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A phase II evaluation of flavopiridol as second-line chemotherapy of endometrial carcinoma: A Gynecologic Oncology Group study
Gynecologic Oncology 98 (2005) 249 – 253 www.elsevier.com/locate/ygyno
A phase II evaluation of flavopiridol as second-line chemotherapy of endometrial carcinoma: A Gynecologic Oncology Group study Edward C. Grendys Jr.a,*,1, John A. Blessing b, Robert Burger c, James Hoffman d,1 a Florida Gynecologic Oncology, Fort Myers, FL 33901, USA Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA c Division of Gynecologic Oncology, Department of Obstetrics/Gynecology, University of California Medical Center, Irvine, Orange, CA 92868, USA d University of Connecticut Health Center, Department of Obstetrics and Gynecology, New Britain General Hospital, New Britain, CT 06052, USA b
Received 6 December 2004 Available online 22 June 2005
Abstract Objective. A phase II study was conducted to determine the efficacy of single agent flavopiridol therapy in patients with recurrent or persistent endometrial adenocarcinoma refractory to established treatments. Methods. Eligible patients with measurable disease who failed primary therapy including one cytotoxic regimen were eligible for the trial. They were treated with single agent flavopiridol (50 mg/m2/day, IV bolus days 1, 2, 3). Treatment was repeated every 21 days with dose adjustments made for toxicity. Patients were treated until progression of disease or adverse side effects precluded further therapy. Results. A total of 26 patients were enrolled in the study of whom, 23 patients were eligible. There were no objective responses. Five patients had stable disease (22%), 15 (65%) had increasing disease, and response could not be assessed in 3 (13%). The most frequent side effects included anemia, neutropenia, and diarrhea, all of which appeared manageable. Conclusion. Flavopiridol as a single agent in the above dosing schedule appears to have minimal activity as second-line chemotherapy of endometrial adenocarcinoma. D 2005 Elsevier Inc. All rights reserved. Keywords: Endometrial cancer; Chemotherapy; Flavopiridol; Flavone
Introduction Endometrial carcinoma is the most common malignant tumor of the female genital tract. Its incidence appears to be increasing and currently represents 13% of female cancers. Approximately 40,100 cases will be diagnosed in the year 2003, and 6800 women will succumb to this disease [1]. The primary treatment modality is surgical extirpation possibly combined with post-operative adjuvant local and/ or regional radiation therapy depending on surgico-pathologic risk factors. The overall 5-year survival is approx-
* Corresponding author. Florida Gynecologic Oncology, 2780 Cleveland Avenue, Suite 717, Fort Myers, FL 33901, USA. Fax: +1 239 992 6222. E-mail address: [email protected] (E.C. Grendys). 1 GOG Affiliate of Tufts-New England Medical Center. 0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.05.017
imately 85%. Localized pelvic disease is obviously managed well with the above-cited modalities; however, patients with extra pelvic disease on primary presentation, or at time of recurrence, have a dismal prognosis. There are multiple active cytotoxic and hormonal chemotherapy agents for the treatment of recurrent and metastatic endometrial cancer including platinum compounds, taxanes, anthracyclines, and topotecan [2 – 8]. These agents (often in combination) have lead to statistically significant improvements in response rates and progressionfree survival albeit often at the cost of significant toxicity. Still, complete response rates and long-term survival is extremely rare. Flavopiridol (NSC#46211) ( )-cis-2-(2-chlorophenyl)5,7-dihydroxy-8-[4R-(3S-hydroxy-1-methyl) piperidinyl)4H-1-benzopyran-4-one hydrochloride) is a synthetic flavone being developed as a novel antineoplastic agent. It is a
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synthetic derivative of the flavonoid rohitukine initially isolated from Dysoxylum binectaisriferum plant indigenous to India [9]. It has been shown to have the potential ability to disrupt cell cycle progression by inhibition of regulatory reactions within the cell cycle and both cytotoxic activity (via apoptosis) and cytostatic activity has been demonstrated [9 –12]. The controlling proteins for these reactions include: epidermal growth factor receptor tyrosine kinase [13,14], serine/threonine kinase, protein kinase C [15], protein kinase A [13,14], and cyclin-dependent kinases (CDK) [16] which appear to be significantly dependent on serum concentrations of drug. CDK activity appears to be important in multiple phases of the cell cycle including G1, G1/S, G2/M and is competitively inhibited at very low concentrations of flavopiridol [16,17]. These concentrations (100 –400 AM) are clinically achievable at doses of 50 mg/ m2/day and appear to correlate with clinical responses in various tumor types [18]. Initial in vitro studies of flavopiridol have demonstrated growth inhibition of several human tumor cell lines in vitro as well as human tumor xenografts (lung, colon, ovary, brain, and breast) in nude mice [15]. Significant inhibitory activity against more than 60 tumor cell lines in the NCI tumor cell line in vitro screening panel was also noted [17,19]. Previous phase I experience has demonstrated a doselimiting toxicity of secretory diarrhea at doses of 62.5 mg/ m2/day. This diarrhea was controllable with the addition of loperamide or cholestyramine as antidiarrheal prophylaxis and dose escalation to 78 mg/m2/day was possible. Other minor acute grade I or II toxicities encountered at this dosing level included anorexia, fatigue, hypotension, fever, tumor pain, dermatitis, nausea, vomiting, and hyperbilirubinemia [18,20]. These trials enrolled a total of 114 patients. Antitumor activity including tumor regression and/or stabilization of disease complete response (CR), partial response (PR), or stable disease (SD) >6 months was observed in patients with tumors from multiple origins including renal, prostate, gastrointestinal, and adenocystic carcinoma of the lacrimal gland [20]. It appears that clinical activity is dose dependent and lower than recommended dosing and subsequent serum concentrations appear to produce minimal clinical activity [21,22]. Senderowicz et al. [18] demonstrated a proinflamatory syndrome with alterations in acute-phase reactants particularly at dose of greater than 50 mg/m2/day. In subsequent phase II studies, investigators have suggested a prothrombotic effect associated with flavopiridol. Schwartz et al. [22] noted 5 patients (33%) developed upper extremity venous thromboses at the central venous catheter directly after completion of the infusion. Stadler et al. [23] reported 3 arterial vascular events (non-fatal myocardial infarction, transient ischemic attack, transient scotomata, and vision loss) and 6 venous thrombotic events (2 associated with vascular access devices) for a total thrombotic event rate of
25%. The relationship of these events to flavopiridol was unclear though appeared to be higher than in the general oncologic population. Given the interesting properties including activity in solid tumors, good tolerance of this agent along with the potential synergistic activity with other active agents, the GOG decided to proceed with clinical phase II testing of this agent in endometrial carcinoma. To date, no previous studies in this tumor type with this agent have been reported.
Materials and methods This phase II study was designed to evaluate the clinical activity of flavopiridol in recurrent or persistent endometrial carcinoma. All histologic subtypes were eligible. Patients were required to have measurable disease as well as at least one target lesion to evaluate response as defined by RECIST criteria. Patients were to have had one prior cytotoxic chemotherapy regimen. Prior cytotoxic therapy must have been discontinued at least 3 weeks prior to registration and hormonal therapy (as treatment) must have been discontinued 1 week prior to registration. Patients with prior treatment with cyclin-dependent kinase inhibitors as well as those with prior radiation to more than 25% of marrowbearing areas were not eligible. Also, patients with prior history of thromboembolic events, thrombophlebitis, recent myocardial infarction, angina, CVA, or transient ischemic attack were similarly not eligible. Patients were required to have a GOG performance status of 0 – 2. Adequate hematologic reserve was required including WBC 3000/Al, ANC 1500/Al, and platelets normal per institutional standards. Serum creatinine was required to be less than or equal to 1.5 institutional norms as was bilirubin. SGOT and alkaline phosphatase were required to be 5 times institutional norms. No significant neuropathy greater than CTC grade 1 and normal coagulation profiles were required. All patients gave appropriate informed consent consistent with all federal, state, and local requirements to sign prior to study entry. A treatment cycle was considered 3 consecutive daily 1-h infusions. Antidiarrheal prophylaxis was given at the investigator’s discretion and coumadin prophylaxis (1 mg/ day) was recommended given previous phase II toxicity experiences. Patients were to be treated until disease progression, voluntary withdrawal, or the presence of unacceptable toxicity. Patients were evaluated for toxicity prior to each cycle and no subsequent cycle was to begin until adequate recovery was noted. Coumadin prophylaxis (1 mg/day) was recommended especially for patients with indwelling catheters, but was not required. Antidiarrheal prophylaxis (loperamide, etc.) was given at the investigator’s discretion. Prophylactic granulocyte-colony stimulating factor (G-CSF) was not allowed unless recurrent neutropenic complications
E.C. Grendys Jr. et al. / Gynecologic Oncology 98 (2005) 249 – 253 Table 1 Patient characteristics Characteristic Age Median Range Performance status 0 1 2 Cell type Endometrioid Serous Mixed epithelial Undifferentiated Adenocarcinoma, (type unspecified) Grade 1 2 3 Unspecified Site of disease Pelvic Extra pelvic Prior chemotherapy Prior radiotherapy Prior hormonal therapy Courses Median Range
Number of cases 63.0 39 – 76 15 6 2 10 6 2 2 3 4 9 9 1 3 20 23 14 5 2 1–9
occurred after appropriate treatment modifications. Patients were allowed to receive erythropoietin after documentation of hemoglobin of less than 10 g/dl. Grade 4 thrombocytopenia/neutropenia (>7 days) or febrile neutropenia required dose reduction. Greater than grade 2 peripheral neuropathy or renal toxicity required a one level dose reduction. Grade 3 liver function abnormalities or diarrhea (grades 3, 4) also required dose reduction. All dose reductions were 30% of initial dose. If no toxicity of greater than grade 1 was encountered, a subsequent dose escalation to 78 mg/m2/day was allowed. Patients who received any treatment were evaluable for toxicity and patients who received one or more cycles were evaluable for response. Response was defined via standard GOG RECIST criteria. A complete response was defined as the disappearance of all target and non-target lesions with no evidence of new lesions lasting at least 4 weeks. Partial response was defined as at least a 30% decrease in the sum of the longest dimensions of all target measurable lesions. There could be no unequivocal progression of non-target lesions and no new lesions noted. Increasing disease was defined as at least a 20% increase in the sum of longest dimensions of target lesions or the appearance of new lesions within 8 weeks of study entry. Progression was defined as greater than 20% of the sum of the longest dimensions, 50% increase in pelvic disease as measured by physical exam only, appearance of one or more new lesions, death due to disease without objective documentation of progression, or unequivocal progression of existing non-target lesions other than pleural
251
effusions. Stable disease was any condition not meeting the above criteria. The study employed a two-stage design with an early stopping rule in the event that the treatment demonstrated insufficient activity. During the first stage of the accrual, 19 – 26 patients were to be entered and evaluated. If at least three responses were observed among the first 19 – 25 patients, or at least four responses were observed among 26 patients, a second phase of accrual was to be initiated which would increase accrual to 44 – 51 patients. The regimen would be considered active if at least seven responses were observed among 44 – 45 patients, or at least eight responses were observed among 46– 51 patients. If the true probability of responding was only 10%, the study design provided a 90% chance of correctly classifying the treatment as inactive. Conversely, if the true response rate was 25%, then the probability of correctly classifying the treatment as active was 90%.
Results Between July 2001 and March 2003, member institutions of the Gynecologic Oncology Group (GOG) entered 26 patients with recurrent or persistent endometrial carcinoma on GOG protocol 129-M. Three cases were deemed ineligible upon review by the GOG Pathology Committee. Patient characteristics for the 23 eligible patients are presented in Table 1. The median age was 63.0 years. Sixty-five percent of patients (17) had a performance status of 0 while 2 patients (9%) had a performance status of 2. Fourteen patients (61%) had received prior pelvic radiotherapy. A median of 2 cycles of chemotherapy (range 1– 8) was administered. Two patients (9%) required a dose reduction. Adverse events are listed in Table 2. The most common significant toxicity was diarrhea. Ninety-one percent of patients reported some diarrhea associated with treatment with 14 patients (61%) experiencing grade 2 and 1 patient reporting grade 4 toxicity. Anemia occurred in 10 patients (43%). Neutropenia appeared manageable with no Table 2 Adverse events (n = 23) Grade
WBC Hemoglobin Platelets ANC/AGC Hematologic Cardiovascular Gastrointestinal Hepatic Infection Metabolic Pain Pulmonary
3 (%)
4 (%)
2 2 2 1 4 1 2 1 1 1 2 2
2 0 0 2 0 1 1 0 0 0 0 0
(8.7) (8.7) (8.7) (4.3) (12.4) (4.3) (8.7) (4.3) (4.3) (4.3) (8.7) (8.7)
(8.7) (0) (0) (8.7) (0) (4.3) (4.3) (0) (0) (0) (0) (0)
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significant septic-related complications. Other reported toxicity included mild thrombocytopenia, elevation of liver function tests and general fatigue. No thrombotic events were noted. No objective responses were observed. Stable disease was noted in 5 patients (21.7%) with median progressionfree interval of 3.2 months (range: 1.8 – 8.6 months). Fifteen patients (65.3%) had increasing disease. Response could not be assessed in 3 cases (13.0%). No patient experienced significant neutropenic-related complications.
Discussion Flavopiridol is a synthetic flavone shown to have specific antineoplastic properties. It appears to be an inhibitor of intracellular protein kinases with particular selectivity for cyclin-dependent kinases (CDK). Because of the role of CDKs in cell division cycle, it appears that inhibition of these specific kinases could lead to inhibition of cell proliferation. It has also demonstrated significant inhibition as a single agent in several human tumor xenografts when administered at appropriate doses and schedules. Single agent flavopiridol was investigated in patients with recurrent endometrial adenocarcinoma. It appeared to be well tolerated in general. The major toxicity appeared to be diarrhea with 91% of patients reporting some diarrhea associated with treatment and 61% experiencing greater than grade 2 gastrointestinal toxicity. Grade 2 or 3 anemia occurred in 8 patients (43%), while grade 2 or greater neutropenia occurred in 5 cases (22%). Our study demonstrates that, in this patient population, flavopiridol appeared to have minimal activity as a single agent with no complete response and one partial response. Therefore, this drug would not be recommended for further testing at this dose schedule. However, flavopiridol has shown in vitro cytotoxic synergy when combined with paclitaxel, cytarabine, topotecan, doxorubicin, etoposide, 5fluorouracil, and cisplatin and therefore may be considered for further testing as a combination agent [24].
Acknowledgments This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical and Data Center (CA 37517). The following Gynecologic Oncology Group member institutions participated in this study: Duke University Medical Center, Abington Memorial Hospital, Walter Reed Army Medical Center, University of Minnesota Medical School, University of Iowa Hospitals and Clinics, University of California Medical Center at Irvine, Tufts-New England Medical Center, Rush-Presbyterian-St. Luke’s Medical Center, The
Cleveland Clinic Foundation, State University of New York at Stony Brook, Columbus Cancer Council, Thomas Jefferson University Hospital, Tampa Bay Cancer Consortium, M.D. Anderson CCOP, Wisconsin. References [1] Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5 – 26. [2] Ball H, Blessing JA, Lentz S, Mutch DG. A phase II trial of paclitaxel in patients with advanced or recurrent adenocarcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 1996;62:278 – 81. [3] Muss HB. Chemotherapy of metastatic endometrial cancer. Semin Oncol 1994;21:107 – 13. [4] Thigpen T, Brady M, Homesley H, Malfetano J, DuBeshter B, Burger R, et al. Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a Gynecologic Oncology Group study. JCO 2004 (Oct 1);22(19):3902 – 8. [5] Fleming G, Filiaci VL, Bentley R, Herzog T, Sorosky J, Vaccarello L, et al. Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-hour paclitaxel + filgrastim in endometrial carcinoma: a Gyncologic Oncology Group study. Ann Oncol 2004;15: 1173 – 8. [6] Fleming G, Brunetto V, Cella D, Look K, Reid G, Munkarah A, et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2004;22:2159 – 66. [7] Thigpen J, Blessing J, DiSaia P, Ehrlich C. Treatment of advanced or recurrent endometrial carcinoma with medroxyprogesterone acetate: a Gynecologic Oncology Group study. Gynecol Oncol 1985;2:250. [8] Fiorica J, Brunetto V, Hanjani P, Lentz S, Mannel R, Andersen W. A phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2004 (Jan);92(1):1 – 3. [9] Naik R, Kattige S, Bhat S, Alreja B, DeSouza NJ, Rupp RH. An antiinflammatory cum immunomodulatory piperinylbenzopyranone from dysoxylum binectariferum: isolation, structure, and total synthesis. Tetrahedron 1988;1944:2081 – 6. [10] Kaur G, Stetler-Stevenson M, Sebers S, Worland P, Sedlacek H, Myers C, et al. Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275. J Natl Cancer Inst 1992;84: 1736 – 40. [11] Kaur G, Stetler-Stevenson M, Sebers S, Worland P, Sedlacek H, Myers C, et al. Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86-8275. J Natl Cancer Inst 1992;84(22):1736 – 40. [12] Bible KC, Kaufmann SH. Flavopiridol: a cytotoxic flavone that induces cell death in noncycling A549 human lung carcinoma cells. Cancer Res 1996;56:4856 – 61. [13] Losiewicz M, Carlson B, Kaur G, Sausville E, Worland P. Potent inhibition of CDC2 kinase activity by the flavonoid L86-8275. Biochem Biophys Res Commun 1994;201:589 – 95. [14] Sedlacek H, Hoffmann D, Czech J, Kolar C, Seemann G, Gussow D, et al. The change in research for the therapy of tumors. Chimia 1991;45:311 – 6. [15] Czech J, Hoffmann D, Naik R, Sedlacek H. Antitumoral activity of flavone L86-8275. Int J Oncol 1995;6:31 – 6. [16] Carlson B, Dubay M, Sausville E, Brizuela L, Worland P. Flavopiridol induces G1 arrest with inhibition of cyclin-dependant kinase (cdk) 2 and cdk 4 in human breast carcinoma cells. Cancer Res 1996;56: 2973 – 8. [17] Arguello F, Alexander M, Sterry JA, Tudor G, Smith EM, Kalavar NT, et al. Flavopiridol induces apoptosis of normal lymphoid cells, causes
E.C. Grendys Jr. et al. / Gynecologic Oncology 98 (2005) 249 – 253 immunosuppression, and has potent antitumor activity in vivo against human leukemia and lymphoma xenografts. Blood 1998;91:2482 – 90. [18] Senderowicz AM, Headlee D, Stinson SF, Lush RM, Kalil N, VIllalba L, et al. Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor in patients with refractory neoplasms. J Clin Oncol 1998;16:2986 – 99. [19] Patel V, Senderowicz A, Pinto D, Igishi T, Raffeld M, QuintanillaMartinez L, et al. Flavopiridol, a novel cyclin-dependent kinase inhibitor, suppresses the growth of head and neck squamous cell carcinomas by inducing apoptosis. J Clin Invest 1998;102:1674 – 81. [20] Thomas JP, Tutsch KD, Cleary JF, Bailey HH, Azroomanian R, Alberti D, et al. Phase I clinical and pharmacokinetic trial of the cyclin-dependent kinase inhibitor flavopiridol. Cancer Chemother Pharmacol 2002 (December);50(6):465 – 72.
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[21] Wright J, Blatner G, Cheson B. Clinical trials referral resource. Clinical trials of flavopiridol. Oncology 1998;12:23 – 4. [22] Schwartz GK, Ilson D, Saltz L, O’Reilly E, Tong W, Maslak P, et al. Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma. JCO 2001;19(7):1985 – 92. [23] Stadler W, Vogelzang N, Amato R, Sosman J, Taber D, Liebowitz D, et al. Flavopiridol, a novel cyclin-dependent kinase inhibitor, in metastatic renal cancer: a University of Chicago Phase II consortium study. J Clin Oncol 2000;18:371 – 5. [24] Bible KC, Kaufmann SH. Cytotoxic synergy between flavopiridol (NSC 649890, L86-8275) and various antineoplastic agents: the importance of sequence of administration. Cancer Res 1997;57: 3375 – 80.
A phase II evaluation of flavopiridol as second-line chemotherapy of endometrial carcinoma: A Gynecologic Oncology Group study Edward C. Grendys Jr.a,*,1, John A. Blessing b, Robert Burger c, James Hoffman d,1 a Florida Gynecologic Oncology, Fort Myers, FL 33901, USA Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA c Division of Gynecologic Oncology, Department of Obstetrics/Gynecology, University of California Medical Center, Irvine, Orange, CA 92868, USA d University of Connecticut Health Center, Department of Obstetrics and Gynecology, New Britain General Hospital, New Britain, CT 06052, USA b
Received 6 December 2004 Available online 22 June 2005
Abstract Objective. A phase II study was conducted to determine the efficacy of single agent flavopiridol therapy in patients with recurrent or persistent endometrial adenocarcinoma refractory to established treatments. Methods. Eligible patients with measurable disease who failed primary therapy including one cytotoxic regimen were eligible for the trial. They were treated with single agent flavopiridol (50 mg/m2/day, IV bolus days 1, 2, 3). Treatment was repeated every 21 days with dose adjustments made for toxicity. Patients were treated until progression of disease or adverse side effects precluded further therapy. Results. A total of 26 patients were enrolled in the study of whom, 23 patients were eligible. There were no objective responses. Five patients had stable disease (22%), 15 (65%) had increasing disease, and response could not be assessed in 3 (13%). The most frequent side effects included anemia, neutropenia, and diarrhea, all of which appeared manageable. Conclusion. Flavopiridol as a single agent in the above dosing schedule appears to have minimal activity as second-line chemotherapy of endometrial adenocarcinoma. D 2005 Elsevier Inc. All rights reserved. Keywords: Endometrial cancer; Chemotherapy; Flavopiridol; Flavone
Introduction Endometrial carcinoma is the most common malignant tumor of the female genital tract. Its incidence appears to be increasing and currently represents 13% of female cancers. Approximately 40,100 cases will be diagnosed in the year 2003, and 6800 women will succumb to this disease [1]. The primary treatment modality is surgical extirpation possibly combined with post-operative adjuvant local and/ or regional radiation therapy depending on surgico-pathologic risk factors. The overall 5-year survival is approx-
* Corresponding author. Florida Gynecologic Oncology, 2780 Cleveland Avenue, Suite 717, Fort Myers, FL 33901, USA. Fax: +1 239 992 6222. E-mail address: [email protected] (E.C. Grendys). 1 GOG Affiliate of Tufts-New England Medical Center. 0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2005.05.017
imately 85%. Localized pelvic disease is obviously managed well with the above-cited modalities; however, patients with extra pelvic disease on primary presentation, or at time of recurrence, have a dismal prognosis. There are multiple active cytotoxic and hormonal chemotherapy agents for the treatment of recurrent and metastatic endometrial cancer including platinum compounds, taxanes, anthracyclines, and topotecan [2 – 8]. These agents (often in combination) have lead to statistically significant improvements in response rates and progressionfree survival albeit often at the cost of significant toxicity. Still, complete response rates and long-term survival is extremely rare. Flavopiridol (NSC#46211) ( )-cis-2-(2-chlorophenyl)5,7-dihydroxy-8-[4R-(3S-hydroxy-1-methyl) piperidinyl)4H-1-benzopyran-4-one hydrochloride) is a synthetic flavone being developed as a novel antineoplastic agent. It is a
250
E.C. Grendys Jr. et al. / Gynecologic Oncology 98 (2005) 249 – 253
synthetic derivative of the flavonoid rohitukine initially isolated from Dysoxylum binectaisriferum plant indigenous to India [9]. It has been shown to have the potential ability to disrupt cell cycle progression by inhibition of regulatory reactions within the cell cycle and both cytotoxic activity (via apoptosis) and cytostatic activity has been demonstrated [9 –12]. The controlling proteins for these reactions include: epidermal growth factor receptor tyrosine kinase [13,14], serine/threonine kinase, protein kinase C [15], protein kinase A [13,14], and cyclin-dependent kinases (CDK) [16] which appear to be significantly dependent on serum concentrations of drug. CDK activity appears to be important in multiple phases of the cell cycle including G1, G1/S, G2/M and is competitively inhibited at very low concentrations of flavopiridol [16,17]. These concentrations (100 –400 AM) are clinically achievable at doses of 50 mg/ m2/day and appear to correlate with clinical responses in various tumor types [18]. Initial in vitro studies of flavopiridol have demonstrated growth inhibition of several human tumor cell lines in vitro as well as human tumor xenografts (lung, colon, ovary, brain, and breast) in nude mice [15]. Significant inhibitory activity against more than 60 tumor cell lines in the NCI tumor cell line in vitro screening panel was also noted [17,19]. Previous phase I experience has demonstrated a doselimiting toxicity of secretory diarrhea at doses of 62.5 mg/ m2/day. This diarrhea was controllable with the addition of loperamide or cholestyramine as antidiarrheal prophylaxis and dose escalation to 78 mg/m2/day was possible. Other minor acute grade I or II toxicities encountered at this dosing level included anorexia, fatigue, hypotension, fever, tumor pain, dermatitis, nausea, vomiting, and hyperbilirubinemia [18,20]. These trials enrolled a total of 114 patients. Antitumor activity including tumor regression and/or stabilization of disease complete response (CR), partial response (PR), or stable disease (SD) >6 months was observed in patients with tumors from multiple origins including renal, prostate, gastrointestinal, and adenocystic carcinoma of the lacrimal gland [20]. It appears that clinical activity is dose dependent and lower than recommended dosing and subsequent serum concentrations appear to produce minimal clinical activity [21,22]. Senderowicz et al. [18] demonstrated a proinflamatory syndrome with alterations in acute-phase reactants particularly at dose of greater than 50 mg/m2/day. In subsequent phase II studies, investigators have suggested a prothrombotic effect associated with flavopiridol. Schwartz et al. [22] noted 5 patients (33%) developed upper extremity venous thromboses at the central venous catheter directly after completion of the infusion. Stadler et al. [23] reported 3 arterial vascular events (non-fatal myocardial infarction, transient ischemic attack, transient scotomata, and vision loss) and 6 venous thrombotic events (2 associated with vascular access devices) for a total thrombotic event rate of
25%. The relationship of these events to flavopiridol was unclear though appeared to be higher than in the general oncologic population. Given the interesting properties including activity in solid tumors, good tolerance of this agent along with the potential synergistic activity with other active agents, the GOG decided to proceed with clinical phase II testing of this agent in endometrial carcinoma. To date, no previous studies in this tumor type with this agent have been reported.
Materials and methods This phase II study was designed to evaluate the clinical activity of flavopiridol in recurrent or persistent endometrial carcinoma. All histologic subtypes were eligible. Patients were required to have measurable disease as well as at least one target lesion to evaluate response as defined by RECIST criteria. Patients were to have had one prior cytotoxic chemotherapy regimen. Prior cytotoxic therapy must have been discontinued at least 3 weeks prior to registration and hormonal therapy (as treatment) must have been discontinued 1 week prior to registration. Patients with prior treatment with cyclin-dependent kinase inhibitors as well as those with prior radiation to more than 25% of marrowbearing areas were not eligible. Also, patients with prior history of thromboembolic events, thrombophlebitis, recent myocardial infarction, angina, CVA, or transient ischemic attack were similarly not eligible. Patients were required to have a GOG performance status of 0 – 2. Adequate hematologic reserve was required including WBC 3000/Al, ANC 1500/Al, and platelets normal per institutional standards. Serum creatinine was required to be less than or equal to 1.5 institutional norms as was bilirubin. SGOT and alkaline phosphatase were required to be 5 times institutional norms. No significant neuropathy greater than CTC grade 1 and normal coagulation profiles were required. All patients gave appropriate informed consent consistent with all federal, state, and local requirements to sign prior to study entry. A treatment cycle was considered 3 consecutive daily 1-h infusions. Antidiarrheal prophylaxis was given at the investigator’s discretion and coumadin prophylaxis (1 mg/ day) was recommended given previous phase II toxicity experiences. Patients were to be treated until disease progression, voluntary withdrawal, or the presence of unacceptable toxicity. Patients were evaluated for toxicity prior to each cycle and no subsequent cycle was to begin until adequate recovery was noted. Coumadin prophylaxis (1 mg/day) was recommended especially for patients with indwelling catheters, but was not required. Antidiarrheal prophylaxis (loperamide, etc.) was given at the investigator’s discretion. Prophylactic granulocyte-colony stimulating factor (G-CSF) was not allowed unless recurrent neutropenic complications
E.C. Grendys Jr. et al. / Gynecologic Oncology 98 (2005) 249 – 253 Table 1 Patient characteristics Characteristic Age Median Range Performance status 0 1 2 Cell type Endometrioid Serous Mixed epithelial Undifferentiated Adenocarcinoma, (type unspecified) Grade 1 2 3 Unspecified Site of disease Pelvic Extra pelvic Prior chemotherapy Prior radiotherapy Prior hormonal therapy Courses Median Range
Number of cases 63.0 39 – 76 15 6 2 10 6 2 2 3 4 9 9 1 3 20 23 14 5 2 1–9
occurred after appropriate treatment modifications. Patients were allowed to receive erythropoietin after documentation of hemoglobin of less than 10 g/dl. Grade 4 thrombocytopenia/neutropenia (>7 days) or febrile neutropenia required dose reduction. Greater than grade 2 peripheral neuropathy or renal toxicity required a one level dose reduction. Grade 3 liver function abnormalities or diarrhea (grades 3, 4) also required dose reduction. All dose reductions were 30% of initial dose. If no toxicity of greater than grade 1 was encountered, a subsequent dose escalation to 78 mg/m2/day was allowed. Patients who received any treatment were evaluable for toxicity and patients who received one or more cycles were evaluable for response. Response was defined via standard GOG RECIST criteria. A complete response was defined as the disappearance of all target and non-target lesions with no evidence of new lesions lasting at least 4 weeks. Partial response was defined as at least a 30% decrease in the sum of the longest dimensions of all target measurable lesions. There could be no unequivocal progression of non-target lesions and no new lesions noted. Increasing disease was defined as at least a 20% increase in the sum of longest dimensions of target lesions or the appearance of new lesions within 8 weeks of study entry. Progression was defined as greater than 20% of the sum of the longest dimensions, 50% increase in pelvic disease as measured by physical exam only, appearance of one or more new lesions, death due to disease without objective documentation of progression, or unequivocal progression of existing non-target lesions other than pleural
251
effusions. Stable disease was any condition not meeting the above criteria. The study employed a two-stage design with an early stopping rule in the event that the treatment demonstrated insufficient activity. During the first stage of the accrual, 19 – 26 patients were to be entered and evaluated. If at least three responses were observed among the first 19 – 25 patients, or at least four responses were observed among 26 patients, a second phase of accrual was to be initiated which would increase accrual to 44 – 51 patients. The regimen would be considered active if at least seven responses were observed among 44 – 45 patients, or at least eight responses were observed among 46– 51 patients. If the true probability of responding was only 10%, the study design provided a 90% chance of correctly classifying the treatment as inactive. Conversely, if the true response rate was 25%, then the probability of correctly classifying the treatment as active was 90%.
Results Between July 2001 and March 2003, member institutions of the Gynecologic Oncology Group (GOG) entered 26 patients with recurrent or persistent endometrial carcinoma on GOG protocol 129-M. Three cases were deemed ineligible upon review by the GOG Pathology Committee. Patient characteristics for the 23 eligible patients are presented in Table 1. The median age was 63.0 years. Sixty-five percent of patients (17) had a performance status of 0 while 2 patients (9%) had a performance status of 2. Fourteen patients (61%) had received prior pelvic radiotherapy. A median of 2 cycles of chemotherapy (range 1– 8) was administered. Two patients (9%) required a dose reduction. Adverse events are listed in Table 2. The most common significant toxicity was diarrhea. Ninety-one percent of patients reported some diarrhea associated with treatment with 14 patients (61%) experiencing grade 2 and 1 patient reporting grade 4 toxicity. Anemia occurred in 10 patients (43%). Neutropenia appeared manageable with no Table 2 Adverse events (n = 23) Grade
WBC Hemoglobin Platelets ANC/AGC Hematologic Cardiovascular Gastrointestinal Hepatic Infection Metabolic Pain Pulmonary
3 (%)
4 (%)
2 2 2 1 4 1 2 1 1 1 2 2
2 0 0 2 0 1 1 0 0 0 0 0
(8.7) (8.7) (8.7) (4.3) (12.4) (4.3) (8.7) (4.3) (4.3) (4.3) (8.7) (8.7)
(8.7) (0) (0) (8.7) (0) (4.3) (4.3) (0) (0) (0) (0) (0)
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significant septic-related complications. Other reported toxicity included mild thrombocytopenia, elevation of liver function tests and general fatigue. No thrombotic events were noted. No objective responses were observed. Stable disease was noted in 5 patients (21.7%) with median progressionfree interval of 3.2 months (range: 1.8 – 8.6 months). Fifteen patients (65.3%) had increasing disease. Response could not be assessed in 3 cases (13.0%). No patient experienced significant neutropenic-related complications.
Discussion Flavopiridol is a synthetic flavone shown to have specific antineoplastic properties. It appears to be an inhibitor of intracellular protein kinases with particular selectivity for cyclin-dependent kinases (CDK). Because of the role of CDKs in cell division cycle, it appears that inhibition of these specific kinases could lead to inhibition of cell proliferation. It has also demonstrated significant inhibition as a single agent in several human tumor xenografts when administered at appropriate doses and schedules. Single agent flavopiridol was investigated in patients with recurrent endometrial adenocarcinoma. It appeared to be well tolerated in general. The major toxicity appeared to be diarrhea with 91% of patients reporting some diarrhea associated with treatment and 61% experiencing greater than grade 2 gastrointestinal toxicity. Grade 2 or 3 anemia occurred in 8 patients (43%), while grade 2 or greater neutropenia occurred in 5 cases (22%). Our study demonstrates that, in this patient population, flavopiridol appeared to have minimal activity as a single agent with no complete response and one partial response. Therefore, this drug would not be recommended for further testing at this dose schedule. However, flavopiridol has shown in vitro cytotoxic synergy when combined with paclitaxel, cytarabine, topotecan, doxorubicin, etoposide, 5fluorouracil, and cisplatin and therefore may be considered for further testing as a combination agent [24].
Acknowledgments This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical and Data Center (CA 37517). The following Gynecologic Oncology Group member institutions participated in this study: Duke University Medical Center, Abington Memorial Hospital, Walter Reed Army Medical Center, University of Minnesota Medical School, University of Iowa Hospitals and Clinics, University of California Medical Center at Irvine, Tufts-New England Medical Center, Rush-Presbyterian-St. Luke’s Medical Center, The
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