In a multicenter, double-blind phase II trial, we compared the efficacy and safety of perifosine plus capecitabine (P-CAP) with placebo plus capecitabine (CAP) in patients with metastatic colorectal ...cancer (mCRC) who had progressed after as many as two prior therapies.
Patients (n = 38) not previously treated with capecitabine received P-CAP (perifosine 50 mg orally once daily, days 1 to 21 and CAP 825 mg/m(2) orally twice daily, days 1 to 14) or CAP (825 mg/m(2) orally twice daily, days 1 to 14) in 21-day cycles until disease progression. The primary end point was time to progression (TTP). Secondary end points included overall survival (OS), overall response rate (ORR), safety, and tolerability.
Twenty patients were randomly assigned to P-CAP and 18 to CAP. Median TTP (27.5 v 10.1 weeks; P < .001) and median OS (17.7 v 7.6 months; P = .0052) were improved in patients receiving P-CAP versus CAP. ORR was 20% v 7% in the P-CAP and CAP groups, respectively, and one patient in the P-CAP group had a complete response. A subset analysis of fluorouracil-refractory patients showed a median TTP of 17.6 v 9.0 weeks (P < .001) and median OS of 15.1 v 6.5 months (P = .0061). Toxicities, including diarrhea, nausea, fatigue, and hand-foot syndrome, were manageable.
P-CAP showed promising clinical activity compared with CAP in previously treated patients with mCRC. A phase III trial is underway comparing P-CAP with CAP in patients with refractory mCRC.
Novel agents have improved patient outcome in relapsed or relapsed/refractory multiple myeloma (MM). Preclinical data show that the novel signal transduction modulator, perifosine, enhances the ...cytotoxicity of dexamethasone and bortezomib. Clinical data suggest that perifosine in combination with dexamethasone has activity in relapsed or relapsed/refractory MM.
In a phase I/II study, perifosine in combination with bortezomib with or without dexamethasone was prospectively evaluated in 84 patients with relapsed or relapsed/refractory MM. All were heavily pretreated and bortezomib exposed; 73% were refractory to bortezomib, and 51% were refractory to bortezomib and dexamethasone. The dose selected for the phase II study was perifosine 50 mg/d plus bortezomib 1.3 mg/m(2), with the addition of low-dose dexamethasone at 20 mg if progression occurred on perifosine plus bortezomib alone.
An overall response rate (ORR; defined as minimal response or better) of 41% was demonstrated with this combination in 73 evaluable patients, including an ORR of 65% in bortezomib-relapsed patients and 32% in bortezomib-refractory patients. Therapy was generally well tolerated; toxicities, including gastrointestinal adverse effects and fatigue, proved manageable. No treatment-related mortality was seen. Median progression-free survival was 6.4 months, with a median overall survival of 25 months (22.5 months in bortezomib-refractory patients).
Perifosine-bortezomib ± dexamethasone demonstrated encouraging activity in heavily pretreated bortezomib-exposed patients with advanced MM. A phase III trial is underway comparing perifosine-bortezomib plus dexamethasone with bortezomib-dexamethasone in patients with relapsed/refractory MM previously treated with bortezomib.
Summary
The combination of lenalidomide–dexamethasone is active in multiple myeloma (MM). Preclinical data showed that the Akt inhibitor, perifosine, sensitized MM cells to lenalidomide and ...dexamethasone, providing the rationale for this Phase I, multicentre, single‐arm study to assess the safety and determine the maximum‐tolerated dose (MTD) of perifosine–lenalidomide–dexamethasone in relapsed and relapsed/refractory MM. Patients received escalating doses of perifosine 50–100 mg daily and lenalidomide 15–25 mg once daily on days 1–21 of each 28‐d cycle, plus dexamethasone 20–40 mg weekly thereafter, as indicated. Thirty‐two patients were enrolled across four dose cohorts. MTD was not reached, with 31 patients evaluable for safety/tolerability. The most common all‐causality grade 1‐2 adverse events were fatigue (48%) and diarrhoea (45%), and grade 3–4 neutropenia (26%), hypophosphataemia (23%), thrombocytopenia (16%), and leucopenia (13%). Among 30 evaluable patients, 73% (95% confidence interval, 57·5–89·2%) achieved a minimal response or better, including 50% with a partial response or better. Median progression‐free survival was 10·8 months and median overall survival 30·6 months. Response was associated with phospho‐Akt in pharmacodynamic studies. Perifosine–lenalidomide–dexamethasone was well tolerated and demonstrated encouraging clinical activity in relapsed and relapsed/refractory MM.
Abstract 3064
Perifosine (Peri) a novel, oral signal transduction modulator with multiple effects including inhibition of Akt and activation of JNK, has demonstrated clinical activity when combined ...with dexamethasone (Dex) in patients (pts) with relapsed/refractory MM (ASH 2007 #1164). Lenalidomide (Revlimid ▪, Rev) a novel, oral immunomodulatory drug has activity against MM when combined with Dex. We previously reported encouraging safety data and observed clinical activity of the oral triplet combination (ASH 2008 # 3691). We now report the final phase I results of this study which aimed to determine the MTD and to evaluate activity of Peri + Rev + Dex, as an oral combination in pts with relapsed or refractory MM.
Four cohorts (▪ 6 pts each) were planned, dosing Peri at 50 or 100mg (daily), Rev 15 or 25mg (d 1–21) and Dex 20mg (d 1–4, 9–12 and 17–20 for 4 cycles, then 20 mg d 1–4) in 28-d cycles. To limit dex-related toxicities, the protocol was amended to use weekly dex (40 mg), applying to cohorts 3, 4, and the MTD cohort. Toxicity was assessed using NCI CTCAE v3.0; DLT was defined as grade (G) 3 non-hematologic toxicity, G4 neutropenia for 5 d and/or neutropenic fever, or platelets <25,000/mm3 on >1 occasion despite transfusion. Response was assessed by modified EBMT criteria. Pts had to have received at least 1 prior therapy and no more than 4. Pts refractory to Rev/Dex were excluded.
32 pts (17M/15F, median age 64 y, range 37 – 79) were enrolled; 6 pts in cohort 1 (Peri 50mg, Rev 15mg, Dex 20mg); 6 pts in cohort 2 (Peri 50mg, Rev 25mg, Dex 20mg); 8 pts in cohort 3 (Peri 100mg, Rev 15mg, Dex 40mg/wk); 6 pts in cohort 4 (Peri 100mg, Rev 25mg, Dex 40mg/wk) and 6 pts at MTD (Cohort 4). Median prior lines of treatment was 2 (range 1–4) with a median PS of 1. Relapsed (53%), Refractory to last therapy prior to study entry (47%). Prior therapy included dex (94%), thalidomide (75%), bortezomib (44%), and stem cell transplant (72%). Two pts (6%) were previously treated with Rev. 63% (15/24) of the prior thalidomide + dex (Thal/Dex) treated pts had progressed on a Thal/Dex regimen while 43% (6/14) of the prior bortezomib (Vel) treated pts had progressed on a prior Vel based regimen. Two pts did not complete one full cycle (non-compliance and adverse event not related to study drugs – both in cohort 3) and were not included in the efficacy analysis. 31/32 pts were evaluable for safety (non-compliant patient never took study drug and was excluded). The most common grade 1/2 events (any causality) included fatigue (48%), diarrhea (45%), upper respiratory infection (35%), nausea (32%) and hyperglycemia (32%). Grade 3/4 events > 10% included neutropenia (26%); hypophosphatemia (23%); thrombocytopenia (16%) and leucopenia (13%). There was one reported DLT in cohort 3 (Nausea). No grade 3/4 events of peripheral neuropathy or DVT were reported. Rev dose was reduced in 11 pts, Peri reduced in 9 pts and Dex reduced in 7 pts: 30 pts are evaluable for response, with best response as follows:
Response: n = 30n (%)ORR (≥PR)Near Complete Response (nCR)4 (7%)15 (50%)Very Good Partial Response (VGPR)3 (10%)Partial Response (PR)8 (33%)Minimal Response (MR)7 (20%)Stable Disease (SD)6 (23%)Progression (PD)2 (7%)
Median progression-free survival (PFS) for all pts was 10.8 mos (CI: 4.6, 27.7) and 7 pts have not progressed. The median overall survival (OS) was 30.6 mos (CI: 16.7, NR) with 15/30 pts still alive. Of the 8 thalidomide naïve pts, 4 have progressed with a median projected PFS of 30 mos and all 8 pts remain alive (range 28 – 43 mos).
Pts have tolerated Peri + Rev + Dex well with manageable toxicity, and with promising clinical activity demonstrated by an ORR (≥ PR) of 50%, an extended PFS and OS. Given that most pts were exposed to Thal/Dex with more than half refractory to a prior Thal/Dex regimen, the encouraging response rates and survival appear to suggest benefit with the addition of perifosine to Rev/Dex. This data thus warrants further study, including a potential randomized trial to confirm the activity of perifosine added to Rev/Dex. A randomized phase III trial of Peri/Vel/Dex vs. Vel/Dex is underway for previously Vel exposed MM patients.
Jakubowiak:Millennium, Celgene, Bristol-Myers Squibb, Johnson & Johnson Ortho-Centocor: Honoraria; Millennium, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millennium, Celgene, Centocor-Ortho Biotech: Speakers Bureau. Off Label Use: Perifosine in combination with Lenalidomide and Dexamethasone. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Zimmerman:Millennium, Celgene: Speakers Bureau. Alsina:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding. Kaufman:Celgene, Millenium: Consultancy; Celgene, Merck: Research Funding. Sportelli:Keryx Biopharmaceuticals: Employment, Equity Ownership. Gardner:Keryx Biopharmaceuticals: Employment, Equity Ownership. Anderson:Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.
Abstract 815▪FN2▪This icon denotes a clinically relevant abstract
Perifosine, an orally-bioavailable, novel signal transduction modulator has multiple pathway effects including inhibition of Akt, ...NFkB and activation of JNK. We conducted a phase I/II study of perifosine + bortezomib (Vel) +/− dexamethasone (Dex) which demonstrated encouraging safety and preliminary clinical activity in relapsed and refractory multiple myeloma (MM) patients (pts) (ASH 2009 # 1869). We report final results, including overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) for the treatment of MM pts previously relapsed from and/or refractory to Vel.
The phase I stage of the study enrolled a total of 18 pts with a selected phase II dose of perifosine 50 mg qd + Vel 1.3 mg/m2 (d 1, 4, 8, 11) in 21-d cycles, which enrolled 66 pts. Dex 20mg (on day of and after each Vel dose) could be added in pts with progressive disease (PD). NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by modified EBMT and Uniform Criteria.
A total of 84 pts were enrolled comprised of 51 men and 33 women, median age 63 y (range 35–89): 88% of pts had relapsed and refractory MM (73% Vel refractory), with a median of 5 lines of prior treatment (range 1–13). Prior therapy included Vel (100%), dex (98%), lenalidomide (76%), thalidomide (75%) and SCT (58%), with pts receiving a median of 2 prior Vel-based treatments. Median interval between diagnosis and inclusion was 4.5 years. Seventy three pts were evaluable for response (having completed at least two or more cycles of therapy), and all 84 were assessed for safety. Most common grade 1/2 events included nausea, diarrhea, fatigue and musculoskeletal pain, which were manageable with supportive care and dose reductions. Grade 3/4 adverse events included thrombocytopenia, neutropenia, anemia, pneumonia and musculoskeletal pain. Two pts had grade 3 peripheral neuropathy (PN), which was reversible with Vel dose reduction and/or treatment discontinuation. No grade 4 PN was observed. Overall 26 (31%) pts had treatment-related PN of any grade. Two pts had perifosine reduced to 50 mg (for GI related toxicity) in the phase 1 portion of the study, and 8 pts reduced to qod dosing in the phase II: 23 pts had Vel dose reductions primarily due to hematologic toxicity. No treatment-related mortality was seen. Eleven pts were inevaluable for response due to unrelated toxicity (n=5), rapid disease progression (< 1 cycle received; n=3), or withdrawal of consent (n=3). For 73 response-evaluable pts, the ORR was 41%, including 4% CR, 18% PR and 19% MR. Prior best response (≥ PR) to last Vel-based regimen was 43% (36/84 pts), of which most were triple drug combinations (eg RVD). Of 53 pts who were refractory to prior Vel, ORR to perifosine, Vel +/− Dex was 32%, including 2% CR, 11% PR and 19% MR. ORR for 20 Vel-relapsed pts was 65%; 10% achieved a CR and 35% a PR. Median PFS was 6.4 mos with a range of 5 wks to over 3 yrs (95% CI: 5.3, 7.1), and 8.0 mos (95% CI: 6.4, 9.8) for the 30 evaluable pts who achieved ≥ MR. Median PFS for the 53 Vel-refractory pts was 5.7 mos (95% CI: 4.3, 6.4), with 40% of pts achieving PFS of > 6 mos. For the 20 Vel-relapsed pts, median PFS was 8.8 mos (95% CI: 6.3, 11.2), with 70% of pts achieving PFS of > 6 mos. Importantly, median PFS for all pts receiving prior Vel-based regimens prior to study entry was 5.3 mos.
As of August 2011, median OS for all evaluable study pts was 25 mos (95% CI: 16.3, 31.1), 22.5 mos (95% CI: 14.2, 31.1) for the Vel-refractory pts and 30.4 mos (95% CI: 17.8, NR) for Vel-relapsed pts. Median OS for those pts who achieved PR + CR was 37 mos (95% CI: 13.8, NR) and for those pts who achieved SD + MR was 29 months (95% CI: 18, 32.4).
Perifosine in combination with Vel (+/− dex) demonstrated impressive and durable activity in both heavily pre-treated, Vel-refractory pts (with an ORR of 32% and median OS of 22.5 mos), and in Vel-relapsed pts (with an ORR of 65%, median PFS of 8.8 mos and OS of 30.4 mos), with manageable toxicity. Survival data were encouraging, even in pts exposed to and refractory to Vel, as well as prior IMiDs, so providing another example of a rational combination strategy integrating novel therapies to further improve patient outcome. An international phase III randomized trial evaluating perifosine vs. placebo when combined with Vel and Dex in Vel-exposed pts with relapsed and refractory MM has been granted special protocol assessment (SPA) status and is currently underway to confirm the efficacy of this approach.
Richardson:Celgene: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Keryx Biopharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Millennium: Membership on an entity’s Board of Directors or advisory committees. Wolf:Millennium: Honoraria, Speakers Bureau. Jakubowiak:Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Onyx: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria; Exelixis: Consultancy, Honoraria. Zonder:Millennium: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Medtronic: Consultancy; Celgene: Speakers Bureau. Lonial:Millennium: Consultancy; Novartis: Consultancy; Celgene: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy. Krishnan:Millennium: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Raje:Celgene: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; Millenium: Membership on an entity’s Board of Directors or advisory committees; Astra Zeneca: Research Funding; Amgen: Membership on an entity’s Board of Directors or advisory committees; Acetylon: Research Funding. Ghobrial:Noxxon: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Munshi:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Allerton:Keryx Biopharmaceuticals: Consultancy. Hideshima:Acetylon: Consultancy. Sportelli:Keryx Biopharmaceuticals: Employment, Equity Ownership. Gardner:Keryx Biopharmaceuticals: Employment, Equity Ownership. Anderson:Celgene: Membership on an entity’s Board of Directors or advisory committees; Millennium: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; Acetylon: Membership on an entity’s Board of Directors or advisory committees.
Abstract 1869
Poster Board I-894
INTRODUCTION: Perifosine is an orally -bioavailable, novel signal transduction modulator with multiple pathway effects including inhibition of Akt and activation of ...JNK. We conducted a phase I/II study of perifosine + bortezomib (Vel) +/− dexamethasone (Dex) which demonstrated encouraging safety and clinical activity in 73 evaluable Vel relapsed and Vel refractory patients (pts) (ASH 2008 # 870). Herein, we report on the updated safety, overall response rate (ORR), time to progression (TTP) and overall survival (OS) results of perifosine + Vel (+/− Dex), in multiple myeloma (MM) pts with advanced disease and who were previously relapsed from and/or refractory to Vel. METHODS: The phase I stage of the study enrolled a total of 18 pts with a selected phase II dose of perifosine 50 mg qd + Vel 1.3 mg/m2 (d 1, 4, 8, 11) in 21-d cycles. The phase II enrolled 66 pts. Dex 20mg (on day of and after each Vel dose) could be added in pts with progressive disease (PD). NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by modified EBMT and Uniform criteria. RESULTS: A total of 84 pts have been enrolled comprised of 51 men and 33 women, median age 63 y (range 35 – 89): 83% of pts had relapsed/refractory MM, with a median of 5 lines of prior treatment (range 1–13). Prior therapy included Vel (100%), dex (98%), lenalidomide (75%), thalidomide (74%) and SCT (57%), with pts receiving a median of 2 prior Vel-based treatments. Seventy three pts were evaluable for response (having completed at least two or more cycles of therapy), and all 84 were assessed for safety. Most common (≥ 10%) grade 1 / 2 events included nausea, diarrhea, vomiting, fatigue and anorexia, which were manageable with supportive care and dose reductions. Grade 3 / 4 adverse events ≥ 5% included thrombocytopenia, neutropenia, anemia, hyponatremia and diarrhea. No DVT has been seen, and only 1 worsening peripheral neuropathy from grade 1 to 3 was reported, which proved reversible after treatment discontinuation. Two pts had perifosine reduced to 50 mg (GI related) in the phase 1 and 5 pts reduced to qod dosing in the phase II: 15 pts had Vel dose reductions primarily due to hematologic toxicity. No treatment related mortality was seen. Of the 11 pts who were inevaluable for efficacy, 6 were due to toxicity resulting in failure to complete two cycles or more of therapy; 3 for withdrawal of consent/ non-compliance, and 2 due to rapid disease progression within 1 cycle. ORR, TTP, and OS are as follows: As of August 2009, the median OS for all evaluable study pts and Vel relapsed pts has not been reached with 40/73 (55%) pts and 14/20 (70%) pts alive, respectively. 26/53 (49%) Vel refractory pts remain alive (range 9 mos to 3 years). The median OS for the 60/73 pts (82%) with stable disease or better is currently 33.4 mos.
NMedian PriorCR / PRORR (MR or >)Median TTP (95% CI)Median OS (95% CI)RxVelPREvaluable Patients73521520%2838%6.4 mos (5.3, 7.1)22.5 mos (14.3, NR)*Vel Relapsed2041840%1155%8.8 mos (6.3, 11.2)25 mos (14.3, NR)*Vel Refractory5362713%1732%5.7 mos (4.3, 6.4)16 mos (11.3, 33.3)*As of August 2009, median is not reached (NR) and ongoing
Perifosine in combination with Vel (+/− dex) has been generally well tolerated and continues to demonstrate impressive activity in both heavily pre-treated, Vel-refractory pts, with an ORR of 38% and OS of 16 mos, and in Vel-relapsed pts with an ORR of 55%, a median TTP of 8.8 months and a median OS of 25 mos, to date. Moreover, 80% of pts achieved stable disease or better, with a median OS of 33.4 mos. A phase III randomized, trial evaluating perifosine vs. placebo when combined with Vel and Dex in Vel-exposed pts with relapsed and refractory MM has been granted special protocol assessment (SPA) and is expected to commence by the end of the year.
Richardson:Keryx Biopharmaceuticals: Honoraria. Gardner:Keryx Biopharmaceuticals: Employment, Equity Ownership. Sportelli:Keryx Biopharmaceuticals: Employment, Equity Ownership. Anderson:Keryx Biopharmaceuticals: Consultancy.
INTRODUCTION: Perifosine (Peri) a novel, oral signal transduction modulator with multiple effects including inhibition of Akt and activation of JNK, has demonstrated clinical activity when combined ...with dexamethasone (Dex) in patients (pts) with relapsed/refractory MM (ASH 2007 #1164). Lenalidomide (Revlimid®, Rev) a novel, oral immunomodulatory drug has single-agent activity against MM and additive effects when combined with Dex. We previously reported encouraging safety data and observed clinical activity of the oral triplet combination in the first 12 pts (ASH 2007 # 1169). We now report the phase I results of this study which aimed to determine the MTD and activity of Peri + Rev + Dex, as an oral combination in pts with relapsed or refractory MM.
METHODS: Four cohorts (≥6 pts each) were planned, dosing Peri at 50 or 100mg (daily), Rev 15 or 25mg (d 1–21) and Dex 20mg (d 1–4, 9–12 and 17–20 for 4 cycles, then 20 mg d 1–4) in 28-d cycles. To limit dex-related toxicities, the protocol was amended to use weekly dex (40 mg), applying to cohorts 3, 4, and the MTD cohort. Toxicity was assessed using NCI CTCAE v3.0; DLT was defined as grade (G) 3 non-hematologic toxicity, G4 neutropenia for 5 d and/or neutropenic fever, or platelets <25,000/mm3 on >1 occasion despite transfusion. Response was assessed by modified EBMT criteria. Pts had to have received at least 1 prior therapy and no more than 4. Pts refractory to Rev/Dex were excluded.
RESULTS: 32 pts (17 men and 15 women, median age 61 y, range 37 – 80) were enrolled; 6 pts in cohort 1 (Peri 50mg, Rev 15mg, Dex 20mg); 6 pts in cohort 2 (Peri 50mg, Rev 25mg, Dex 20mg); 8 pts in cohort 3 (Peri 100mg, Rev 15mg, Dex 40mg/wk); 6 pts in cohort 4 (Peri 100mg, Rev 25mg, Dex 40mg/wk) and 6 pts at MTD (Cohort 4). Median prior lines of treatment was 2 (range 1–4). Prior therapy included dex (94%), thalidomide (83%), bortezomib (47%), and stem cell transplant (47%). 37% of pts had progressed on prior Thal/Dex. Two pts did not complete one full cycle (noncompliance and adverse event not related to study drugs – both in cohort 3) and were not included in the safety and efficacy analysis. Of the 30 pts evaluable for safety, the most common (≥ 10%) grade 1/2 events included nausea (13%); diarrhea (17%); weight loss (17%); upper respiratory infection (23%); fatigue (30%); thrombocytopenia (20%); neutropenia (20%); hypophosphatemia (23%); increased creatinine (23%); anemia (36%); hypercalcemia (47%). Grade 3/4 adverse events ≥ 5% included neutropenia (20%); hypophosphatemia (17%); thrombocytopenia (13%); anemia (10%), fatigue (7%). There was one reported DLT in cohort 3 (Nausea). Rev was reduced in 8 pts, Peri reduced in 8 pts and Dex reduced in 6 pts. All 30 pts in the analysis are evaluable for response, with best response as follows:
Response: N = 30N (%)Duration (wks)ORR (≥PR)Near Complete Response (nCR)2 (7%)79+, 15+Very Good Partial Response (VGPR)3 (10%)62+, 34, 1715 (50%)Partial Response (PR)10 (33%)26+ (range 11 – 54+)Minimal Response (MR)6 (20%)17+ (range 9 – 30+)Stable Disease (SD)7 (23%)14+ (range 8 – 19)Progression (PD)2 (7%)8, 4stable disease: < 25% reduction in M-protein
As of August 2008, the median time to progression (TTP) for pts achieving ≥ PR is 31 wks (range 11–79), and the median TTP for all 30 pts is 23 wks (range 4 – 79). The median TTP has not been met with 11/30 pts continuing on active treatment. Survival for all study pts remains at 90%.
CONCLUSIONS: Patients have tolerated Peri + Rev + Dex well with manageable toxicity, and with encouraging clinical activity demonstrated by an ORR (≥ PR) of 50%. Accrual is complete and the final analysis for all pts will be presented at the meeting.
INTRODUCTION: Perifosine (Peri) is an orally -bioavailable, novel signal transduction modulator with multiple pathway effects including inhibition of Akt and activation of JNK. Peri first ...demonstrated activity in combination with dexamethasone (dex) in patients (pts) with advanced, relapsed/refractory multiple myeloma (MM) (ASH 2007 #1164). Of interest were experiments conducted combining Peri with bortezomib (Velcade®, Vel). In vitro, Peri + Vel shows at least additive cytotoxicity against MM cells with Peri inhibiting Vel induced Akt activation (Hideshima et. al, BLOOD 2006). We conducted a phase I/II study with encouraging safety and clinical activity of the combination seen in the phase I portion of the trial, including a 56% ORR (ASH 2007 # 1170). Herein, we report on the combined phase I/II results (n=76) which determined the safety and activity of Peri + Vel 322 PATTerNS of CAre 2008 ASH ANNUAl MeeTiNG ABSTrACTS, VolUMe 112, iSSUe 11, NoVeMBer 16, 2008 (+/− dex), in pts with relapsed and relapsed/refractory MM, who were previously relapsed from or refractory to Vel.
METHODS: The phase I stage of the study enrolled a total of 18 pts in 4 cohorts (≥3 pts each) with dosing of Peri 50 mg or 100 mg (daily) and Vel 1.0 or 1.3 mg/m2 (d 1, 4, 8, 11) in 21-d cycles. The selected dose for phase II was Peri 50 mg qd + Vel 1.3 mg/m2 (d 1, 4, 8, 11) in 21-d cycles, with a planned enrollment of 64 pts. Dex 20mg (on day of and after each Vel dose) could be added in pts with progressive disease (PD). NCI CTCAE v3.0 was used for toxicity assessment. For the phase I portion, DLT was defined as any grade (G) 3 non-hematologic toxicity, G4 neutropenia for 5 d and/or neutropenic fever, or platelets <10,000/mm3 on >1 occasion despite transfusion. Response was assessed by modified EBMT and Uniform criteria.
RESULTS: A total of 76 pts have been enrolled (18 pts in phase I and 58 in phase II) comprised of 45 men and 31 women, median age 63 y, (range 41 – 89). 84% of pts had relapsed/refractory MM, with a median of 6 lines of prior treatment (range 2–13). Prior therapy included Vel (100%), dex (95%), thalidomide (79%), lenalidomide (71%) and SCT (57%). 63 pts have completed at least one cycle and were evaluable for safety (13 pts are currently not evaluable; 3 were removed in cycle 1 and 10 are too early in their treatment). Most common (□ 10%) grade 1/2 events were nausea, diarrhea, fatigue and myelosuppression, which were manageable with supportive care and growth factors. Grade 3/4 adverse events 5% included thrombocytopenia (40%); lymphopenia (36%); neutropenia (21%); anemia (14%); hyponatremia (13%); leukopenia (11%); proteinuria (8%), and upper respiratory infection (6%). No DVT has been seen, and only 1 worsening peripheral neuropathy from grade 1 to 3 has been reported to date: 2 pts had Peri reduced to 50 mg (nausea, fatigue) in the phase 1 cohort, and 7 pts had Vel dose reductions primarily due to hematologic toxicity. 57 pts have completed at least 2 cycles and are evaluable for response, with best response to Peri + Vel (+/− dex) as follows:
CRPRMRORRSDAll Patients:Best ResponseN=5724%712%1425%2340%2340%Peri + Vel5712%59%814%1424%1730%With dex added*3112%23%611%916%611%(* as a subset of the evaluable population)
9 of 76 pts (12%) rapidly progressed without response or stable disease, including 6 pts in whom dex was also added. As of August 2008, the median time to progression (TTP) for pts achieving PR is 34 wks, and for all pts achieving MR is 33 wks. The median TTP for all study pts is 19 wks (range 3 – 103 wks). The median TTP for responders and for all pts has not been met. In a subset analysis of Vel refractory pts (35/57), the reported ORR (□ MR), and median TTP were as follows:
Vel Refractory:N= 35CRPRMRORRSDPeri + Vel (+/− dex)13%411%823%1337%1234%Median TTP (wks/range): Responders (n=13)10317 (11 – 24)40 (19 – 76)37 (11 – 103)21 (9 – 32)Median TTP (wks/range): All pts (n=35)23 wks (3 – 103 wks)
CONCLUSIONS: Peri in combination with Vel (+/− dex) was generally well tolerated and is remarkably active in a heavily pre-treated, Vel-exposed pt population, with an ORR of 40%, including an ORR of 37% and a median TTP of 9.25 months in responding but previously Vel –refractory pts. Responses have been durable overall with clinical benefit seen, as reflected by an encouraging TTP in this setting. Additional analysis will be reported at the meeting and further trials, including randomized studies earlier in relapsed disease, are planned.
Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol-Myers-Squibb, is a potent NS5A inhibitor currently ...under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl-imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)-1-((S)-2-(4-(4-(6-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)quinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (17), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half-life. This compound represents a promising lead that warrants further evaluation.
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