ALBERT

Description: Imatinib (Im), a rationally designed inhibitor of the Bcr/Abl kinase as well as other kinases, represents the standard treatment for Bcr/Abl+ malignancies. Im as a single agent, however, is not curative. Flavopiridol (Fl), an investigational cyclin dependent kinase inhibitor, is broadly active in vitro against human leukemia cells (Blood91:2482,1998). Previously we have shown that simultaneous disruption of a survival signaling pathway and a cell cycle regulatory pathway results in a pronounced increase in leukemic cell death (Cancer Res.61:5106,2001) and in more recent preclinical studies demonstrated synergistic interactions between Im and Fl in Bcr/Abl+ leukemia cells, including some that were resistant to Im (Clin Cancer Res8;2976,2002). Based on these considerations, we have initiated a phase I trial to identify appropriate doses of Im+Fl for further investigation. Eligible patients (pts) have CML with a suboptimal response to prior Im, CML in blast crisis, or Bcr/Abl+ acute lymphocytic leukemia (ALL). CML-BC and ALL patients may be Im-naïve. Pts receive Im by continuous daily oral dosing and Fl by 1 hour intravenous infusion weekly x 3 repeated every 4 weeks. Targeted dose levels are (Fl/Im; mg/m2): 30/400, 30/600, 45/600, 60/600, 60/800, 60/1000. Patients are divided into 2 strata based upon blast percentage in peripheral blood or bone marrow: stratum 1, 1 week or grade ≥ 3 non-heme toxicity; for stratum 2, DLT is profound marrow hypoplasia in the absence of persistent leukemia. In stratum 1, 16 pts have been treated at 4 dose levels; in stratum 2, 5 pts in the 1st and 3rd dose level. In stratum 1, 1 DLT has occurred at dose level 4 (cholecystitis requiring cholecystectomy); in stratum 2, 1 DLT has occurred at dose level 3 (sepsis/multi-organ failure which was not clearly related to treatment). The only frequent toxicities have been hematological. 4 pts have experienced objective responses including complete hematological remissions in 2 pts in stratum 1 treated with Im/Fl 30/600 who had been previously treated with Im 800 and complete hematological remissions in 2 pts in stratum 2 (who had not received prior Im). Preliminary studies indicate no Fl impact upon Im pharmacokinetics, and variable post-treatment effects on signaling pathways in CML cells. These findings indicate that a regimen consisting of Fl and Im is tolerable and active in at least some patients with Bcr/Abl+ hematologic malignancies, including some with Im-resistant disease. Pending identification of the MTD and the recommended Phase II dose (RPTD), Phase II trials will be necessary to assess the activity of this strategy more definitively.

Description: Preclinical studies suggest that neoplastic cells may be particularly sensitive to simultaneous interruption of cell-cycle and survival signaling pathways. In accord with this concept, we have shown that flavopiridol (F), a CDK inhibitor, interacts with bortezomib (B), a proteasome inhibitor, to induce mitochondrial injury and apoptosis in human leukemia, myeloma, and lymphoma cells (Dai et al, Oncogene22:7108, 2003; Dai et al, Blood104:509, 2004). These actions were associated with inhibition of NF-kappaB DNA binding, increased expression of phospho-JNK, and downregulation of XIAP and Mcl-1. Based on these findings, a phase I trial has been initiated to identify appropriate doses of B+F for further investigation. Eligible patients (pts) include those with multiple myeloma or indolent B-cell neoplasms, and recurrent or refractory disease following at least 1 prior systemic therapy (excluding allogeneic stem cell transplantation). In the initial stage of the trial, pts received B (iv push) immediately followed by F bolus (1- hour infusion) on d1, 4, 8, and 11 out of a 21-day (d) cycle. Dose levels were, in mg/m2 (B/F): 1.0/15, 1.3/15, 1.3/22, 1.3/30, 1.3/40, 1.3/50, and 1.3/60. Subsequently, a “hybrid” F infusion schedule (30 minute load followed by a 4-hour infusion) was adopted based on evidence of activity of this schedule in chronic lymphocytic leukemia. With the hybrid schedule, all pts receive B (iv push) 1.3 mg/m2 on d1, 4, 8 and 11. Targeted F dose levels using the hybrid schedule are (Fload/Finfusion; mg/m2): 20/20 on d1 and 8; 30/30 on d1 and 8; 30/50 on d1 and 8; 30/30 on d1, 4, 8 and 11; 30/50 on d1, 4, 8 and 11. Dose limiting toxicity (DLT) is defined as NCI CTCAE grade 4 ANC/platelets for 〉 1 week or grade ≥ 3 non-heme toxicity. 38 pts have been enrolled. 29 pts were treated at 7 dose levels with the bolus schedule, after which development of the hybrid schedule was begun. With the hybrid schedule, 11 pts have been treated at 3 dose levels. To date, one DLT (grade 3 lower back pain) was observed at level 5 of the bolus schedule and one DLT (grade 3 fatigue) was seen at the 1st hybrid dose level. The MTD of the hybrid schedule has not been reached. Non-DLT toxicities include herpes zoster (2 disseminated), peripheral neuropathy, fatigue, postural hypotension, syncope, diarrhea and ≤ grade 3 cytopenias. Of 35 pts evaluable for response, there have been 2 complete responses (1 lymphoma and 1 mantle cell lymphoma), 7 partial responses (5 myeloma and 2 lymphoma), 3 minor responses (2 myeloma and 1 extramedullary plasmacytoma), 15 patients with stable disease (5 myeloma, 7 lymphoma, 1 Waldenstrom’s and 2 mantle cell lymphomas). Of the 3 pts who had received prior bortezomib, 2 had minor responses and 1 had disease progression. To date, hyperacute tumor lysis has not occurred with the hybrid schedule, but aggressive prophylaxis and monitoring are integral to the treatment plan. Correlative laboratory studies involving bone marrow CD138+ cells from patients with myeloma revealed a reduction in post-treatment NF-kappaB nuclear localization in 4 of 5 evaluable patients. Variable effects on myeloma cell expression of phospho-JNK, Mcl-1, and XIAP have been observed. Collectively, these findings indicate that a regimen combining bortezomib and flavopiridol, including the use of a hybrid flavopiridol schedule, is well tolerated in patients with progressive B-cell malignancies, and has clear activity in some patients refractory to standard therapy. Pending identification of the MTD and RPTD (recommended phase II dose), phase II evaluation of this therapeutic strategy should define its activity more definitively.

Description: Based on preclinical findings demonstrating marked antileukemic synergism between the HDAC inhibitor vorinostat and the CDK inhibitor flavopiridol (Almenara et al., Leukemia16:1331–43, 2002), a Phase I trial of these agents has been initiated in patients with refractory AML/MDS. Eligible patients (pts) have acute leukemia (AL) refractory to standard therapy or de novo AL with poor risk factors (age 〉60 or antecedent myelodysplastic syndrome), imatinib-refractory chronic myeloid leukemia in blast crisis, or RAEB-2. Pts are excluded for prior auto- or allogeneic marrow or stem cell transplantation, significant comorbidities or organ dysfunction, and QTc interval 〉0.470 seconds. All pts receive oral vorinostat (V) 200 mg 3 times daily. In the initial stages of the trial, pts also received flavopiridol (F) by 1-hour bolus infusion on days 1–5 out of a 21-day cycle. Initial F dose levels were (mg/m2): 10, 20, 30, 40. Subsequently, a “hybrid” F infusion schedule (30 minute load followed by 4 hour infusion) was adopted based on recent evidence of activity of this schedule in CLL. With the hybrid schedule, F is given on a combination of days (d) 1, 3, 8 and 11. Targeted F dose levels are, in mg/m2 (Fload/Finfusion): 20/20 on d1 and 8; 30/20 on d1 and 8; 30/30 on d1 and 8; 30/50 on d1 and 8; 30/50 on d1, 3 and 8; 30/50 on d 1,3, 8 and 11. Dose limiting toxicity (DLT) is defined as NCI CTCAE grade 4 non-hematologic (heme) toxicity (except that related to cytopenias, infection or hyperbilirubinemia), grade 3 non-heme toxicity which lasts 〉7 days, or grade 4 ANC/platelet toxicity that persists for 〉 6 weeks in absence of leukemia. 28 pts have been enrolled. With the bolus schedule 14 pts were treated at 4 dose levels without identification of an MTD, after which development of the hybrid schedule was begun. Since initiation of the hybrid schedule, 8 pts have been treated at 3 dose levels. One DLT (infectious colitis with sepsis) was seen on level 4 of the bolus schedule and one DLT (gr 3 atrial fibrillation) was seen at the 3rd hybrid dose level. The MTD of the hybrid schedule has not been reached. Non-DLT toxicities include diarrhea, anorexia, nausea, weight loss, fatigue, electrolyte abnormalities, hyperbilirubinemia, dyspnea, confusion, febrile neutropenia and infectious complications (including atypical infections). Of 22 pts treated, 20 are evaluable for response. Thus far, there have been no complete remissions in this heavily pretreated population. However, 10 pts experienced some clinical benefit despite meeting criteria for “remission induction failure” – of those, 3 were treated with ≥ 5 cycles. 10 pts had a best response of progressive disease. One heavily pre-treated pt with refractory AML, who progressed after FLAG x2 followed by gemtuzumab ozogamycin, remains in treatment following 7 cycles with improved PS and QOL, a marked improvement in peripheral WBC, and a normocellular marrow with 6% blasts. To date, hyperacute tumor lysis has not been seen with the hybrid schedule, but aggressive prophylaxis and monitoring remain integral to the treatment plan. QTc evaluation and monitoring has been implemented because of V interactions with concurrent medications commonly used in this population (azole antifungals, among others). Correlative laboratory studies reveal a regular increase in acetylated tubulin but heterogeneous post-treatment effects on p21CIP1, Mcl-1, and other proteins in leukemic blasts. Collectively, these findings indicate that a regimen combining vorinostat and flavopiridol is well tolerated in patients with refractory or high-risk AML, and may have some activity in patients highly resistant to standard therapy. Pending identification of the MTD and RPTD (recommended phase II dose), Phase II evaluation of this therapeutic strategy should define its activity more definitively.

Description: Preclinical studies suggest that neoplastic cells may be particularly sensitive to simultaneous interruption of cell-cycle and survival signaling pathways. In accord with this concept, we have shown that flavopiridol (F), a CDK inhibitor, interacts with Bortezomib (B), a proteasome inhibitor, to induce mitochondrial injury and apoptosis in human leukemia, myeloma, and lymphoma cells (Dai et al, Oncogene22:7108, 2003; Dai et al, Blood104,509,2004). These actions were associated with inhibition of NF-kappaB DNA binding, and diminished expression of phospho-JNK, XIAP, and Mcl-1. Based on these findings, we have initiated a phase I trial to identify appropriate doses of B+F for further investigation. Eligible patients (pts) include those with multiple myeloma, indolent B-cell lymphoma, or a related disorder, and must have recurrent or refractory disease following at least 1 prior systemic therapy (excluding allogeneic stem cell transplantation). Pts receive B (iv bolus) immediately followed by F (1 hour infusion) on days 1, 4, 8, and 11; courses are repeated every 21 days. Targeted dose levels are (B/F; mg/m2): 1.0/15, 1.3/15, 1.3/22, 1.3/30, and 1.3/40. Dose limiting toxicity (DLT) is defined as NCI CTCAE grade 4 ANC/platelet for 〉 1 week or grade ≥ 3 non-heme toxicity. 14 pts have been treated at 4 dose levels. There have been no DLT to date. There have been 3 episodes of herpes zoster (2 disseminated), 4 cases of exacerbation of pre-existing peripheral neuropathy, and 8 pts have discontinued study treatment after 1 to 5 cycles due to non-DLT toxicities. Among 11 patients evaluable for response and who are Bortezomib-naive, there has been 1 complete response (mantle cell lymphoma; MCL), 3 partial responses (2 myeloma, 1 lymphoma), and 5 patients with stable disease (3 myeloma, 1 lymphoma, 1 Waldenstrom’s). The patient with MCL who achieved a CR had previously received CHOP, Rituximab-CHOP, and fludarabine-Rituximab x 2. Correlative laboratory studies involving bone marrow CD138+ cells from patients with myeloma revealed a reduction in post-treatment NF-kappaB nuclear localization in 4/5 evaulable patients. Variable effects on myeloma cell expression of phospho-JNK, Mcl-1, and XIAP have been observed. Additional patients who previously received Bortezomib have now been entered on the study, but it is too early to evaluate their responses. Collectively, these findings indicate that a regimen combining Bortezomib and flavopiridol is well tolerated in patients with progressive B-cell malignancies, and has clear activity in some patients refractory to standard therapy. Pending identification of the MTD and RPTD (recommended phase II dose), Phase II evaluation of this therapeutic strategy should define its activity more definitively.