PANORAMA 2: Panobinostat Combined with Bortezomib and Dexamethasone in Patients with Relapsed and Bortezomib-Refractory Multiple Myeloma

Abstract Abstract 1852 Background: There are limited treatment options for patients (pts) with multiple myeloma (MM) whose disease is refractory to bortezomib (BTZ) and are relapsed and/or refractory, intolerant or ineligible to receive an immunomodulatory (IMiD) drug. These pts have a poor prognosis with a response rate for subsequent BTZ-containing regimens of 20% and median event-free survival of 5 months (Kumar S, et al. Leukemia. 2011). Panobinostat (PAN) is an oral pan-deacetylase inhibitor (pan-DACi) that has low nanomolar activity against all class I, II, and IV histone deacetylase enzymes, including those implicated as potential targets in MM. PAN synergizes with BTZ to inhibit both the aggresome and proteasome pathways in preclinical studies. Phase 1 results with PAN + BTZ demonstrated clinical responses in pts with BTZ-refractory disease. PANORAMA 2 expands upon these results and evaluates whether PAN can recapture responses in BTZ-refractory MM pts. Methods: Pts with relapsed and BTZ-refractory MM (≥2 prior lines of therapy including an IMiD and who had progressed on or within 60 days of the last BTZ-based therapy) were treated in this single-arm, phase 2 study with PAN + BTZ + dexamethasone (Dex) in 2 phases. Treatment phase 1 (TP1) consisted of 8 three-week cycles of oral PAN (20 mg) + intravenous BTZ (1.3 mg/m2) + oral Dex (20 mg). Pts demonstrating clinical benefit (≥stable disease [SD]) could proceed to treatment phase 2 (TP2), which consisted of 6-week cycles until disease progression. The primary endpoint was overall response rate (≥partial response [PR]), as defined by the European Group of Blood and Marrow Transplantation (EBMT) 1998 criteria, in TP1. Secondary efficacy endpoints included minimal response (MR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), time to progression (TTP), and overall survival (OS). Secondary safety endpoints included safety and tolerability. Results: Fifty-five pts with BTZ-refractory MM were enrolled (median age, 61 years [range, 41–88 years]). Pts were heavily pretreated with a median of 4 prior regimens (range, 2–11), and a median of 2 prior BTZ-containing regimens (range, 1–6). All pts (100%) were previously treated with BTZ, Dex, and at least 1 IMiD (lenalidomide [98%], thalidomide [69%]). The majority of pts received prior autologous stem cell transplant (64%). Forty-five pts (82%) received Dex with their last BTZ-containing regimen. In the most recent prior line of therapy, 27 pts (49%) had BTZ. As of the February 20, 2012, cutoff, all pts had completed TP1 or stopped treatment, and 7 of the 18 pts who entered TP2 were ongoing. The overall response rate was 35% (1 near complete response [nCR] and 18 PR or better, with 3 pts [5%] achieving a very good partial response [VGPR; Table]). An additional 10 pts achieved MR, for a clinical benefit rate of 53%. The median duration of exposure was 4.6 months (range, < 1–14.8 months). The median PFS and TTP were 4.9 months. The PFS rates for pts whose disease progressed on BTZ (n = 39) and within 60 days of BTZ (n = 16) were 4.2 and 7.6 months, respectively. In pts who achieved a response, the mean TTR was 1.7 months (range, 0.1–3.9), and the median DOR was 6.0 months. With a median follow-up time of 8.1 months, the median OS has not been reached. Common adverse events (AEs) of any grade regardless of study drug relationship included diarrhea (71%), fatigue (69%), thrombocytopenia (65%), nausea (60%), anemia (47%), dyspnea (44%), decreased appetite (42%), and peripheral edema (40%). Common grade 3/4 AEs regardless of study drug relationship included thrombocytopenia (64%), fatigue (20%), diarrhea (20%), anemia (15%), pneumonia (15%), and neutropenia (15%). Only 1 pt (2%) experienced grade 3 peripheral neuropathy. Conclusions: PAN, when combined with BTZ and Dex can recapture responses in heavily pretreated, BTZ- and Dex-refractory MM pts. The regimen was tolerable with manageable toxicities, with 33% of pts on therapy for > 8 cycles. The combination of PAN, BTZ and Dex is therefore an important potential therapeutic option for relapsed and refractory MM pts, including those with BTZ, Dex, and IMiD resistance. Disclosures: Richardson: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Alsina:Millenium: Consultancy, Research Funding. Weber:Novartis: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy. Gasparetto:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mukhopadhyay:Novartis: Employment. Ondovik:Novartis: Employment, Equity Ownership. Khan:Novartis: Employment. Paley:Novartis: Employment, Equity Ownership. Schlossman:Celgene: Membership on an entity's Board of Directors or advisory committees.

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Phase II Study of the Pan-Deacetylase Inhibitor Panobinostat in Combination with Bortezomib and Dexamethasone in Relapsed and Bortezomib-Refractory Multiple Myeloma (PANORAMA 2)

Blood ◽

10.1182/blood.v118.21.814.814 ◽

2011 ◽

Vol 118 (21) ◽

pp. 814-814 ◽

Cited By ~ 8

Author(s):

Paul G. Richardson ◽

Melissa Alsina ◽

Donna M. Weber ◽

Steven E. Coutre ◽

Sagar Lonial ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Treatment Phase ◽

Employment Equity ◽

Advisory Committees ◽

Overall Response ◽

Equity Ownership ◽

Grade 3 ◽

Stage 1

Abstract Abstract 814FN2 Background: Patients with refractory multiple myeloma (MM) have limited treatment options and an extremely poor prognosis. A recent study of patients who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive an immunomodulatory drug (IMiD, thalidomide or lenalidomide) demonstrated a median event-free survival of only 5 months (Kumar S et al, Leukemia, 2011). Panobinostat is an oral pan-deacetylase inhibitor (pan-DACi) that increases acetylation of proteins involved in multiple oncogenic pathways. Preclinical studies have demonstrated synergistic anti-myeloma activity of the combination of panobinostat and bortezomib through dual inhibition of the aggresome and proteasome pathways. In a phase I study (B2207) of patients with relapsed or relapsed/refractory MM treated with panobinostat + bortezomib, clinical responses (≥ minimal response [MR]) were observed in 65% of patients, including in patients with bortezomib-refractory disease. PANORAMA 2 seeks to expand upon these preliminary results and seeks to determine whether panobinostat can sensitize resistant patients to a bortezomib-containing therapeutic regimen. Methods: PANORAMA 2 is a single arm, phase II study of panobinostat + bortezomib + dexamethasone in patients with bortezomib-refractory MM. Patients with relapsed and bortezomib-refractory MM (≥ 2 prior lines of therapy including an IMiD and who had progressed on or within 60 days of the last bortezomib-based therapy) are treated in 2 phases. Treatment phase 1 consists of 8 three-week cycles of oral panobinostat (20 mg days 1, 3, 5, 8, 10, 12) + intravenous bortezomib (1.3 mg/m2 days 1, 4, 8, 11) + oral dexamethasone (20 mg on day of and after bortezomib). Patients demonstrating clinical benefit (≥ stable disease) can proceed to treatment phase 2, consisting of 4 six-week cycles of panobinostat (20 mg TIW 2 weeks on 1 week off, and repeat) + bortezomib (1.3 mg/m2 days 1, 8, 22, 29) + dexamethasone (20 mg on day of and after bortezomib). The primary endpoint is overall response (≥ partial response [PR]), as defined by the European Group of Blood and Marrow Transplantation 1998 criteria, in the first 8 cycles of treatment phase 1. A Simon 2-stage design is used to test the primary endpoint where ≥ 4 responses (≥ PR) in 24 patients are needed in stage 1 in order to proceed to stage 2, where ≥ 9 responses in all patients (N = 47) are required to reject the null hypothesis (overall response rate ≤ 10%). Results: A sufficient number of responses ≥ PR were observed in stage 1 to allow for enrollment to continue to stage 2. As of 15 July 2011, 53 patients with bortezomib-refractory MM were enrolled. Safety and demographic data were available for 48 patients. The median age was 61 (41–88) years. Patients were heavily pretreated, with a median of 4 (2–14) prior regimens, and most patients (69%) received prior autologous stem cell transplant. Efficacy data were available for 44 patients. At the time of this analysis, 9 patients achieved ≥ PR (2 near CR [nCR] and 7 PR) as best overall response, and an additional 7 patients achieved an MR. Responders exhibited a long duration on therapy, and, to date, 8 patients have proceeded to treatment phase 2. The 2 patients with nCR have received ≥ 10 cycles of treatment (duration of therapy 190 and 253 days). Four patients who achieved PR have received ≥ 9 cycles (duration of therapy 155–225 days). Updated response data will be presented. Common adverse events (AEs) of any grade included, fatigue (52%), diarrhea (41%), thrombocytopenia (38%), nausea (38%), and anemia (21%). Gastrointestinal AEs were generally mild, with a relatively low incidence of grade 3/4 events. Grade 3/4 AEs were generally hematologic in nature, with grade 3/4 thrombocytopenia, anemia, and neutropenia reported in 38%, 12%, and 10% of patients, respectively. Other common nonhematologic grade 3/4 AEs included fatigue (10%) and pneumonia (10%). Of note, to date, a relatively low rate of peripheral neuropathy (17%) has been observed. No grade 3/4 peripheral neuropathy has been observed. Conclusions: The combination of panobinostat and bortezomib is a promising treatment for patients with bortezomib-refractory MM. These data, along with forthcoming data from the phase III study of panobinostat/placebo + bortezomib + dexamethasone in patients with relapsed MM (PANORAMA 1), will further define the potential role of panobinostat in the treatment of patients with MM. Disclosures: Richardson: Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Alsina:Novartis: Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding; Onyx: Research Funding; Millennium: Consultancy, Research Funding. Weber:Millennium: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Merck: Consultancy; Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy. Gasparetto:Millennium: Speakers Bureau. Warsi:Novartis: Employment, Equity Ownership. Ondovik:Novartis: Employment, Equity Ownership. Mukhopadhyay:Novartis: Employment, Equity Ownership. Snodgrass:Novartis: Employment, Equity Ownership.

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Efficacy of Melflufen, a Peptidase Targeted Therapy, and Dexamethasone in an Ongoing Open-Label Phase 2a Study in Patients with Relapsed and Relapsed-Refractory Multiple Myeloma (RRMM) Including an Initial Report on Progression Free Survival

Blood ◽

10.1182/blood.v126.23.3029.3029 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3029-3029

Author(s):

Peter M. Voorhees ◽

Valeria Magarotto ◽

Pieter Sonneveld ◽

Torben Plesner ◽

Ulf-Henrik Mellqvist ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Phase 1 ◽

Study Drug ◽

Progression Free Survival ◽

Hematologic Toxicity ◽

Advisory Committees ◽

Free Survival

Abstract Background: Melflufen is a highly potent anti-angiogenic compound that triggers rapid, robust and irreversible DNA damage and exerts its cytotoxicity through alkylation of DNA. The lipophilicity of melflufen leads to rapid and extensive distribution into tissues and cells where it binds directly to DNA or is readily metabolized by intracellular peptidases into hydrophilic alkylating metabolites. With targeted delivery of alkylating metabolites to tumor cells in vitro (such as multiple myeloma that are rich in activating peptidase), melflufen exerts a 20-100 fold higher anti-tumor potency and produces a 20 fold higher intracellular concentration of alkylating moieties compared with melphalan. Methods: Melflufen is evaluated in combination with dexamethasone (dex) 40 mg weekly in an ongoing Phase 1/2a study. RRMM patients with measurable disease and at least 2 prior lines of therapy are eligible (NCT01897714). Phase 1 established the maximum tolerated dose (MTD) of melflufen to be 40 mg every 3 weeks in combination with low dose dex. The primary objective of Phase 2a is the overall response rate and safety of the MTD in a total of 55 patients. Response was investigator assessed at the end of each cycle by IMWG criteria. Here we present the Phase 2 data as of 14 July 2015 data-cut. Results: Thirty-one patients were dosed at the MTD. The median time from initial diagnosis to first dose of melflufen was 6 years (1-15). The median number of prior therapies was 4 (2-9). 97% of patients were exposed to immunomodulatory drugs (IMiDs), 90% to proteasome inhibitors (PIs), 77% to melphalan, and 71% had received prior autologous stem cell transplant. 58% were double refractory (IMiDs and PIs) and 42% were triple refractory (IMiDs, PIs and alkylators). In total, 121 doses of melflufen have been given (1-11 cycles). Median treatment duration was 13 weeks with 9 patients still ongoing. One patient completed therapy as planned, 15 patients discontinued due to AEs (48%) and 6 due to progression (19%). Twenty-three patients were evaluable for response (protocol defined as ≥2 doses of melflufen with baseline and follow-up response assessments). One patient achieved a very good partial response and 10 patients achieved partial response (PR) (1 unconfirmed, still ongoing) for an overall response rate (ORR) of 48%. Three additional patients achieved minimal response (MR) for a clinical benefit rate (CBR) of 61%. Time to clinical benefit and response was rapid with 93% of patients achieving ≥ MR after 1-3 cycles and 64% achieving PR after only 1-3 cycles. Eight patients maintained stable disease and 1 patient had early progressive disease. Similar ORRs were seen in PI-refractory (43%), IMiD-refractory (40%), alkylator-refractory (62%), double-refractory (38%) and triple-refractory (50%) patients. The median progression free survival (PFS) is currently at 7.6 months (95% confidence interval: 3.4 - ∞) based on 14 events in 30 patients. The most frequent adverse events (AE), all grades, occurring in >10% of patients, regardless of relationship to study drug were thrombocytopenia (94%), anemia (84%), neutropenia (61%), leukopenia (42%), pyrexia (36%), asthenia (32%), fatigue and nausea (26%), bone pain (19%), cough, diarrhea, dyspnea, mucosal inflammation and upper respiratory infection (16%) and constipation and epistaxis (13%). Treatment-related Grade 3 or 4 AEs were reported in 27 patients (87%). Those occurring in >5% of patients were thrombocytopenia (68%), neutropenia (55%), anemia (42%), leukopenia (32%) and febrile neutropenia, fatigue, pyrexia, asthenia and hyperglycemia each occurred in 6% of patients. Serious AEs occurred in 9 patients (29%), but were only assessed as related to study drug in 5 patients (16%) including 3 febrile neutropenia, 1 fever and 1 pneumonia. Cycle length has recently been increased to 28 days to improve tolerability with respect to hematologic toxicity. Conclusion: Melflufen has promising activity in heavily pretreated RRMM patients where conventional therapies have failed. The current ORR is 48% and CBR is 61%. Similar results were seen across patient populations regardless of refractory status. The median PFS is encouraging at 7.6 months. Hematologic toxicity was common, but non-hematologic AEs were infrequent. Updated results will be presented at the meeting. Disclosures Voorhees: Millennium/Takeda and Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Array BioPharma, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy; Janssen, Celgene, GlaxoSmithKline,Onyx Pharmaceuticals and Oncopeptides: Consultancy, Research Funding. Sonneveld:Janssen: Speakers Bureau; Takeda: Research Funding; Celgene and Onyx: Research Funding, Speakers Bureau. Plesner:Roche and Novartis: Research Funding; Janssen and Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees. Mellqvist:Celgene, Amgen, Mundipharma and Novartis: Honoraria. Byrne:Oncopeptides: Consultancy. Harmenberg:Oncopeptides: Consultancy. Nordstrom:Oncopeptides: Employment. Palumbo:Amgen: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Array BioPharma: Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Sanofi-Aventis: Honoraria. Richardson:Oncopeptides, Celgene and Takeda: Membership on an entity's Board of Directors or advisory committees.

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Phase 1b Study of PD-1 Blockade with Pembrolizumab in Patients with Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

Blood ◽

10.1182/blood.v126.23.3986.3986 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3986-3986 ◽

Cited By ~ 13

Author(s):

Pier Luigi Zinzani ◽

Vincent Ribrag ◽

Craig H. Moskowitz ◽

Jean-Marie Michot ◽

John Kuruvilla ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Employment Equity ◽

Advisory Committees ◽

Humanized Monoclonal Antibody ◽

Heavily Pretreated ◽

Phase 1B ◽

Equity Ownership ◽

Grade 3

Abstract Introduction: Like classical Hodgkin lymphoma (cHL), PMBCL frequently harbors genetic alterations of the 9p24.1 locus, leading to overexpression of the PD-1 ligands, PD-L1 and PD-L2. This provides a possible mechanism of immune evasion and suggests that PMBCL could have a genetically determined vulnerability to PD-1 blockade. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands. Pembrolizumab has already demonstrated robust antitumor activity in advanced solid tumors and in cHL. KEYNOTE-013 (NCT01953692) is a multicenter, multicohort phase 1b trial testing the safety and preliminary efficacy of pembrolizumab in patients with hematologic malignancies. Based on its genetics, PMBCL was included as an independent cohort in this trial. Here we report the preliminary results in this patient population. Methods: The PMBCL cohort of KEYNOTE-013 is enrolling patients with relapsed/refractory (R/R) disease who have relapsed after or are ineligible for autologous stem cell transplant (ASCT). Pembrolizumab is administered intravenously at a dose of 10 mg/kg every 2 weeks for up to 2 years or until confirmed disease progression or unacceptable toxicity. The primary end points are safety and antitumor activity. Response is being evaluated using computed tomography (CT) and positron emission tomography (PET) at week 12 and every 8 weeks thereafter, using IHP 2007 criteria. Other end points include complete remission (CR) rate, duration of response (DOR), and exploratory biomarker analyses. Results: As of July 23, 2015, 10 patients with R/R PMBCL with a median age of 28 (23-62) years have been enrolled in this cohort. Patients were heavily pretreated: 40% had ≥4 prior lines of therapy, and 60% had prior radiation. Six patients (60%) experienced at least 1 adverse event (AE) of any grade related to study treatment. These treatment-related AEs, all grade 1/2, were: hypothyroidism and decreased appetite (2 patients each), and diarrhea, nausea, vomiting, fatigue, edema, weight loss, and arthralgia (1 patient each). There were no grade 3-5 treatment-related AEs. Two patients experienced a serious AE (grade 3 infectious pneumonia) unrelated to study drug. No patient discontinued for toxicity. Nine patients were evaluable for response (1 discontinued treatment based on clinical progression before week 12). The objective response rate (ORR) was 44% (4/9), with 1 patient achieving a CR and 3 patients achieving a partial response. The intent-to-treat ORR was 40%. With a median follow-up of 144 days, the median DOR has not been reached (1+ to 291+) days, with all 4 responses ongoing at the time of data cutoff. Six of 10 patients have discontinued study treatment because of disease progression, and 4 patients remain on study. Conclusion: The preliminary results of KEYNOTE-013 indicate that PD-1 blockade with pembrolizumab is associated with a tolerable safety profile and a promising response rate in heavily pretreated patients with R/R PMBCL. Those patients often have a very poor outcome with conventional therapy, justifying further studies of pembrolizumab in this population. Disclosures Zinzani: Gilead: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Off Label Use: The PD-1 pathway is an important mechanism of immune evasion for many tumors. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction of PD-1 with its ligands PD-L1 and PD-L2 on the tumor cell surface and, based upon pembrolizumab's antitumor immune activity in several solid tumors, it may be an effective option for treating hematological malignancies.. Ribrag:Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Esai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Moskowitz:Genentech: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Research Funding; Pharmacyclics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Kuruvilla:Merck: Honoraria; Bristol-Myers Squibb: Honoraria; Hoffmann LaRoche: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy; Karyopharm: Honoraria. Balakumaran:Merck: Employment, Equity Ownership; Amgen: Equity Ownership. Snyder:Merck: Employment, Equity Ownership. Marinello:Merck: Employment, Equity Ownership. Shipp:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Armand:Infinity: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Sequenta, Inc.: Research Funding; BMS: Research Funding.

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A Phase I Study of Vorinostat, Lenalidomide, and Dexamethasone In Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Excellent Tolerability and Promising Activity In a Heavily Pretreated Population

Blood ◽

10.1182/blood.v116.21.1951.1951 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1951-1951 ◽

Cited By ~ 4

Author(s):

Paul Richardson ◽

Donna Weber ◽

Constantine S. Mitsiades ◽

Meletios A. Dimopoulos ◽

Jean-Luc Harousseau ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Phase I Study ◽

Response Rate ◽

Advisory Board ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 1951 Background: Although novel treatment combinations for multiple myeloma (MM) have improved outcomes, the disease remains incurable and new drug combinations are urgently needed. Vorinostat is an oral histone deacetylase inhibitor approved in the United States for treatment of patients (pts) with advanced cutaneous T-cell lymphoma who failed prior therapies. Vorinostat alters gene expression and protein activity, promoting MM cell death through multiple pathways, and has been shown in preclinical studies to synergistically enhance the anti-MM activity of bortezomib and immunomodulatory drugs, including lenalidomide, with or without dexamethasone. Aims: The primary objective of this Phase I study was to determine the maximum tolerated dose (MTD) of vorinostat plus lenalidomide and dexamethasone in pts with relapsed or relapsed and refractory MM. Secondary objectives included overall safety, tolerability, response rate, duration of response, and time to progression (TTP). Methods: Pts in this Phase I multicenter open-label study were sequentially enrolled into 1 of 5 escalating doses of the combination regimen using a standard 3 + 3 design for ≤8 cycles. Pts who tolerated treatment and experienced clinical benefit were eligible for enrollment in an extension phase. Toxicity was evaluated using the National Cancer Institute Common Terminology Criteria (version 3.0). Response was assessed using the modified European Group for Blood and Marrow Transplantation criteria and International Myeloma Working Group Uniform Criteria. Safety and efficacy data were analyzed using summary statistics, except for TTP, which was estimated by the Kaplan-Meier method. Results: As of July 15, 2010, 31 pts were treated and evaluable for toxicity; 4 pts remain on study. Most pts had received prior thalidomide (n=22; 71%), bortezomib (n=20; 65%), or lenalidomide (n=14; 45%), with a median of 4 prior therapies (range, 1–10). The patient population contained both high-risk and low-risk pts, based on cytogenetic and/or fluorescence in situ hybridization analyses. Most adverse events (AEs) were mild or moderate in severity. The most common grade ≥3 treatment-related AEs, experienced by 19 (61%) pts, were neutropenia (26%), thrombocytopenia (16%), diarrhea (13%), anemia (10%), and fatigue (10%); 8 pts discontinued due to toxicity. One dose-limiting toxicity (grade 3 diarrhea lasting >48 h) was observed at the maximum assessed dose (level 5), but MTD was not reached (Table) and there were no treatment-related deaths. Among 30 pts evaluable for response, the median TTP was 32 weeks (5 mo), and 4 pts remain on study as of the data cutoff date; 26 of 30 pts (87%) have achieved at least stable disease (SD). Best single responses included 2 complete responses, 3 very good partial responses (VGPR), 11 partial responses (PR), and 5 minimal responses (MR), with 5 pts achieving SD and 4 developing progressive disease, resulting in an overall response rate (ORR; PR or better) of 53%. Of 13 evaluable pts who had previously received lenalidomide, a best single response of SD or better was observed in 9 (69%; 2 VGPR, 3 PR, 1 MR, 3 SD), resulting in a 38% ORR. Notably, SD or better (2 PR, 1 MR, 3 SD) was observed in 60% of 10 evaluable pts who were relapsed, refractory, or intolerant to previous lenalidomide-containing regimens. Conclusions: Preliminary data from this Phase I study suggest that vorinostat plus lenalidomide and dexamethasone is a convenient and generally well-tolerated regimen with promising activity for relapsed or relapsed and refractory MM. The MTD for this combination was not reached. Importantly, responses were observed in pts who had received prior lenalidomide, bortezomib, and thalidomide. Further evaluation of this regimen is planned in future trials. Disclosures: 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; 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. Off Label Use: Vorinostat, Lenalidomide, and Dexamethasone for treatment in Multiple Myeloma. Weber:Novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; Celgene- none for at least 2 years: Honoraria; Millenium-none for 2 years: Honoraria; Celgene, Millenium, Merck: Research Funding. Mitsiades:Millennium: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Merck & Co.: Consultancy, Honoraria; Kosan Pharmaceuticals: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; Centrocor: Consultancy, Honoraria; PharmaMar: Patents & Royalties; OSI Pharmaceuticals: Research Funding; Amgen Pharmaceuticals: Research Funding; AVEO Pharma: Research Funding; EMD Serono: Research Funding; Sunesis: Research Funding; Gloucester Pharmaceuticals: Research Funding; Genzyme: Research Funding. Dimopoulos:MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Harousseau:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Houp:Merck Research Laboratories: Employment. Graef:Merck Research Laboratories: Employment. Gause:Merck Research Laboratories: Employment. Byrne:Celgene Corporation: Employment, Equity Ownership. Anderson:Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; BMS: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board.

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Updated Interim Results of the Safety and Efficacy of Different Lenalidomide Starting Dose Regimens in Patients with Relapsed or Refractory (rel/ref) Chronic Lymphocytic Leukemia (CLL) (CC-5013-CLL-009 Study)

Blood ◽

10.1182/blood.v120.21.3925.3925 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3925-3925 ◽

Cited By ~ 2

Author(s):

Clemens Wendtner ◽

Michael Hallek ◽

Graeme Fraser ◽

Anne-Sophie Michallet ◽

Peter Hillmen ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Median Number ◽

Advisory Committees ◽

Starting Dose ◽

Purine Analog ◽

Equity Ownership ◽

Grade 3 ◽

Dose Levels

Abstract Abstract 3925 Introduction: CLL patients (pts) who relapse following purine-analog or bendamustine-based treatments have a poor prognosis. These pts have limited therapeutic options and novel agents with alternative mechanisms of action are needed. Several phase 1 and 2 trials in rel/ref CLL showed promising activity with escalating dose regimens of lenalidomide (LEN). In other phase II studies improved clinical responses to lenalidomide appeared to correlate with dose levels > 5mg/day. This phase 2 trial investigates the safety of LEN initiated at 3 different starting doses followed by a step-wise dose escalation as tolerated in rel/ref CLL. Methods: In this ongoing trial, eligible pts with rel/ref CLL who have received ≥ 1 prior treatment regimen containing purine-analog or bendamustine are being enrolled. The objectives of this study are to evaluate primarily the safety and secondarily the efficacy of different LEN dose regimens. Pts are randomized 1:1:1 to receive a double-blinded starting dose of 5 mg, 10 mg, or 15 mg oral LEN on days 1–28 of each 28-day cycle. In all 3 treatment arms, the dose is escalated by 5 mg increments every 28 days to reach a maximum dose of 25 mg/d, depending on tolerability. In instances of poor tolerability, dose reductions also occur in 5 mg steps. Pts are stratified by relapsed versus refractory status to their last purine-analog or bendamustine-based treatment regimen and according to age (< 65 vs ≥ 65 years). Tumor lysis syndrome (TLS) prophylaxis comprises of oral hydration and allopurinol 300 mg/day and is initiated ≥ 3 days prior to starting study drug and for a minimum of the first 3 treatment cycles. A total of 105 pts are planned for enrollment to the study. Per protocol, unblinded interim analyses were conducted by the independent Data Monitoring Committee (DMC) after 18 subjects completed 1 cycle and continue at 13-week intervals. Results: To date, 95 pts are enrolled at a median age of 64 years (range 32–81). Enrolled pts are primarily male (67%) and Caucasian (92%). Cytogenetic data are available for 73 pts; 21% have del(17p), 55% have del(13q), 25% have del(11q), and of 72 patients evaluable for trisomy 12, 11 patients (15%) tested positive. IGVH is unmutated in 77% of 77 evaluable pts and 44% of 84 evaluable pts are ZAP70-positive. Based on the Binet and Rai staging systems 9 (10%), 25 (26%) and 24 (25%) of subjects are stage A, B and C, respectively; 7 (7%), 12 (13%) and 16 (17%) subjects are low, intermediate or high-risk disease, respectively. For 2 (2%) subjects the Binet/Rai staging is currently unknown. Overall, 19 pts (20%) received prior bendamustine-containing treatment and 71 pts (75%) received prior fludarabine-based treatment. The median number of prior therapies was 3 (range 1–10). Most common hematological grade ≥ 3 AEs include neutropenia (62%) and thrombocytopenia (34%). At baseline, 19% of pts presented with grade 1–2 neutropenia. The most common non-hematological ≥ grade 3 AEs include pneumonia (13%), tumor flare (13%), and fatigue (11%). TLS was reported in 3 pts (3%): grade 1, 3, and 4. In total, 8 grade 5 events were reported, 3 of which were suspected to be related to LEN: 2 cases of pneumonia and 1 death for unknown cause. At the time of the cut-off, 59 pts (62%) have discontinued treatment. Most common reasons for treatment discontinuation include disease progression (n = 20) and AEs (n = 20). To date, 47 pts (49%) have dose escalated above their starting dose levels of which 12 patients escalated to the highest dose level (25 mg daily). 18 subjects have had no dose level reduction or escalations and 1 patient is still in the first cycle of the study. Average duration of treatment is 6.5 cycles, and median number of cycles is 4. Efficacy evaluations are completed monthly after 3 months of study drug treatment. At time of the data reporting, 5 pts were on study drug but did not reach the first assessment at cycle. For the 90 pts evaluable for response, the investigator's assessment indicates 2 pts (2%) reached CR, 36 (40%) achieved PR, 33 (37%) patients had SD, and 19 (21%) pts progressed. Conclusion: The independent DMC, as of 14 June, 2012 (N=95), recommended that accrual into all three treatment arms should continue as planned, suggesting all three starting doses were well tolerated. To date, the ORR is 42% and 49% of pts were dose escalated at least once. In this rel/ref CLL population LEN appears active, and completion of accrual will clarify the appropriate dose at which to initiate therapy. Disclosures: Wendtner: Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: use of lenalidomie in relapsed/refractory CLL. Hallek:Celgene Corporation: Consultancy, Honoraria, Research Funding. Hillmen:Celgene Corporation: Honoraria. Gregory:Celgene Corporation: Honoraria, Research Funding. Stilgenbauer:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Kipps:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Purse:Celgene Corporation: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Mei:Celgene Corporation: Employment.

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Selinexor Demonstrates Marked Synergy with Dexamethasone (Sel-Dex) in Preclinical Models and in Patients with Heavily Pretreated Refractory Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v124.21.4773.4773 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4773-4773 ◽

Cited By ~ 4

Author(s):

Christine I. Chen ◽

Martin Gutierrez ◽

David S. Siegel ◽

Joshua R. Richter ◽

Nina Wagner-Johnston ◽

...

Keyword(s):

Board Of Directors ◽

Transcriptional Activation ◽

Nuclear Export ◽

Research Funding ◽

Phase 1 ◽

Advisory Committees ◽

Nuclear Retention ◽

Heavily Pretreated ◽

Equity Ownership

Abstract Introduction: The nuclear export protein exportin 1, (XPO1) is overexpressed in a wide variety of cancers including MM and often correlate with poor prognosis. Selinexor (KPT-330) is an oral Selective Inhibitor of Nuclear Export (SINE) XPO1 antagonist in Phase 1 and 2 clinical studies. Selinexor forces nuclear retention and reactivation of tumor suppressor proteins (TSPs) and reduction of many proto-oncogenes, including MDM2, MYC and Cyclin D. In addition, selinexor potently deactivates NF-κB, through forced nuclear retention of IκBα. Together these effects induce selective apoptosis in MM cells and inhibition of NF-κB dependent osteoclast activation. XPO1 is also responsible for nuclear export of the glucocorticoid receptor (GR). We hypothesized that selinexor will enhance the activity of dexamethasone (DEX)-bound GR, resulting in synergistic tumor cell killing. Methods: In vitro tumor cell viability measurements were based on MTT (CellTiter 96¨/Promega) and combination indices were calculated using CalcuSyn software. For xenograft studies, utilized NOD-SCID mice with subcutaneous inoculation of MM.1s cells. GR nuclear localization was measured with immunofluorescent anti-GR (phosphor-S211) antibody and quantitative imaging. To assess GR transcriptional activation, GR binding to a GCR consensus sequence was measured in nuclear extracts using an ELISA method (GR ELISA kit/Affymetrix). Patients (pts) with heavily pretreated refractory MM were dosed with oral selinexor at doses of up to 60 mg/m2 (8-10 doses/4 wk cycle) as part of a Phase 1 program in advanced hematological malignancies. Response we defined based on the IMWG criteria. The effect of combining DEX with selinexor was analyzed in all pts who received selinexor at moderate to high doses (30-60 mg/m2). Safety and efficacy were analyzed separately in three groups: no DEX, <20 mg DEX and 20 mgs DEX. Results: In MM.1s cells Sel-Dex showed synergy for nuclear retention of the DEX activated GR (Ser211-phosphorylated) and concomitant GR transcriptional activation. Sel-Dex showed highly synergistic cytotoxicity in MM.1s cells in vitro and in vivo, with a corresponding increase in apoptosis. Selinexor alone was potently cytotoxic in the DEX resistant MM cell lines MM.1R and ANBL6, but addition of DEX provided no additional effect. Twenty-eight pts with heavily pretreated refractory MM (16 M, 12 F; median age 62; ECOG PS 0/1: 7/21; median prior regimens: 6) received selinexor at 30 – 60 mg/m2 with either 0, <20, or 20 mgs DEX. All pts have received a proteasome inhibitor and an Imid and the majority of the pts have received pomalidomide (68%) and/or carfilzomib (36%). The most common Grade 1/2 AEs for these three groups were: nausea (82%/86%/70%), fatigue (55%/86%/40%), anorexia (36%/71%/60%), and vomiting (36%/57%/10%). Of the 28 pts treated; 10 heavily pretreated refractory MM pts treated with a combination of selinexor (45 mg/m2 twice weekly) and DEX (20 mg with each selinexor dose) were found to have dramatically improved disease response (n=10, ORR 60%), with one stringent complete response (sCR, 10%), 5 partial responses (PR, 50%) and clinical benefit rate (CBR) rate of 80% (Figure 1). Treatment with ³30mg/m2 selinexor and <20 mg DEX (n=7), resulted in ORR of 14% and CBR of 86%, while treatment with selinexor (30-60 mg/m2) without DEX (n=12) showed best response of stable disease (50%). Sel-Dex was also associated with an increase in time on study relative to selinexor alone, with 7 of out 10 pts in the 20 mg DEX combo group still on study (11-25 weeks). Five additional pts were treated with selinexor at a dose of 60 mg/m2 in combination with 20 mg DEX. Response evaluation is pending. Conclusions: Sel-Dex combination is markedly synergistic in preclinical models, which is supported by the preliminary clinical data presented. One potential mechanism underlying this synergy is the amplification of GR activity due the combined effects of selinexor-induced nuclear retention of activated GR coupled with DEX-mediated GR agonism. These results provide a promising basis for the continuing study of Sel-Dex for treatment of pts with refractory MM. Phase 2 studies of Sel-Dex in pts with MM refractory to both pomalidomide and carfilzomib are planned for early 2015. Disclosures Chen: Celgene: Honoraria; Janssen: Honoraria. Off Label Use: Lenalidomide maintenance therapy after ASCT. Gutierrez:Senesco: PI Other. Siegel:Celgene, Millennium, Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baz:Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Kukreti:Celgene: Honoraria. Azmi:Karyopharm Therpeutics: Research Funding. Kashyap:Karyopharm Therapeutics: Employment. Landesman:Karyopharm Therapeutics: Employment. Marshall:Karyopharm Therpeutics: Employment. McCartney:Karyopharm Therpeutics: Employment. Saint-Martin:Karyopharm Therpeutics: Employment. Norori:Karyopharm Therpeutics: Consultancy. Savona:Karyopharm Therpeutics: Membership on an entity's Board of Directors or advisory committees. Rashal:Karyopharm Therapeutics: Employment. Carlson:Karyopharm Therapeutics: Employment. Mirza:Karyopharm Therpeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership. Reece:Millennium: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; BMS: Research Funding; BMS: Research Funding; Novartis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen : Honoraria; Amgen : Honoraria.

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Long-Term Follow-up of Patients with Mantle Cell Lymphoma Treated with Venetoclax Monotherapy

Blood ◽

10.1182/blood-2018-99-117210 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2883-2883

Author(s):

Matthew S. Davids ◽

Andrew W. Roberts ◽

William G. Wierda ◽

Kathryn Humphrey ◽

Debbie J Alter ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Progressive Disease ◽

Response Rate ◽

Study Drug ◽

Employment Equity ◽

Advisory Committees ◽

Mantle Cell ◽

Equity Ownership

Abstract Introduction: Venetoclax is a selective, oral inhibitor of BCL2, a key regulator of the intrinsic apoptotic pathway. The dose-escalation phase 1 study of venetoclax in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) enrolled 106 patients from June 2011, and the overall response rate across the entire NHL cohort was 44%. The highest response rate (75%) was seen in the 28 patients with mantle cell lymphoma (MCL) (Davids et al., J Clin Oncol. 2017). Here, we report longer-term outcomes for those patients, now with a median of 27 months (range: 0.2 - 59) follow up. Methods: Venetoclax was administered in dose cohorts ranging from a maximum dose of 300-1200 mg and continued until progressive disease (PD) or unacceptable toxicity; intra-patient dose escalation was allowed. Adverse events (AEs) were assessed by NCI-CTCAE v4.0 and responses were assessed using 2007 Cheson IWG response criteria, utilizing CT scans beginning at week 6. The data cut off for this analysis was June 4th, 2018. Results: For the 28 patients with MCL, the median age was 72 years (range: 35 - 85). They had received a median of 3 (range: 1 - 7) prior treatments; 5 patients received prior PI3K inhibitor (but no prior ibrutinib). The median time from the preceding treatment to start of venetoclax was 13 months (range: 2 - 148). The median dose of venetoclax was 400 mg/day; 25/28 received at least 400mg/day. Median time on study drug was 11 months (range: 0.2 - 59). Three patients have been on therapy for over 4 years. The overall response rate was 75%, with 6 (21%) patients achieving complete remission (CR) and 15 (54%) partial response (PR). The median duration of response was 16 months (95% CI: 4, 30) and median progression free survival was 11 months (95% CI: 5, 21) for all patients (Figure). The 2 year PFS estimate was 30% (95% CI: 14%, 47%) for all patients, 83% (95% CI: 27%, 97%) for patients who achieved CR and 14% (95% CI: 2%, 37%) for patients who achieved PR. One patient who achieved PR proceeded to allogeneic stem cell transplant and remained disease free at the last protocol defined follow-up (24 months after coming off study). Three patients developed progressive disease after receiving venetoclax for more than two years of therapy (time to progression: 31, 33, and 33 months). Two patients with CR continue on study without evidence of progression, currently at 47 and 59 months of venetoclax monotherapy. The most common (≥25% of patients with MCL) all grade treatment emergent AEs were nausea (57%), diarrhea (50%), fatigue (39%), constipation (29%) and upper respiratory infection (25%). The most common (≥10% of patients with MCL) grade 3/4 AEs were neutropenia (14%), anemia (14%), pneumonia (11%), and thrombocytopenia (11%). Biochemical tumor lysis syndrome (TLS), without accompanying clinical features, was reported in one patient considered high risk for TLS. Specific interventions were not required, and the patient continued on study drug. Conclusions: Venetoclax monotherapy leads to durable remission in a meaningful proportion of patients with pretreated MCL. Further studies in MCL are currently investigating potential biomarkers for durable response to venetoclax combination regimens, including a Phase 3 randomized study with ibrutinib (SYMPATICO, NCT03112174). Disclosures Davids: Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Merck: Consultancy; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; MEI Pharma: Consultancy, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Surface Oncology: Research Funding. Roberts:Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax; AbbVie: Research Funding; Genentech: Research Funding; Janssen: Research Funding. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Alter:AbbVie, Inc: Employment, Equity Ownership. Masud:AbbVie, Inc: Employment, Equity Ownership. Buss:Abbvie, Inc: Employment, Equity Ownership. Verdugo:AbbVie, Inc: Employment, Equity Ownership. Seymour:Janssen: Honoraria, Research Funding; Celgene: Consultancy; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Research Funding.

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Updated Results from an Open-Label, Multicenter, Expanded Treatment Protocol (ETP) Phase (Ph) 3b Study of Ruxolitinib (RUX) in Patients (Pts) with Polycythemia Vera (PV) Who Were Hydroxyurea (HU) Resistant or Intolerant and for Whom No Alternative Treatment (Tx) Was Available

Blood ◽

10.1182/blood-2018-99-111479 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1774-1774 ◽

Cited By ~ 2

Author(s):

Lynda Foltz ◽

Gian-Matteo Pica ◽

Hacene Zerazhi ◽

Jan Van Droogenbroeck ◽

Sorin Visanica ◽

...

Keyword(s):

Cell Carcinoma ◽

Board Of Directors ◽

Research Funding ◽

Blood Count ◽

Study Drug ◽

Employment Equity ◽

Advisory Committees ◽

Medical Need ◽

Equity Ownership ◽

Grade 3

Abstract BACKGROUND Few Tx options are available for pts with inadequately controlled PV. European LeukemiaNet defined resistance/intolerance was seen in ≈25% pts treated with HU (Alvarez-Larran et al, 2012). In the HU-resistant/intolerant PV pts evaluated in the pivotal RESPONSE study (week [wk] 208), RUX was well tolerated and superior to standard therapy in achieving durable hematocrit (HCT) control, hematologic response, and spleen size and symptom reductions. This Ph 3b ETP study was planned to provide RUX Tx to HU-resistant/intolerant PV pts, who have no alternative standard Tx, and are not eligible for any ongoing clinical studies. Results from wk 24 data cutoff of this study (Devos et al) were presented at ASH 2017. Here, we report consolidated findings from the ETP study at wk 96 data cutoff (Dec 29, 2017 [final database lock]) to further support the use of RUX in this pt population with an unmet medical need. METHODS RUX Tx was initiated at a starting dose of 10 mg bid (could be titrated to a maximum of 25 mg bid). Visits were scheduled every 4 wks until wk 24 and every 12 wks thereafter; final analysis was done when all pts had been followed for 30 days after discontinuation of Tx or completion of Tx per protocol (transitioned to commercial RUX or until Dec 31, 2017, whichever date occurred first). The primary endpoint was to assess the safety of RUX. Secondary endpoints included change in HCT level, change in spleen length, and pt-reported outcomes (change in MPN-SAF TSS score). HCT control at wk 24 was defined by absence of phlebotomy (PBT) eligibility starting at wk 8 and continuing through wk 24, with no more than 1 PBT eligibility occurring after first dose date and prior to wk 8. PBT eligibility was defined by confirmed HCT >45% (at least 3 percentage points higher than HCT at baseline [BL]), or confirmed HCT >48%. Blood count remission at wk 24 was defined by HCT control, and white blood cell count <10 × 109/L, and platelet count ≤400 × 109/L. RESULTS At data cutoff, 161 pts with PV were enrolled (BL characteristics similar to that presented at ASH 2017). End of Tx was reported for all 161 pts: Tx duration completed per protocol (141 pts), adverse event (AE [12 pts]), consent withdrawal (3 pts), pt decision (2 pts), disease progression (2 pts), and death (due to accident [1 pt]). The median exposure was 25.1 wks (range, 0.4-104.7), and median dose intensity of RUX was 20.0 mg/day (range, 6.7-47.7). AEs (regardless of study drug relationship) led to dose adjustment/interruption in 37.9% pts and study drug discontinuation in 8.7% pts. The most common hematologic AEs (rate=number of events per 100 pt-year exposure [pt-year exposure=110.2]; all grades]) included anemia (31.8) and thrombocytosis (10.0), while headache (24.5), diarrhea (14.5), constipation (12.7), and fatigue (12.7) were the most frequent non-hematologic AEs. For all reported grade 3/4 AEs, exposure-adjusted rate was less than 3. Thromboembolic events (all grade; Standardized MedDRA Query) were reported in 3 pts. Disease progression was reported in 4 pts (myelofibrosis=3 pts; acute myeloid leukemia=1 pt). The incidence of other neoplasms (regardless of study drug relationship) was low (leiomyoma, malignant melanoma, marginal zone lymphoma, renal cancer [1 pt each]; squamous cell carcinoma [2 pts]; basal cell carcinoma [3 pts]). Infections (all grades) were reported in 57 pts (grade 3/4 in 5 pts). At wk 24, 73 pts (45.3% [95% CI, 37.5%-53.4%]) achieved HCT control; hematologic remission was seen in 29 pts (18% [95% CI 12.4%-24.8%]). Changes in blood count parameters over time are shown in Fig. 1. In evaluable pts (N=105), use of PBT decreased from BL (39 PBTs between screening and BL) to end of Tx (5 PBTs in 12 wks prior). Best spleen response from BL for each pt by wk 96 is shown in Fig. 2. At least 50% spleen length reduction was seen in 86.7% (78/90) of pts from BL at any time in the study. Overall, 33.8% (46/136) of pts had ≥50% reduction in MPN-SAF TSS from BL at the end of Tx. CONCLUSION The observed safety profile of RUX in the ETP study was consistent with that of the RESPONSE studies. Efficacy results were close to the observed values in the RESPONSE studies. RUX Tx resulted in HCT control, hematologic remission, spleen response, and symptom reduction in this HU-resistant/intolerant pt population in need of a viable Tx option. Safety and efficacy findings from this ETP study support the use of RUX for pts with inadequately controlled PV, an unmet medical need. Disclosures Foltz: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Promedior: Research Funding; Gilead: Research Funding. Leber:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. de Almeida:Celgene: Speakers Bureau; Novartis: Speakers Bureau. Ranta:Novartis: Consultancy. Cartes:Novartis: Honoraria. Kiladjian:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Chrit:Novartis: Employment, Equity Ownership. Yin:Novartis: Employment. Morando:Novartis: Employment, Equity Ownership. Devos:Celgene: Consultancy; Novartis: Consultancy; Takeda: Consultancy.

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Phase 1 Clinical Trial of the Novel Structure Proteasome Inhibitor NPI-0052 in Patients with Relapsed and Relapsed/Refractory Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v114.22.431.431 ◽

2009 ◽

Vol 114 (22) ◽

pp. 431-431 ◽

Cited By ~ 8

Author(s):

Paul Richardson ◽

Craig Hofmeister ◽

Andrzej Jakubowiak ◽

Todd M. Zimmerman ◽

Matthew A. Spear ◽

...

Keyword(s):

Board Of Directors ◽

Light Chain ◽

Safety Profile ◽

Research Funding ◽

Phase 1 ◽

Proteasome Inhibition ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 431 Background: NPI-0052 has a novel, non-peptide based, bicyclic structure resulting in a unique proteasome inhibition and safety profile. In contrast to other proteasome inhibitors, NPI-0052 produces rapid, broad and prolonged inhibition of all 3 catalytic activities. Preclinical data subsequently suggested improvements in toxicology and efficacy, including activity MM resistant to bortezomib (BZ) and other agents (Chauhan et al, Cancer Cell 2005), thus this Phase 1 dose escalation trial in patients (pts) with relapsed/refractory MM was initiated. Materials and Methods: Patients (pts) were treated with NPI-0052 IV weekly for 3 weeks in 4-week cycles. Measurable disease by EBMT criteria was not required. The dose of NPI-0052 was escalated using a combination of accelerated titration and 3+3 design. PK and proteasome inhibition (blood and PBMCs) were assayed after the first and third doses. Preliminary Results: 27 pts have been treated at doses ranging from 0.025 to 0.7 mg/m2; median age is 62; 18 males/9 females; IgG/IgA/light chain/non-secretory 14/4/2/6; median of 4 prior regimens and 27% refractory to prior bortezomib. Reversible DLT was observed in two out of eight patients treated at 0.7 mg/m2 (Grade 3 fatigue; Grade 3 mental status changes and loss of balance), with 2 additional pts undergoing dose reductions in Cycle 1 (nausea and vomiting; vertigo and confusion/word-finding difficulties). Prophylactic anti-emetics have been instituted with a decrease in infusion-related nausea; similarly, pts with dizziness/vertigo have been administered meclizine with symptomatic improvement. Other drug-related adverse events have consisted principally of mild-to-moderate fatigue, nausea, vomiting, dizziness, headache and diarrhea; interestingly, myelosuppression, neuropathy and thrombosis do not appear to be elicited by NPI-0052. PK assessment demonstrates a rapid elimination half-life (<20 minutes) and relatively large Vz. NPI-0052 produces dose dependent proteasome inhibitions. At 0.7 mg/m2, Day 1/Day 15 inhibition of chymotrypsin-like activity in whole blood is 73% and 99%, respectively (the value for bortezomib at 1.3 mg/m2 is 65%). One patient with IgA MM (4 prior regimens plus ASCT; relapsed after prior BZ, not refractory) had a 71% decrease in M-protein (unconfirmed PR; off study after 3 cycles). A second pt with non-secretory disease (4 prior regimens;relapsed after prior BZ, not refractory) had a nearly 50% reduction in involved light chain; this pt remains active on study at 5+ months. In addition, 8 pts with relapsed/refractory MM remained on study for between 6-15 months (3 pts were on-study for over one year) with stable disease and no significant toxicity; 2 of these pts were BZ-refractory. Conclusions: Tolerability of 0.7 mg/m2 continues to be investigated in pts with MM, with prophylactic antiemetics and meclizine to reduce common drug-related toxicities of nausea and dizziness. The safety profile of NPI-0052 is importantly different from bortezomib in spite of higher and more durable proteasome inhibition; peripheral neuropathy and thrombocytopenia were not seen. Accrual continues to expand upon these results and assess the new lyophile formulation of NPI-0052. Disclosures: Richardson: Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees; Gentium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Vorinostat is a histone deacetylase (HDAC) inhibitor that was approved in the FDA in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following two systemic therapies. Jakubowiak:Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria; Exelixis: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria. Spear:Nereus Pharmaceuticals: Employment, Equity Ownership. Palladino:Nereus Pharmaceuticals: Employment, Equity Ownership. Longenecker:Nereus Pharmaceuticals: Employment, Equity Ownership. Neuteboom:Nereus Pharmaceuticals: Employment, Equity Ownership. Cropp:Nereus Pharmaceuticals: Consultancy. Lloyd:Nereus Pharmaceuticals: Employment, Equity Ownership. Hannah:Nereus Pharmaceuticals: Consultancy. Anderson:Nereus Pharmaceuticals: Consultancy, Research Funding.

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Initial Findings From the PACE Trial: A Pivotal Phase 2 Study of Ponatinib in Patients with CML and Ph+ ALL Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I Mutation

Blood ◽

10.1182/blood.v118.21.109.109 ◽

2011 ◽

Vol 118 (21) ◽

pp. 109-109 ◽

Cited By ~ 8

Author(s):

Jorge E. Cortes ◽

Dong-Wook Kim ◽

Javier Pinilla-Ibarz ◽

Philipp D. Le Coutre ◽

Charles Chuah ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Initial Response ◽

Employment Equity ◽

Advisory Committees ◽

Primary Endpoints ◽

T315i Mutation ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 109 Background: Despite progress in chronic myeloid leukemia (CML) therapy with tyrosine kinase inhibitors (TKIs), patients (pts) who fail dasatinib or nilotinib or pts with T315I mutation have no treatment options. Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation. Methods: The PACE trial (Ponatinib Ph+ALL and CML Evaluation) was initiated in September 2010. The objective of this international, single-arm, open-label, phase 2 trial is to establish the efficacy and safety of ponatinib. Pts with refractory CML in chronic, accelerated or blast phase (CP, AP or BP), or Ph+ acute lymphoblastic leukemia (ALL), resistant or intolerant (R/I) to dasatinib or nilotinib or with the resistant T315I mutation received 45 mg ponatinib orally once daily in one of 6 cohorts: CP R/I; CP T315I; AP R/I; AP T315I; BP/ALL R/I; BP/ALL T315I. The primary endpoints are major cytogenetic response (MCyR) for CP and major hematologic response (MaHR) for AP, BP or ALL. The trial is ongoing; projected enrollment is approximately 450. Data as of 18 July 2011 are reported. Results: At analysis, 403 pts were enrolled; 397 were treated and eligible. The median age was 59 (range, 18–94) years, 52% were male. Diagnoses were: CP R/I, n=188; CP T315I, 48; AP R/I, 52; AP T315I, 15; BP/ALL R/I, 51; BP/ALL T315I, 43. Median time from initial diagnosis to start of ponatinib was 6.2 years. Prior TKIs included imatinib (93%), dasatinib (85%), nilotinib (66%), and bosutinib (8%); 94% failed >2 prior TKIs, and 57% failed >3 prior TKIs. Overall, 88% had a history of resistance to dasatinib or nilotinib, and 12% were purely intolerant. Mutation status was determined centrally by MolecularMD. Overall, 106 pts had the T315I mutation. Of 291 R/I pts, 110 (38%) had non-T315I BCR-ABL mutations, most frequently F317L (10%), F359V (5%), E255K (4%), and G250E (4%). To date, 343 (85%) pts remain on therapy, 60 (15%) have discontinued (42 BP/ALL): 24 (6%) progressive disease (20 BP/ALL); 11 (3%) AE (3 pain, 3 thrombocytopenia, 1 each haemorrhage, loss of consciousness, enterocolitis, cytokine release syndrome, hepatotoxicity/pleuro-pericardial effusion after overdose); 8 (2%) died (3 related; 7 BP/ALL); 17 (4%) other. The most common drug-related AEs (≥10% any grade) were thrombocytopenia (19%; 15% grade 3/4), rash (18%), dry skin (13%), myalgia (12%), abdominal pain (11%; 3% grade 3/4), headache (11%), arthralgia (11%). Overall, 67 (17%) pts experienced at least 1 related SAE. The most common related SAEs (>5 cases) were pancreatitis 15 cases (3.7%), 5 cases each (1.2%) diarrhea, anemia, febrile neutropenia, and pyrexia. At the time of reporting, 159/397 eligible pts were evaluable for the primary endpoints. Median follow-up was 57 days. Of CP pts, 83 had an assessment at 3 months (10 at 6 months) or discontinued. In CP R/I, 25/60 (42%) attained MCyR (15 CCyR). In CP T315I, 13/23 (57%) had MCyR (11 CCyR). The overall CP MCyR rate was 38/83 (46%) (26 CCyR). Of AP, BP/ALL pts, 76 had an assessment at 1 month or later or discontinued. In AP, 17/23 (74%) R/I and 1/1 T315I pts achieved MaHR. In BP/ALL, 11/30 (37%) R/I and 6/22 (27%) T315I pts had MaHR. Conclusion: In this first analysis of the pivotal PACE trial, ponatinib has a favorable early safety profile, similar to that observed in phase 1, but with a lower incidence of pancreatitis. Initial response data after short follow-up indicate ponatinib has substantial anti-leukemic activity in this heavily pretreated population, and in pts with refractory T315I. These early efficacy signals replicate initial response results reported in the phase 1 setting. Updated data will be presented at the annual meeting. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Research Funding. Pinilla-Ibarz:ARIAD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Le Coutre:Novartis: Honoraria, Research Funding, Speakers Bureau; ARIAD: Research Funding. Paquette:ARIAD: Membership on an entity's Board of Directors or advisory committees. Apperley:Novartis: Honoraria, Research Funding; Bristol Myers Sqibb: Honoraria; Ariad: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. DiPersio:Genzyme: Honoraria. Rea:Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Talpaz:ARIAD: Research Funding. Abruzzese:Novartis: Consultancy; BMS: Consultancy. Baccarani:Pfizer Oncology: Consultancy; Novartis: Consultancy; BMS: Consultancy; Ariad: Consultancy; Novartis: Research Funding; Pfizer Oncology: Honoraria; Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees. Wong:MolecularMD: Employment, Equity Ownership. Lustgarten:ARIAD: Employment. Turner:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Kantarjian:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Research Funding.

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