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Clinical Cancer Research Vol. 10, 924-928, February 2004
© 2004 American Association for Cancer Research

Clinical Trials

A Phase II Trial of Flavopiridol (NSC #649890) in Patients with Previously Untreated Metastatic Androgen-Independent Prostate Cancer

Glenn Liu1, David R. Gandara2, Primo N. Lara, Jr.2, Derek Raghavan3, James H. Doroshow4, Przemyslaw Twardowski4, Philip Kantoff5, William Oh5, KyungMann Kim1 and George Wilding1

1 University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin; California Cancer Consortium, 2 University of California Davis Cancer Center, Sacramento, California, 3 University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, and 4 City of Hope Medical Center, Duarte, California; and 5 Dana Farber Cancer Institute, Boston, Massachusetts


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Flavopiridol is a cyclin-dependent kinase inhibitor with preclinical activity against prostate cancer cell lines. A Phase II trial was conducted to determine the activity of flavopiridol in patients with metastatic hormone-refractory prostate cancer.

Experimental Design: A total of 36 patients was enrolled from several institutions and treated with a 72-h continuous infusion of flavopiridol every 14 days at the eventual starting dose of 40 mg/m2/day. Dose escalation up to 60 mg/m2/day was permitted if no significant toxicity was observed. Responses were assessed every 12 weeks. Only those patients completing four courses of the 72-h infusion were considered evaluable for response because the primary objective was to determine progression-free survival at 6 months given the cytostatic nature of the agent.

Results: This study was conducted in a two-stage fashion. During the first stage, at least 20 evaluable patients needed to be enrolled to assess response. There were 22 of 36 patients evaluable for response. No objective responses were observed. Only 4 patients had stable disease for 16, 26, 29, and 48 weeks, respectively, stopping the trial by design as only 3 of 22 (14%) of the patients met the 6-month progression-free survival end point. The most common toxicities were diarrhea (grade 1 and 2) and nausea, although some grade 3 and 4 diarrhea (11 and 6%, respectively) were evident.

Conclusions: Flavopiridol has disappointing single-agent activity in hormone-refractory prostate cancer when administered at this dose and schedule. Its use in prostate cancer should be reserved for evaluation in combination therapies or alternative schedules.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Prostate cancer is the most common solid tumor diagnosed in men in the United States, accounting for ~220,900 new cases and 28,900 deaths in the year 2003 alone (1) . Despite the high control rate with androgen ablation, virtually all men with metastatic prostate cancer will eventually develop androgen-independent disease. Although chemotherapy may then be used to provide symptom palliation, no regimen to date has ever been shown to improve overall survival. Clearly, examining new agents for treatment in this disease setting is needed.

Cyclin-dependent kinases (CDKs) are important regulators that control the transition between the phases in the cell cycle machinery (2) . In a disease such as cancer where growth is deregulated, inhibiting CDK activity is one approach that may be useful in disrupting the cell cycle to achieve growth arrest (3) . Flavopiridol is a synthetic flavone identical to the parent compound derived from the Indian plant Dysoxylum binectiferum (4) and is the first pan-CDK inhibitor studied in clinical trials. Flavopiridol has been shown to inhibit several tumor cell lines in vitro (5, 6, 7, 8) , with its antiproliferative effects being attributed to potent inhibition of CDK1, CDK2, CDK4, and CDK6 (9, 10, 11) . This antiproliferative effect could be demonstrated with flavopiridol at an IC50 between 100 and 400 nM. In preclinical models, flavopiridol was cytostatic in prostate cancer xenografts when administered using a protracted schedule (12) . Because of encouraging preclinical data, two separate Phase I trials were conducted using a 72-h continuous i.v. infusion. In the study conducted at the University of Wisconsin, we reported a maximum-tolerated dose of 40 mg/m2/day for 3 days with the main dose-limiting toxicities being gastrointestinal (diarrhea). At that dose, the steady-state plasma flavopiridol concentration was 416 ± 98.9 nM, which exceeded the minimum concentration needed to see cell cycle arrest and induce apoptosis in vitro (13) . One patient with gastric cancer achieved a complete response (CR). In the study conducted at the National Cancer Institute, the maximum-tolerated dose was defined as 50 mg/m2/day for 3 days with secretory diarrhea again being the predominant dose-limiting toxicity (14) . One partial response (PR) was seen in a patient with renal cancer in that trial. Given signs of preliminary activity, several Phase II trials were designed using the 50 mg/m2/day dose. It should be mentioned that in the Wisconsin study, no patients at the 50 mg/m2/day for 3 days cohort experienced a dose-limiting toxicity. However, in our patients that dose was felt to be poorly tolerated, leading to the lower recommended Phase II dose of 40 mg/m2/day.

Since then, Phase II trials of flavopiridol have been completed in gastric (15) , lung (16) , colon (17) , and renal cell cancers (18) , using the 50 mg/m2/day for 3 days dose. Although little objective responses were observed, some patients did show evidence of disease stabilization. Here, we report the results of the multicenter Phase II trial of flavopiridol in previously untreated, metastatic hormone-refractory prostate cancer.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eligibility.
All patients were required to have histologically confirmed metastatic adenocarcinoma of the prostate that was progressive despite an adequate trial of hormonal therapy. Patients were ambulatory with an Eastern Cooperative Group performance status of 0–2 and had an estimated life expectancy of at least 3 months. One prior secondary hormonal agent was allowed, but it must have been discontinued at least 4 weeks before to exclude an antiandrogen withdrawal response. No prior chemotherapy, experimental therapy, strontium, or suramin therapy was allowed. Prior radiation therapy was permitted provided that at least 4 weeks had elapsed from the day of the last treatment. Patients who did not have an orchiectomy were continued on their luteinizing hormone-releasing hormone injections, but no other hormonal agent was allowed while on study. Other requirements included: adequate bone marrow function with absolute neutrophil count >= 1200/µl, hemoglobin >= 8 g/day, and platelets >= 100,000/µl; stable renal function with creatinine <= 1.5 upper limits of normal; and adequate hepatic reserve with bilirubin <= 1.5 and asparatase aminotransferase <= 2.5 times the upper limit of normal. A prostate-specific antigen (PSA) >= 10 ng/ml was required if the patient had bone only metastases. No serious concurrent illnesses, previous or concurrent malignancy (except nonmelanoma skin cancer treated with curative intent; other cancers allowed only if the patient has been disease free for 5 years), or history of central nervous system metastasis was allowed. A written informed consent was obtained from all patients before registration. Appropriate Institutional Review Boards approved the project.

Treatment.
On the basis of the National Cancer Institute Phase I trial, flavopiridol was initially administered via a battery-powered ambulatory infusion pump connected to a central venous catheter as a 72-h continuous infusion at the starting dose of 50 mg/m2/day. However, it was soon noted that that dose was poorly tolerated without the use of binding agents such as questran. During the initial phase of this study, the maximum-tolerated dose in the Wisconsin trial Phase I was determined to be 40 mg/m2/day, so the protocol was modified to make that the starting dose for all subsequent patients. The flavopiridol cassette was changed daily with courses repeated every 14 days until disease progression or overt toxicity. For patients completing two courses at 40 mg/m2/day without >=grade 3 toxicity (except alopecia), their dose could be escalated to 50 mg/m2/day at the discretion of the investigator. If the subsequent two courses are again tolerated, another dose escalation to 60 mg/m2/day could be performed. All patients who were undergoing dose escalation were required to use antidiarrheal prophylaxis with loperamide with/without questran. For all patients experiencing a grade >= 2 increase in creatinine, grade >= 4 hematological toxicity, or other grade >= 3 toxicity, the infusion was held until resolution of the toxicity to grade <= 1, at which time, the drug was resumed at the next lowest dose level (the lowest level allowed was 30 mg/m2/day). If the toxicity did not resolve by day 14, the patient was removed from the study. For nausea/vomiting and diarrhea, no dose reduction was performed unless the toxicities persisted despite maximal antiemetic and antidiarrheal prophylaxis. No dose re-escalation was allowed.

End Points.
The primary end points of this study were response rate and toxicity. After the baseline assessments, the complete blood counts and serum chemistries were repeated weekly for the first month, then at the beginning of each new course (every 2 weeks) of therapy. Vitals signs, performance status, and toxicity were also assessed weekly for the first month and then at the beginning of each additional course of therapy as well. PSA was obtained every 4 weeks, and computed tomography scans and/or bone scans were repeated every 12 weeks while on study. All patients receiving flavopiridol were considered evaluable for toxicity (using National Cancer Institute Common Toxicity Criteria, version 1.0), but only those patients completing at least four courses of therapy (8 weeks) were considered evaluable for response. Any patients receiving less than four cycles of therapy (unevaluable for response) were replaced because it was felt that <8 weeks of drug was inadequate to evaluate for any potential objective response using a cytostatic agent. A CR was defined as disappearance of all measurable disease and normalization of the bone scan for 4 weeks. A PR was defined as >=50% decrease from baseline in the sum of the products of the maximum perpendicular diameters for indicator lesions with no progressive disease observed for at least 4 weeks. For patients with bone scan only abnormalities, a PR requires >=50% decrease in the number of lesions. Stable disease (SD) was defined as the absence of a CR, PR, or disease progression. Progressive disease (PD) was defined as unequivocal increase of at least 25% in the size of any measurable lesion or the appearance of any new lesion. Serum PSA levels were not used in the response assessment.

Statistical Methods.
Although preclinical models did show some tumor shrinkage, the clinical benefit of flavopiridol may only manifest itself as disease stabilization. Thus, we used progression-free survival (PFS) as the primary end point. Because the median survival in metastatic androgen-independent prostate cancer at the time of the study was only 12–18 months, we chose PFS at 6 months (defined as achieving CR, PR, or SD at month 6) to be the primary end point. A review of prior studies being performed at that time showed a CR/PR rate ~19% with SD ~13%. Because different criteria for responses were used, the data were difficult to compare. We chose a 30% PFS and an objective tumor response rate of 12.5% to be of interest.

A two-stage design was used to allow the possibility of early stopping due to lack of efficacy (19) . Initially, 20 patients were to be accrued in the first stage of the study. If <5 patients exhibited PFS at 6 months, then the trial would be terminated because of lack of clinical efficacy. Otherwise, an additional 20 patients would be enrolled for a total of 40 evaluable patients. If >11 patients then exhibited PFS for >=6 months, the agent would be considered worth of additional testing in this disease. This design results in a 63% chance of early termination and a 92% chance of a negative result if the true 6-month SD rate is <=20%. However, if the true 6-month SD is >=40%, there is a 5% chance of early termination and >90% chance of a positive result. Survival probabilities were calculated by the method of Kaplan and Meier (20) .


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics and Treatment.
From June 1998 to May 2000, a total of 36 patients with metastatic hormone-refractory prostate cancer was enrolled in the study by the five participating cancer centers. The median age was 71.5 years with the various ethnicity, performance status, and sites of disease shown in Table 1Citation . Of the 36 patients enrolled on this study, 14 patients were unevaluable for response (did not receive at least four full 72-h infusions of drug), leaving us with a total of 22 evaluable patients. Of the 14 unevaluable patients, 2 died (1 patient developed grade 4 shortness of breath secondary to disease progression; the other died secondary to aspiration pneumonia), 1 developed a pathological fracture in his femur, whereas 5 patients were removed secondary to toxicity. Four patients refused additional therapy, 1 other was removed per physician discretion (grade 2 transaminases). The last patient developed grade 3 anemia and thrombocytopenia on day 21 of the study. This was felt secondary to early disease progression as he had significant bone marrow involvement with cancer.


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  		Table 1 Patient characteristics (n = 36)

 
Flavopiridol was administered as a 72-h continuous infusion every 14 days. Although the starting dose of flavopiridol was 50 mg/m2/day, after 11 patients, the starting dose was reduced to 40 mg/m2/day because of reasons previously described. The median number of infusions administered was 6 (range, <1–20). Three patients were able to escalate their flavopiridol dose (1–50 and 2–60 mg/m2/day). Two patients required a dose reduction to 30 mg/m2/day. A total of 158 infusions was given to the evaluable patients supporting the feasibility of this schedule in this patient population.

Toxicity.
Overall, the main toxicities associated with this drug were grade 1 and 2 diarrhea and nausea. Unfortunately, symptoms resulted in 10 patients stopping drug early because of consent withdrawal, the development of unacceptable toxicity, or physician removal because of safety concerns. A list of observed toxicities is shown in Table 2Citation . Consistent with the Phase I and reported Phase II studies, the primary toxicity was gastrointestinal, with very few hematological or neurological events observed. The diarrhea seen occurred mainly during and immediately after flavopiridol infusions and could typically be controlled with loperimide therapy.


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  		Table 2 Toxicitiesa

 
Nausea, fatigue, and anorexia were frequently seen. Other adverse events such as tumor pain flair, orthostatic hypotension, and tachycardia appeared less frequent than that in the two Phase I trials and some of the reported Phase II studies, although still observed. Two thrombotic events were seen [both patients had a deep venous thrombosis (DVT), whereas one also had a pulmonary embolism]. Two cases of local infusion site phlebitis were present.

Efficacy.
No objective responses were observed. Four patients met RECIST criteria for disease stabilization but only 3 of the patients maintained PFS for >=6 months (SD at week 26, 29, and 48), which was our defined primary end point for assessing drug benefit (Table 3)Citation . Although it is always difficult to discern slow disease progression from true disease stabilization, the patient that remained on study the longest (48 weeks) did have both bony metastasis as well as soft tissue disease (lymphadenopathy), suggesting that he may have received some benefit from the drug. The serum PSA was not used as a marker for disease response in this trial. Most patients showed a continually rising PSA while on study. Fig. 1Citation shows the PSA trends in all patients achieving PFS at 6 months. The median survival was 10.7 months (95% confidence interval, 6.7–16.7 months).


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  		Table 3 Response

 


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  		Fig. 1. Prostate-specific antigen (PSA) values of all patients with stable disease >= 6 months while on study.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We have conducted a multicenter Phase II study of the CDK inhibitor flavopiridol in patients with metastatic hormone-refractory prostate cancer. Flavopiridol appeared tolerable at the 40 mg/m2/day for 3 days, when given every 2 weeks. As reported in other Phase II trials evaluating flavopiridol, the main toxicity was grade 1 and 2 gastrointestinal events (diarrhea and nausea), which was seen in nearly one-half of our treated patients. Seventeen percent of our patients developed grade 3 or 4 diarrhea consistent with our Phase I experience. The nature of this diarrhea is likely multifactorial. It has been reported that the degree of hepatic glucuronidation of flavopiridol can be correlated with the degree of diarrhea observed (low systemic glucuronide associated more diarrhea than high glucuronide levels; Ref. 21 ). This suggests a genetic etiology for flavopiridol-induced diarrhea. It has also been shown that endogenous secregogues such as acetylcholine and bile acids may interact with flavopiridol, leading to a secretory diarrhea (22) . Regardless of the etiology, this toxicity appears remarkable consistent in all of the reported trials using this agent. No correlation between diarrhea severity and prior radiation therapy to the pelvis was noted.

The development of a venous thrombosis with this drug has been observed much more frequently than one would expect in this patient population. For example, the Phase II gastric cancer trial (15) observed 5 patients developing a catheter-related thrombosis, the renal trial (18) reported 6 cases of DVT, and the non-small cell lung trial (16) had 7 thrombotic events (DVT and catheter-related events). We did have 1 patient develop a lower extremity DVT on this study. Although the investigator did not feel that this event was related to the drug (patient with bulky lymphadenopathy in pelvis), the possible contribution of the study drug in this event cannot be excluded. The other patient was being treated empirically for pneumonia because of shortness of breath before receiving study drug. While on study, he experienced worsening lower extremity edema, and a Doppler ultrasound confirmed bilateral DVTs. A subsequent spiral computed tomography scan of his chest revealed multiple pulmonary emboli, which was felt by the investigator to have likely been the etiology of his prestudy shortness of breath as his sputum and blood cultures were unremarkable. Nevertheless, a clear relationship between CDK inhibitors and thrombosis has yet to be established. During our Phase I trial (13) , we did have thrombotic events occur in 7 (35%) patients. Four Port-a-cath clots were seen, two of which developed within 24 h of the first flavopiridol infusion. Two other patients were found to have a DVT after their first or second infusion, and another patient had an intermediate probability ventilation-perfusion scan for a pulmonary embolism. There is no clear dose-dependent or concentration-dependent relationship with flavopiridol and a thrombotic event. Previous trials did not note any significant change in coagulation factors to explain these events. Future trials with flavopiridol should include more detailed evaluation of the various mechanisms of hypercoagulability.

Despite the encouraging preclinical data in prostate cancer (23 , 24) , no cytotoxic activity with flavopiridol was seen in these patients with hormone-refractory prostate cancer. Although several patients may have had disease stabilization for many weeks, the duration of response was not clinically significant given the toxicity of the therapy and the low numbers of patients that maintained PFS at month 6. The steady-state plasma flavopiridol level at this dose (40 mg/m2/day) was previously determined to be 416.6 ± 98.9 µM. At this concentration, there should be adequate flavopiridol levels in the subjects to induce antitumor activity. Thus, either the dosing schedule is inappropriate or the drug is simply ineffective for patients with metastatic hormone-refractory prostate cancer. From the other Phase II trials, it is clear that flavopiridol is not effective in solid malignancies when used as a single agent at this dose and schedule. Interestingly, although no significant activity was seen in patients with relapsed or refractory mantle cell lymphoma when flavopiridol was administered using the 72-h infusion (25) , when given at 50 mg/m2/day for 3 days every 21 days using a bolus (1-h) infusion, modest activity [3 (11%) PR and 20 (71%) SD] was observed, making this agent worthy of additional considerations in that disease entity, using the bolus infusion schedule (26) .

Despite the poor response of single-agent flavopiridol in solid tumors, this does not exclude its further evaluation in combination therapies. There have been other drugs such as oxaliplatin that exhibited a small single-agent response rate (27) but showed significant benefit when used in combination with other agents. Preclinical studies demonstrate synergistic activity of flavopiridol with various cytotoxic chemotherapies (28 , 29) . A Phase I trial using paclitaxel with flavopiridol has already been performed showing that combination therapy with flavopiridol is possible, with some promising responses noted (30) .

In conclusion, although single-agent flavopiridol had no activity in patients with advanced hormone-refractory prostate cancer at the dose and schedule used, the continued evaluation of this drug in combination with chemotherapy or other novel agents might be of interest. Better understanding of the gastrointestinal toxicities and thrombotic tendencies will first need to be performed to improve the safety and tolerability of the agent, especially when combined with other agents with similar side effects. As we gain more appreciation of the cell cycle biology and apoptotic pathway, perhaps we can better decide which novel agent will be best served for use in combination therapy with this unique CDK inhibitor.


   ACKNOWLEDGMENTS
 
We thank the research personnel at each participating site for their assistance. We also thank Katherine Oliver, Mary Jane Staab, Dorothea Horvath, Dona Alberti, and Rhoda Arzoomanian for their assistance in conducting this trial and in preparing this manuscript.


   FOOTNOTES
 
Grant support: The Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland and CaPCure.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: George Wilding, Department of Medicine, Medical Oncology Section, 600 Highland Avenue, Madison, WI 53792. Phone: (608) 263-8160; Fax: (608) 265-5146.

Received 8/18/03; revised 9/19/03; accepted 10/ 3/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Sequential combination of flavopiridol and docetaxel reduces the levels of X-linked inhibitor of apoptosis and AKT proteins and stimulates apoptosis in human LNCaP prostate cancer cells
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O. Illanes, S. Anderson, M. Niesman, L. Zwick, and B. A. Jessen
Retinal and Peripheral Nerve Toxicity Induced by the Administration of a Pan-Cyclin Dependent Kinase (cdk) Inhibitor in Mice
Toxicol Pathol, April 1, 2006; 34(3): 243 - 248.
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J. A. Whitlock, M. Krailo, J. M. Reid, S. L. Ruben, M. M. Ames, W. Owen, and G. Reaman
Phase I Clinical and Pharmacokinetic Study of Flavopiridol in Children With Refractory Solid Tumors: A Children's Oncology Group Study
J. Clin. Oncol., December 20, 2005; 23(36): 9179 - 9186.
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C. Richard, D. Matthews, W. Duivenvoorden, J. Yau, P. S. Wright, and J. P.H. Th'ng
Flavopiridol Sensitivity of Cancer Cells Isolated from Ascites and Pleural Fluids
Clin. Cancer Res., May 1, 2005; 11(9): 3523 - 3529.
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Z. N. Demidenko and M. V. Blagosklonny
Flavopiridol Induces p53 via Initial Inhibition of Mdm2 and p21 and, Independently of p53, Sensitizes Apoptosis-Reluctant Cells to Tumor Necrosis Factor
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