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Phase II Study of R115777, a Farnesyl Transferase Inhibitor, in Myelodysplastic Syndrome

From the Departments of Bioimmunotherapy, Hematopathology, and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Johnson & Johnson Pharmaceutical Research and Development, Titusville, NJ, and Beerse, Belgium.

Address reprint requests to Razelle Kurzrock, MD, FACP, Department of Bioimmunotherapy, UT M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 422, Houston, TX 77030; e-mail: rkurzroc{at}mdanderson.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To perform a phase II study of the farnesyltransferase inhibitor R115777 (Zarnestra; Johnson and Johnson Pharmaceutical Research and Development, Raritan, NJ) in patients with myelodysplastic syndrome (MDS), using doses recommended in a phase I study in relapsed/refractory leukemia.

PATIENTS AND METHODS: Patients with MDS were treated with R115777 at doses of 600 mg orally (PO) bid in cycles of 4 weeks of therapy followed by a 2-week rest period. Dose reduction rules for toxicity were applied.

RESULTS: Twenty-seven of the 28 patients treated were assessable. Three patients responded (complete remission, n = 2; partial remission, n = 1). Responders included two patients with refractory anemia with excess blasts and one patient with refractory anemia with excess blasts in transformation. Two of the responders had a diploid karyotype and one had multiple cytogenetic abnormalities including monosomy 5 and 7. The starting dose of 600 mg PO bid resulted in side effects (myelosuppression, fatigue, neurotoxicity, rash, or leg pain) necessitating dose reduction (n = 4) or discontinuation of therapy (n = 7) in 11 (41%) of 27 patients during the induction period (12 weeks). Lower doses of 300 mg PO bid were well tolerated. All responses occurred in patients who had been reduced to this dose level during the initial two cycles.

CONCLUSION: This study suggests that R115777 has modest activity in MDS patients, but that, in this patient population, 4 weeks of daily doses of 600 mg PO bid is not tolerated. Further exploration of the optimal dose/schedule and correlation with biologic end points are warranted.

	INTRODUCTION

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Myelodysplastic syndrome (MDS) is a group of hematologic disorders characterized by peripheral cytopenias and a dysplastic marrow. MDS usually occurs in elderly patients.^1-4 The pathophysiology of the disease appears to be an initial increase in apoptosis of the primitive stem cells with compensatory marrow proliferation, and later escape of clonal disease with potential for transformation to acute leukemia.^1,3,4 Overall, approximately 30% of patients transform to acute myelogenous leukemia (AML), while the others die of complications of cytopenias (infections, bleeding) while in the MDS phase. MDS is divided into low-, intermediate-, and high-risk categories with median survivals ranging from 3 to 5 years (or more) to less than 12 months.^5,6

There is no standard of care in MDS except for supportive care.² Low-risk MDS is usually observed and later treated, depending on complications, with red cell or platelet transfusions, antibiotics, or growth factors (erythropoietin, granulocyte colony-stimulating factor). High-risk MDS is often treated with cytarabine-based acute leukemia-type regimens, investigational strategies, or allogeneic stem-cell transplant.^7-9 Investigational drugs include a wide variety of agents, the only one of which has shown a convincing impact on the course of MDS is azacytidine.¹⁰

Farnesyltransferase inhibitors (FTIs) are a novel class of compounds that inhibit an enzymatic step (farnesylation) critical to the activation of several cellular proteins. Most extensively studied are the RAS proteins, in particular, those that are the products of mutant ras genes.^9,11 The original interest in FTIs as potential anticancer agents was based on several findings: 1) The crucial role played by RAS proteins as molecular switches that regulate a multitude of cellular functions;^9,12 2) the fact that transforming ras mutations are frequently found in diverse cancers including MDS;¹³ and 3) the observation that RAS can be aberrantly activated by other genetic alterations, even in the absence of mutation in the ras gene.¹⁴ More recently, it has become apparent that several oncoproteins other than RAS also undergo farnesylation,^15-17 suggesting that the mechanism of action of FTIs is significantly more complex than initially presumed.

R115777 (Zarnestra; Johnson and Johnson Pharmaceutical Research and Development, Raritan, NJ), a novel, nonpeptidomimetic, competitive FTI has already undergone phase I and II studies in leukemias and phase I, II, and III studies in solid tumors. Myelosuppression defined the maximum-tolerated dose (MTD), whereas nonhematologic toxicity was limited both in frequency and in severity.^18-20 In a phase I study in refractory leukemias, a 30% response rate (complete and partial remission) was observed.¹⁸ R115777 doses of 600 mg orally (PO) bid were recommended.¹⁸ Herein, we report the results of a phase II study of R115777 (600 mg PO bid for 4 weeks followed by a 2-week rest) in patients with MDS.

	PATIENTS AND METHODS

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Eligibility
Patients were eligible if they were 12 years or older and had MDS including refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts (RAEB), or RAEB in transformation (RAEBT) with intermediate (INT-1 to INT-2) or high-risk MDS by International Prognostic Scoring System (IPSS) scores.⁶ Patients had to have a performance of 2 on the Zubrod scale, and preserved hepatic (bilirubin 2.0 mg/dL) and renal function (creatinine 2.0 mg/dL). Patients with severe heart disease (New York Heart Association Class III or IV) were excluded. All patients signed an informed consent in keeping with the policies of the Surveillance Committee of the M.D. Anderson Cancer Center (Houston, TX).

Treatment Plan
Patients were treated with a starting dose of 600 mg PO bid of R115777 for 28 days followed by a 2-week rest period (6 weeks = 1 course). Patients who showed no antitumor effects after two courses were taken off study. Patients who developed grade 3 or 4 toxicity, but had significant antitumor effect could be continued on study with a one dose level reduction (ie, a reduction in dose to 300 mg PO bid). Patients achieving a response were allowed to receive maintenance therapy according to the induction schedule for 12 months.

Evaluation During Study
Complete history and physical examination as well as complete blood count with differential, platelet counts, SMA-12, and bone marrow aspirate and biopsy with cytogenetics were measured at baseline. Complete blood counts with differential and platelet counts were again measured approximately every 7 days during the initial induction, and SMA-12 was evaluated every 1 to 2 weeks during induction, then every 4 to 6 weeks. Bone marrow aspirate, biopsy, and cytogenetics were evaluated after the first two courses, and then after every two courses (3 months).

Response Definitions
Complete remission (CR) was defined by a bone marrow with 5% blasts or less and with resolution of dysplasia, and peripheral blood with granulocytes over 10⁹/L and with no abnormal cells (eg, blasts), and platelet counts greater than 100 x 10⁹/L lasting for at least 4 weeks. This was in addition to the disappearance of pre-existing splenomegaly. Partial response was defined by improvement in at least two parameters if abnormal at the start. Parameters included: marrow blasts reduction to 5% or less if they were 10% in a normocellular marrow; hemoglobin increase by at least 2 gm/dL and to above 9 gm/dL plus transfusion independence; platelet counts increase by 100% and to above 50 x 10⁹/L plus transfusion independence; granulocyte increased by 100% and to above 10⁹/L; and reduction of splenomegaly by 50%. Responses had to last for at least 8 weeks to fulfill the response criteria.

Plasma Vascular Endothelial Growth Factor (VEGF) and Basic Fibroblast Growth Factor (bFGF) Enzyme-Linked Immunoassay
Samples of VEGF and bFGF levels were obtained pretreatment to determine if baseline levels correlated with response. Commercially available kits (R&D Systems, Minneapolis, MN) were used to measure VEGF and bFGF levels. Briefly, 100 µL of plasma for VEGF and 200 µL for bFGF were added to separate microplates, each containing a monoclonal antibody specific for either VEGF or bFGF. The mixtures were incubated at room temperature for 2 hours. The plates were washed three times to remove any unbound substances. Enzyme-linked polyclonal antibodies specific for each protein were added to the wells, and the mixtures were incubated at room temperature for 2 hours followed by another washing to remove any unbound antibody or enzyme reagent. A substrate solution was added to the wells, and a blue color developed; the intensity of the blue was proportionate to the amount of VEGF or bFGF bound in the initial step. The color development was stopped, and the intensity of the color was measured and compared with a standard curve. Reading was done at 450 nm wavelength. Results were expressed in pg/mL. Lower limit of sensitivity was 5 pg/mL for VEGF and 3 pg/mL for bFGF.

Detection of Mutations in Ras Oncogenes by Fluorescence-Based Automated DNA Sequencing
High molecular weight DNAs were prepared from bone marrow samples obtained from leukemia patients. Four polymerase chain reactions (PCRs) were performed on each bone marrow sample using primers flanking the mutation hot spots at codons 12/13 and codon 61 of N-ras and K-ras oncogenes, respectively. Sequences and names of the primer pairs are as follows: first primer set (for Codons 12/13 of N-ras) (M13N12/13-F): 5'-tgtaaaacgacggccagt GGTCTTGCTGGTGTGAAAGA-3' (M13N12/13-R): 5'-caggaaacagctatgacc CTCTATGGTGGGATCATATTC-3'. Second primer set (for codon 61 of N-ras) (M13N61-F): 5'-tgtaaaacgacggccagt AACAAGT GGTTATAGATGGTG-3' (M13N61-R): 5'-caggaaacagctatgacc CTGTAGAGGTTAAT ATCCCA-3'. Third primer set (for codon 12/13 of K-ras) (M13K12/13-F): 5'-tgtaaaac gacggccagtCGCCTGCTGAAAATGACTG-3', (M13K12/13-R): 5'-caggaaacagctatgacc GTTGGATCATATTCGTCACA-3'. Fourth primer set (for codon 61 of K-ras) (M13K61-F): 5'-tgtaaaacgacggccagt ATTCCTAC AGGAAGCAAGT-3' (M13K61-R): 5'-caggaaacagctatgaccCCACCTATAATGGTGAAT ATCT-3'. The sequences in capital at the 3' side are derived from ras oncogenes. The sequences in lower case at the 5' side are adaptor sequences derived from M-13 which enable the use of M-13 sequences as primers for DNA sequencing on the PCR products, thereby streamlining eight different sequencing reactions into only two directions (ie, forward and reverse). The sequencing reactions were based on the fluorescence dye terminator chemistry using fluorescence-labeled dideoxynucleotides (each of the four dideoxynucleotides is tagged with a different fluorescence dye) and an unlabeled M-13 sequencing primer. The cycle sequencing reactions were then loaded on an ABI 3700 genetic analyzer which took advantage of capillary electrophoresis and distinguished four different termination reactions (A, G, C, T) in the same capillary. All samples were first screened with both forward and reverse sequencing reactions. If no mutation was found, the sample was recorded as negative. If there was a mutation observed in both forward and reverse directions, another PCR reaction covering this mutation was performed and cycle sequencing was repeated to confirm the mutation. To determine the sensitivity of our assays, we performed dilution studies using sw480 colon cancer cells with a K-RAS mutation, HL-60 leukemia cells with an N-RAS mutation, and normal donor cells with wild type K-RAS and N-RAS genes. The sensitivities of our sequencing reactions were limited at approximately 5% of malignant cells.

	RESULTS

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Patient Characteristics
Twenty-eight patients were entered onto the study. All were assessable for toxicity. One patient was not assessable for response because of an accident (fall resulting in hip fracture requiring surgery) necessitating discontinuation of treatment on day 6. Consistent with the demographics of MDS, there were more men than women treated (Table 1). The median age of patients was 66 years. Most patients had IPSS INT-2 disease with an IPSS score of 1.5 to 2.0.⁶ Fourteen patients had diploid cytogenetics, whereas the others showed a variety of karyotypic abnormalities. Ten patients had no prior therapy, while the others had failed diverse treatments, including chemotherapy, gemtuzumab ozogamicin, amifostine, azacytidine, autologous transplant, retinoids, and others (Table 1).

Toxicity
The side effects of R115777 are shown in Table 2. The most common side effects were myelosuppression, fatigue, and nausea, all of which occurred in over 60% of patients. Headache, diarrhea, rash, stomatitis, dyspnea, and chest pain or palpitations (the latter ones generally linked to significant anemia), mostly grade 1 to 2 and reversible, occurred in 20% to 40% of patients. Neutropenic fever was seen in eight patients (29%). Since many of these individuals were neutropenic at the start of therapy, the relationship to R115777 is uncertain. Less common side effects included reversible changes (grade 1 to 2) in renal function tests and hepatic enzyme levels. Two patients died while on therapy. One patient died of respiratory insufficiency as a result of pneumonia or alveolar hemorrhage; the cause of death was unknown in the second patient. Because many of the patients were elderly and had other concomitant medical problems, it is unclear to what extent some of the reported side effects were related to R115777.

Angiogenic Factors
Plasma concentrations of angiogenic factors, including VEGF and bFGF, were measured at baseline. Evaluation was available for 25 patients (89%), including two of the three responders. The median baseline level for VEGF was 31 pg/mL (range, 21 to 681 pg/mL). The two responders had VEGF levels of 74 pg/mL and 23 pg/mL. The median baseline level for bFGF was 8 pg/mL (range, 4.9 to 1,477 pg/mL; Fig 1). Of interest, one of the responders had the highest bFGF level (1,477 pg/mL; assay was repeated three times for verification in this patient); this level was far higher than any other patient, with the second highest level in any patient on study being 81 pg/mL. However, the other responder tested had a plasma bFGF level of 8.4 pg/mL; this level was close to the median level for patients with MDS. There was no correlation between baseline VEGF or bFGF level and disease classification or IPSS score.

View larger version (21K): [in this window] [in a new window]   Fig 1. Baseline plasma vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) levels (pg/mL as measured by enzyme-linked immunoassay) in 25 myelodysplastic syndrome patients. Denotes plasma VEGF levels; • plasma VEGF level in responders; denotes plasma bFGF levels; denotes plasma bFGF level in responder. Lower limit of assay sensitivity is 5 pg/mL for VEGF and 3 pg/mL for bFGF.

	DISCUSSION

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In this trial, we used the dose of R115777 (600 mg PO bid) recommended in the first phase I study in AML.¹⁸ However, a more prolonged administration schedule was utilized, with 4 instead of 3 consecutive weeks of continuous twice-daily treatment, followed by a protracted drug-holiday of 2 weeks instead of 1 week (even so, the total number of weeks of therapy would be 8 during the 12-week induction in the current trial, while the number of weeks of therapy during a 3 week on/1 week off schedule would be 9 during this same time period.) The number of patients in our current study requiring dose reduction or discontinuation of therapy suggests that this dose was too high or that the duration of exposure to this dose was too long for our MDS population. These data are consistent with those from our simultaneously performed phase I study of R115777 in MDS. A major aim of that study was to ascertain the correlation between dose and effect on target molecules. At the time the study was performed, it was believed that an MTD had already been identified, based on the previously published study in acute leukemia.¹⁸) Even so, that study, like this one, demonstrated that the MTD for our MDS patient population was below the 600 mg PO bid dose previously recommended. Specifically, the MTD for R115777 was 400 mg PO bid (3 weeks on/1 week off).²² This schedule was used in the AML study as well as in other phase II and phase III studies in solid tumors.^18-20 Furthermore, the optimal biologic dose may be lower yet, based on the marked inhibition of farnesyltransferase activity observed.

MDS is an umbrella term for a heterogeneous group of hematopoietic stem-cell disorders usually affecting the elderly.²³ These disorders have in common an underlying ineffectiveness of hematopoiesis that is reflected by dysplasia of bone marrow precursors, peripheral cytopenias, and a tendency to progress to AML. In most patients with MDS who are not eligible for allogeneic transplantation, the disease is fatal. Approximately two thirds of patients succumb within 3 to 4 years after presentation, and individuals with high-risk MDS generally survive about 1 year. Except for azacytidine (an investigational hypomethylating agent),¹⁰ none of the other currently available therapeutic agents for MDS extends survival, and many are highly toxic. In our study, three patients achieved either CR (n = 2) or PR (n = 1). These responders were all dose-reduced to 300 mg PO bid, a dose with mild to no side effects. Therefore, a subset of patients with MDS, even those with advanced disease such as RAEBT, can respond to well-tolerated doses of R115777.

The actual mechanism of action of FTIs remains uncertain. Clinical responses in this trial and others^18,22,24 have been unrelated to ras mutations. As mentioned earlier, RAS can be activated by other mechanisms and, to date, no trial has measured RAS activation status. Furthermore, farnesylation is not unique to RAS, and RAS-independent mechanisms of cell growth inhibition by FTI such as prenylation of Rhoß and of the mitotic kinasins CENP-E and CENP-F have been reported.^16,17 In addition, a recently proposed mechanism of action of FTIs is through inhibition of angiogenesis.^25-27 RAS activation upregulates VEGF expression, and suppression of RAS activity through FTI inhibition has led to significant decreases in the expression and secretion of VEGF in preclinical models.^16,17 We have previously reported a significant increase in angiogenesis in patients with hematologic disorders,²⁸ and our recent studies suggest that responses to R115777 in myeloproliferative disorders might correlate with higher levels of plasma angiogenic factors at baseline.^22,24 Consistent with our previous report,²⁸ plasma concentrations of VEGF and bFGF were elevated at baseline in many patients with MDS treated in the current study. In addition, one of the two responders with available data had dramatically increased baseline plasma levels of bFGF (the highest levels by far in the study), as well as high levels of VEGF (Fig 1; plasma levels of these two cytokines were not elevated in the other responder). The small sample size precludes definite conclusions but, taken together with the results of previous studies,^22,24 suggests that assessment of the correlation between response to FTIs and baseline levels of angiogenic factors, as well as changes in levels during treatment, merits a systematic examination in future studies.

In conclusion, the FTIs are a targeted therapy that function by modulating tumor signaling cascades via inhibition of farnesyl protein transferase. Both this study and our phase I study of R115777 in MDS²² demonstrate that responses, including CRs and PRs, can be achieved in patients with MDS, including those that have poor prognostic factors, at doses that are tolerable in elderly individuals. However, doses of R115777 of 600 mg PO bid given for 28 consecutive days, as used at the outset in this trial, may be too toxic for many MDS patients. Furthermore, drug-induced myelosuppression with prolonged use of these doses may mask clinically relevant hematologic improvements. The latter may explain why the response rate was higher (30%) in our phase I study.²² Further studies with this FTI and others in this class, either alone or in combination with other available agents, are warranted. Finally, it is important to recognize that MDS is a tremendously heterogenous disease.²³ Proteomic and/or genomic analyses are, therefore, needed to answer a fundamental issue—the identification of the molecular subsets most likely to respond.

	Authors' Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Razelle Kurzrock, Johnson and Johnson Pharmaceutical Research and Development. Received more than $2,000 a year from a company for either of the last 2 years: Razelle Kurzrock, Johnson and Johnson Pharmacuetical Research and Development.

	NOTES

 
Supported in part by Johnson & Johnson Pharmaceutical Research & Development, LLC.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted August 12, 2003; accepted January 12, 2004.

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