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Dr. Richardson - An Overview of Studies of the New Agent Perifosine (KRX-0401) Alone and in Combination for Patients with Relapsed/Refractory Multiple Myeloma
Paul Richardson, MD
Jerome Lipper Myeloma Center
Dana Farber Cancer Institute
Boston, MA
Member, IMF Board of Scientific Advisors
01.02.08

"In terms of next steps with Perifosine, larger confirmatory trials are planned, and I think these will be very important in establishing the role of this new agent in myeloma."
Dr. Paul Richardson


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PERIFOSINE ABSTRACTS:

[1164] Multi-Center Phase II Study of Perifosine (KRX-0401) Alone and in Combination with Dexamethasone (dex) for Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Promising Activity as Combination Therapy with Manageable Toxicity. Session Type: Poster Session, Board #318-I

Paul Richardson, S. Lonial, A. Jakubowiak, A. Krishnan, J. Wolf, J. Densmore, S. Singhal, I. Ghobrial, J. Stephenson, J. Mehta, K. Colson, D. Francis, T. Kendall, N. Obadike, K. Sullivan, J. Martin, T. Hideshima, L. Lai, P. Sportelli, L. Gardner, R. Birch, I.C. Henderson, K. Anderson Dana-Farber Cancer Inst., MA, USA; Emory Winship Cancer Inst., GA, USA; Univ. of Michigan, MI, USA; City of Hope, CA, USA; UC San Francisco, CA, USA; Univ. of Virginia, VA, USA; Northwestern, IL, USA; Cancer Ctr of Carolinas, SC, USA; Keryx Biopharmaceuticals, NY, USA

INTRODUCTION: Perifosine (peri) is an oral, novel synthetic alkylphospholipid, with multiple effects on signal transduction pathways, including inhibition of Akt and activation of JNK. In vitro studies showed that peri induces cytotoxicity in both MM cell lines and patient (pt) MM cells resistant to conventional therapies, and augments dexamethasone (dex) and bortezomib-induced MM cell cytotoxicity (Hideshima T. et. al. BLOOD 2006). In vivo studies showed antitumor activity in a human plasmacytoma mouse model. Here we report the results of a phase II trial of peri, alone and + dex, in pts with relapsed or relapsed / refractory MM.

METHODS: Pts received 150 mg of peri daily for a 21 day (d) cycle, and were assessed every cycle by serum- and/or urine-electrophoresis. Eligible pts had symptomatic relapsed or relapsed / refractory MM. Pts were permitted to receive bisphosphonate treatment. Concomitant steroids (prednisone > 10 mg/d), creatinine of > 3.0 mg/dL, and hemoglobin < 8.0 g/dL within 14 d of enrollment were exclusion criteria. Progressing pts, documented on 2 occasions at least one week apart, had dex 20 mg twice per week added to peri. Toxicities were assessed by NCI-CTCAE, v3.0. RESULTS: 64 pts (35 M/ 29 F, median age 62, range 38 79) have been treated to date. Median lines of prior treatment was 4 (range 1-11); 32 (50%) pts had relapsed and refractory MM. Prior therapy included dex (95%), thalidomide (89%), bortezomib (73%), lenalidomide (30%) and ASCT (61%). Among 48 pts currently evaluable for response, best response (EBMT criteria) to single agent peri after 2 cycles was MR in 1 pt, stable disease (< 25% reduction in M-protein) in 22 pts (46%). Dex was added in 37 pts with PD, with 31 pts evaluable for response on the combination as follows:

Peri + Dex N (%) Duration (wks)
PR 4 (13%) 17, 24, 44+, 46+
MR 8 (25%) 3+, 12+, 19, 21, 25, 30, 32, 55+
Stable Disease 15 (47%) 6+ 46 (median 12)*
*4 pts ongoing at 6, 9, 11 and 24 wks

Most common adverse events included nausea (74%, 8% G3); vomiting (61%, 5% G3); diarrhea (65%, 2% G3); fatigue (31%, 2% G3), increased creatinine (51%, 7% G3/4 in the context of PD and light chain nephropathy but reversible) and anemia (63%, 5% G3). 10 pts had G3/4 neutropenia which resolved. Dose reduction was required to 100 mg/d (n=16) or to 50 mg/d (n=4). 9 pts discontinued treatment due to side effects. Attributable toxicities otherwise proved manageable with supportive care and no peripheral neuropathy or DVT seen.

CONCLUSION: Perifosine as monotherapy has modest activity, but in combination with dex showed significant activity in pts with relapsed/refractory MM, achieving PR + MR in 38%, and/or stabilization of disease in 47% of evaluable pts to date. It was generally well tolerated, although caution in pts with renal dysfunction is warranted. PK, IHC and gene array studies are ongoing. Other novel studies with peri in combination with bortezomib and with lenalidomide +/-dex are underway.
Abstract #1164 appears in Blood, Volume 110, issue 11, November 16, 2007


[1170] Phase I/II Report from a Multicenter Trial of Perifosine (KRX-0401) + Bortezomib in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma Previously Treated with Bortezomib. Session Type: Poster Session, Board #324-I

Paul Richardson, A. Jakubowiak, J. Wolf, J. Allerton, J. Zonder, S. Lonial, A. Krishnan, J. Densmore, I. Ghobrial, K. Colson, T. Kendall, C. Leister, B. Martineau, T. Hideshima, T. Facon, P. Sportelli, L. Gardner, R. Birch, I.C. Henderson, K. Anderson Dana-Farber Cancer Inst., MA, USA; Univ. of Michigan, MI, USA; UC San Francisco, CA, USA; Guthrie Cancer Ctr, PA, USA; Karmanos Cancer Ctr., MI, USA; Emory Winship Cancer Inst., GA, USA; City of Hope, CA, USA; Univ. of Virginia, VA, USA; Alta Bates, CA, USA; Hematology, Huriez Hospital, Lille, France; Keryx Biopharmaceuticals, NY, USA

INTRODUCTION: Perifosine (peri) is an oral, signal transduction modulator with multiple pathway effects including inhibition of Akt and activation of JNK. In vitro, peri + bortezomib (Velcade, Vel) shows additive cytotoxicity against MM cells with peri inhibiting Vel induced Akt activation. Peri with dexamethasone (dex) has activity in patients (pts) with advanced, relapsed/refractory MM (ASH 2006 #3582). This phase I/II study sought to determine MTD and evaluate the activity of peri plus Vel +/- dex in pts with relapsed and relapsed/refractory MM, who were either previously treated or refractory to Vel.

METHODS: 4 cohorts (at least 3 pts each) were planned, 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. 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; 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: 18 pts (11 M/ 7 F, median age 64 y, range 42 87) have been enrolled; 3 pts in cohort 1 (peri 50mg, Vel 1.0mg/m2), 3 pts in cohort 2 (peri 100mg, Vel 1.0mg/m2), 6 pts in cohort 3 (peri 50mg, Vel 1.3mg/m2) and 6 pts in cohort 4 (peri 100mg, Vel 1.3mg/m2). 14 pts (78%) had relapsed/refractory MM, with a median of 5 lines of prior treatment (range 2-7). Prior therapy included Vel (100%), dex (89%), thalidomide (67%), lenalidomide (33%) and SCT (56%). 16/18 pts were evaluable for toxicity with most common AEs as follows:

Adverse Event (N = 16) Grade 1/2 Grade 3/4
Nausea 31% 0%
Vomiting 13% 0%
Diarrhea 44% 0%
Fatigue 13% 6%
Thrombocytopenia 13% 25%
Anemia 6% 13%


No DVT and no G3 peripheral neuropathy have been reported. 1 pt had peri reduced to 50mg due to persistent G2 nausea and 3 pts had Vel reduced from 1.3 to 1.0mg/m2 secondary to hematologic toxicity (n=2) and rash (n=1). 15/18 pts are evaluable for response, with best response to peri + Vel, or peri + Vel + dex after 2 cycles as follows:

Response (N = 15) N (%) Duration (wks)
PR after Peri + Vel 2 (13%) 24, 13+
MR after Peri + Vel 1 (7%) 10+
MR after Peri + Vel + Dex *2 (13%) 38+, 18+
SD after Peri + Vel 3 (20%) 18+, 16+, 13+
SD after Peri + Vel + Dex 3 (20%) 38, 22+, 12+
SD: < 25% reduction in M-protein *Pts refractory to prior Vel + Dex

Dex was added in 6/18 pts with PD, with 5 pts evaluable for response to date on the dex combination. 10 pts remain on study.

CONCLUSIONS: Peri in combination with Vel (+/- dex) was generally well tolerated and active in a heavily pre-treated pt population (78% had relapsed/refractory MM and 100% prior Vel). Responses seen in every cohort with greater toxicity reported in cohorts with 100 mg/d of peri. The phase II portion has now been initiated with peri 50 mg qhs and Vel 1.3mg/m2 days 1, 4, 8 and 11 every 21 days.
Abstract #1170 appears in Blood, Volume 110, issue 11, November 16, 2007


[1169] A Multiple Myeloma Research Consortium (MMRC) Multicenter Phase I Trial of Perifosine (KRX-0401) in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (MM): Updated Results. Session Type: Poster Session, Board #323-I

Andrzej Jakubowiak, Todd Zimmerman, Melissa Alsina, Paul Richardson, Jonathan Kaufman, T. Kendall, C. Brozo, A. McAllister, C. Leister, T. Hideshima, P. Sportelli, L. Gardner, R. Birch, I.C. Henderson, K. Giusti, Kenneth Anderson Univ. of Michigan Cancer Ctr., MI, USA; Univ. of Chicago Cancer Ctr., IL, USA; H. Lee Moffitt Cancer Ctr., FL, USA; Dana-Farber Cancer Inst., MA, USA; Emory Winship Cancer Inst., GA, USA; Keryx Biopharmaceuticals, Inc., NY, USA; Multiple Myeloma Research Foundation, CT, USA

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 2006 #3582). Lenalidomide (Revlimid, Rev) a novel, oral immunomodulatory drug has additive effects when combined with Dex. Pre-clinical studies demonstrate increased cytotoxicity against MM cells when Peri is combined with Rev/Dex compared to each drug alone or in combination (Hideshima, T.et al Data on File). The addition of Peri to Rev/Dex may therefore enhance its clinical activity. This phase 1 study aimed to determine MTD and activity of Peri + Rev + Dex, in pts with 2nd or 3rd line MM.

METHODS: Four cohorts (6 pts each) are 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. Toxicity assessment uses NCI CTCAE v3.0; DLT is 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 is assessed by modified EBMT criteria.

RESULTS: 12 pts (6 M / 6 F, median age 62 y, range 40 78) have been enrolled; 6 pts in cohort 1 (Peri 50mg, Rev 15mg, Dex 20mg) and 6 pts in cohort 2 (Peri 50mg, Rev 25mg, Dex 20mg). 7 pts (58%) had relapsed/refractory MM, with a median of 2 lines of prior treatment (range 1-3). Prior therapy included dex (100%), thalidomide (83%), bortezomib (58%), stem cell transplant (67%) and one patient who had relapsed on prior Rev/Dex. 10 pts have completed one full cycle of treatment and the most common adverse events ( 10%) have been as follows:

Adverse Event Grade 1 Grade 2 Grade 3
Nausea 10% 0% 0%
Vomiting 10% 0% 0%
Diarrhea 30% 10% 10%
Fatigue 20% 20% 10%
Thrombocytopenia 10% 10% 20%
Increase Creatinine 10% 10% 0%
Neutropenia 0% 0% 20%
Leukopenia 0% 0% 20%

No DLTs or G 4 events have been reported. Rev was reduced in 1 patient and dex was reduced in 3 pts. 9 of 12 pts are evaluable for response, with best response (EBMT and Uniform criteria) after 2 cycles was as follows:

Response N (%) Duration (wks)
Near Complete Response (nCR) 1 (11%) 28+
Very Good Partial Response (VGPR) 1 (11%) 21+
Partial Response (PR) 3 (33%) 31+, 12+, 8+
Minimal Response (MR) 1 (11%) 21+
Stable Disease (SD) < 25% reduction in M-protein 1 (11%) 16
Progressive Disease (PD) 2 (22%) 8, 4

7/10 pts remain on study.

CONCLUSIONS: Pts to date have tolerated Peri + Rev + Dex well with no unexpected toxicities and clinical activity has been noted within the first 2 cohorts with 5 of 9 (56%) of pts achieving at least PR. To limit dex-related toxicities, the protocol will be amended to use weekly Dex as per Rajkumar et al. (ASCO 2007), which will apply to cohorts 3 and 4. Accrual is ongoing and additional results will be updated at the meeting.
Abstract #1169 appears in Blood, Volume 110, issue 11, November 16, 2007


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