Advertisement
Journal of Clinical Oncology  
Search for:
Limit by:
  Browse by Subject or Issue
Home Search or Browse JCO My JCO Subscriptions Customer Service Site Map

Originally published as JCO Early Release 10.1200/JCO.2007.15.9319 on May 12 2008

Journal of Clinical Oncology, Vol 26, No 19 (July 1), 2008: pp. 3196-3203
© 2008 American Society of Clinical Oncology.
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lacy, M. Q.
Right arrow Articles by Gualberto, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lacy, M. Q.
Right arrow Articles by Gualberto, A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Phase I, Pharmacokinetic and Pharmacodynamic Study of the Anti–Insulinlike Growth Factor Type 1 Receptor Monoclonal Antibody CP-751,871 in Patients With Multiple Myeloma

Martha Q. Lacy, Melissa Alsina, Rafael Fonseca, M. Luisa Paccagnella, Carrie L. Melvin, Donghua Yin, Amarnath Sharma, M. Enriquez Sarano, Michael Pollak, Sundar Jagannath, Paul Richardson, Antonio Gualberto

From the Mayo Clinic, Divisions of Hematology and Cardiovascular Diseases, Rochester, MN; H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL; Mayo Clinic, Division of Hematology, Scottsdale, AZ; Pfizer Global Research & Development, New London, CT; St Vincent's Comprehensive Cancer Center, New York, NY; Dana Farber Cancer Institute Boston, MA; and the McGill University and Lady Davis Research Institute, Montreal, Quebec, Canada

Corresponding author: Antonio Gualberto, MD, PhD, Pfizer Global Research & Development, 50 Pequot Ave, MS6025-A3266, New London, CT 06320; e-mail: antonio.gualberto{at}pfizer.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Purpose A phase I first-in-human study was conducted to characterize the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of the anti–insulinlike growth factor 1 receptor (IGF-IR) monoclonal antibody CP-751,871.

Patients and Methods After informed consent and screening, 47 patients with multiple myeloma in relapse or refractory phase were enrolled into 11 dose-escalation cohorts of CP-751,871 at doses from 0.025 to 20 mg/kg for 4 weeks. Patients with less than a partial response to CP-751,871 treatment were eligible to receive CP-751,871 in combination with oral dexamethasone at the discretion of the investigator. Treatment with CP-751,871 and rapamycin with or without dexamethasone was also offered to patients enrolled in the 10 and 20 mg/kg cohorts with less than a partial response to initial therapy with single-agent CP-751,871.

Results No CP-751,871-related dose-limiting toxicities were identified. Plasma CP-751,871 concentrations increased with dose and concentration-time profiles were consistent with those of antibodies with target-mediated disposition. Importantly, CP-751,871 administration led to a decrease in granulocyte IGF-IR expression and serum insulinlike growth factor 1 accumulation at high doses, suggesting systemic IGF-IR inhibition. Tumor response was assessed according to the European Group for Blood and Marrow Transplantation criteria. Nine responses were reported in 27 patients treated with CP-751,871 in combination with dexamethasone. Of interest, two of the patients with a partial response were progressing from dexamethasone treatment at study entry.

Conclusion These data indicate that CP-751,871 is well tolerated and may constitute a novel agent in the treatment of multiple myeloma.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Signaling through the anti–insulinlike growth factor 1 receptor (IGF-IR) has been extensively studied in multiple myeloma. Elevated insulinlike growth factor 1 (IGF-1) levels and IGF-IR expression are associated with worse disease prognosis.1-4 IGF-IR is highly expressed in multiple myeloma cells,5,6 where it regulates growth,7-13 survival,14-16 adhesion, and invasiveness.17-21 Likewise, IGF-IR inhibition has been long proposed as a cancer treatment strategy22 and IGF-IR inhibitors have been shown to block the growth myeloma tumor models.6,23-25 We have previously described the characterization of CP-751,871, a fully human IgG2 monoclonal antibody with high affinity for the IGF-IR.26 CP-751,871 blocks ligand binding (IGF-1, IGF-2) and induces IGF-IR downregulation by promoting its internalization and degradation.26

We conducted a first-in-human phase I, open-label, dose escalation study of CP-751,871 with a primary objective to test the safety and tolerability of CP-751,871 in patients with relapsed or refractory multiple myeloma.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Patient Selection
Patients with multiple myeloma who had relapsed or were refractory to at least one standard therapy, including autologous stem-cell transplant or tandem transplant, were candidates for this study. Inclusion criteria were as follows: age ≥ 18 years; life expectancy ≥ 3 months; Eastern Cooperative Oncology Group performance status ≤ 2; quantifiable serum (M spike ≥ 1 g/dL) and/or serum free light chain (≥ 20 mg/L) and/or urine (≥ 200 mg/24-hour) M protein; adequate bone marrow function within 2 weeks before treatment defined as an absolute neutrophil count ≥ 1,000/mm3 and platelets ≥ 75,000/mm3 (patients who were transfusion- or growth factor-dependent were allowed, provided these values could be achieved with transfusion); adequate organ function within 2 weeks before treatment, defined as: serum creatinine ≤ 2 mg/dL, total bilirubin ≤ 1.5 x the upper limit of normal, AST and ALT ≤ 2.5 x the upper limit of normal, a 12-lead ECG with normal tracing, or nonclinically significant changes that do not require medical intervention, and a transthoracic echocardiography with Doppler with mitral valve thickness ≤ 4 mm, mitral valve gradient ≤ 4 mmHg, and mitral valve regurgitation ≤ mild; and signed written informed consent. Exclusion criteria included any of the following: prior allogeneic stem-cell transplant; or myelosuppressive, immune, radiation, surgical, or investigational therapy within 3 weeks before treatment with CP-751,871; history of second cancer; concurrent significant medical disease; active bleeding; cardiac disease, including valvular dysfunction; symptomatic amyloidosis, cirrhosis, active pancreatitis, active uncontrolled infection; and history of HIV, hepatitis B or C. All patients were required to practice effective birth control. This study was approved by local institutional review boards.

Study Design
Primary end points included safety and tolerability. Secondary end points included pharmacokinetic (PK) parameters of CP-751,871, IGF-IR expression on granulocytes using fluorescence activated cell sorting, serum IGF-1 levels, and antitumor activity as defined by the European Group for Blood and Marrow Transplantation (EBMT) criteria.27 Toxicities were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Dose-limiting toxicities (DLTs) included any of the following cycle 1 events: grade ≥ 3 treatment-related hematologic adverse events (AEs) that lasted longer than 7 days and/or required therapy; grade ≥ 3 treatment-related nonhematologic, noncardiac AEs despite optimal supportive care; grade ≥ 2 clinical symptoms of hypersensitivity; grade ≥ 2 treatment-related cardiovascular toxicity including arrhythmia, ischemia/infarction, decrease in left ventricular function, cardiac troponin I and T elevation, hypertension or hypotension despite optimal supportive care, myocarditis, pericardial effusion or pericarditis; and any structural and/or functional threshold nonsymptomatic changes in transthoracic Doppler echocardiography parameters, including mitral valve thickness greater than 5 mm, mitral valve gradient larger than 5 mmHg, and/or mitral valve regurgitation more than mild.

Treatment
CP-751,871 was administered intravenously on day 1 of 4-week treatment cycles at doses of 0.025 to 20 mg/kg in dose-doubling dose escalation cohorts of three to six patients.28 For cohorts one to nine, the dose of CP-751,871 administered on cycle 2 and beyond was reduced by 50% from the dose administered in cycle 1. Cohorts 10 and 11 tested multiple dosing of 10 and 20 mg/kg of CP-751,871, respectively. For each dose escalation, at least three patients had to complete cycle 1 without a DLT. The 10- and 20-mg/kg cohorts were extended to obtain further safety information. At the investigator's discretion, patients could receive salvage therapy with CP-751,871 in combination with dexamethasone in two circumstances: patients at cycle 2 and beyond who would be otherwise discontinued from the study due to disease progression; and patients at cycle 4 or beyond who had experienced less than a partial response to CP-751,871 alone.29 The dose of dexamethasone administered in combination with CP-751,871 was 40 mg every day orally on days 1 to 4, 9 to 12, and 17 to 20 of the 4-week CP-751,871 cycle for up to three cycles, and 40 mg twice daily orally on days 1 to 4 in all subsequent cycles. Rapamycin alone or with dexamethasone in combination with CP-751,871 was offered to patients enrolled in the 10th and 11th cohorts (10-20 mg/kg CP-751,871) who experienced less than a partial response to single agent CP-751,871 as described earlier. The recommended rapamycin regimen was 2 mg/d orally continuous. Patients could receive CP-751,871 (alone or in combination) therapy until disease progression or intolerable toxicity was observed.

Safety Parameters
Before enrollment, at each treatment visit, and at treatment discontinuation, patients underwent clinical safety laboratory testing (blood chemistry, hematology, urinalysis) and were queried for AEs and concomitant medication use. Transthoracic Doppler echocardiograms were recorded at baseline and within 72 hours before dosing at each treatment cycle. Mitral valve thickness, pressure gradient, and regurgitation were determined. All Doppler echocardiograms were centrally read at the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic (Rochester, MN). Plasma samples for detection of anti-drug antibodies were also collected before infusion at each cycle and at the end of the study.

PK
All patients had PK blood samples taken at 30 minutes before infusion and at 1 hour and 1, 2, 3, 7, 14, and 21 days after the end of infusion during cycle 1. For subsequent cycles, PK samples were collected at 30 minutes before infusion and 1 hour after the end of infusion. Plasma concentrations of CP-751,871 were analyzed as described previously.30

Pharmacodynamics
Blood samples for the measurement of IGF-1, IGFBP-3, and the acid labile subunit were collected 30 minutes before CP-751,871 infusion and 48 and 72 hours postinfusion on cycle 1, and 30 minutes before infusion on subsequent cycles. Blood samples for the measurement of IGF-IR on circulating granulocytes were collected 30 minutes before infusion and on days 2, 3, 4, 8, 15, and 22 on cycle 1. On subsequent cycles, additional samples were collected 30 minutes before infusion. IGF-IR assays were conducted as previously described.37 Responses were assessed using the EBMT criteria.27


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Patient Characteristics
A total of 47 patients were enrolled. Patients received a total of 252 treatment cycles of CP-751,871 with a median of four cycles per patient (range, one to 17). Treatment is ongoing at the 10 and 20 mg/kg cohorts. Table 1 provides a dosing summary for these patients. Demographic characteristics, performance status, disease stage at diagnosis, and prior therapies are detailed in Table 2.


View this table:
[in this window]
[in a new window]

  		Table 1. Dosing Summary

 

View this table:
[in this window]
[in a new window]

  		Table 2. Demographic Characteristics

 
Safety Profile
No CP-751,871-related events of severity higher than grade 3 by National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 were reported. All cases of grade 3 toxicity, and grade 1 and 2 toxicities with a frequency higher than 4% attributed by investigators to CP-751,871 or to the combination of CP-751,871 and dexamethasone are listed in Table 3. No AEs were attributed to the combination of CP-751,871 and rapamycin. A grade 3 event of hyperglycemia was reported at cycle 1 in a patient treated with 20 mg/kg of CP-751,871. This patient discontinued treatment and received one dose of fast acting insulin and oral hypoglycemic agents. Normoglycemia was observed 60 days after CP-751,871 discontinuation. No cycle 1 DLTs were then identified. Grade 3 events of accidental fall and muscle weakness were reported at cycle 3 in a patient who received 20 mg/kg of CP-751,871 in combination with rapamycin and dexamethasone. Study treatment was discontinued in this patient. Anemia was the most common grade 2 AE (five instances), while asthenia was the most common grade 1 toxicity (four instances).


View this table:
[in this window]
[in a new window]

  		Table 3. Adverse Events Attributed to CP-751,871

 
Due to the potential cardiovascular effects of an anti–IGF-IR inhibitor, all patients were monitored using Doppler echocardiogram at the completion of each treatment cycle. Echocardiograms (n = 223) were centrally reviewed at the Mayo Clinic Foundation (Rochester, MN). No medically significant findings were reported. No statistically significant dose-related changes in the echocardiogram parameters investigated were identified. No quantifiable anti-drug antibodies was detected.

Figure 1A depicts the mean plasma concentration-time profiles of CP-751,871 in cycle 1. Plasma CP-751,871 concentrations were mostly below the lower limit of quantification for the two lowest dose levels (0.025 and 0.05 mg/kg). At 0.1 and 0.2 mg/kg, the plasma concentrations declined very rapidly after the end of infusion and were not quantifiable within 7 days. At 1.5 mg/kg and higher dose levels, the decline in plasma concentrations was slower. Plasma CP-751,871 concentration at the end of infusion (C1 hour) and AUC0-day29 increased with dose (Table 4). The increase in AUC0-day29 was approximately dose proportional at dose levels higher than 1.5 mg/kg. Furthermore, dose increases led to decreases in mean plasma clearance and increases in the apparent disposition half-life (t1/2) of CP-751,871, likely reflecting an involvement of the IGF-IR in CP-751,871 disposition with saturation of accessible IGF-IR at high CP-751,871 doses. At 20 mg/kg, the plasma clearance and t1/2 were not determined since PK sampling within the 28-day cycle did not allow for full characterization of the terminal disposition phase.


Figure 1
View larger version (23K):
[in this window]
[in a new window]
[PowerPoint Slide for Teaching]
  		Fig 1. (A) Mean (± standard deviation) plasma concentration-time profiles of CP-751,871 in multiple myeloma patients after cycle 1 CP-751,871 treatment. (B) Anti–insulinlike growth factor 1 receptor (IGF-IR) expression on granulocytes after CP-751,871 infusion. Data are represented as percentage of baseline fluorescence intensity. (C) Serum insulinlike growth factor 1 (IGF-1) levels in patients receiving CP-751,871 alone. Data are represented as percentage of baseline levels.

 

View this table:
[in this window]
[in a new window]

  		Table 4. Pharmacokinetic Parameters of CP-751,871 in Patients With Multiple Myeloma During Cycle 1 Treatment

 
Pharmacodynamic Analysis
Figure 1B shows the relative expression of IGF-IR on granulocytes after infusions of CP-751,871 at doses from 0.025 to 20 mg/kg. At doses equal or greater than 0.8 mg/kg, a complete downregulation of granulocyte IGF-IR expression was achieved for the entire dosing period. Similarly, serum IGF-1 concentrations appeared to increase with CP-751,871 dose (Fig 1C), although, in this case, sustained serum IGF-1 elevation was only apparent at doses equal or greater than 6 mg/kg. Similar dose-dependent increases were also observed in circulating acid labile subunit and IGFBP3 (not shown).

Efficacy
No objective responses according to EMBT criteria were seen when CP-751,871 was given as a single agent. However, 28 patients experienced disease stabilization with this agent, despite progression at study entry. Median number of treatment cycles with CP-751,871 alone was three. Median duration of stable disease was 2 months (range, 1 to 11). Six patients were stable for at least 6 months with single-agent CP-751,871.

Dexamethasone was added to the treatment regimen of 27 study patients, including two patients who received CP-751,871 with dexamethasone and rapamycin. Nineteen patients experienced disease progression on treatment with CP-751,871 alone. Two patients received only rapamycin and CP-751,871. Eighteen patients opted to discontinue study participation on progression on CP-751,871 alone, were not eligible or not willing to receive dexamethasone or rapamycin. Six partial responses and three minimal responses were observed in patients receiving CP-751,871 in combination with dexamethasone. The characteristics of the responses are summarized in Table 5. Interestingly, two patients with a partial response appeared to be refractory to dexamethasone treatment at study entry. Most of the responses took place at the first cycle of combination regimen and were observed in patients with one to two previous treatments. Median duration of response was 8 months (range, 2 to 14). In addition, 13 patients receiving CP-751,871 and dexamethasone had stable disease (range 2 to 6 months). No objective responses were observed in patients receiving rapamycin.


View this table:
[in this window]
[in a new window]

  		Table 5. Objective Responses

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
First-in-human studies for monoclonals antibodies in oncology have been historically conducted as "single-agent single-dose" trials.31,32 Single-dose phase I studies are followed by "single-agent multiple-dose" and subsequently by multiple-dose phase Ib trials of combination with other agents. This approach weighs patient safety but extends phase I testing and is unlikely to provide benefit to patients in its initial steps. In other to expedite the development of CP-751,871 and to provide an opportunity for clinical benefit while ensuring patient safety, the following elements were incorporated in the study design: target patient population was relapsed or refractory to standard therapy; patients had to meet inclusion criteria at each treatment cycle; the dose of CP-751,871 administered on cycle 2 and beyond was reduced to 50% from the cycle 1 dose; patient must have responded to therapy on study or remain stable for readministration; patients who experienced disease progression with single-agent CP-751,871 had to add dexamethasone (dexamethasone and/or rapamycin for cohorts 10 and 11) to their CP-751,871 regimen (salvage therapy) to continue on study. Dose reduction at cycle 2 and beyond was conducted to minimize the potential for drug accumulation (ie, CP-751,871 plasma concentrations would not exceed those already tested at cycle 1, assuming a half-life close to that of a natural immunoglobulin). The addition of salvage therapy with dexamethasone provided an opportunity to extend CP-751,871 testing, including multiple dose PK, and to explore the safety of CP-751,871 with an agent commonly employed in multiple myeloma regimens that has shown synergy with anti–IGF-IR therapy in preclinical models.6 Addition of rapamycin was considered at cohorts 10 and 11 based on a potential synergy of mammalian target of rapamycin inhibitors with dexamethasone33,34 and IGF-IR inhibitors.35-36

CP-751,871 was safe and well tolerated as a single agent and in combination with dexamethasone. Addition of rapamycin also appeared safe, but further testing is necessary due to the limited number of subjects that received that agent. A grade 3 event of hyperglycemia was reported. Hyperglycemia has also been observed in other CP-751,871 studies.30 Its mechanism is currently unknown; however, multiple evidence support a role the IGF-IR pathway in glucose metabolism.38-41 One case of grade 3 and two cases of grade 2 anemia were observed. A role for IGF-1 in erythropoiesis have been long proposed, and the IGF-IR is found on both erythrocyte precursors as well as mature erythrocytes.42,43 However, anemia is also commonly found in patients with refractory multiple myeloma and was reported as a prestudy condition in 15 of our study patients. Mild diarrhea and other transient nonspecific gastrointestinal symptoms were reported. This is not surprising as the IGF-IR is expressed in the gastrointestinal track.44 Gastrointestinal symptoms are frequently observed with somatostatin analogs that suppress IGF-1 production.45 In summary, systemic inhibition of the IGF-IR in patients with myeloma did not translate to significant toxicity. CP-751,871 did not appear to affect the toxicity profile of dexamethasone or rapamycin; however, this is difficult to determine due to the absence of a control arm and the small number of patients in this study.

PK and pharmacodynamic of CP-751,871 were also characterized. Escalating doses of CP-751,871 resulted into increasing plasma exposures (C1 hour and AUClast) and PK profiles were consistent with target-mediated disposition.46 Based on results from this and three other CP-751,871 phase I studies, the t1/2 of CP-751,871 at the 20 mg/kg dose is estimated to approach that of endogenous IgG2 (approximately 20 days). At doses of 0.8 mg/kg or higher, CP-751,871 induced a sustained lack of expression of granulocyte IGF-IR receptor. IGF-IR downregulation by internalization and degradation appears to be a common effect of antibodies against this receptor.26,47,48 Of note, a residual expression of approximately 25% to 30% of the baseline levels was observed despite excess CP-751,871. This is likely to be an artifact due to nonspecific binding of the 1H7 anti–IGF-IR analytic antibody to human leukocytes. Doses equal or greater than 1.5 mg/kg caused transient increases in serum IGF-1; however, sustained IGF-1 accumulation was only apparent at doses equal or greater than 6 mg/kg. IGF-1 accumulation has been previously reported in children born with inactivating mutations of the IGF-IR,49 suggesting that high doses of CP-751,871 result into systemic IGF-IR inhibition. Importantly, doses of 6 mg/kg for 4 weeks resulted in end of cycle plasma concentrations of CP-751,871 similar to those needed for complete downregulation of the IGF-IR in tumor xenografts, approximately 35 µg/mL.26

Six patients that received only CP-751,871 had a best response of stable disease ≥ 6 months. This activity was encouraging, given that all patients were progressing at enrollment. Furthermore, nine of 27 patients experienced objective responses according to EMBT criteria when CP-751,871 was combined with dexamethasone. This included two patients who received also rapamycin but did not experience a response. This response rate (33%) is similar to that observed with dexamethasone alone in the refractory myeloma setting (18%).50 Of interest, two patients with a partial response were progressing from dexamethasone regimens at study entry, suggesting that IGF-IR may act as a mechanism of resistance to dexamethasone-induced tumor cell death.6,14,51 However, formal phase II testing will be required to support that hypothesis.

In conclusion, CP-751,871 was safe and well tolerated in patients with multiple myeloma. On the basis of its safety, PK and pharmacodynamic profiles the dose regimens of 6-20 mg/kg for 4 weeks have been selected for further investigation in phase II studies.


   AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
AUTHOR CONTRIBUTIONS
 REFERENCES
 
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: M. Luisa Paccagnella, Pfizer Inc (C); Carrie L. Melvin, Pfizer Inc (C); Donghua Yin, Pfizer Inc (C); Amarnath Sharma, Pfizer Inc (C); Antonio Gualberto, Pfizer Inc (C) Consultant or Advisory Role: None Stock Ownership: M. Luisa Paccagnella, Pfizer Inc; Carrie L. Melvin, Pfizer Inc; Donghua Yin, Pfizer Inc; Amarnath Sharma, Pfizer Inc; Antonio Gualberto, Pfizer Inc Honoraria: None Research Funding: Martha Q. Lacy, Pfizer Inc; Melissa Alsina, Pfizer Inc; Rafael Fonseca, Pfizer Inc; M. Enriquez Sarano, Pfizer Inc; Michael Pollak, Pfizer Inc; Sundar Jagannath, Pfizer Inc; Paul Richardson, Pfizer Inc Expert Testimony: None Other Remuneration: None


   AUTHOR CONTRIBUTIONS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
REFERENCES
 
Conception and design: Martha Q. Lacy, Melissa Alsina, Rafael Fonseca, M. Luisa Paccagnella, Carrie L. Melvin, Donghua Yin, Amarnath Sharma, M. Enriquez Sarano, Michael Pollak, Antonio Gualberto

Financial support: Antonio Gualberto

Provision of study materials or patients: Martha Q. Lacy, Melissa Alsina, Rafael Fonseca, M. Enriquez Sarano, Sundar Jagannath, Paul Richardson

Collection and assembly of data: M. Luisa Paccagnella, Carrie L. Melvin, Donghua Yin

Data analysis and interpretation: M. Luisa Paccagnella, Donghua Yin, Amarnath Sharma, M. Enriquez Sarano, Michael Pollak, Antonio Gualberto

Manuscript writing: M. Luisa Paccagnella, Donghua Yin, Amarnath Sharma, Antonio Gualberto

Final approval of manuscript: Martha Q. Lacy, Melissa Alsina, Rafael Fonseca, M. Luisa Paccagnella, Carrie L. Melvin, Donghua Yin, Amarnath Sharma, M. Enriquez Sarano, Michael Pollak, Sundar Jagannath, Paul Richardson, Antonio Gualberto


   ACKNOWLEDGMENTS
 
We thank the patients for their participation in this trial, as well as Sharon Pontney, Ann M. Birgin, Jeff Petersen, Kristin Awerkamp, Stephanie Blocksom, Brendan Connell, Katherine Loftus, Deborah Doss, Lynette Lacey, Julie A. Lanier, Larry Giove, and Janelle E. Laskowski for their important contributions to the conduct of the study.


   NOTES
 
published online ahead of print at www.jco.org on May 12, 2008.

Supported in part by Pfizer Inc (M.Q.L., M.A., R.F., M.M.P., S.J., P.R.).

Presented at the 49th Annual Meeting of the American Society of Hematology.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on www.JCO.org.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
1. Bataille R, Robillard N, Avet-Loiseau H, et al: CD221 (IGF-IR) is aberrantly expressed in multiple myeloma, in relation to disease severity. Haematologica 90:706-707, 2005[Abstract/Free Full Text]

2. Chng WJ, Gualberto A, Fonseca R: IGF-IR is overexpressed in poor-prognostic subtypes of multiple myeloma. Leukemia 20:174-176, 2006[CrossRef][Medline]

3. Standal T, Borset M, Lenhoff S, et al: Serum insulin-like growth factor is not elevated in patients with multiple myeloma but is still a prognostic factor. Blood 100:3925-3929, 2002[Abstract/Free Full Text]

4. Tucci A, Bonadonna S, Cattaneo C, et al: Transformation of a MGUS to overt multiple myeloma: The possible role of a pituitary macroadenoma secreting high levels of insulin-like growth factor 1 (IGF-1). Leuk Lymphoma 44:543-545, 2003[CrossRef][Medline]

5. Freund GG, Kulas DT, Way BA, et al: Functional insulin and insulin-like growth factor-1 receptors are preferentially expressed in multiple myeloma cell lines as compared to B-lymphoblastoid cell lines. Cancer Res 54:3179-3185, 1994[Abstract/Free Full Text]

6. Mitsiades CS, Mitsiades NS, McMullan CJ, et al: Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell 5:221-230, 2004[CrossRef][Medline]

7. Georgii-Hemming P, Wiklund HJ, Ljunggren O, et al: Insulin-like growth factor I is a growth and survival factor in human multiple myeloma cell lines. Blood 88:2250-2258, 1996[Abstract/Free Full Text]

8. Li W, Hyun T, Heller M, et al: Activation of insulin-like growth factor I receptor signaling pathway is critical for mouse plasma cell tumor growth. Cancer Res 60:3909-3915, 2000[Abstract/Free Full Text]

9. Freund GG, Kulas DT, Mooney RA: Insulin and IGF-1 increase mitogenesis and glucose metabolism in the multiple myeloma cell line, RPMI 8226. J Immunol 151:1811-1820, 1993[Abstract]

10. Jelinek DF, Witzig TE, Arendt BK: A role for insulin-like growth factor in the regulation of IL-6-responsive human myeloma cell line growth. J Immunol 159:487-496, 1997[Abstract]

11. Georgii-Hemming P, Stromberg T, Janson ET, et al: The somatostatin analog octreotide inhibits growth of interleukin-6 (IL-6)-dependent and IL-6-independent human multiple myeloma cell lines. Blood 93:1724-1731, 1999[Abstract/Free Full Text]

12. Descamps G, Pellat-Deceunynck C, Szpak Y, et al: The magnitude of Akt/phosphatidylinositol 3'-kinase proliferating signaling is related to CD45 expression in human myeloma cells. J Immunol 173:4953-4959, 2004[Abstract/Free Full Text]

13. Frostad S, Bjerknes R, Hervig T, et al: Malignancy: Insulin-like growth factor-1 (IGF-1) is a costimulator of the expansion of lineage committed cells derived from peripheral blood mobilized CD34+ cells in multiple myeloma patients. Hematology 4:217-229, 1999[Medline]

14. Xu F, Gardner A, Tu Y, et al: Multiple myeloma cells are protected against dexamethasone-induced apoptosis by insulin-like growth factors. Br J Haematol 97:429-440, 1997[CrossRef][Medline]

15. Ferlin M, Noraz N, Hertogh C, et al: Insulin-like growth factor induces the survival and proliferation of myeloma cells through an interleukin-6-independent transduction pathway. Br J Haematol 111:626-634, 2000[CrossRef][Medline]

16. Ge NL, Rudikoff S: Insulin-like growth factor I is a dual effector of multiple myeloma cell growth. Blood 96:2856-2861, 2000[Abstract/Free Full Text]

17. Asosingh K, Gunthert U, Bakkus MH, et al: In vivo induction of insulin-like growth factor-I receptor and CD44v6 confers homing and adhesion to murine multiple myeloma cells. Cancer Res 60:3096-3104, 2000[Abstract/Free Full Text]

18. Vanderkerken K, Asosingh K, Braet F, et al: Insulin-like growth factor-1 acts as a chemoattractant factor for 5T2 multiple myeloma cells. Blood 93:235-241, 1999[Abstract/Free Full Text]

19. Suzuki A, Iida S, Kato-Uranishi M, et al: ARK5 is transcriptionally regulated by the Large-MAF family and mediates IGF-1-induced cell invasion in multiple myeloma: ARK5 as a new molecular determinant of malignant multiple myeloma. Oncogene 24:6936-6944, 2005[CrossRef][Medline]

20. Nishiura T, Karasuno T, Yoshida H, et al: Functional role of cation-independent mannose 6-phosphate/insulin-like growth factor II receptor in cell adhesion and proliferation of a human myeloma cell line OPM-2. Blood 88:3546-3554, 1996[Abstract/Free Full Text]

21. Asosingh K, De Raeve H, Croucher P, et al: In vivo homing and differentiation characteristics of mature (CD45-) and immature (CD45+) 5T multiple myeloma cells. Exp Hematol 29:77-84, 2001[CrossRef][Medline]

22. Arteaga CL, Kitten LJ, Coronado EB, et al: Blockade of the type I somatomedin receptor inhibits growth of human breast cancer cells in athymic mice. J Clin Invest 84:1418-1423, 1989[Medline]

23. Araki K, Sangai T, Miyamoto S, et al: Inhibition of bone-derived insulin-like growth factors by a ligand-specific antibody suppresses the growth of human multiple myeloma in the human adult bone explanted in NOD/SCID mouse. Int J Cancer 118:2602-2608, 2006[CrossRef][Medline]

24. Wu KD, Zhou L, Burtrum D, et al: Antibody targeting of the insulin-like growth factor I receptor enhances the anti-tumor response of multiple myeloma to chemotherapy through inhibition of tumor proliferation and angiogenesis. Cancer Immunol Immunother 56:343-357, 2007[CrossRef][Medline]

25. Menu E, Jernberg-Wiklund H, Stromberg T, et al: Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: An in vitro and in vivo study in the 5T33MM mouse model. Blood 107:655-660, 2006[Abstract/Free Full Text]

26. Cohen BD, Baker DA, Soderstrom C, et al: Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody CP-751,871. Clin Cancer Res 11:2063-2073, 2005[Abstract/Free Full Text]

27. Bladé J, Samson D, Reece D, et al: Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation: Myeloma Subcommittee of the EBMT: European Group for Blood and Marrow Transplant. Br J Haematol 102:1115-1123, 1998[CrossRef][Medline]

28. Simon R, Freidlin B, Rubinstein L, et al: Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst 89:1138-1147, 1997[Abstract/Free Full Text]

29. Jagannath S, Richardson PG, Barlogie B, et al: Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica 91:929-934, 2006[Abstract/Free Full Text]

30. Haluska P, Shaw HM, Batzel GN, et al: Phase I dose escalation study of the anti insulin-like growth factor-I receptor monoclonal antibody CP-751,871 in patients with refractory solid tumors. Clin Cancer Res 13:5834-5840, 2007[Abstract/Free Full Text]

31. Maloney DG, Liles TM, Czerwinski DK, et al: Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 84:2457-2466, 1994[Abstract/Free Full Text]

32. Baselga J, Pfister D, Cooper MR, et al: Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol 18:904-914, 2000[Abstract/Free Full Text]

33. Yan H, Frost P, Shi Y, et al: Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Cancer Res 66:2305-2313, 2006[Abstract/Free Full Text]

34. Stromberg T, Dimberg A, Hammarberg A, et al: Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone. Blood 103:3138-3147, 2004[Abstract/Free Full Text]

35. Shi Y, Yan H, Frost P, et al: Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Mol Cancer Ther 4:1533-1540, 2005[Abstract/Free Full Text]

36. O'Reilly KE, Rojo F, She QB, et al: MTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66:1500-1508, 2006[Abstract/Free Full Text]

37. Gualberto A, Alsina M, Lacy MQ, et al: Inhibition of the insulin like growth factor 1 receptor by a specific monoclonal antibody in multiple myeloma. J Clin Oncol 23:203s, 2005 (abstr 3048)

38. Guler HP, Zapf J, Froesch ER: Short-term metabolic effects of recombinant human insulin-like growth factor I in healthy adults. N Engl J Med 317:137-140, 1987[Abstract]

39. Moses AC, Young SC, Morrow LA, et al: Recombinant human insulin-like growth factor I increases insulin sensitivity and improves glycemic control in type II diabetes. Diabetes 45:91-100, 1996[Abstract]

40. Clemmons DR: Involvement of insulin-like growth factor-I in the control of glucose homeostasis. Curr Opin Pharmacol 6:620-625, 2006[CrossRef][Medline]

41. Pennisi P, Gavrilova O, Setser-Portas J, et al: Recombinant human insulin-like growth factor-I treatment inhibits gluconeogenesis in a transgenic mouse model of type 2 diabetes mellitus. Endocrinology 147:2619-2630, 2006[Abstract/Free Full Text]

42. Kurtz A, Jelkmann W, Bauer C: A new candidate for the regulation of erythropoiesis: Insulin-like growth factor I. FEBS Lett 149:105-108, 1982[CrossRef][Medline]

43. Aron DC: Insulin-like growth factor I and erythropoiesis. Biofactors 3:211-216, 1992[Medline]

44. El Yafi F, Winkler R, Delvenne P, et al: Altered expression of type I insulin-like growth factor receptor in Crohn's disease. Clin Exp Immunol 139:526-533, 2005[CrossRef][Medline]

45. Clemmons DR, Chihara K, Freda PU, et al: Optimizing control of acromegaly: Integrating a growth hormone receptor antagonist into the treatment algorithm. J Clin Endocrinol Metab 88:4759-4767, 2003[Abstract/Free Full Text]

46. Mager DE: Target-mediated drug disposition and dynamics. Biochem Pharmacol 72:1-10, 2006[CrossRef][Medline]

47. Burtrum D, Zhu Z, Lu D, et al: A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. Cancer Res 63:8912-8921, 2003[Abstract/Free Full Text]

48. Maloney EK, McLaughlin JL, Dagdigian NE, et al: An anti-insulin-like growth factor I receptor antibody that is a potent inhibitor of cancer cell proliferation. Cancer Res 63:5073-5083, 2003[Abstract/Free Full Text]

49. Abuzzahab MJ, Schneider A, Goddard A, et al: Intrauterine Growth Retardation (IUGR) Study Group: IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 349:2211-2222, 2003[Abstract/Free Full Text]

50. Richardson PG, Sonneveld P, Schuster MW, et al: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487-2498, 2005[Abstract/Free Full Text]

51. Ogawa M, Nishiura T, Oritani K, et al: Cytokines prevent dexamethasone-induced apoptosis via the activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways in a new multiple myeloma cell line. Cancer Res 60:4262-4269, 2000[Abstract/Free Full Text]

Submitted December 20, 2007; accepted March 14, 2008.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 Mayo Clin Proc.Home page
S. G. Holtan, D. J. Creedon, P. Haluska, and S. N. Markovic
Cancer and Pregnancy: Parallels in Growth, Invasion, and Immune Modulation and Implications for Cancer Therapeutic Agents
Mayo Clin. Proc., November 1, 2009; 84(11): 985 - 1000.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
P. Sabbatini, S. Korenchuk, J. L. Rowand, A. Groy, Q. Liu, D. Leperi, C. Atkins, M. Dumble, J. Yang, K. Anderson, et al.
GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers
Mol. Cancer Ther., October 1, 2009; 8(10): 2811 - 2820.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
D. D. Karp, L. G. Paz-Ares, S. Novello, P. Haluska, L. Garland, F. Cardenal, L. J. Blakely, P. D. Eisenberg, C. J. Langer, G. Blumenschein Jr, et al.
Phase II Study of the Anti-Insulin-Like Growth Factor Type 1 Receptor Antibody CP-751,871 in Combination With Paclitaxel and Carboplatin in Previously Untreated, Locally Advanced, or Metastatic Non-Small-Cell Lung Cancer
J. Clin. Oncol., May 20, 2009; 27(15): 2516 - 2522.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
A. C. Sprynski, D. Hose, L. Caillot, T. Reme, J. D. Shaughnessy Jr, B. Barlogie, A. Seckinger, J. Moreaux, M. Hundemer, M. Jourdan, et al.
The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor
Blood, May 7, 2009; 113(19): 4614 - 4626.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
P. Sabbatini, J. L. Rowand, A. Groy, S. Korenchuk, Q. Liu, C. Atkins, M. Dumble, J. Yang, K. Anderson, B. J. Wilson, et al.
Antitumor Activity of GSK1904529A, a Small-molecule Inhibitor of the Insulin-like Growth Factor-I Receptor Tyrosine Kinase
Clin. Cancer Res., May 1, 2009; 15(9): 3058 - 3067.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
D. L. Kleinberg, T. L. Wood, P. A. Furth, and A. V. Lee
Growth Hormone and Insulin-Like Growth Factor-I in the Transition from Normal Mammary Development to Preneoplastic Mammary Lesions
Endocr. Rev., February 1, 2009; 30(1): 51 - 74.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
M. M. Chitnis, J. S.P. Yuen, A. S. Protheroe, M. Pollak, and V. M. Macaulay
The Type 1 Insulin-Like Growth Factor Receptor Pathway
Clin. Cancer Res., October 15, 2008; 14(20): 6364 - 6370.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lacy, M. Q.
Right arrow Articles by Gualberto, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lacy, M. Q.
Right arrow Articles by Gualberto, A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

About
JCO		 Editorial
Roster		 Advertising
Information		 Librarians &
Institutions		 Rights &
Permissions		 PDA Services

Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
Terms and Conditions of Use
  HighWire Press HighWire Press™ assists in the publication of JCO Online