ALBERT

Description: Key Points Cytoreduction with obinutuzumab and ibrutinib followed by the addition of venetoclax has acceptable safety with no tumor lysis syndrome. This combination has preliminary activity including complete remissions with undetectable residual disease in relapsed or refractory CLL.

Description: We previously reported interim results of a phase 1 trial in patients with chronic lymphocytic leukemia (CLL) whereby flavopiridol was administered intravenously as a 30-minute bolus followed by 4-hour infusion. We now report full pharmacokinetic (PK) data, correlations of PK with clinical outcomes, and final response and progression-free survival (PFS). Twenty-one (40%) of 52 patients with relapsed CLL achieved a partial response (PR) with a median PFS of 12 months. Responders included 17 (40%) of 43 fludarabine refractory patients, 7 (39%) of 18 patients with del(17p13), and 14 (74%) of 19 patients with del(11q22). Six responders received repeat therapy at relapse, and 5 responded again with a second median PFS of 10 months. Noncompartmental analysis and nonlinear mixed effects modeling was used to estimate PK parameters and evaluate covariates. Two-compartment population parameter estimates were 31.4 L/h, 65.8 L, 8.49 L/h, and 157 L for CL, V1, Q, and V2, respectively. Flavopiridol area under the plasma concentration-time curve (AUC) correlated with clinical response and cytokine release syndrome, and glucuronide metabolite AUC correlated with tumor lysis syndrome. These composite results confirm high activity of this pharmacokinetically derived schedule in relapsed, genetically high-risk CLL. Furthermore, PK describes some, but not all, variability in response and toxicity.

Description: Background: Relapsed CLL patients (pts) with del(17p13) and other high-risk genetic features respond poorly to most standard therapies. Flavopiridol (alvocidib) induces p53-independent apoptosis of CLL cells in vitro. We previously conducted a phase I study of flavopiridol using a pharmacokinetically (PK) derived dosing schedule of 30-min IV bolus (IVB) followed by 4-hr continuous IV infusion (CIVI). Clinical activity (response rate 45%) was seen in high-risk pts, but several pts required hemodialysis for severe tumor lysis syndrome (TLS) and hyperkalemia. Study Design and Treatment: We report preliminary results of an ongoing phase II study of flavopiridol in relapsed CLL. Pts with symptomatic, relapsed CLL who have failed (or could not receive) fludarabine and have WBC 〈 200 × 109/L are eligible. Pts receive flavopiridol by 30-min IVB followed by 4-hr CIVI weekly for 4 doses, every 6 weeks for up to 6 cycles. Pts receive 30 mg/m2 IVB + 30 mg/m2 CIVI for dose 1, and pts receive 30 mg/m2 IVB + 50 mg/m2 CIVI with the second and all subsequent doses if severe TLS is not observed. Results: We report results of the first 31 pts (19 male). Median age was 65 years (range, 41–82), with 9 pts ≥ 70 years of age. Median number of prior therapies was 6 (range, 1–11), and 30 pts had failed fludarabine. Pts had bulky Rai stage I/II (n=5), III (n=5) or IV (n=21) disease, and 27 pts had bulky lymphadenopathy ≥ 5 cm. Therapy was well tolerated. No patients required hemodialysis, and toxicity was otherwise similar to the phase I study. Cytokine release syndrome related to interleukin (IL)-6 was observed in a majority of pts, and symptoms responded to dexamethasone. Pts received a median of 3 cycles (range, 0.25–6). Two pts completed all 6 cycles, and 2 pts continue to receive therapy. The most common reasons for early discontinuation of therapy were failure to respond (n=11) and patient choice (n=6). Fifteen of 31 pts responded (48%) by NCI Working Group criteria; 13 pts achieved a partial response (PR), and 2 pts attained CR. One CR pt achieved a flow negative bone marrow (BM), and the other CR pt had 〈 1% residual CLL in BM by flow cytometry. Five of 9 pts with del(17p13) responded (56%), 5 of 15 pts with del(11q22) responded (33%), and 7 of 18 pts with a complex karyotype responded (39%). Follow-up remains short, but progression-free survival will be updated. Conclusions: This study confirms the significant clinical activity of flavopiridol in heavily pretreated, relapsed CLL pts with bulky adenopathy and poor-risk cytogenetic features. Furthermore, 2 pts achieved CR, including 1 pt with flow-negative BM. Limiting eligibility to WBC 〈 200 × 109/L improved safety, and no pts required dialysis. However, cytokine release syndrome related to IL-6 was common and caused pts to elect to end therapy. Therefore, this study has been amended to give prophylactic dexamethasone, and the schedule has been shortened with the use of prophylactic pegfilgrastim, in order to improve tolerability. Accrual to the amended study is ongoing.

Description: Background: The cyclin-dependent kinase inhibitor flavopiridol (alvocidib) induces p53-independent apoptosis and may be able to eliminate tumor cells resistant to fludarabine and rituximab. Study Design and Treatment: We report final results of a phase I dose escalation study of flavopiridol in combination with fludarabine and rituximab (FFR) in patients (pts) with mantle cell lymphoma (MCL), indolent B-cell non-Hodgkin’s lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL). Pts had ANC 3 1500, hemoglobin 3 9.0, platelets 3 100,000, adequate organ function, and ECOG performance status 0–2, and provided informed consent. Pts received fludarabine 25 mg/m2 IV on day 1–5 and rituximab 375 mg/m2 on day 1 every 28 days for up to 6 cycles. Flavopiridol was administered 50 mg/m2 by 1-hr IV bolus on day 1 (cohort 1, n=15) or day 1 and 2 (cohort 2, n=6) of each cycle. Based on promising results with a novel single agent dosing schedule in CLL, the study was amended to give flavopiridol by 30-min IV bolus followed by 4-hr IV infusion at a dose of 20 mg/m2 + 20 mg/m2 (cohort 3, n=3) or 30 mg/m2 + 30 mg/m2 (cohort 4, n=14) beginning with cycle 2. Pts were placed on prophylactic Bactrim and Valtrex. Growth factor support was allowed in cohorts 3 and 4. Results: Thirty-eight pts were enrolled. Median age was 62 years (range, 38–81), and 22 pts were male (58%). Pts had CLL (11), MCL (10), follicular (FL, 9), small lymphocytic (3), marginal zone (4) or lymphoplasmacytic lymphoma (1). Sixteen pts had received 1 or 2 prior therapies; 22 pts were previously untreated. Two of 6 pts in cohort 2 developed dose limiting toxicity; 1 pt developed grade 3 confusion and grade 3 seizures, and 1 pt developed nausea and diarrhea resulting in grade 3 acute renal failure. Fifteen pts were enrolled in cohort 1 and 14 pts were enrolled in cohort 4, to better define toxicity and efficacy. Pts received a median of 4 cycles (range 1–6), and 16 of 38 pts completed all 6 planned cycles. Cytopenias (10), fatigue (3), fever (2) and progression (2) were the most common reasons for early discontinuation of therapy. Response was graded by NCI 96 criteria (CLL) or IWG criteria (NHL). Overall response rate (ORR) was 82% (CR 50%, CRu 5%, PR 26%). Median progression-free survival (PFS) of responders was 25.5 months. ORR (82% vs. 81%), CR (50% vs. 50%) and median PFS (25.7 vs. 25.1 months) were similar for previously untreated and relapsed pts. Thirteen pts remain in remission with a median PFS of 33.5 months (range, 17.5–59.5), and 3 other pts died of unrelated causes. Eight of 10 MCL pts (median age 68, range 62–81) responded (7 CR, 1 PR). Two responders with blastoid variant MCL relapsed within 1 year, but median PFS of the other 6 responding MCL pts was 33.5 months. All 9 FL pts responded (5 CR, 2 CRu, 2 PR) with a median PFS of 25.1 months (range, 4.0–46.3). Conclusions: FFR exhibited significant clinical activity in indolent B-NHL, MCL and CLL. FFR was effective in both relapsed and previously untreated pts and showed promising clinical activity in older MCL pts. Changing from 1-hr IV bolus dosing to 30- min IV bolus followed by 4-hr IV infusion did not improve the response rate, suggesting that 1-hr IV bolus dosing may be effective when flavopiridol is given as part of combination chemotherapy. This regimen warrants further study.

Description: Background: Flavopiridol induces p53-independent apoptosis in CLL cells in vitro. Clinical studies using 24–72-hr continuous IV infusion (CIVI) schedules showed little activity, due to increased drug binding to human plasma proteins and inadequate free drug concentrations in vivo. Pharmacokinetic (PK) modeling indicated that giving flavopiridol by IV bolus (IVB) followed by 4-hr CIVI would achieve the necessary concentration to induce apoptosis of CLL cells. Methods: We conducted a phase I study in relapsed CLL using this PK-derived dosing schedule. Patients (pts) received flavopiridol by 30-min IVB followed by 4-hr CIVI weekly for 4 doses, every 6 weeks for up to 6 cycles. Results: Fifty-eight pts (43 male) with relapsed CLL (n=48) or small lymphocytic lymphoma (n=10) were enrolled. Median age was 60 years (range, 38–84). Median number of prior therapies was 4 (range, 1–14); 57 pts had failed fludarabine, with 48 pts refractory to or intolerant of fludarabine. Pts had bulky Rai stage I/II (n=13) or III/IV (n=45) disease. In the initial 2 cohorts, pts received 30 mg/m2 IVB + 30 mg/m2 CIVI (cohort 1, n=20) or 40 mg/m2 IVB + 40 mg/m2 CIVI (cohort 2, n=3). DLT was acute tumor lysis syndrome (TLS) in 2 pts in cohort 2. The 0.5 and 4.5 hr Cmax were 2.08 μM and 0.96 μM. PK modeling indicated that increasing the 4-hr CIVI dose would attain the target 4.5 hr Cmax of 1.5 μM. Thus, 14 of 19 pts in cohort 3 underwent dose escalation to 30 mg/m2 IVB + 50 mg/m2 CIVI beginning with cycle 2. Five pts were not dose escalated due to severe TLS with dose 1. Increased anti-tumor activity was observed with dose escalation. Median LDH was 344 U/L (range, 147–5591) with dose 1, and 858 U/L (range, 215–2658) with dose 1 of cycle 2. Eleven of 19 pts (58%) in cohort 3 achieved PR, including 10 of 14 pts (71%) undergoing dose escalation. The 0.5 and 4.5 hr Cmax were 1.95 μM and 1.54 μM at the escalated dose. Five of 8 pts with WBC ≥ 200 x 109/L in cohorts 1–3 required hemodialysis for severe TLS with dose 1, compared to 1 of 34 pts with WBC 〈 200 x 109/L. To determine if dose escalation could be safely performed earlier in pts at lesser risk of TLS, cohort 4 enrolled 16 pts with WBC 〈 200 x 109/L, with dose escalation at dose 2 of cycle 1. One 1 pt required dialysis, and 14 pts were dose escalated. Preliminary results of cohort 4 indicate modestly greater clinical activity at the escalated dose; median LDH was 280 U/L (range, 119–1616) with dose 1, and 377 U/L (range, 140–2547) with dose 2. Six of 16 pts in cohort 4 achieved PR, and 2 additional pts experienced 〉 50% reduction of disease without improvement in counts. PK data from cohort 4 is being analyzed. In total, 28 pts were dose escalated beginning at cycle 2 (n=14) or dose 2 of cycle 1 (n=14); 4 pts required transient dialysis with dose escalation but were able to receive additional doses of flavopiridol, and 15 pts attained PR (54%). Conclusions: Flavopiridol can be safely dose escalated to 30 mg/m2 IVB + 50 mg/m2 CIVI in pts with WBC 〈 200 x 109/L if there is not severe TLS with dose 1. Increasing the 4-hr CIVI dose achieves the target 4.5 hr Cmax and translates into higher clinical activity. Multi-center phase II studies to further investigate the safety and clinical activity of this dose escalation schedule are underway.

Description: The cyclin-dependent kinase inhibitor flavopiridol was inactive when administered as a 72-hour infusion, but a 1-hr IV bolus dosing schedule demonstrated clinical activity in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Flavopiridol induces apoptosis via a p53-independent mechanism. Thus, we hypothesized that flavopiridol may eliminate tumor cells resistant to fludarabine and rituximab. We report preliminary results of an ongoing phase I dose escalation study of flavopiridol in combination with fludarabine and rituximab in patients (pts) with MCL, CLL and other indolent B-cell lymphoproliferative disorders. Pts had adequate marrow function (ANC ≥ 1500, hemoglobin ≥ 9.0, platelets ≥ 100,000), organ function, and performance status (ECOG 0–2) and provided informed consent. Pts in all cohorts received fludarabine 25 mg/m2 IV on days 1–5 and rituximab 375 mg/m2 on day 1 of each 28-day cycle. The planned dose escalation of flavopiridol was 50 mg/m2 by 1-hr IV bolus on day 1 (cohort 1), days 1–2 (cohort 2), or days 1–3 (cohort 3) of each cycle. Treatment was for up to 6 cycles, and pts were placed on prophylactic Bactrim and Valtrex. Fifteen pts have been enrolled to date, and 9 pts are evaluable for toxicity and response. Median age of these 9 pts was 67 years (range, 43–72), and 4 pts were male. Pts had the following diagnoses: CLL (5), MCL (2) and follicular lymphoma (FL; 2). Four pts had received 1–2 prior therapies; 5 pts were previously untreated. CLL pts had Rai stage III/IV disease (2) or required treatment for Rai stage I/II disease (3) by NCI 96 criteria. MCL/FL pts were stage III/IV (3) or had progressive stage II disease (1). Three pts were treated in cohort 1; 2 pts completed 6 cycles, but 1 pt was removed from study after cycle 3 due to prolonged cytopenias. Six pts were treated in cohort 2. Two pts developed dose-limiting toxicity; 1 pt developed grade 3 confusion and grade 3 generalized seizures during cycle 2, and 1 pt developed nausea and diarrhea, which resulted in grade 3 acute renal failure. Infectious toxicity was limited to 1 pt who was hospitalized for 48 hrs with a grade 3 upper respiratory infection and febrile neutropenia. Three pts in cohort 2 were removed from study for prolonged cytopenias after 3, 3 and 4 cycles; only 1 pt in cohort 2 completed 6 cycles. Two of the 6 pts in cohort 2 did not receive flavopiridol after cycles 2 and 3, due to life threatening tumor lysis in our single agent flavopiridol study. Response was graded by NCI 96 criteria (CLL) or IWG criteria (MCL/FL). Overall response rate (ORR) was 100%; 7 pts (78%) achieved CR, and 2 pts achieved PR (22%). Two pts relapsed after 7 and 8 months; 7 pts remain in remission a median of 9 (range,7–12) months after therapy. Of note, all 4 MCL/FL pts remain in CR. An ongoing expansion of 12 pts at the cohort 1 dose level is being conducted, to better define toxicity and efficacy; 6 pts have been enrolled to date. In conclusion, flavopiridol, fludarabine and rituximab exhibited significant clinical activity in a small group of pts, with a 78% CR rate. This combination warrants further study, particularly with consideration to an altered flavopiridol schedule using our highly active 30-minute bolus followed by 4-hour infusion regimen.

Description: Abstract 3446 Poster Board III-334 Background Chronic lymphocytic leukemia (CLL) is a disease characterized by both humoral and cellular immune defects. Lenalidamide is an immunomodulatory drug that has clinical activity in multiple myeloma and myelodysplastic syndrome. Although the exact mechanism of action is unknown, lenalidomide has been reported to promote cellular and innate immune activation; interfere with the tumor microenvironment, angiogenesis, and cytokine production; and induce the tumor suppressor gene SPARC. Two prior phase II studies in patients with relapsed/refractory CLL using higher doses of lenalidomide have shown clinical activity (Chanan-Khan et al J CLin Oncol 2006; Ferrajoli et al Blood 2008), although 58% of patients developed tumor flare and two patients developed acute tumor lysis in the former and 27% of patients developed tumor flare in the latter. In addition, a phase II study of lenalidomide in previously untreated, symptomatic CLL patients (Chen et al ASH 2008) demonstrated clinical activity using lower doses of lenalidomide after acute tumor lysis was seen at higher doses. We present preliminary data of a phase I dose escalation study of lenalidomide to determine the maximum tolerated dose (MTD), toxicities and preliminary efficacy in patients with relapsed CLL. Methods Eligibility criteria included patients with a diagnosis of B-cell CLL or SLL requiring therapy, who previously received treatment with one or more chemotherapy regimens, had an absolute lymphocyte count 〈 200,000, and an ECOG performance status 0-2. Patients were treated with lenalidomide daily days 1-21 of a 28 day cycle at a starting dose of 25 mg. Results Three patients were enrolled at the starting dose of 25 mg and have previously been reported (Andritsos et el J Clin Oncol 2009). One patient was treated off study per protocol. Three of these patients experienced significant tumor flare, resulting in one death, and the fourth patient developed grade 3 neutropenia with sepsis. The protocol was amended to reduce the dose of lenalidomide and include an intrapatient dose escalation (Table 1). The starting dose was 2.5 mg. Fourteen patients have been accrued since the amendment. Eight males and six females were enrolled with median age of 57 (range 37-73) and median number of prior therapies of 4.5 (range 1-9). Dose limiting toxicity (DLT) occurred in 3 of 6 patients treated in the cohort receiving 2.5 mg daily week 1, 5 mg week 2, and 7.5 mg week 3 and thereafter. Dexamethasone prophylaxis (4mg/day) was administered for 7 days. DLT included grade 4 thrombocytopenia in one patient, grade 4 neutropenia in one patient, grade 3 neutropenia with pneumonia in one patient and grade 2 tumor flare in one patient. All of these patients were heavily pre-treated. Non-DLT hematologic toxicities included grade 3 anemia (2) and grade 3-4 neutropenia (3). Non-DLT hematologic toxicity included grade 2 tumor flare (1), grade 3 hemolysis (1), grade 3 pneumonia (3) and grade 3 fatigue (1). Two patients experienced tumor flare at the 2.5 mg dose level prior to initiating corticosteroids on day 3. To date, ten patients are evaluable for response. One patient treated at the highest dose level who was subsequently dose reduced to 5 mg had a partial response, and 2 patients had stable disease. 5 patients treated at 5 mg continuous dosing (the MTD) had stable disease. 2 patients had progressive disease at continuous dosing of 5 mg and 7.5 mg. Evidence of B-cell activation in vivo was observed including up-regulation of multiple NF-κB target genes. In one patient with lenalidomide induced tumor flare and associated hypercalcemia, treatment-induced tumor PTH-RP production was noted that reversed with cessation of therapy. Conclusions Lenalidomide can induce tumor flare even at very low doses in patients with active CLL. The MTD of lenalidomide in heavily pre-treated CLL patients is 2.5 mg orally daily week one escalating to 5 mg orally daily for subsequent weeks with continuous dosing. We have limited our dose escalation of lenalidomide to less heavily treated patients and accrual continues. Our laboratory data suggest that B-cell activation may correlate with development of tumor flare and other toxicities including hypercalcemia observed in a subset of CLL patients. Disclosures Off Label Use: Lenalidomide, an immunomodulatory agent approved in MM and MDS, is used in this phase I clinical study to determine maximum tolerated dose and toxicities in CLL. Blum:Celgene: Research Funding. Andritsos:Celgene: Research Funding.

Description: Background: Relapsed CLL patients (pts) with high-risk cytogenetic features have limited treatment options. Flavopiridol induces p53-independent apoptosis of CLL cells in vitro. We previously demonstrated that a pharmacokinetically (PK) derived dosing schedule administering flavopiridol by 30-min IV bolus (IVB) followed by 4-hr continuous IV infusion (CIVI) achieves the necessary serum concentration to induce apoptosis and is clinically active in pts with relapsed, genetically high-risk CLL. Study Design and Treatment: We report response and median progression free survival (PFS) results for 117 pts with relapsed CLL (n=107) or small lymphocytic lymphoma (n=10) treated on successive phase 1–2 studies of this PK-derived schedule. Pts received flavopiridol by 30-min IVB followed by 4-hr CIVI weekly for 4 doses every 6 weeks (n=79), or weekly for 3 doses every 4 weeks with pegfilgrastim support (n=38), for up to 6 cycles. Twenty pts received 30 mg/m2 IVB + 30 mg/m2 CIVI, and 3 pts received 40 mg/ m2 IVB + 40 mg/m2 CIVI. The remaining pts received 30 mg/m2 IVB + 30 mg/m2 CIVI for the first 1 or 5 dose(s) followed by dose escalation to 30 mg/m2 IVB + 50 mg/m2 CIVI beginning with dose 2 or dose 6 if severe tumor lysis was not observed. Pt Characteristics: Eighty pts were male (68%), median age was 60 years (range, 36–84), and 22 pts were age 70 or older (19%). Median number of prior therapies was 4 (range, 1–14); 116 pts had received prior purine analog therapy, and 85 pts (73%) were refractory to (n=82) or intolerant of purine analog (n=3). Ninety-three pts were Rai stage III/IV (79%), and 85 pts had bulky lymph nodes □ 5 cm (73%). Response Assessment: All 117 pts were evaluated for response by NCI 1996 Working Group criteria. Overall response rate (ORR) was 48%, including 52 partial responses (PR), 3 nodular PR (nPR), and 1 complete response (CR). Seven responders were taken to reduced intensity allogeneic stem cell transplants (SCT) and were censored. Median PFS of the 49 other responders was 10 months. Ten pts remain in remission with a median PFS of 12 months (range, 7–22.5). Six responders relapsed and received repeat flavopiridol therapy; 5 pts responded (4 PR, 1 CR) with a median PFS of 12.5 months. Forty-one of 85 pts (48%) with bulky adenopathy; 23 of 53 pts (43%) with a complex karyotype; 20 of 40 pts (50%) with del(17p13), resulting in loss of p53; and 29 of 49 pts (59%) with del(11q22), resulting in loss of the ATM tumor suppressor gene; responded to therapy. Median PFS was 10–12 months in all cytogenetic groups. Conclusions: Flavopiridol achieves durable responses in heavily treated, relapsed CLL pts with bulky adenopathy and poor-risk cytogenetic features. Flavopiridol allows pts who are not SCT candidates to achieve sufficient reduction of their disease to undergo reduced intensity allogeneic SCT. Pts who respond to flavopiridol and subsequently relapse may respond to repeat therapy. Based on these promising results, a phase 2 registration study is ongoing. All Patients Complex del(17p13) del(11q22) N 117 53 40 49 Response rate 48% 43% 50% 59% Median PFS 10.0 months 10.0 months 12.0 months 10.7 months

Description: Background: Treatment options for relapsed CLL patients (pts) with high-risk genetic features, such as del(17p13) or a complex karyotype, are limited. Flavopiridol induces p53-independent apoptosis in CLL cells in vitro, but increased drug binding to human plasma proteins resulted in lack of clinical activity using 24–72-hr continuous IV infusion (CIVI) schedules. Pharmacokinetic (PK) modeling indicated that administering flavopiridol by IV bolus (IVB) followed by 4-hr CIVI would achieve the necessary concentration to induce apoptosis of CLL cells. Study Design and Treatment: We conducted a phase I study of this PK-derived dosing schedule in relapsed CLL. Pts received flavopiridol by 30-min IVB followed by 4-hr CIVI weekly for 4 doses, every 6 weeks for up to 6 cycles. Fifty-eight pts (43 male) with relapsed CLL (n=48) or small lympocytic lymphoma (n=10) were enrolled. Median age was 60 years (range, 38–84). Median number of prior therapies was 4 (range, 1–14); 57 pts had received prior fludarabine, with 48 pts refractory to or intolerant of fludarabine. Pts had bulky Rai stage I/II (n=13) or III/IV (n=45) disease. In the initial 2 cohorts, pts received 30 mg/m2 IVB + 30 mg/m2 CIVI (n=20) or 40 mg/m2 IVB + 40 mg/m2 CIVI (n=3). Dose limiting toxicity was acute tumor lysis syndrome (TLS) in 2 pts in cohort 2. Thirty-five pts were enrolled in cohorts 3 and 4, in which flavopiridol was dose escalated to 30 mg/m2 IVB + 50 mg/m2 CIVI beginning with cycle 2 (n=14) or dose 2 of cycle 1 (n=14) if severe TLS was not observed. Seven pts experienced severe TLS and did not undergo dose escalation. Response Assessment: Fifty-two of 58 pts were evaluable for response. Six pts who received only one dose of study drug due to grade 4–5 acute TLS and other complications were not evaluable for response. Twenty-six pts achieved a partial response (PR; 50%) by NCI Working Group response criteria. Median progression free survival (PFS) of all responders is 11 months (range, 5–29), and 10 pts remain in remission. Twenty-one of 39 evaluable pts with bulky adenopathy 〉 5 cm attained PR (54%). Thirteen of 27 evaluable pts with a complex karyotype achieved PR (48%); median PFS is 10 months (range, 5–16), and 4 pts remain in remission. Nine of 19 evaluable pts with del(17p13), corresponding to loss of the p53 tumor suppressor gene, attained PR (47%); median PFS is 10 months (range, 8–16), and 5 pts remain in remission. Seventeen of 21 evaluable pts with del(11q22), resulting in loss of the ATM tumor suppressor gene, achieved PR (81%); median PFS is 11 months (range, 8–15 months), and 6 pts remain in remission. Conclusions: Flavopiridol is highly active in heavily pretreated, relapsed CLL pts with bulky adenopathy and poor-risk cytogenetic features such as a complex karyotype or del(17p13). Flavopiridol appears to be particularly active in pts with del(11q22), corresponding to loss of the ATM tumor suppressor gene. The mechanism of action of flavopiridol is under active investigation. Response by Cytogenetic Abnormality Outcome All patients (n=58) Complex karyotype (n=29) Deletion of 17p13 (n=20) Deletion of 11q22 (n=22) Partial response 26 13 9 17 No response 26 14 10 4 Not evaluable 6 2 1 1 Median PFS 11 months 10 months 10 months 11 months

Description: Flavopiridol is a broad cyclin dependent kinase inhibitor that induces p53/IL4 independent apoptosis in CLL cells. Despite potent pre-clinical activity, phase I/II studies of both a 24 and 72-hour continuous IV (CI) schedule demonstrated no activity in CLL or other cancers. Discordant binding of flavopiridol to human plasma proteins as compared to fetal calf serum prompted us to perform pharmacokinetic modeling from the Aventis-sponsored CI studies. This suggested optimal dosing would be a 30-minute IV bolus followed by 4-hour infusion. We report a mature phase I dose escalation study of flavopiridol with this schedule. We enrolled 23 pts (median age 61, range 44–84, 8 female) previously treated for CLL (median prior therapies 3, range 2–13) . At study entry, 21 pts had no response to their last therapy, 9 had intermediate risk disease, and 14 were stage III/IV. Pts received 50% of the flavopiridol dose IV over 30 minutes, the remaining 50% followed over 4 hours. This was repeated weekly 4 times on a 6-week cycle. Six pts in cohort 1 received 60 mg/m2/dose with 1 dose limiting toxicity (DLT, neutropenic fever) and 3 pts in cohort 2 received 80 mg/m2/dose. The maximally tolerated dose was exceeded in cohort 2. Acute tumor lysis syndrome (TLS) following the first flavopiridol dose was the DLT. One pt developed TLS that was controlled with aggressive medical management. The 2nd pt with TLS died with hyperkalemia before dialysis could be initiated, and on autopsy had extensive apoptosis/necrosis of diffuse intra-abdominal lymphadenopathy. No additional pts were treated at this dose, but a 3rd pt previously without TLS at the 80 mg/m2/dose developed TLS on day 1,cycle 2 at the 60 mg/m2 dose. An inpatient management plan to prevent further life-threatening TLS was initiated. We enrolled 14 additional pts. Several pts developed transient tumor lysis upon initial treatment, with increased serum potassium, phosphate, and LDH, but only 1 pt required temporary dialysis. Other manageable toxicities observed included neutropenia, anemia, thrombocytopenia, fatigue, nausea, diarrhea, and anorexia. Twenty-two patients have been followed long enough for NCI 96 response assessment. Nine pts achieved a PR (41%); 7 pts remain in remission (3–11+ months), and 2 pts relapsed at 7 and 12 months, respectively. Of the 9 responding pts, 8 were fludarabine refractory or intolerant, 8 had bulky LN (〉 5cm), and 8 had del(11q) [n=6] or del(17p) [n=3] abnormalities. Additionally, opportunistic infections have not been noted to date. Eight of 9 responding pts with enlarged LN had a 50% reduction with the 1st treatment, compared to 2 of 10 who did not ultimately achieve a PR. The AUC of flavopiridol did not increase proportionally with dose, but pharmacologic data support our hypothesis that the clinical activity and toxicity of flavopiridol may be directly related to the Cmax, AUC, and Css. In summary, single agent flavopiridol given with this novel, pharmacologically modeled schedule has significant clinical activity in pts with fludarabine-refractory, genetically high-risk CLL. Further study of flavopiridol in CLL and other B-cell diseases using this pharmacokinetically modeled schedule is warranted.