Current Clinical Trials of Flavopiridol

September 1, 2002

Flavopiridol [2-(2-chlorophenyl 5 ,7-dihydroxy-8-[cis-(3-hydroxy-1-methyl-4-piperidinyl)-4H-1-benzopyran-4-one, hydrochloride] is a semisynthetic flavone with a novel structure compared with that of polyhydroxylated flavones, such as quercetin and genistein.[1] It is derived from rohitukine, an alkaloid isolated from the stem bark of Dysoxylum binectariferum, a plant indigenous to India.[2] Originally synthesized and supplied by Hoechst India Limited, flavopiridol is provided to the Division of Cancer Treatment and Diagnosis of the National Cancer Institute (NCI) by Aventis Pharmaceuticals, Inc.

Clinical Trials Referral Resource is designed to serve as a ready reference for oncologists to help identify clinical trials that might be suitable for their patients. We hope it will also enhance accrual to clinical trials by informing practicing oncologists of ongoing protocols. Currently in the United States less than 10% of eligible adult patients are entered into clinical trials. The result is a delay in answering important therapeutic and scientific questions and disseminating therapeutic advances to the general oncology community.

It should be emphasized that including a specific trial does not imply that it is more important than another trial. Among the criteria for selection are that the trial is addressing an important question and is not expected to close in the immediate future (less than 1 year), and that initial staging or laboratory tests required for patient eligibility are widely practiced and available. Information on other protocols can be accessed via Physician’s Data Query (PDQ).*

We emphasize that this is an attempt to encourage referral of patients to these trials. We are specifically not soliciting additional members for the cooperative groups, nor are we suggesting how practicing oncologists should be treating patients who are not in a study.

This month’s installment of Clinical Trials Referral Resource is devoted to current clinical trials of the Cancer Trials Support Unit, a National Cancer Institute pilot program.

For patient entry information, see the individual trials.

* PDQ is a comprehensive database service provided by the National Cancer Institute’s International Cancer Information Center and Office of Cancer Communications for retrieval of cancer treatment information, including peer-reviewed statements on treatment options, supportive care, screening, and prevention; and an international clinical trials registry. For more information on PDQ, online access is available at www.cancer.gov/cancer_information/pdq/, or contact the Cancer Information Service offices (1-800-4-CANCER).

Flavopiridol [2-(2-chlorophenyl 5 ,7-dihydroxy-8-[cis-(3-hydroxy-1-methyl-4-piperidinyl)-4H-1-benzopyran-4-one,hydrochloride] is a semisynthetic flavone with a novel structure compared withthat of polyhydroxylated flavones, such as quercetin and genistein.[1] It isderived from rohitukine, an alkaloid isolated from the stem bark of Dysoxylumbinectariferum, a plant indigenous to India.[2] Originally synthesized andsupplied by Hoechst India Limited, flavopiridol is provided to the Division ofCancer Treatment and Diagnosis of the National Cancer Institute (NCI) by AventisPharmaceuticals, Inc.

Mechanism of Action

Cell-cycle regulation is dependent on cyclin-dependent kinases (cdks), whichrequire association with cyclin proteins for activation.[3] Flavopiridol was thefirst compound with the potent ability to disrupt cell-cycle progression byinhibition of regulatory phosphorylations to be considered for clinicaldevelopment.

Flavopiridol inhibits several cellular kinases and has demonstratedcytostatic and cytotoxic activity in vitro and in vivo in numerous human tumorcell lines and xenograft models (including human breast, prostate, and lungcarcinoma) at clinically achievable concentrations.[1,4] Flavopiridol is capableof disrupting progression of cells through the cell cycle at the G1/S and G2/Mtransitions.[1,5,7] The direct inhibition of cdks 1, 2, and 4 via competitiveinhibition of adenosine triphosphate binding by flavopiridol has beendemonstrated.[5,7,9] Flavopiridol also inhibits cdk7/cyclin H, thus preventingthe phosphorylation and subsequent activation of several cdks[6,8] anddown-regulates cyclin D1, the cyclin associated with cdks 4 and 6.[10]

Flavopiridol-induced G1 arrest may be related to inhibition of cdk 2 and 4activity, as well as diminution of cyclin D levels; G2/M arrest may be due inpart to inhibition of cdk1 activity. Cdk4 and 2 kinase activities, as well ascyclins D, E, and A protein levels, are diminished following flavopiridolexposure in a number of in vitro models. In MCF-7 cells, flavopiridol-inducedG1/S arrest is associated with the loss of cdk4 and 2 activity and reducedcyclin D levels preceded by hypophosphorylation of Rb protein. The flavopiridol-induceddecline in cyclin D1 is an early, specific event, due in part to thetranscriptional repression of the cyclin D1 promoter.[11] Similarly, incdk4-deficient MCF-10A breast epithelial cells, flavopiridol-induced G1 arrestcoincided with Rb dephosphorylation and dose-dependent inhibition of cdk6-kinaseactivity associated with the loss of cyclin D1 expression.[12]

The efficacy of flavopiridol is not based solely on cell cycle arrest, sincethis agent induces death in noncycling A549 lung cancer cells by a process thatdepends on RNA and protein synthesis.[4] Parker and co-investigators[13]observed apoptosis in SUDHL-4 leukemia cells without evidence of cell-cyclearrest, suggesting that the antiproliferative effects can be separated from theproapoptotic activity of this agent.

Regulation of gene expression is another potential mechanism of action forflavopiridol. In human monocytes, flavopiridol causes down-regulation ofvascular endothelial growth factor (VEGF) messenger (m)RNA and proteinexpression induced by hypoxia. Flavopiridol does not affect hypoxia-inducedtranscriptional activation of VEGF but significantly decreases the VEGF mRNAhalf-life, suggesting that flavopiridol may have antiangiogenic activity.[14]Flavopiridol also inhibits the positive transcription elongation factor, whichis a protein kinase composed of cdk9 and a cyclin subunit (cyclin T1 or cyclinT2)[15] and controls the elongation phase of transcription by RNA polymeraseII.[16] The IC50 of flavopiridol is directly related to the concentration of thepositive transcription elongation factor.[17] (It is not known if theantiproliferative effects of flavopiridol are due to inhibition of the positivetranscription elongation factor or other cyclin-dependent kinases). Acomprehensive review of the mechanisms of action of flavopiridol was recentlypublished.[18]

Preclinical Activity

Flavopiridol should exert cytostatic activity because of the pivotal role ofthe cdks in the cell division cycle. Evidence demonstrating its cytostaticactivity includes the finding that it inhibits the growth of a broad spectrum ofhuman tumor cell lines in vitro. In the NCI tumor cell line panel, flavopiridolhad significant inhibitory activity against all of the more than 60 human tumorcell lines with no clear selectivity for tumor type. IC50 values ranged fromapproximately 50 to 200 nM,[1] similar to concentrations required to inhibitcdks. Flavopiridol-induced growth inhibition seems to be independent of tumor Rb,cyclin D1, p16, and p53 status.[19,21]

Administration of flavopiridol after or concomitant with antineoplasticagents, including mitomycin C (Mutamycin), paclitaxel, gemcitabine (Gemzar),SN-38 (the active metabolite of CPT-11), imatinib mesylate (Gleevec), anddoxorubicin can promote chemotherapy-induced apoptosis.[22-29] Recent reportssuggest a marked increase in apoptosis when differentiating agents such asphorbol 12-myristate 13-acetate (PMA), suberoylanilide hydroxamic acid (SAHA),and depsipeptide are combined with flavopiridol.[30-32] Cytotoxic synergy wasmore pronounced when non-small-cell lung cancer (NSCLC) A549 cells wereexposed to flavopiridol after rather than before or concomitant with paclitaxel,cytarabine, topotecan (Hycamtin), doxorubicin, and etoposide.[33]

Clinical Data

NCI-sponsored clinical trials of flavopiridol were initiated in 1994.Preclinical data suggested that prolonged exposure was necessary to achievemaximal antitumor effect.[1] Two phase I trials used a 72-hour infusionevery-2-weeks schedule. In a trial at the NCI, diarrhea was dose-limiting, andthe maximum tolerated dose was 50 mg/m²/24h ´ 3.[34] Aggressive prophylaxis ofdiarrhea allowed for further dose escalation to a maximum tolerated dose of78 mg/m²/24h ´ 3, with dose-limiting hypotension seen at higher doses.Anorexia and asthenia were additional major toxicities. Mean steady state plasmaflavopiridol concentrations achieved at the maximum tolerated doses were 271 nM(range: 174-2,943 nM) and 344 nM (range: 130-1557 nM), respectively, withpostinfusion peaks suggestive of enterohepatic recirculation.

Diarrhea was also dose limiting in a trial using the same schedule conductedat the University of Wisconsin.[35,36] The maximum tolerated dose was 40mg/m²/24h ´ 3; nausea, vomiting, and orthostatic hypotension occurred at themaximum tolerated dose. In this trial, a steady state concentration of 415 nMwas achieved at the maximum tolerated does. Antitumor activity against renalcell carcinoma, colon carcinoma, non-Hodgkin lymphoma, and gastric carcinoma (aprolonged complete response) was seen in these studies.

Results of four single-agent flavopiridol studies incorporating a continuousinfusion 50 mg/m²/24h ´ 3 every 14 days in patients with renal cell, gastric,colon, and non-small- cell lung carcinoma confirmed an adverse event profiledominated by diarrhea, nausea, vomiting, and asthenia.[37-40] In addition, 19 of89 patients (21%) experienced venous thromboses, including 12 at the centralvenous catheter site. Two patients experienced transient ischemic attacks, andone, a myocardial infarction. Two complete responses in patients with renal cellcancer were the only objective responses reported in these trials.

Additional schedules of administration are being pursued because of thedisappointing degree of antitumor activity achieved with the 72-hour scheduleand because of additional preclinical data that suggested higher plasmaconcentrations of flavopiridol may be necessary to obtain tumoricidalactivity.[41] NCI investigators followed their original phase I infusional studywith an exploration of daily 1-hour infusions for 1 to 5 days every 21 days.They defined maximum tolerated doses of 37.5, 50, and 62.5 mg/m²/d for 5-, 3-,and 1-day administrations, respectively, and documented median peak plasmaconcentrations of 1.7, 3.2, and 3.8 µM with these schedules.[42,43] Neutropeniawas the primary dose-limiting toxicity, but diarrhea and a proinflammatorysyndrome of anorexia, tumor pain, fever, and asthenia were also prominent. Fivepatients (9%) experienced thrombotic events (three lower-extremity deep-veinthromboses and two catheter-related thromboses).

Investigators at the National Cancer Center East in Japan determined that 80mg/m² was tolerable on a weekly 24-hour infusion schedule and achieved a meanCmax of 718 nM.[44]

Phase II Trials

The NCI is sponsoring seven phase II single agent trials of flavopiridolutilizing 1-hour infusion schedules in patients with the following cancers:endometrial, head and neck, melanoma, renal cell, soft-tissue sarcoma, chroniclymphocytic leukemia, and mantle cell lymphoma. Published data are available fortwo trials in which patients with mantle cell lymphoma[45] and previouslyuntreated metastatic malignant melanoma[46] were treated at 50 mg/m²/d ´ 3days every 21 days. No objective responses were seen in 17 patients withmelanoma. Of 25 evaluable patients with mantle cell lymphoma, 3 achievedpartialresponses lasting 2.8 to 9.1 months, and 18 patients had stable disease for 1.3to 10.3 months. of the 27 patients with mantle cell lymphoma, 16 had receivedprior chemotherapy. Significant toxicities in these trials included grade 3 and4 neutropenia, fatigue, and diarrhea, and grade 3 nausea, tumor pain, cough,dyspnea, and anorexia.

Phase I Trials

The NCI is also the sponsor of a number of clinical trials of flavopiridol incombination with FDA-approved anticancer compounds. Reported results of phase Icombination studies are summarized here.

Schwartz and colleagues conducted a two-part dose-finding trial to define themaximum tolerated dose of the combination of paclitaxel on day 1 followed byflavopiridol on day 2 and the maximum tolerated dose of a three-drug sequence ofpaclitaxel on day 1 followed by flavopiridol and cisplatin on day 2. In thetwo-drug trial, pulmonary toxicity was dose-limiting, and the recommended phaseII dose was 3-hour paclitaxel at 175 mg/m² on day 1 followed by 24-hourflavopiridol, 70 mg/m², on day 2 of a 21-day cycle.[47] Flavopiridol doseescalation to 80 mg/m² with 175 mg/m² of paclitaxel was also tolerated.

Objective responses were achieved in patients with adenocarcinoma of theesophagus (one complete response, one partial response), prostate cancer (oneminor response) and adenocarcinoma of the lung (one minor response). Whenescalating doses of cisplatin were added to fixed doses of the same sequence ofpaclitaxel and flavopiridol, the maximum tolerated dose was paclitaxel at175 mg/m² on day 1 followed by cisplatin at 50 mg/m² given justprior to flavopiridol at 80 mg/m² on day 2.[48] Neutropenia, nausea, andcardiac toxicity were dose-limiting. Clinical responses were obtained inpatients with esophageal and lung cancer.

Gries and colleagues recently reported the results of a phase I trial offlavopiridol in combination with paclitaxel and carboplatin (Paraplatin).[49]Patients with previously untreated advanced NSCLC were treated with a regimenconsisting of a 3-hour infusion of paclitaxel at 175 mg/m² followed bycarboplatin at an area under the concentration-time curve of 5 on day 1 and a24-hour infusion of flavopiridol in escalating doses of 30 to 85 mg/m² on day2. The maximum tolerated dose of flavopiridol was 70 mg/m², defined by grade 3anemia, heart arrest, leukopenia, and one patient with a myocardial infarctionat the next higher dose. One patient experienced deep-vein thrombosis, another apulmonary embolus.

A preliminary report on the combination of docetaxel and flavopiridol inbreast cancer patients found that neutropenia was dose-limiting when docetaxel,60 mg/m² on day 1, was followed by a 72-hour infusion of flavopiridol on days2, 3, and 4, both at the starting flavopiridol dose of 50 mg/m²/24h and areduced dose of 28 mg/m²/24h.[50] Pharmacokinetic activity of the flavopiridolwas in the range seen with single-agent flavopiridol, but no docetaxelpharmacokinetic data were reported. Accrual to cohorts receiving 50 mg/m² ofdocetaxel on a revised 1-hour infusion schedule of flavopiridol is ongoing.Additional studies exploring alternative schedules of the combination ofdocetaxel and flavopiridol are under way.

Bible and colleagues established 60 mg/m² of cisplatin and 100 mg/m² offlavopiridol (24-hour infusion) as the maximum tolerated dose in a phase I studyof 25 patients.[51] Principle significant toxicities were gastrointestinal—nausea,vomiting, and diarrhea. The trial continues to accrue to acarboplatin-plus-flavopiridol arm.

Shah and colleagues recently reported the preliminary results of a phase Itrial of the combination of irinotecan (CPT-11, Camptosar) with flavopiridol,both on a weekly every-4-of-6-weeks schedule [52]. The flavopiridol wasadministered as a 1-hour infusion, 7 hours after the irinotecan, based on animalmodel data suggesting timing of administration was relevant to maximize theantitumor effect of the combination. The maximum tolerated dose on this schedulewas irinotecan at 100 mg/m² with flavopiridol at 60 mg/m². Dose-limitingneutropenia and diarrhea prevented further dose escalation of flavopiridol.Preliminary pharmacokinetic data suggest a metabolic interaction betweenirinotecan and flavopiridol. Enrollment continues to cohorts being treated withirinotecan at125 mg/m²/wk with dose escalation of flavopiridol.

Future Directions

The Cancer Therapy Evaluation Program (CTEP) will continue to support theclinical development of flavopiridol. Presently, the three primary areas forcontinued clinical development are:

(1) Abbreviated infusional schedules of flavopiridol, both as a single agentand in combination with other agents

(2) Studies designed to ask questions concerning the anticancer effects offlavopiridol in combination with other drugs

(3) Studies designed to ask questions concerning the purported molecularmechanisms of the anticancer effects of flavopiridol in humans. These studiesare designed to promote acquisition of relevant human specimens both before andafter flavopiridol administration, especially in patients whose tumors havemolecular pathophysiology that includes targets with which flavopiridol mightdirectly interact.

Phase II

Title: Phase II Trial of Flavopiridol and Paclitaxel in Patients withPaclitaxel-Refractory Esophageal Cancer
Protocol Number: 1672
Participating Institutions: Memorial Sloan-Kettering Cancer Center,National Cancer Institute Surgery Branch
Protocol Status: Active
Contact: Gary Schwartz, MD, (212) 639-8324

Title: A Phase II Study of Flavopiridol (NSC #649890) in Patients withFludarabine Refractory B-Cell Chronic Lymphocytic Leukemia
Protocol Number: CALGB-19805
Participating Institution: Cancer and Leukemia Group B
Protocol Status: Active
Contact: John Byrd, MD, (614) 293-9321

Title: A Phase II Evaluation of Flavopiridol (NSC# 648890, IND# 46211)in the Treatment of Recurrent or Persistent Endometrial Carcinoma
Protocol Number: GOG-0129M
Participating Institutions: Gynecologic Oncology Group, University ofChicago
Protocol Status: Active
Contact: Edward Grendys, MD, (813) 972-8478

Title: A Phase II Trial of Daily Bolus Flavopiridol for FiveConsecutive Days in Patients with Recurrent/Metastatic Squamous Cell Carcinomaof the Head and Neck (SCCHN)
Protocol Number: T99-0066
Participating Institution: National Cancer Institute Medicine Branch
Protocol Status: Active
Contact: Edward Sausville, MD, (301) 496-8720

Phase I/II 

Title: A Phase I/II Trial of Docetaxel Followed by Flavopiridol inPatients with Previously Treated Locally Advanced or Metastatic Breast Cancer
Protocol Number: 952
Participating Institutions: National Cancer Institute Medicine Branch
Protocol Status: Active
Contact: Sandra Swain, MD, (301) 451-6882

Title: A Phase I/II Study of Flavopiridol (NSC 649890, IND 46,211) inTimed Sequential Combination with Cytosine Arabinoside (Ara-C) and Mitoxantronefor Adults with Poor Risk Acute Leukemia and Myelodysplasia
Protocol Number: 3170
Participating Institutions: Mayo Clinic, University of Maryland CancerCenter, Walter Reed Army Medical Center
Protocol Status: Active
Contact: Judith Karp, MD, (410) 328-7394

Phase I

Title: An Open-Labeled, Non-Randomized Phase I Study of FlavopiridolAdministered with Irinotecan (CPT-11) in Patients with Advanced Solid Tumors
Protocol Number: 2272
Participating Institution: Memorial Sloan-Kettering Cancer Center
Protocol Status: Active
Contact: Gary Schwartz, MD, (212) 639-8324

Title: Phase I Study of Flavopiridol in Combination with5-Fluorouracil, Leucovorin and Irinotecan in Patients with Advanced Malignancies
Protocol Number: 2450
Participating Institution: Mayo Clinic
Protocol Status: Active
Contact: Keith Bible, MD, (507) 284-2511

Title: An Open-Labeled, Non-Randomized Phase I Study of FlavopiridolAdministered with Irinotecan (CPT-11) and Fluorouracil/Leucovorin in Patientswith Advanced Solid Tumors
Protocol Number: 5757
Participating Institution: Memorial Sloan-Kettering Cancer Center
Protocol Status: Active
Contact: Gary Schwartz, MD, (212) 639-8324

Title: Phase I Study of Trastuzumab (Herceptin)/Flavopiridol in HER-2Positive Metastatic Breast Cancer
Protocol Number: 5867
Participating Institutions: Dana-Farber Cancer Center
Protocol Status: Active
Contact: Lyndsay Harris, MD, (617) 632-6766

Title: A Phase I Study of Flavopiridol in Patients with Relapsed orRefractory Pediatric Solid Tumors
Protocol Number: ADVL0017
Participating Institutions: Children’s Oncology Group
Protocol Status: Active
Contact: James Whitlock, MD, (615) 936-1762

Title: Phase I Study of Flavopiridol in Combination with Cisplatin orCarboplatin in Patients with Advanced Malignancies
Protocol Number: T97-0032
Participating Institution: Mayo Clinic
Protocol Status: Active
Contact: Keith Bible, MD, (507) 284-2511

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48. Shah MA, Kaubisch A, O’Reilly E, et al: A phase IB clinical trial ofthe sequence dependent combination of paclitaxel (P) and cisplatin (C) with thecyclin dependent kinase (CDK) inhibitor flavopiridol in patients with advancedsolid tumors. Proc Am Assoc Cancer Res:A2917, 2001.

49. Gries J-M, Kasimis B, Schwarzenberger P, et al: Phase I study of HMR1275(flavopiridol) in non-small cell lung cancer (NCSLC) patients after 24hr IVadministration in combination with paclitaxel and carboplatin). Proc Am Soc ClinOncol:A372, 2002.

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