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The Oncologist, Vol. 7, No. 5, 393–400, October 2002
© 2002 AlphaMed Press

FDA COMMENTARY

U.S. Food and Drug Administration Drug Approval Summaries: Imatinib Mesylate, Mesna Tablets, and Zoledronic Acid

Martin H. Cohen, Ramzi Dagher, Donna J. Griebel, Amna Ibrahim, Alison Martin, Nancy S. Scher, Gerald H. Sokol, Grant A. Williams, Richard Pazdur

Division of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland, USA

Correspondence: Martin H. Cohen, M.D., Food and Drug Administration, HFD-150, 5600 Fishers Lane, Rockville, Maryland 20857, USA. Phone: 301-594-2473; Fax: 301-594-0499; e-mail: cohenm{at}cder.fda.gov


   ABSTRACT
Top
 Abstract
GleevecTM (Imatinib Mesylate)
 Mesnex(R) (Mesna) Tablets
 Zometa(R) (Zoledronic Acid,...
 References
 
The purpose of this report is to summarize information on drugs recently approved by the U.S. Food and Drug Administration. Three drugs have recently been approved: GleevecTM (imatinib mesylate) at a starting dose of 400 or 600 mg daily for the treatment of malignant unresectable and/or metastatic gastrointestinal stromal tumors; Mesnex® (mesna) tablets as a prophylactic agent to reduce the incidence of ifosfamide-induced hemorrhagic cystitis, and Zometa® (zoledronic acid) for the treatment of patients with multiple myeloma and for patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. The recommended dose and schedule is 4 mg infused over 15 minutes every 3-4 weeks. These three drugs represent three different types of drug approval: Gleevec is an accelerated approval and supplemental new drug application (NDA); Mesnex tablets represent an oral formulation of a drug approved 14 years ago as an intravenous formulation, and Zometa represents a standard NDA for a noncytotoxic, supportive-care drug. Information provided includes rationale for drug development, study design, efficacy and safety results, and pertinent literature references.

Key Words. Imatinib mesylate • Gastrointestinal stromal tumors • Mesna • Ifosfamide • Zoledronic acid • Bone metastases • Bisphosphonates


   GLEEVECTM (IMATINIB MESYLATE)
Top
 Abstract
 GleevecTM (Imatinib Mesylate)
Mesnex(R) (Mesna) Tablets
 Zometa(R) (Zoledronic Acid,...
 References
 
GleevecTM (Novartis Pharmaceuticals) is indicated for the treatment of malignant unresectable and/or metastatic gastrointestinal stromal tumors (GISTs). The recommended Gleevec starting dose is 400 mg or 600 mg daily.

GISTs are soft tissue sarcomas thought to arise from mesenchymal stem cells within the gastrointestinal (GI) tract. These tumors are usually located in the stomach and small intestine; however, they may occur throughout the GI tract [1]. In addition to histologic considerations, immunohistochemistry currently provides more specific diagnostic criteria for GISTs based on the expression of the cell surface marker CD117 [2]. CD117 is an epitope on the extracellular domain of the transmembrane tyrosine kinase receptor, Kit, the product of the proto-oncogene, c-kit. [3]. CD117 can be detected on the cell surface of malignant GIST tissues in 95%-100% of cases examined. Mutations of the c-kit oncogene have been demonstrated in a number of CD117-positive GISTs, including activating mutations of exon 11, and rarely exons 9 and 13 [4–7].

The 5-year survival for malignant GI mesenchymal tumors varies widely and has been reported to be from 28%-80% [1, 8–10]. The median survival from the time of diagnosis of metastatic or recurrent disease has been reported to be from 12-19 months [8, 9]. Chemotherapy regimens have not proven effective in the treatment of GISTs. Although anthracycline-based regimens have resulted in response rates of 10%-30% for other soft tissue sarcomas, the response rate of GISTs to these regimens is 0%-5% [9, 10]. Radiation therapy also has not been shown to be effective.

Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the bcr-abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome in chronic myeloid leukemia (CML) [11–13]. This drug also inhibits the receptor tyrosine kinases for platelet-derived growth factor and stem cell factor c-kit [14].

Imatinib mesylate was assessed in a single, open-label trial involving one center in Europe and three centers in the U.S. Study eligibility required a histologically and immunohistochemically confirmed diagnosis of metastatic and/or unresectable GIST, at least one site of measurable disease that had not been previously embolized or irradiated, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-3. Patients were excluded if they had received chemotherapy within 4 weeks prior to enrollment or if they had received radiotherapy to >=25% of the bone marrow. Patients who had evidence of disease progression while receiving 400 mg daily of imatinib mesylate were allowed to have a dose increase to 600 mg daily. Patients who progressed on 600 mg daily were to be discontinued from the study. The primary efficacy end point was confirmed objective tumor response rate (two assessments at least 4 weeks apart).

A total of 147 patients were enrolled. Seventy-three patients were randomized to receive an imatinib mesylate dose of 400 mg daily and 74 were to receive 600 mg daily. There were 83 males and 64 females. The median age at enrollment was 54 years. Eighty-one percent of patients had an ECOG PS of 0/1, 18% had an ECOG PS of 2, and one patient had an ECOG PS of 3. Ninety-eight percent had received prior surgery, 51% had prior chemotherapy, and 15% had received prior radiotherapy. At the last date of assessment prior to the study report cutoff, the majority of patients on study had a duration of treatment of <=6 months.

A confirmed partial response (PR) was documented in 56 patients (38%). Table 1Go summarizes response rate by dose. There was no statistically significant difference in response rates between the two dose groups. The response rates in the male and female populations were 35% (29/83) and 42% (27/64), respectively. At the cutoff date for the study report, 55 of 56 patients with a confirmed PR had a maintained, ongoing PR. It is, therefore, too early to determine response duration. The majority of responding patients had onset of response by day 89 after starting treatment.


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  		Table 1. GIST tumor response by imatinib mesylate dose
 
Of 12 patients who were randomized to imatinib mesylate 400 mg daily with dose increases to 600 mg daily for progressive disease, none had a subsequent confirmed assessment of a complete or partial response.

Serious adverse events were reported in 29% of patients in the GIST safety database. As observed in the CML database, grade 3/4 fluid retention, edema, diarrhea, vomiting, abdominal pain, and hepatotoxicity were noted in patients with GIST but in a relatively low percentage of patients for each unique adverse event. Serious hemorrhage at the tumor site and/or at extratumoral GI sites occurred in 7 patients (5%) and was not correlated with thrombocytopenia or tumor bulk. Table 2Go summarizes observed adverse events. Small differences in the safety profile between the two imatinib mesylate dose levels studied did not conclude that the risk/benefit ratio of one dose level was superior to the other.


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  		Table 2. Adverse experiences reported in the GIST trial*
 
The accelerated approval of imatinib mesylate was based on response rate, a surrogate end point judged to be reasonably likely to predict clinical benefit in oncology clinical trials. Accelerated approval requires a postmarketing study to demonstrate clinical benefit. Additional patient follow-up from this study to demonstrate that imatinib mesylate responses are durable may satisfy this requirement.

Imatinib mesylate treatment of malignant unresectable and/or metastatic GISTs was submitted as a supplemental new drug application (NDA). Imatinib mesylate had previously received accelerated approval for the treatment of CML in blast crisis, in accelerated phase, and in chronic phase, after interferon-{alpha} failure or intolerance.


   MESNEX® (MESNA) TABLETS
Top
 Abstract
 GleevecTM (Imatinib Mesylate)
 Mesnex(R) (Mesna) Tablets
Zometa(R) (Zoledronic Acid,...
 References
 
Mesnex® (Baxter Healthcare Corporation) is indicated as a prophylactic agent to reduce the incidence of ifosfamide-induced hemorrhagic cystitis. On March 21, 2002, the U.S. Food and Drug Administration (FDA) approved mesna tablets as a prophylactic agent to reduce the incidence of ifosfamide-induced hemorrhagic cystitis [15–18]. Mesna for i.v. administration was initially approved for this indication in 1988. To prevent the necessity for prolonged hospitalization, an oral formulation was sought. Ultimately a 400-mg film-coated tablet was developed (Pharmacoat film coating), which provided a stable formulation resistant to change in dissolution rate with storage and an acceptable taste. After ifosfamide and the first dose of mesna are administered intravenously, subsequent doses of mesna may be given intravenously or orally. The efficacy and safety of oral mesna was supported by a comparative pharmacokinetic (PK) study and two clinical trials conducted in the U.S. and Europe.

Mesna is a thiol compound that is rapidly oxidized in plasma to mesna disulfide (dimesna), its major metabolite [19–21]. Dimesna, since it is hydrophilic, remains in the intravascular compartment and is rapidly eliminated by the kidneys. In the kidney, dimesna is reduced to the free thiol compound, mesna, which reacts chemically with urotoxic ifosfamide metabolites (acrolein and 4-hydroxyifosfamide), resulting in their detoxification.

Ifosfamide has dose-dependent PKs in humans. At doses of 2-4 g/m2 i.v., its terminal elimination half-life is about 4-8 hours. As a result, repeated doses of mesna are required to maintain adequate levels of mesna in the urinary bladder for uroprotection. Following oral administration of single doses ranging from 600-2,400 mg in male volunteers, approximately 90% of mesna is absorbed.

Comparative PK Study
An open-label, randomized, multiple-dose, two-way crossover PK study was submitted. The primary objective was to compare the PK of mesna and dimesna in plasma (day 5) and urine (days 1 and 5) after 5 days of ifosfamide with mesna given either as an i.v.-i.v.-i.v. or i.v.-oral-oral regimen. Secondary objectives of the study included evaluation of ifosfamide PK in blood and clinical tolerability (including hematuria).

A total of 17 patients with a diagnosis of sarcoma were randomly assigned to one of the two study treatments for the first cycle, followed by crossover to the alternate mesna dosing regimen for the second cycle. PK analysis demonstrated that the i.v.-oral-oral regimen reached an overcompensation in plasma area under the concentration time curve ([AUC] 129%-151%) on day 5 compared to the i.v.-i.v.-i.v. regimen. Likewise, the urinary levels of mesna for the i.v.-oral-oral regimen on day 5 were higher than for the iv.-i.v.-i.v. regimen, suggesting the likelihood of at least comparable uroprotection against ifosfamide. Ifosfamide PK profiles of the two regimens were determined to be similar. A gender effect analysis was conducted in four male and four female volunteers; no differences in plasma PKs were detected. No specific studies have been conducted to assess the effect of age or ethnicity; however, no differences are noted in subgroups in the larger clinical database.

There were two instances of grade 3/4 hematuria, one in each regimen. The incidence of nausea was higher in patients receiving mesna on the i.v.-oral-oral regimen (88% versus 56%). Exploratory analysis suggested a potential relationship between mesna exposure (AUC) and time to first occurrence of nausea (p = 0.026 for AUC). Exploratory analyses also suggest the possibility of a threshold effect for concentration of mesna and reduction of incidence of severe hematuria. Based on findings from this PK study, the convenience of an oral regimen must be weighed against the possibility of a greater incidence of nausea as seen in this small number of patients.

Clinical Trials
Two clinical trials were submitted, one performed in Germany and the other in the U.S. Both were open-label, randomized, multiple-dose efficacy and safety studies comparing the i.v.-i.v.-i.v. versus i.v.-oral-oral mesna dosing regimens in ifosfamide-treated patients. The objectives of the trials were to compare incidence of severe hematuria, as well as the safety and tolerability of the two mesna regimens.

Fifty-four patients were randomized in the German trial. Data on incidence of hematuria were collected for cycle one only and patients did not crossover to the other arm. One patient in each arm developed grade 3/4 hematuria. Equivalence was demonstrated in both the intent-to-treat population (all randomized patients) and per protocol population (prospectively defined patient population considered likely to benefit from protocol treatment). In the U.S. trial, 66 of a planned 120 patients were randomized to either mesna dosing regimen for the first cycle, after which patients crossed over to the alternative regimen for the second cycle. Although only one patient on either mesna regimen had grade 3/4 hematuria, equivalence could not be demonstrated for the first cycle, possibly due to a smaller than planned sample size. Equivalence was reached when counting first- and second-cycle data together; however, results may be biased by a 15% dropout rate.

There was an unexplained higher incidence of death (4 patients) noted in the U.S. trial in patients treated with i.v.-oral-oral mesna versus one death on the iv.-i.v.-i.v. regimen. No greater incidence of death has been seen in the i.v.-oral-oral regimen in other submitted studies.

Integrated Summary of Safety
In a meta-analysis of four controlled studies (Germany, U.S., and two PK trials), the safety profile of the i.v.-oral-oral regimen (n = 119) was similar to the all i.v. regimen (n = 119). Nausea and vomiting were the most common adverse events (55% versus 54% and 29% versus 38% for the all i.v. versus the i.v.-oral regimen, respectively). Because mesna is used in combination with ifosfamide, it is difficult to distinguish the adverse reactions that may be due to mesna from those caused by the concomitantly administered cytotoxic agent. The most frequently reported adverse reactions from single-dose phase I studies of i.v. mesna alone were headache, injection-site reactions, flushing, dizziness, nausea, vomiting, somnolence, diarrhea, anorexia, fever, pharyngitis, hyperesthesia, influenza-like symptoms, and coughing.

The sponsor reported a higher incidence of acidosis in the i.v.-oral-oral sequence. Review of the case report forms, however, indicated an equal incidence of acidosis in both groups of patients. Two patients on the i.v.-oral-oral regimen who had acidosis had esophageal obstruction or stasis and may not have been suitable candidates for the study of an oral medication. Details related to acidosis were not collected prospectively (including arterial pH), and therefore, a full discussion is not possible. Acidosis in conjunction with ifosfamide therapy has been previously reported.

A general concern with chemotherapy protectants is the potential for tumor protection and/or a drug-drug interaction resulting in inactivation of the therapeutically active species of the antineoplastic agent. Current and previously submitted data arguing against these concerns include stoichiometric considerations, animal modeling of PK/pharmacodynamic data, clinical response rates from controlled trials, and hematologic toxicity with or without mesna. The body of evidence does not indicate that mesna is tumor protective.

The proposed dose and schedule of mesna are supported by the data in the NDA and current amendment. It is not known if lower doses of mesna tablets might be equally efficacious and lessen the incidence of nausea, and it is not clear whether the recommended ratio of i.v. and oral mesna are appropriate for all doses of ifosfamide. Future studies must address those concerns.

Dosage and Administration
The recommended i.v. and oral mesna regimens differ in the ratio of mesna:ifosfamide and times of administration after ifosfamide. The recommended dosing schedules are as follows: the i.v.-i.v.-i.v. mesna regimen is given as an i.v. bolus injection in a dosage equal to 20% of the ifosfamide dosage at the time of ifosfamide administration, and 4 and 8 hours after each dose of ifosfamide. The total daily dose of mesna is 60% of the ifosfamide dose.

The i.v.-oral-oral mesna regimen is given as an i.v. bolus injection in a dosage equal to 20% of the ifosfamide dosage at the time of ifosfamide administration. Mesna tablets are given orally in a dosage equal to 40% of the ifosfamide dose at 2 and 6 hours after each dose of ifosfamide. The total daily dose of mesna is 100% of the ifosfamide dose. Patients who vomit within 2 hours of taking oral mesna should repeat the dose or receive i.v. mesna. The efficacy and safety of this ratio of i.v.-oral-oral mesna has not been established as being effective for daily doses of ifosfamide higher than 2.0 g/m2 for 3-5 days.


   ZOMETA® (ZOLEDRONIC ACID, ZOLEDRONATE)
Top
 Abstract
 GleevecTM (Imatinib Mesylate)
 Mesnex(R) (Mesna) Tablets
 Zometa(R) (Zoledronic Acid,...
References
 
Zoledronate (Zol; Novartis Pharmaceuticals) is indicated for the treatment of patients with multiple myeloma and for patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. The recommended dose and schedule is 4 mg infused over 15 minutes every 3-4 weeks.

Zol is a bisphosphonate, a class of drugs that inhibit osteoclastic bone resorption [22]. Individual bisphosphonates have been approved for treating hypercalcemia of malignancy, osteoporosis, and cancer bone metastases. Until now, pamidronate (Aredia®) was the only bisphosphonate approved for treating bone metastases, and the indication was limited to treatment of patients with osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma [23–24]. Zol approval extends also to osteoblastic metastases and to all other tumors metastatic to bone.

Results of three randomized studies of Zol for patients with bone cancer metastases were the basis of approval. In each of the studies, the primary end point was the proportion of patients with skeletal-related events (SREs). SRE is an aggregate end point: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. Change in chemotherapy due to increased pain was an SRE in the prostate cancer study only.

Two placebo-controlled randomized studies compared Zol 4 mg (Zol 4) and Zol 8 mg (Zol 8) to placebo in patients with prostate cancer (study 039) or patients with solid tumors other than breast cancer and prostate cancer (study 011). The third trial was an active control trial comparing Zol 4 and Zol 8 with pamidronate 90 mg in patients with breast cancer and myeloma. Early in the studies, because of renal toxicity, the Zol infusion duration was increased from 5 to 15 minutes. After accrual was complete for all studies, but while many patients were still on study, the dose for patients on the Zol 8 arm of each study was reduced to 4 mg because of continued renal toxicity.

Efficacy Results
The efficacy results are summarized in Tables 3 and 4GoGo. The patients entering study 039 had prostate cancer with prostate-specific antigen progression while on first-line hormonal therapy for metastatic disease. Except for seven patients, all patients had at least one bone metastasis. Six hundred forty-three patients were randomized to the three arms. Efficacy analyses showed significantly less skeletal morbidity on the Zol 4 arm than on the placebo arm by both the protocol-specified primary analysis of proportions of patients with at least one SRE (33% versus 44%, respectively, p = 0.02) and by the FDA-preferred analysis of time to first SRE (p = 0.01). By both analyses, however, the Zol 8 arm failed to demonstrate a statistically significant difference from placebo (proportions, 38% versus 44%, respectively, p = 0.22; time to SRE, p = 0.54). The FDA and Novartis Pharmaceuticals were not able to provide a good explanation for significant benefit demonstrated at the lower dose of 4 mg but not at 8 mg. After multivariate analyses that included potential prognostic factors, the conclusions remained unchanged. Analysis of time to first SRE, which pooled the results from patients on the Zol 4 and Zol 8 arms of the study, also supported the efficacy of Zol (hazard ratio = 0.78; confidence interval [CI] = 0.60-1.01, p = 0.06).


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  		Table 3. Zoledronate placebo-controlled studies 039 (prostate cancer) and 011 (other solid tumors)
 

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  		Table 4. Active control study 010 (myeloma and breast cancer)
 
The FDA also found that the efficacy of Zol in bone metastases from other cancers was supportive of its efficacy in prostate cancer. Even though metastases in these other cancers were predominantly osteolytic while prostate cancer metastases are predominantly osteoblastic, the mechanism of action of Zol appears to provide benefit in both groups. In both lytic and blastic disease, osteoclastic bone destruction plays an important role in bone morbidity, and Zol inhibits this activity [25].

Other Solid Tumors
In study 011, 773 patients with a variety of solid cancers metastatic to bone were randomized 1:1:1 to treatment with Zol 4, Zol 8, or placebo to evaluate the effect of Zol on SREs. Randomization was stratified according to cancer type as either non-small cell lung cancer or other tumors.

The proportion of patients with an SRE was lower on the 4 mg arm than placebo, but the difference was not statistically significant (37% versus 44%, respectively, p = 0.13). The comparison of the 8 mg group with placebo showed a significant difference (35% versus 44%, respectively, p = 0.02). Time to first SRE was 67 days longer in the 4 mg arm than placebo (230 days versus 163 respectively, p = 0.02) and was also significantly longer for the 8 mg arm (p = 0.04).

Myeloma and Breast Cancer
Study 010 was an international, multicenter, stratified, double-blind study that randomized patients 1:1:1 to Zol 4, Zol 8, or pamidronate 90 mg i.v. every 3-4 weeks for 12 months. Randomization was stratified by center and three disease strata: myeloma, breast cancer treated with hormones, and breast cancer treated with chemotherapy. The primary analysis was a noninferiority analysis of the proportion of patients having an SRE within 13 months of study entry.

A total of 1,648 patients were randomized to the three study arms. Results showed that Zol 4 is effective in decreasing the skeletal morbidity of myeloma and breast cancer metastatic to bone. Noninferiority methodology using the two 95% CI methods of estimation demonstrates that Zol retains at least 49.3% of the pamidronate effect (Table 4Go).

Safety
Renal toxicity was the only serious safety finding after Zol treatment. Renal toxicity was related to dose (more from 8 mg than 4 mg), duration of infusion (more from infusion over 5 minutes than over 15 minutes), and total number of infusions. Table 5Go compares the incidence of renal deterioration in patients receiving Zol 4 to patients receiving placebo or pamidronate. The risk of renal deterioration with Zol was greater than placebo, but similar to pamidronate. Most instances of renal dysfunction were mild and reversible, with rare episodes of acute renal failure. Renal dialysis was required by 30 of the 2,873 patients who participated in the three randomized trials. The majority of these patients had multiple myeloma or prostate cancer (23 of 30), diseases which would be expected to be associated with an incidence of renal dysfunction.


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  		Table 5. Incidence of renal function* deterioration in patients receiving Zol 4 infused over 15 minutes
 
Zol must be infused over at least 15 minutes, and clinical monitoring of serum creatinine should be done before each dose to minimize renal risk. In the trials, Zol was held for renal deterioration until the creatinine returned to within 10% of baseline. Caution is indicated for patients with elevated baseline creatinine, particularly since the study population excluded patients with creatinine greater than 3.0 mg/dl, and the drug is excreted unchanged by the kidneys. The study population did not have extensive concomitant exposure to other potentially nephrotoxic drugs. As the treatment population is expanded, it will be necessary to monitor for possible synergistic nephrotoxic drug effects.

Symptoms possibly associated with bisphosphonates as a class, such as arthralgias and pyrexia, as well as electrolyte disturbances and hypocalcemia, were noted for Zol and pamidronate, but did not necessitate discontinuation of treatment. Anemia was slightly more common with Zol 4 than with placebo.


   ACKNOWLEDGMENT
Top
 Abstract
 GleevecTM (Imatinib Mesylate)
 Mesnex(R) (Mesna) Tablets
 Zometa(R) (Zoledronic Acid,...
 References
 
The views expressed are the result of independent work and do not necessarily represent the views and findings of the U.S. FDA.


   REFERENCES
Top
 Abstract
 GleevecTM (Imatinib Mesylate)
 Mesnex(R) (Mesna) Tablets
 Zometa(R) (Zoledronic Acid,...
 References
 

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Received May 1, 2002; accepted for publication July 9, 2002.




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Ann. Clin. Lab. Sci., July 1, 2004; 34(3): 251 - 262.
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