy or dalotuzumab. Neutropenia was the most common reason for chemotherapy dose delays with four delays occurring across the three patients treated at dose level 1 and seven occurrences across the nine patients treated at dose level 2.

Table 2
Table 2
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Hematological toxicities occurred frequently (Table 3). Grade 3/4 neutropenia occurred in the majority of patients (92%) and grade 3/4 thrombocytopenia was also common (25%). There was one episode of febrile neutropenia and one episode of fatal neutropenic sepsis. All reported nonhematological toxicities are summarized in Table 3 (all grades ≥10%, or any grade 3/4 toxicity). The most frequent grade 3/4 nonhematological toxicities were fatigue (33%), thrombosis (25%), and joint pain (17%). Grade 2 or 3 hyperglycemia occurred in one of three patients in dose level 1 and five of nine patients in dose level 2, suggesting this was a dose-dependent toxicity. One case of grade 3 hearing loss was attributed to cisplatin.

Table 3
Table 3
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Seven serious adverse events (SAEs) related to one or more of the drugs in the protocol therapy were observed among three patients. One patient experienced neutropenic sepsis during cycle 1 and died. A second patient experienced an asymptomatic pulmonary embolism during cycle 2 and had a second SAE of febrile neutropenia during cycle 6. A third patient experienced four separate SAEs: chest discomfort and syncope during cycle 1; fatigue and stomach pain during cycle 3; fatigue and cough during cycle 4; and fatigue, joint pain, and dyspnea while on single-agent dalotuzumab. One additional SAE of back pain was considered unrelated to protocol therapy and secondary to disease progression. All 12 patients had baseline serum collected, and all but one patient had two or more samples taken on treatment (median 4 time points). A total of 51 samples were analyzed for human-antihumanized antibody and all were negative.

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DISCUSSION

This phase I trial demonstrated that dalotuzumab can be combined safely with standard doses of cisplatin and etoposide in patients with ES SCLC. With the exception of hyperglycemia, the toxicity of dalotuzumab in combination with chemotherapy was similar to what would be expected from cisplatin and etoposide alone. The dominant adverse events were hematological toxicities and fatigue. These toxicities are frequent in this patient population, which generally suffers from multiple comorbidities and routinely experiences significant neutropenia with standard therapy. This study is in contrast to studies with other IGF-R inhibitors that have documented significant increases in hyperglycemia and associated adverse events such as anorexia and dehydration.12 Some dose-dependent hyperglycemia was observed, related to dalotuzumab therapy. However, dalotuzumab in combination with chemotherapy could be administered at its recommended phase 2 single-agent dose of 10mg/kg weekly and the addition of dalotuzumab did not seem to reduce the deliverable dose intensity of cisplatin or etoposide.

Despite the preclinical rationale for the importance of the IGF-R pathway in SCLC, the addition of dalotuzumab did not result in a clinically meaningful increase in response rate beyond what would be expected from cisplatin and etoposide alone.5 What is unclear is whether IGF-R suppression is an unsuccessful strategy in lung cancer in general, or whether this strategy should be evaluated in selected patients demonstrating high levels of serum IGF.12 Unfortunately, there are too few patients in the current study to allow any meaningful biomarker analysis.

To date, studies of targeted agents have proven unsuccessful in SCLC, despite biological rationale for their evaluation.8 Inhibition of angiogenesis pathways,13,14 or proapoptotic pathways such as BCL 2,15 have failed to improve survival. In addition to increased serum vascular endothelial growth factor, abnormalities of cell-cycle regulators, such as P53 mutations and loss of the retinoblastoma gene occur frequently. Gene ampliication, or protein overexpression of proto-oncogenes such as c-MYC and BCL-2 are also frequently observed in SCLC. Given the complexity of molecular abnormalities in SCLC, inhibition of a single molecular pathway may be an ineffective strategy. Novel approaches such as the combination of agents to inhibit more than one molecular pathway should be investigated.

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ACKNOWLDEGMENT

The study was supported by the Canadian Cancer Society Research Institute (grant #021039).

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REFERENCES

1. . American Cancer Society, Cancer Facts and Figures 2012. 2012 Atlanta American Cancer Society

2. Shepherd FA, Crowley J, Van Houtte P, et al.International Association for the Study of Lung Cancer International Staging Committee and Participating Institutions. The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol. 2007;2:1067–1077

3. Chute JP, Chen T, Feigal E, Simon R, Johnson BE. Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress. J Clin Oncol. 1999;17:1794–1801

4. Feld R, Evans WK, Coy P, et al. Canadian multicenter randomized trial comparing sequential and alternating administration of two non-cross-resistant chemotherapy combinations in patients with limited small-cell carcinoma of the lung. J Clin Oncol. 1987;5:1401–1409

5. Murray N, Livingston RB, Shepherd FA, et al. Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol. 1999;17:2300–2308

6. Niell HB, Herndon JE II, Miller AA, et al.Cancer and Leukemia Group. Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin Oncol. 2005;23:3752–3759

7. Humblet Y, Symann M, Bosly A, et al. Late intensification chemotherapy with autologous bone marrow transplantation in selected small-cell carcinoma of the lung: a randomized study. J Clin Oncol. 1987;5:1864–1873

8. Blackhall FH, Shepherd FA. Small cell lung cancer and targeted therapies. Curr Opin Oncol. 2007;19:103–108

9. Quinn KA, Treston AM, Unsworth EJ, et al. Insulin-like growth factor expression in human cancer cell lines. J Biol Chem. 1996;271:11477–11483

10. Izycki T, Chyczewska E, Naumnik W, Ossolinska M. Serum levels of IGF-I and IGFBP-3 in patients with lung cancer during chemotherapy. Oncol Res. 2006;16:49–54

11. Scartozzi M, Bianconi M, Maccaroni E, Giampieri R, Berardi R, Cascinu S. Dalotuzumab, a recombinant humanized mAb targeted against IGFR1 for the treatment of cancer. Curr Opin Mol Ther. 2010;12:361–371

12. Jassem J, Langer CJ, Karp DD, et al. Randomized, open label, phase III trial of figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin in patients with non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts. 2010;28:7500

13. Arnold AM, Seymour L, Smylie M, et al.National Cancer Institute of Canada Clinical Trials Group Study BR.20. Phase II study of vandetanib or placebo in small-cell lung cancer patients after complete or partial response to induction chemotherapy with or without radiation therapy: National Cancer Institute of Canada Clinical Trials Group Study BR.20. J Clin Oncol. 2007;25:4278–4284

14. Lee S-M, Woll PJ, James LE, et al. A phase III randomised, double blind, placebo controlled trial of etoposide/carboplatin with or without thalidomide in advanced small cell lung cancer (SCLC): PRS-04. J Thor Oncol. 2007;2:S306–S7 10.1097/01.JTO.0000283089.56099.79

15. Langer CJ, Albert I, Kovacs P, et al. A randomized phase II study of carboplatin (C) and etoposide (E) with or without pan-BCL-2 antagonist obatoclax (Ob) in extensive-stage small cell lung cancer (ES-SCLC). ASCO Meeting Abstracts. 2011;29:7001

Small-cell lung cancer; Chemotherapy; Insulin-like growth factor; Monoclonal antibody; Phase I clinical trial

Copyright © 2014 by the European Lung Cancer Conference and the International Association for the Study of Lung Cancer.

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