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Platelet-Derived Growth Factor Receptor Inhibitor Imatinib Mesylate and Docetaxel: A Modular Phase I Trial in Androgen-Independent Prostate Cancer

From the Departments of Genitourinary Medical Oncology, Biostatistics, Cancer Biology, and Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Paul Mathew, MD, Department of Genitourinary Medical Oncology, Unit 427, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: pmathew{at}mdanderson.org

	ABSTRACT

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PURPOSE: To study the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate in androgen-independent prostate cancer (AIPC), alone and in combination with docetaxel, we designed a modular phase I trial. Our goals were to (1) evaluate the toxicity and maximum-tolerated dose of docetaxel with imatinib, and (2) evaluate the decline of prostate-specific antigen (PSA) induced by imatinib alone, and imatinib and docetaxel.

PATIENTS AND METHODS: Twenty-eight men with AIPC and bone metastases were enrolled to receive imatinib 600 mg daily lead-in for 30 days, then imatinib 600 mg daily and one of six possible doses of docetaxel weekly for 4 weeks every 6 weeks.

RESULTS: During the imatinib lead-in module, one dose-limiting toxicity (DLT) event was observed, while two (7%) of 28 had PSA decline (both < 50%). With imatinib and docetaxel, cycle 1 DLT was found in three of 12 patients at docetaxel 30 mg/m², in three of four patients at docetaxel 45 mg/m², and in five of six patients at docetaxel 35 mg/m². DLTs (n = 40 total events) were principally fatigue (35%) and nausea (20%). Eight (38%) of 21 had PSA decline greater than 50%, and six (29%) of 21 had PSA decline less than 50%. Serial PSA declines beyond 18 months were observed. PDGFR-expressing tumor declined on serial bone marrow biopsies with combination therapy alone.

CONCLUSION: With imatinib 600 mg daily, the maximum-tolerated dose of docetaxel was determined to be 30 mg/m² weekly for 4 weeks every 6 weeks. Long-term responses were observed. The role of imatinib in modulating outcomes to docetaxel in AIPC is being tested in a randomized phase II trial.

	INTRODUCTION

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Although chemotherapy yields consistent palliative responses in metastatic androgen-independent prostate cancer (AIPC), the overall survival duration is limited.^1,2 Mechanisms of disease progression have suggested additional therapeutic targets. The bone microenvironment is a preferred site for prostate cancer metastases; the bone-epithelium interaction results in a metastatic phenotype that is highly conserved and characterized clinically by osteoblastic lesions. The burden of metastases in bone largely defines the symptoms of metastatic prostate cancer and serves as an independent prognostic marker for survival.³ Radioisotope-based targeting of bone metastases in prostate cancer may prolong survival,⁴ suggesting that a bone-directed approach may alter the natural history of the disease.

Several lines of evidence implicate the platelet-derived growth factor receptor (PDGFR) in prostate cancer progression in bone. PDGFR is a transmembrane tyrosine kinase receptor that is overexpressed in the majority of bone metastases from prostate cancer,^5,6 as well as in primary prostatic adenocarcinomas.^7,8 Prostate cancer cells also express the receptor ligand PDGF,⁸ a known mitogen for osteoblasts, and this could contribute to the striking osteoblastic phenotype. Autocrine and paracrine signaling via the PDGFR may, therefore, play a role in the pathophysiology of prostate cancer progression in bone. These lines of evidence led us to study the therapeutic potential of PDGFR inhibition in vivo in an animal model of prostate cancer bone metastases. The results of these studies demonstrated that the PDGFR inhibitor imatinib mesylate (STI571, Gleevec; Novartis Pharmaceuticals, East Hanover, NJ),⁹ in combination with taxane therapy, had greater antitumor efficacy than either agent alone.¹⁰

We felt that the finding worthy of validation was that the combination of a taxane and PDGFR inhibition was superior to PDGFR inhibition alone in tumors expressing PDGFR. To efficiently study the effect of a PDGFR inhibitor in prostate cancer, alone and in combination with cytotoxic therapy, we designed a modular phase I trial. Its purpose was to characterize the toxicity of imatinib alone and of the combination of imatinib plus docetaxel, and to obtain a preliminary screen of efficacy of imatinib alone and imatinib plus docetaxel. By serially treating each patient with single-agent imatinib followed by the combination, we assessed the toxicity and modulation of prostate-specific antigen (PSA) for each module of therapy.

	PATIENTS AND METHODS

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Patient Selection
Men with progressive AIPC and bone metastases were eligible for this study. All patients had progressive disease by clinical, radiological or PSA-based criteria. PSA progression was defined as two consecutive rises in the PSA level of at least 1 ng/mL over 4 weeks. When relevant, withdrawal of antiandrogen therapy was required. Patients had an Eastern Cooperative Oncology Group performance status of 2 or better, a serum testosterone level 30 ng/dL, and were maintained on luteinizing hormone-releasing hormone (LHRH) agonist therapy. Adequate organ functions were required and were defined as an absolute neutrophil count 1,500/mm³, platelet count 100,000/mm³, serum bilirubin 1.5 mg/dL, AST and ALT 2x the upper limit of normal, serum creatinine clearance 40 mL/min, or serum creatinine less than 1.5x the upper limit of normal. Patients with comorbidities including symptomatic congestive heart failure, unstable angina or recent myocardial infarction, and oxygen-dependent lung disease were excluded. Chemotherapy or radiation therapy within the last 30 days and systemic radioisotope therapy within the last 90 days were not permitted. All patients gave written informed consent according to federal and institutional guidelines.

Dosage and Drug Administration
Lead-in period. Patients were treated initially with imatinib mesylate at 600 mg daily in single or divided doses, for 30 days. Tolerance and compliance were assessed during and at the end of the lead-in. Patients who took 80% of the prescribed drug were eligible for combination therapy. Imatinib capsules were supplied by Novartis Pharmaceuticals.

Combination therapy. Patients eligible to proceed to combination therapy received intravenous docetaxel, at one of six possible doses, weekly for 4 consecutive weeks (days 1, 8, 15, and 22) every 6 weeks as outpatients. Oral steroid premedication for docetaxel was dexamethasone 10 mg, 12 and 2 hours before docetaxel, and 8 hours after docetaxel. Oral imatinib was continued at 600 mg daily for the full 6 weeks. Patients were enrolled in cohorts of six. The six potential docetaxel dose levels were 20, 25, 30, 35, 40, or 45 mg/m² weekly.

Statistical Design
Dose finding for docetaxel was performed using the continuous reassessment method (CRM).¹¹ Patients were treated in cohorts of six; as many eight cohorts were possible. The first cohort was treated at 30 mg/m². Fixed probabilities of toxicity (p₁, p₂, p₃, p₄, p₅, p₆ equalling 0.07, 0.16, 0.30, 0.40, 0.46, 0.53, respectively) were used for implementing the CRM under the model

with the parameter "a" following a Gaussian prior with mean 0 and variance 2. The fixed probabilities were selected based on the basis of assumptions derived from clinical experience. Patients who could not be assessed for toxicity during the combination therapy because of dropout during the lead-in period or early combination therapy period were replaced. The maximum-tolerated dose (MTD) was defined a priori as the dose level of docetaxel in combination with oral imatinib at 600 mg daily that achieved a dose-limiting toxicity (DLT) rate closest to 30%. For implementing the CRM, the definition of DLT was any toxicity that resulted in a delay of 1 week or more in the administration of either docetaxel or imatinib during the combination module of the study. Similarly, any toxicity that resulted in a dose-reduction during the combination module of the study was defined as DLT. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (Version 2.0).

Dose Reductions
Dose reductions by one level (both drugs) were permitted for intolerable nonhematologic grade 2 toxicity or any grade 3 or 4 toxicity after both drugs were held and toxicity resolved or improved to grade 2 or less. Recurrent toxicity of similar severity would result in another dose reduction by one level, but patients requiring more than two dose reductions or any delay by 2 weeks or more in scheduled therapy as a result of toxicity were withdrawn from the study. Successive dose levels for imatinib, if dose reduction was required, were 400 mg (level 1) and 300 mg (level 2) daily, respectively. All patients were required to have absolute neutrophil counts greater than 1,500/mm³ and platelet count more than 75,000/mm³ for treatment on D1 of each cycle of combination therapy.

Pretreatment and Follow-Up Studies
Historical data collected on each patient included performance status, prior cancer therapy, current medications, and a Brief Pain Inventory. Physical examination and routine laboratory evaluations, including PSA, were performed. A bone scan and computed tomography scan of the abdomen and pelvis were required. Serial unilateral bone marrow biopsies from the posterior superior iliac crest were obtained in consenting patients at baseline and at the start of the first two cycles of combination therapy. PDGFR immunohistochemistry (goat anti-PDGFR-b, goat antiphospho-PDGFR-b; Santa Cruz Biotechnology Inc, Santa Cruz, CA) was performed on sections from decalcified and paraffin-embedded bone biopsy specimens. Radiological studies were repeated after every two cycles of combination therapy or to evaluate symptoms or signs of progressive disease. Weekly monitoring during combination therapy included weight, CBCs, liver function tests, and creatinine.

Definition of Treatment Outcomes
PSA-defined partial response to therapy was defined as a decline in PSA level by 50% of entry level value (before lead-in), sustained for at least 8 weeks. Partial response in measurable disease was defined as 50% reduction in the products of the diameters of all index lesions in patients with measurable disease, sustained for at least 8 weeks. Progressive disease was defined as three consecutive increases in PSA level by at least 1 ng/mL, the first value 25% above nadir or baseline, measured at least 2 weeks apart; any increase greater than 25% in the products of diameters of any measurable lesion; or the appearance of an unequivocally new lesion. Whenever possible, patients received at least two cycles of combination therapy before a designation of progression was made. Time to progression was measured from the time of entry into protocol to the earliest of signs or symptoms secondary to progressive disease, radiological progression, or, if defined by PSA level alone, the time to first of three consecutive PSA elevations above 125% of the nadir or baseline PSA value. Patients were removed from the study for unacceptable toxicity, noncompliance, refusal to continue therapy, or progressive disease.

	RESULTS

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General
Twenty-eight men were enrolled. Patient characteristics presented in Table 1 indicate a heavily pretreated and largely symptomatic group of patients.

PSA outcomes. Of 28 patients enrolled onto the study, 24 completed the lead-in period. Three patients were removed from the study within the first 2 weeks because of rapid disease progression, characterized by debilitating bone pain and fatigue. By the end of the lead-in period, two patients had PSA declines less than 50%, and the remainder had increases in PSA levels from baseline (range, 1.03 to 7.8-fold; median, 1.8-fold). Sixteen patients (67%) had a PSA increase greater than 50% from the baseline value. Changes in measurable disease were not assessed. No reductions in imatinib dose were necessary. By the end of the lead-in period, all remaining 24 patients were eligible to proceed to combination therapy.

Docetaxel and Imatinib (cycle 1) Toxicity
Of the 24 patients who received combination therapy, 21 completed one cycle of therapy and were assessable for response. Three patients were removed from the study during the first cycle of therapy and could not be assessed for response—one, for rapid progression after receiving only one dose of docetaxel; one, for toxicity (grade 3 fatigue) after three doses of docetaxel; and a third, for accelerated angina requiring emergent coronary artery bypass graft surgery.

The rates of first-cycle DLTs per cohort, which were the basis for the CRM dose-finding algorithm, are presented in Table 2. Because the trial design allowed dose-levels to be skipped while escalating, the absence of any DLTs (0 of six patients) at the starting dose level (30 mg/m²) led to assignment of 45 mg/m² to the second cohort. However, the observation of excessive toxicity (three of four patients with DLT) at the 45 mg/m² dose level led us to curtail enrollment of the second cohort early, at four patients, and recompute the posterior distribution based on the data from these first 10 patients, rather than 12. This led the CRM to assign 35 mg/m² as the next dose level for the third cohort of six patients. Per the CRM, the fourth cohort was treated at a dose level of 30 mg/m², and based on the toxicity data at that point, it was then decided to terminate the trial. The cumulative DLT rates for all patients per dose level are presented in Table 3 and include toxicity experience in later cycles, including those DLTs observed after dose reductions. Using a first-cycle DLT rate closest to 0.3 to define the MTD, we estimated the MTD for docetaxel as 30 mg/m² weekly for 4 weeks, in 6-week cycles in combination with 600-mg imatinib daily.

View larger version (12K): [in this window] [in a new window]   Fig 1. Prostate-specific antigen (PSA) fluctuations noted in a long-term responder to combination therapy. The first 30 days are on imatinib alone.

Altogether, of the 28 patients who were registered, five remain on treatment, five were removed from study for toxicity, one had an intercurrent event unrelated to therapy, and 17 had progressive disease. Time to progression from study entry varied from 2 weeks to 10 months (median, 2 months). To date, 20 patients (71%) remain alive with a median follow-up duration of 10 months.

Pain Outcomes
Pain scores (range, 0 to 10) from the Brief Pain Inventory were tabulated at baseline, after imatinib alone, and after one cycle of combination therapy. The mean worst pain score rose to 3.75 (range, 0 to 10) after imatinib, compared with 2.0 (range, 0 to 6) at baseline. Similarly the mean average pain score rose to 2.5 (range, 0 to 6) from 1.4 (range, 0 to 3). With combination therapy, the mean worst pain score fell to 1.3 (range, 0 to 4), and mean average pain, to 1.0 (range, 0 to 3). In all cases, pain was of bony origin.

Analysis of PDGFR Status in Bone Lesions
Serial bone marrow biopsies were performed in eight patients at baseline, after the lead-in period with imatinib alone, and after cycle 1 of combination docetaxel plus imatinib. Of these eight, two had serial bone marrow specimens with tumor that was amenable to serial PDGFR and phospho-PDGFR staining. As shown in the example in Figure 2, there was no readily discernible change in PDGFR expression from baseline (Fig 2A) with imatinib alone (Fig 2B). With combination therapy, however, the percentage of tumor expressing PDGFR declined markedly (Fig 2C). No differences between tumor expression of PDGFR and phospho-PDGFR were noted. In this patient, the decline in percentage of tumor expressing PDGFR was associated with a decline in PSA level after combination therapy, whereas the PSA level rose during lead-in with imatinib alone.

View larger version (84K): [in this window] [in a new window]   Fig 2. Platelet-derived growth factor receptor expression in bone marrow biopsies from a patient at (A) baseline, (B) after 30 days of imatinib therapy, and (C) after one cycle of imatinib plus docetaxel therapy.

	DISCUSSION

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The combination of daily imatinib at 600 mg and a weekly regimen of docetaxel for 4 of 6 weeks at 30 mg/m² was initially well tolerated by most patients, while up to 60% required dose-reductions eventually. Nevertheless, we showed that chronic combination therapy over 18 months is feasible in patients who are both free from progressive disease and significant cumulative toxicity. A marked increase in first-cycle DLT rate was noted at higher doses. Further studies are needed to clarify whether a drug interaction was responsible for this finding.

During combination therapy, hematological toxicity proved trivial in this heavily pretreated group of patients, and nonhematological toxicity, principally nausea and fatigue, dominated the DLT picture. At least one source of potentially life-threatening toxicity with this regimen is noncardiogenic pulmonary edema or pneumonitis. Chronic fatigue and nausea may have an insidious progression, with serial declines in performance scores and weights. With continued therapy for more than 12 months, however, no cumulative DLTs have been recognized. A larger experience with this combination will better characterize the full DLT spectrum.

Of patients who received at least one full cycle of combined imatinib plus docetaxel, 24% experienced a decline in entry-level PSA by 50% that maintained for 8 weeks. There are two prior phase II studies of weekly docetaxel therapy for comparison with the results from this phase I trial. Both these studies were in taxane-naïve AIPC with minimal or no prior chemotherapy, in contrast to our patient population (Table 1). Berry et al¹² treated 60 patients with weekly docetaxel at 36 mg/m² for 6 of 8 weeks. A 41% rate of PSA decline by 50% maintained for 4 weeks was observed, with a median duration of PSA response of 5 months and time to progression of 6.6 months (range, 3.2 to 18.2 months) for PSA responders. Beer et al¹³ treated 25 patients in a similar schedule and observed a 46% (95% CI, 25% to 67%) decline in PSA by 50% maintained for 4 weeks. The median time to PSA progression among responders was 20 weeks (range, 12 to 87 weeks). The median time to PSA response by 50% with weekly docetaxel alone is close to 30 days. In our study, the pattern and duration of responses with docetaxel and imatinib in combination appear qualitatively different from the historical single-agent data, with a prolonged median time to response (150 days), variable PSA fluctuations, and long periods of disease control in responding patients. Two of these responses are ongoing beyond 18 months. The median duration of PSA response of 8 months, and progression-free survival interval of 11 months for responders, appear superior to results obtained with single-agent docetaxel in populations with minimal prior exposure to chemotherapy.

As described earlier, one patient experienced an apparent reversal of docetaxel resistance with imatinib after previous disease progression on docetaxel was noted. This singular observation raises the possibility that signaling pathways that are inhibited by imatinib, such as those mediated by PDGFR, may play a role in docetaxel resistance. We speculate that a significant decline in PDGFR-expressing tumor burden in the bone marrow on combination therapy, but not single-agent therapy, infers successful targeting of PDGFR-expressing tumor in a preferential manner with combination therapy. If validated, expression profiling of PDGFR-negative tumors may offer insights into resistance to PDGFR-targeted therapy.

The significance of these several observations can only be estimated by a properly designed phase II trial, such as a randomized design that harmonizes eligibility and response outcomes and stratifies patients on entry for prognostic factors of importance.

We believe that the usefulness of combining the PDGFR inhibitor imatinib mesylate with docetaxel in prostate cancer is worthy of formal study. An ongoing randomized placebo-controlled phase II study of docetaxel and imatinib in AIPC with bone metastases in patients with no prior taxane exposure, will evaluate differences in time to progression, as well as whether PDGFR expression in tumor in bone affects outcome. A crossover provision for the placebo arm will offer insights into the potential for imatinib to reverse docetaxel resistance.

	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. Owns stock (not including shares held through a public mutual fund): Peter F. Thall, Millenium Pharma. Acted as a consultant within the last 2 years: Isaiah J. Fidler, Novartis; Paul Mathew, Aventis, Novartis; Christopher Logothetis, Aventis, Novartis; Peter F. Thall, Orphan Medical, Novartis. Performed contract work within the last 2 years: Isaiah J. Fidler, Novartis. Received more than $2,000 a year from a company for either of the last 2 years: Peter F. Thall, Orphan Medical, Novartis; Isaiah J. Fidler, Novartis; Paul Mathew, Aventis, Novartis.

	NOTES

 
Supported by Novartis Pharmaceuticals.

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

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

	REFERENCES

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1. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: A Canadian randomized trial with palliative end points. J Clin Oncol 14:1756-1764, 1996[Abstract/Free Full Text]

2. Kantoff PW, Halabi S, Conaway M, et al: Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: Results of the Cancer and Leukemia Group B 9182 study. J Clin Oncol 17:2506-2513, 1999[Abstract/Free Full Text]

3. Matzkin H, Perito PE, Soloway MS: Prognostic factors in metastatic prostate cancer. Cancer 72:3788-3792, 1993[CrossRef][Medline]

4. Tu SM, Millikan RE, Mengistu B, et al: Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: A randomised phase II trial. Lancet 357:336-341, 2001[CrossRef][Medline]

5. Chott A, Sun Z, Morganstern D, et al: Tyrosine kinases expressed in vivo by human prostate cancer bone marrow metastases and loss of the type 1 insulin-like growth factor receptor. Am J Pathol 155:1271-1279, 1999[Abstract/Free Full Text]

6. Ko Y-J, Small EJ, Kabbinavar F, et al: A multi-institutional Phase II study of SU101, a platelet-derived growth factor receptor inhibitor, for patients with hormone-refractory prostate cancer. Clin Cancer Res 7:800-805, 2001[Abstract/Free Full Text]

7. Singh D, Febbo PG, Ross K, et al: Gene expression correlates of clinical prostate cancer behavior. Cancer Cell 1:203-209, 2002[CrossRef][Medline]

8. Fudge K, Wang CY, Stearns ME: Immunohistochemistry analysis of platelet-derived growth factor A and B chains and platelet-derived growth factor alpha and beta receptor expression in benign prostatic hyperplasia and Gleason-graded human prostate adenocarcinomas. Mod Pathol 7:549-554, 1994[Medline]

9. Buchdunger E, Cioffi CL, Law N, et al: ABL protein-kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295:139-145, 2000[Abstract/Free Full Text]

10. Uehara H, Kim SJ, Karashima T, et al: Effects of blocking platelet-derived growth factor-receptor signaling in a mouse model of experimental prostate cancer bone metastases. J Natl Cancer Inst 95:458-470, 2003[Abstract/Free Full Text]

11. O’Quigley J, Pepe M, Fisher L: Continual reassessment method: A practical design for phase I clinical trials in cancer. Biometrics 46:33-48, 1990[CrossRef][Medline]

12. Berry W, Dakhil S, Gregurich MA, et al: Phase II trial of single-agent weekly docetaxel in hormone-refractory, symptomatic, metastatic carcinoma of the prostate. Semin Oncol 28:8-15, 2001[CrossRef]

13. Beer TM, Pierce WC, Lowe BA, et al: Phase II study of weekly docetaxel in symptomatic androgen-independent prostate cancer. Ann Oncol 12:1273-1279, 2001[Abstract/Free Full Text]

Submitted October 21, 2003; accepted June 17, 2004.

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