Annals of Oncology Advance Access originally published online on March 15, 2008
Annals of Oncology 2008 19(7):1320-1326; doi:10.1093/annonc/mdn050
hematologic malignancies |
Report of an international expanded access program of imatinib in adults with Philadelphia chromosome positive leukemias
1 Clinical Development, Novartis Oncology, Basel, Switzerland
2 PPD, Brussels, Belgium
* Correspondence to: Dr R. Capdeville, Clinical Development, Novartis Oncology, WSJ 103-3.09.09 CH-4002 Basel, Switzerland. Tel: +41-61-324-01-28; Fax: +41 61 324 00 46; E-mail: renaud.capdeville{at}novartis.com
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Abstract |
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Background: Imatinib is a selective inhibitor of the BCR/ABL tyrosine kinase. The remarkable initial results of the first phase I clinical trial published in 1999 prompted the rapid initiation of large phase II trials. They also generated intense media coverage and significant interest from patients and clinicians and demand for access to imatinib before marketing approval. In response, a worldwide expanded access program (EAP) for imatinib was implemented in May 2000.
Patients: In total, 7380 patients with chronic myeloid leukemia (CML) and acute lymphoblastic leukemia failing prior therapies were enrolled in 106 centers in 34 countries.
Results: Time to progression and overall survival, as well as the safety profile, were similar to those observed in published phase II studies. At the end of the program, patients benefiting from treatment were continued on imatinib therapy by transferring to national health care systems or patient assistance programs.
Conclusion: The imatinib EAP successfully provided therapy to patients with CML before marketing approval. The program provides an efficient framework for the development of global EAPs for innovative investigational anticancer agents in patients without a satisfactory therapeutic alternative.
Key words: chronic myeloid leukemia (CML), expanded access program (EAP), Glivec, imatinib
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Imatinib is a selective inhibitor of the BCR/ABL tyrosine kinase that is constitutively activated in chronic myeloid leukemia (CML). Its clinical development began in June 1998. The initial outstanding results of the first phase I study showing a high level of hematologic and cytogenetic response were presented in December 1999 [1, 2]. Subsequently, three large multicenter phase II studies were initiated in chronic phase (CP), accelerated phase (AP), and myeloid blast crisis (MBC) CML [3]. By June 2000, these trials had completed enrollment with a total of 1027 CML patients in France, Germany, Italy, UK, United States, and Switzerland [4–6]. The results of these studies were used as the basis for filing a worldwide New Drug Application in February 2001. The application received an accelerated review with marketing approval of imatinib by the US Food and Drug Administration (FDA) in May 2001. The European Medicine Evaluation Agency approval was obtained in November 2001 [7] (Figure 1).
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Intense media coverage of the presentation of the phase I data triggered high expectations and demands for rapid access to the drug from patients with CML [8]. It was quickly recognized that enrollment into the three phase II registration studies would not meet the demand because of sample size and geographic limitations. Additionally, while initial clinical results were encouraging, the knowledge of the safety profile of imatinib was limited at that time. Expanding access to a promising investigational drug has to follow existing regulations while ensuring the integrity of the established scientific process of clinical trials conducted to bring the new drug to the market [9]. This expansion may involve a variety of options, including compassionate use programs, random access programs [10], expanded access programs (EAPs), or the organization of very large clinical trials [11, 12]. In the case of imatinib, after consultation with patient representatives and experts in the management of CML and patient access programs, the framework of an EAP was selected. An important objective was to set up a program with a broad geographic reach. To this end, a single program was established with a consistent policy across participating countries.
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patients and methods |
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The primary objective of the EAP was to provide access to imatinib to as many patients as possible. The program included three phase II, open-label, nonrandomized, multicenter trials. Trial centers were required to have a high level of expertise in dealing with patients with leukemias and to have the ability to comply with the Good Clinical Practice requirements of the protocol, including prospective review of the protocol by an Institutional Review Board/Independent Ethics Committee. Additionally, the EAP protocols could not compete with ongoing trials. Patients were required to give written informed consent. In some countries (e.g. Italy, Korea, Thailand), the EAP was implemented as local independent clinical trials which have been conducted and reported separately from the trials reported in this report [13].
Patients 
18 years with the following disease characteristics were eligible: CML-CP hematologically or cytogenetically resistant or refractory to, or intolerant of interferon-
(IFN-); CML-AP, Ph+ acute lymphoblastic leukemia (Ph+ ALL), CML in MBC or lymphoid blast crisis (LBC), or Ph+ acute myelogenous leukemia (AML). Enrollment criteria were similar to those used in phase II studies of imatinib [4–6, 14]. Patients were excluded if they had prior hematopoietic stem-cell transplantation without full hematopoietic recovery, grade 3/4 cardiac disease as defined by the New York Heart Association criteria, serum creatinine, liver transaminase, or bilirubin above the upper limit of the normal range, Eastern Cooperative Oncology Group performance status 3, females with childbearing potential and negative pregnancy test, serious concomitant medical condition, history of noncompliance to medical regimens or patients who were considered potentially unreliable, or who had discontinued from another trial with imatinib.
Imatinib [Glivec®, Novartis Oncology (Gleevec in the United States)] was supplied as 50- and 100-mg capsules. CML-CP patients initiated imatinib at a dose of 400 mg daily, while all others initiated therapy at 600 mg daily. Dose escalation to a maximum of 800 mg daily (400 mg twice daily) was permitted for CML-CP patients who had not achieved CHR at 3 months or complete or major cytogenetic response at 12 months, or who had a loss of response, and for AP and blast crisis or acute leukemia patients who had a lack of, or relapse from CHR. Treatment reductions or interruptions for toxicity were defined as in previous trials [4–6]. Treatment with imatinib was continued until death, disease progression (in the case of CML-CP patients), development of intolerable toxicity, the investigator felt it was no longer in the best interests of the patient to continue therapy, or imatinib became commercially available and the patient was able to continue therapy via prescription or a patient assistance program.
Because of the availability of data from the analysis of the three parallel registration phase II trials and the rapid expansion of the EAP enrolling a high number of patients, the collection of data on hematologic and cytogenetic response was discontinued in an amendment in February 2001 which removed efficacy as a study objective, and refocused the studies on their primary objective of providing expanded access to imatinib. Therefore, in this program, overall survival (OS) and time to progression (TTP) represent the most reliable measures of efficacy. Until the protocol amendment of February 2001, safety assessments which were collected on the case record form included adverse events (AE) and laboratory monitoring. AE were graded according to National Cancer Institute Common Toxicity Criteria. Data regarding serious adverse events (SAEs) were collected throughout the study.
statistical methods
Data were analyzed on all patients who received at least one dose of study drug. For all patients, demographics, disease state at baseline, and duration of treatment were summarized. TTP was defined as the time between the start of treatment and either discontinuation due to ‘progressive disease’ (PD), ‘unsatisfactory effect’, or death. Analysis of OS considered time from study entry to death due to any cause during treatment as well as any death reported after drug discontinuation. If no death was reported, OS was censored at date of last treatment. OS and TTP analyses used the Kaplan–Meier method. TTP was censored at discontinuation unless termination reason was death during study or unsatisfactory therapeutic effect. TTP and OS were compared with data from the previously published phase II trials [4–6, 14].
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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patients and treatment
Between May 2000 and November 2002, a total of 7380 patients were enrolled in 106 centers in 34 countries. Of these, 7370 patients received at least one dose of study drug (Table 1) and were analyzed for study outcomes. Patients’ characteristics and study drug exposure are shown in Table 2 for the patients with CML-CP, CML-AP, MBC, and Ph+ ALL. With the exception of Ph+ ALL patients who were younger, the median age of patients in these subgroups was similar (53–54 years). The median time from initial diagnosis of leukemia ranged from 29 to 35 months; it was shorter for Ph+ ALL (5.0 months). In the group of patients with CML-CP, 16% were categorized as ‘hematologic failure’, 44% as ‘cytogenetic failure’, and 39% as intolerant to IFN-
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Patients with CML-CP received the longest median duration of treatment (9.4 months) followed by AP patients (7.6 months). The majority of patients with CML-CP (90.2%) or AP (69.4%) exited the program because they transferred to national health care systems or to a patient assistance program. Disease progression or death was a more common reason for discontinuing imatinib among AP patients and was the most common reason in the MBC and Ph+ ALL patients.
In addition, the EAP program enrolled 212 patients with CML in LBC and patients with Ph negative (but BCR–ABL positive) CML-AP (n = 62) or blast crisis (n = 46), 33 patients with Ph+ AML, and 28 patients for whom the specific diagnosis of the leukemia was not available.
Within 1 year following initiation of the program, >5000 patients were enrolled (Figure 2). The median time between local health authority approval and last patient completing the program was 7.5 months (range 1.5–20.0 months) (Table 1). This was influenced, on occasion, by the prolonged time required between regulatory approval and reimbursement approval. This was also related to the enrollment in some countries of patients coming from another country not participating in the EAP, and who had subsequently to be transferred back to their homeland health care system or patient assistance programs. These cases were managed on a case-by-case basis. As of June 2003, all patients had completed the study after local regulatory approval of imatinib.
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efficacy outcomes
The estimated percentage of patients without PD at 12 months was 93.4% [95% confidence interval (CI) 92–95], 71.8% (95% CI 69–75), and 17.3% (95% CI 13–21) among CML CP, AP, and MBC, respectively. The estimated percentage of patients alive at 12 months was 97.0% (95% CI 96.3–97.7), 84.1% (95% CI 82.2–86.6), and 33.0 (95% CI 27–39) among CML CP, AP, and MBC, respectively. One-year OS rates were 40.8% (95% CI 28–54) for Ph+ ALL and 39.4% (95% CI 28–51) for LBC.
The TTP and OS among the subgroups of patients were plotted against data from similar subgroups of patients enrolled in prior phase II studies [4–6, 14]. For CML-CP and MBC, both TTP and OS were almost identical (Figure 3A and C). For CML-AP, the survival curves for both TTP and OS were slightly better for the EAP cohorts (Figure 3B). In the CML-CP study, at least one cytogenetic assessment was available for 528 patients. Among them, 154 (29%) and 126 (24%) achieved a complete and partial cytogenetic response, respectively.
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safety
The median dose of imatinib was very close to the protocol intended dose: 400 mg for CML-CP, 575 mg for CML-AP, and 600 mg for MBC or LBC (Table 2). The proportion of patients discontinuing treatment as a result of AEs was lower in CML-CP (2%) compared with CML-AP (3.2%) and LBC or MBC (2.8%). In the CML-CP study, a total of 67 patients (1.8%) died during the study, with the most frequent causes of death being PD (0.7%), cardiac disorders (0.3%), and infections (0.2%). In the CML-AP trial, 210 patients (9.5%) died during the study, with the most frequent causes of death being PD (4.3%), infections (1.8%), intracranial hemorrhages or cerebrovascular accidents (CVA) (0.8%), respiratory disorders (0.7%), and cardiac disorders (0.6%). In the CML-MBC trial, the main causes of death for the 281 (35.8%) patients who died during study were PD (18.6%), infections (4.3%), and CVA (3.5%). No death was attributed to the study drug by the treating physicians.
The percentage of patients with a report of at least one SAE was higher in patients with more aggressive disease (AP-CML, MBC-CML, Ph+ ALL) (Table 3). The most frequently reported SAEs were related to myelosuppression, infection, and vomiting (each with a >1% incidence). Laboratory data were collected only until February 2001. Considering only the patients enrolled until that date (1379 in CP-CML, 892 in CML-AP, and 349 in MBC), the frequency of patients with treatment-emergent grade 3 or 4 elevations in aspartate aminotransferase and alanine aminotransferase were 0.3% and 0.6% in CP-CML, 0.8% and 1.1% in AP-CML, and 0.6% and 2.3% in MBC, respectively.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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With the enrollment of 7380 patients over a 30-month period, the imatinib EAP met its primary objective of expanding access to imatinib to a large number of centers in 34 countries. The interpretation of the results of the EAP should take into account that only limited efficacy and safety data were collected, and that the length of follow-up was directly related to, and limited by, the date when imatinib became commercially available. Despite these limitations, it is encouraging that TTP and OS were similar to the previously published results of the phase II studies which led to the worldwide regulatory approval of the drug [4–6, 14].
As per protocol, detailed information on AEs was not collected. However, clinically meaningful assessments of the safety of imatinib can be made with respect to selected safety outcomes in comparison with the registration phase II studies. The percentages of patients discontinuing study drug due to AEs or laboratory abnormalities were similar to the rates observed in the phase II trials with a longer duration of follow-up (2.4% in CP-CML, 8% in AP-CML, 9% in MBC, and 5% in acute leukemias) [4–6, 14]. Median doses of imatinib administered in the EAP were also similar, as were the median duration of therapy in patients with Ph+ ALL, MBC, or LBC (2.3, 4, and 1.8 months in the phase II trials, respectively) [6, 14]. This short duration of treatment most likely reflects the natural history of a more advanced stage of the disease with a high rate of discontinuation due to PD (42.5%, 32.1%, and 44.8%, of patients, respectively). Finally, the percentage of patients with SAEs, as well as the type of SAEs recorded, was also not different. In the subset of patients enrolled before February 2001 and for whom laboratory data are available, the frequency of elevation of liver enzymes was consistent with prior reports [4–6, 14].
A variety of options for providing access to imatinib were evaluated in designing this EAP [11, 12]. A compassionate case program was rejected due to the inability of assuring the same level of safety monitoring as in the clinical trials. Similarly, additional large-scale clinical trials were not considered due to the logistical constraints of setting up such studies over an acceptable time course. There is no consensus definition of what constitutes an EAP. Since 1987, the US FDA has had a regulatory process that increases the availability of promising products to severely ill patients before approval and marketing begins labeled as EAPs in a broad sense. Legislation regarding this process is currently under revision [9]. The legislation was developed in part in response to the need to make treatments for human immune deficiency (HIV)/acquired immune deficiency syndrome more widely available, and the use of the EAP framework was utilized for several HIV products before 2000 [15–18]. EAPs have also been used in the United States for oncology drugs such as gefinitib [19] and pemetrexed [20]. However, not all national regulatory agencies have similar guidelines or legislation in place and EAPs are usually implemented only at a national level.
The imatinib EAP represents the first program for an investigational anticancer agent implemented at a global level. Following regulatory approval of imatinib, a global international patient assistance program (GIPAP) was subsequently initiated to provide imatinib at no cost to patients with Ph+ CML or gastrointestinal stromal tumors, who had no access to reimbursement, were not insured, and could not afford to pay. This program used a novel direct-to-patient approach. By August 2005, the GIPAP had provided imatinib to >21 000 patients treated by 782 registered physicians working in 286 institutions in 81 countries across the world and is still ongoing [21].
In conclusion, the imatinib EAP provides a framework for early global access programs for breakthrough therapeutic agents in oncology while providing adequate measures to guarantee patient safety and proper use of a new drug.
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Acknowledgements |
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RC, TK, AH, JMF and IG are employees of Novartis. IVH is an employee of PPD.
The following investigators participated in the imatinib EAP: Argentina—E. Bullorsky, P. Rendo, E. Lanari, E. Palazzo, J. Garcia; Australia—C. Arthur, K. Taylor, T. Hughes, J. Szer, R. Hermann; Austria–G. Gastl, W. Lli, K. Lechner; Belgium—G. Verhoef, L. Noens, P. Martiat, N. Straetmans; Brazil—P. Dorliac Llacer, N. Hamerschlak, C. Chiattone, R. Pasquini, D. Trabak; Canada—J. Shepard, A. Keating, C. Shistik, D. Forrest, A. R. Turner, M. Kovacs; Chile—A. Majlis, L. Bronfman, M. E. Cabrera; China—L. Dao-Pei; Colombia—E. Pedraza; Czech Republic—J. Volgova, K. Indrak; Denmark—H. Hasselbach; Eucador—C. Canizares; France—F. Guilhot, J. Reiffers, T. Facon, M. Tulliez, P. Rousselot, M. Michallet, D. Blaise, F. Maloisel, J. L. Harousseau, A. P. Guerci-Bredler; Germany—T. Fischer, D. Niederwieser, A. Hochhause, O. Ottmann, P. Le Coutre, C. Peschel, G. Ehninger, M. Griesshammer, N. Gattermann; Hong Kong—R. Liang; Hungary—H. Losonczy, G. Halm; Ireland—S. R. McCann; Israel—D. Ben-Yehuda, J. Rowe; Mexico—J. Gonzalez-Llaven, J. Pizzuto, R. Hurtado; The Netherlands—J. J. Cornelissen, G. Ossenkoppele; New Zealand—P. Browett; Norway—T. Gedde-Dahl; Peru—O. Lopez, L. Casanova; Poland—Lech Konopka, J. Holowiecki; Portugal—J. Forjaz de Lacerda; Russia—A. Tourkina, S. Loria, N. Khoroshko; Singapore—G. Tee; South Africa—P. Jacobs, P. Ruff, D. Moodley; Spain—F. Cervantes, M. Fernandez, J. Hernandez Boulda, A. Grañesa, J. Steegman, C. Cañizo, J. Odriozola, E. Conde, A. Torres, M. Sanz Alonso, M. Gonzalez, J. Sierra, J. Diaz; Sweden—B. Simonsson; Switzerland—U. Hess, A. Gratwohl, B. Chapuis; UK—G. Mufti, S. Rule, J. Goldman, A. L. Lennard, S. O'Brien, N. Russell, T. Holyoake, R. Clark, A. R. Green, A. Burnett, G. Lucas; United States—R. Stone, E. Berman, M. Tallman, T. Loughran, C. Miller, S. Coutre, R. Brown, R. Silver, T. Shea, D. Snyder, B. Druker, R. Paquette, C. Schiffer, M. Talpaz, R. Larson, R. Bhatia, A. Langston, H. Saba, L. Popplewell, K. Lund, J. Liesveld, L. Klaman, J. Greer, M. Kalaycio; Uruguay—M. Nese; Venezuela—J. Lopez.
Received for publication November 18, 2007. Revision received January 30, 2008. Accepted for publication February 1, 2008.
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