A Phase II Multicenter Study of the Histone Deacetylase Inhibitor (HDACi) Abexinostat (PCI-24781) in Relapsed/Refractory Follicular Lymphoma (FL) and Mantle Cell Lymphoma (MCL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 55-55 ◽  
Author(s):  
Andrew M. Evens ◽  
Julie M Vose ◽  
Wael Harb ◽  
Leo I. Gordon ◽  
Robert Langdon ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Safety Profile ◽  
Tumor Size ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Employment Equity ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 55 Background: Abexinostat (PCI-24781) is a novel oral pan-HDACi that has previously demonstrated potent preclinical activity in lymphoma cell lines and animal models (Evens et al, Clin Ca Res 2009) as well as a tolerable safety profile in phase I solid tumor clinical studies (Undevia et al, ASCO 2008). In a phase I single-agent clinical trial in patients (pts) with multiply relapsed/refractory lymphoma and leukemia, anti-tumor activity was noted in FL and MCL; 4/4 FL pts showed durable clinical benefit with median time on treatment of >8 months; 1 of 2 MCL pts had a complete remission (CR) and remains on treatment for >3 years. Based on these encouraging single-agent abexinostat data, a phase II extension study was completed in relapsed/refractory FL and MCL. Methods: The primary objective of this phase II study was objective response rate (ORR, complete [CR] and partial remission [PR]), while reduction in tumor size (CR + PR + stable disease) and safety were also examined. Abexinostat was given orally twice daily at 45mg/m2 on a 4-week cycle for 7 days/week every other week, which is the previously established dose and schedule identified in the phase I study. For pharmacodynamic correlative analyses, tubulin and histone acetylation were measured in peripheral blood mononuclear cells (PBMCs) at pre-dose and 4 hours after the first dose of abexinostat. Results: A total of 30 pts were enrolled (n=16 FL and n=14 MCL pts) of which 25 were response-evaluable. The median age was 67 years (36–81) and the median prior therapies were 3 (1–5), 77% of which were rituximab-containing and one-third (33%) had undergone prior autologous stem cell transplant (31% FL, 36% MCL). The ORR in all pts was 48% (12/25). A reduction in tumor size was observed in 86% (12/14) of FL pts, while the ORR in FL was 64% (9/14); the FL intent-to-treat ORR was 56%. With a median follow-up of 10.3 months (1.2–20.9), the progression-free probability was 86% in FL pts. Furthermore, the median duration of response (DOR) in FL pts has not been reached, as 5 responders remain on study. Notably, 4 FL pts were on treatment for over 16 months. Among MCL pts, reduction in tumor size was noted in 27% (3/11), while the ORR was similar at 27% (3/11). The median progression-free survival (PFS) in MCL pts was 4 months (1–12), while the DOR in the 3 responding patients were 2+, 3, and 6+ months. Therapy was overall well tolerated. The most common treatment-related adverse events (AEs) of any grade (> 20% incidence) include: nausea (60%), fatigue (57%), diarrhea (50%), thrombocytopenia (37%), vomiting (30%), anemia (27%), decreased appetite (23%), dysgeusia (20%) and neutropenia (20%). The most common grade 3/4 related AEs (> 5% incidence) were thrombocytopenia (17%), neutropenia (13%), fatigue (13%), and anemia (7%). There were no deaths reported on the study. Pharmacodynamic analyses revealed that a majority of pts had increased tubulin acetylation in PBMCs, however this finding did not correlate with response or toxicity. Conclusion: In this phase II study, the novel pan-HDACi, abexinostat, was clinically active and overall well tolerated in relapsed/refractory B-cell lymphoma. The safety profile was consistent with this class of agents with <20% of subjects experiencing grade 3/4 cytopenias (during the course of prolonged treatments). Moreover, there was significant clinical activity noted in FL with an ORR of 64%, which included several durable responses in this multiply-relapsed pt population. Further examination of single-agent abexinostat in FL is warranted. Disclosures: Off Label Use: PCI24781 is not FDA approved; it is an investigational agent. Plasencia:Pharmacyclics: Employment, Equity Ownership. Sirisawad:Pharmacyclics: Employment, Equity Ownership. Yue:Pharmacyclics: Employment, Equity Ownership. Luan:Pharmacyclics: Employment, Equity Ownership. Siek:Pharmacyclics: Employment, Equity Ownership. Zhou:Pharmacyclics: Consultancy. Balasubramanian:Pharmacyclics: Employment, Equity Ownership.

scholarly journals Comparison of 2 Doses of Intravenous (IV) Temsirolimus (Temsr) in Patients with Relapsed/Refractory Mantle Cell Lymphoma (MCL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1775-1775
Author(s):  
Wojciech Jurczak ◽  
Sundra Ramanathan ◽  
Pratyush Giri ◽  
Francesco Di Raimondo ◽  
Heidi Mocikova ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Disease Progression ◽  
Safety Profile ◽  
Dose Regimen ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Employment Equity ◽  
Mantle Cell ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Temsr (Torisel®) administered at 175 mg IV once weekly for first 3 weeks, followed by 75mg IV once weekly (Temsr 175/75 mg) is approved in the European Union for the treatment of adult patients with relapsed and/or refractory MCL based on an overall positive benefit-risk relationship demonstrated for this treatment regimen in the pivotal phase III study (Hess et al. J Clin Oncol. 2009;27:3822-9). This ongoing phase 4, multicenter, randomized, open-label study was conducted to explore whether similar efficacy can be achieved for the treatment of patients with relapsed/refractory MCL with a Temsr regimen that is expected to yield fewer side effects than the Temsr 175/75 mg dose regimen, by skipping the first 3 doses of Temsr 175 (Clinicatrials.gov: NCT01180049). Methods: In this study, previously treated (2-7 lines of prior therapy) patients with relapsed/refractory mantle cell lymphoma were stratified by the histologic subtype (blastoid vs. non blastoid vs unknown histology) and randomized (1:1) to receive Temsr 175/75 mg, or 75mg IV once weekly (Temsr 75 mg). Treatment continued until disease progression, provided that patients were tolerating treatment and achieving clinical benefit. The primary endpoint was progression-free survival (PFS) based on independent assessment. Secondary endpoints included objective response rate (ORR), overall survival (OS) and safety with a particular focus on bleeding- and infection-related adverse events (AEs). Results: Of the 90 patients (77.8% males; 93.3% white, mean age 66.6 years) randomized, 47 were treated with Temsr 175/75 mg, 42 were treated with Temsr 75 mg, and 1 patient was randomized but not treated. At the cutoff date for analysis (November 12, 2015), 39 (83.0%) patients in Temsr 175/75 mg arm and 41 (95.3%) patients in Temsr 75 mg arm discontinued treatment with the primary reason being objective disease progression (53.8% in Temsr 175/75 mg and 56.1% in Temsr 75 mg). Median duration of treatment was comparable in the Temsr 175/75 mg arm and Temsr 75 mg arm (3.2 vs. 3.1 months). Median PFS (80% CI) was 4.3 (3.3-6.4) months in Temsr 175/75 mg arm versus 4.5 (2.7-4.9) months in Temsr 75 mg arm (hazard ratio [HR] 0.731; 80% CI 0.520-1.027). ORR (80% CI) was 27.7% (19.1%-37.7%) in Temsr 175/75 mg arm versus 20.9% (13.0%-31.0%) in Temsr 75 mg arm. Median OS (80% CI) was 18.7 (7.5-48.2) months in Temsr 175/75 mg arm versus 11.0 (6.3-16.2) months in Temsr 75 mg arm (HR 0.681, 80% CI 0.472-0.982). Median duration of response was comparable in both treatment arms (9.0 vs. 8.7 months in Temsr 175/75 mg and Temsr 75 mg arms, respectively). Overall, the safety profile was comparable in both treatment arms, although the number of patients with serious AEs, dose reduction and deaths was lower in the 175/75mg arm compared with 75 mg arm (57.4%, 48.9% and 48.9% vs. 73.8%, 64.3% and 65.1%, respectively), and the number of treatment discontinuations due to AEs was higher in the Temsr 175/75mg arm compared with 75mg arm (19.1% vs. 14.3%). Common (>10%) grade ≥3, all-causality, treatment-emergent AEs in the Temsr 175/75 mg arm and Temsr 75 mg arm, respectively, were thrombocytopenia (46.8% vs. 38.1%), neutropenia (25.5% vs. 21.4%), and pneumonia (10.6% vs. 19.0%). Treatment-emergent bleeding-related grade ≥2 AEs in the Temsr 175/75 mg arm and Temsr 75 mg arm, respectively, included epistaxis (10.6% vs. 2.4%) and ecchymosis (2.1% vs. 0). Only 1 grade 3 AE of epistaxis which was not related to Temsr was reported in the Temsr 175/75 arm, and no grade 3 events were reported in Temsr 75 arm. Pneumonia was the most commonly occurring treatment-emergent infection-related grade ≥2 AEs 12.8% in Temsr 175/75 mg arm and 19.0% in Temsr 75 mg arm. Of the 51 deaths reported during the study, none were treatment-related and most were due to disease progression. Conclusions: Overall, PFS, ORR and OS favored the Temsr 175/75 arm, although no formal statistical conclusions were made as the study was not powered for differences. The safety profile in both study arms was comparable, but there was a lower incidence of serious AEs, dose reductions and deaths in the 175/75 mg arm. Temsr 175/75 mg remains the preferred dose regimen for patients with relapsed/refractory MCL. Disclosures Jurczak: Sandoz - Novartis, Morphosys, Roche: Speakers Bureau; Acerta, Novartis, Pfizer, Celgene, Gillead, Janssen, Celtrion, Bayer, Morphosys, Takeda, Servier, Teva, and Roche: Research Funding; Morphosys: Consultancy. Clancy:Pfizer Inc: Consultancy. Lechuga:Pfizer Inc: Employment, Equity Ownership. Casey:Pfizer Inc: Employment, Equity Ownership. Boni:Pfizer Inc: Employment, Equity Ownership. Hess:Roche, CTI, Pfizer, Celgene: Research Funding; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria.

The Bruton's Tyrosine Kinase Inhibitor PCI-32765 Is Highly Active As Single-Agent Therapy in Previously-Treated Mantle Cell Lymphoma (MCL): Preliminary Results of a Phase II Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 442-442 ◽  
Author(s):  
Luhua Wang ◽  
Peter Martin ◽  
Kristie A. Blum ◽  
Brad S. Kahl ◽  
Lauren S. Maeda ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Employment Equity ◽  
Mantle Cell ◽  
Previously Treated ◽  
Equity Ownership

Abstract Abstract 442 Introduction: Bruton's tyrosine kinase (Btk) is a central mediator of B-cell receptor signaling which is essential for normal B-cell development. PCI-32765 is an orally administered irreversible inhibitor of Btk that induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. In a phase I trial of PCI-32765 in relapsed B-cell malignancies, objective responses were observed in seven of nine patients with MCL. Reported here are preliminary results of an ongoing phase II study of single-agent PCI-32765 in previously treated MCL. Methods and Patients: Patients with relapsed or refractory MCL who were either bortezomib-naïve or bortezomib-exposed (prior treatment with at least 2 cycles of bortezomib) were eligible for study PCYC-1104. PCI-32765 was administered orally at 560mg daily (in continuous 28-day cycles) until disease progression. Bortezomib-naive and bortezomib-exposed cohorts were evaluated separately. Tumor response was evaluated every 2 cycles and classified by 2007 NHL IWG criteria. Results: A total of 48 patients (29 bortezomib-naive, 19 bortezomib-exposed) have been enrolled on study PCYC-1104 between February 16, 2011 and July 20, 2011. The median age is 67 years (62–72). The median number of prior treatment regimens is 2 (1–5). Five patients (13%) had received prior autologous or allogeneic stem cell transplantation. Seven patients (15%) had bulky disease. Thirty-nine patients who have initiated treatment and have reported adverse event (AE) information are the subject of this preliminary report. Twenty-four patients (12 bortezomib-naive, 12 bortezomib-exposed) have undergone at least 1 follow-up tumor assessment and are evaluable for efficacy. Treatment has been well tolerated. No patients have discontinued treatment due to AEs. Grade 1 or 2 diarrhea, fatigue, and nausea have been the most frequently reported AEs. Grade >3 AEs considered potentially related to PCI-32765 have occurred in 4/39 patients (11%). Serious AEs (SAEs) have occurred in 8/39 patients (21%); 2 SAEs (1 rash, 1 febrile neutropenia) were considered potentially related to PCI-32765. One death, in a patient who was enrolled but did not receive PCI-32765 due to rapid disease progression, has occurred on study. The objective response rate (ORR) by IWG criteria is 67% (16/24); ORR is 58% (7/12) in the bortezomib-naive cohort and 75% (9/12) in the bortezomib-exposed cohort. To date, 35/39 patients remain on PCI-32765; reasons for discontinuation include progressive disease (n=3) and investigator decision (n=1). Conclusions: Preliminary data from a phase II trial suggests that the potent Btk inhibitor PCI-32765 is well tolerated and induces a high rate of objective responses in patients with relapsed or refractory MCL. More mature safety and efficacy data will be updated in the presentation. Phase III trials of PCI-32765 in MCL are planned. Disclosures: Wang: Pharmacyclics: Research Funding. Off Label Use: PCI-32765 in mantle cell lymphoma in a phase 2 clinical trial. Martin:Pharmacyclics: Research Funding. Blum:Pharmacyclics: Research Funding. Kahl:Pharmacyclics: Research Funding. Maeda:Pharmacyclics: Research Funding. Advani:Pharmacyclics: Research Funding. Williams:Pharmacyclics: Research Funding. Rule:Pharmacyclics: Research Funding. Rodriguez:Pharmacyclics: Employment, Equity Ownership. Pang:Pharmacyclics: Consultancy. Hedrick:Pharmacyclics: Employment, Equity Ownership. Goy:Pharmacyclics: Research Funding.

scholarly journals Phase II Study of an AKT Inhibitor MK2206 in Patients with Relapsed or Refractory Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3093-3093
Author(s):  
Yasuhiro Oki ◽  
Michelle A. Fanale ◽  
Jorge E. Romaguera ◽  
Luis Fayad ◽  
Nathan Fowler ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Treatment Regimen ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Classical Hodgkin Lymphoma ◽  
Akt Inhibitor ◽  
Refractory Lymphoma ◽  
Grade 3

Abstract Aberrant activation of the PI3K/AKT/mTOR pathway has been implicated in promoting lymphoma cell growth and survival. Several agents targeting this pathway at the PI3K or mTOR levels have demonstrated clinical activity in a variety of lymphoma subtypes. However, there has been no clinical data with AKT inhibitors in lymphoma. MK-2206 is the first oral non-ATP competitive allosteric inhibitor of AKT 1, 2, and 3 which entered clinical development. MK-2206 demonstrated AKT inhibition and antiproliferative activity as single agent and in combination with other agents in multiple human cancer cell lines. MK-2006 synergized antitumor effects of chemotherapeutic agents in vivo and in vitro. To investigate the potential therapeutic value of targeting AKT in lymphoma, we conducted a phase II study of MK2206 in patients with relapsed or refractory lymphoma. Eligible patients were required to have lymphoma of any histology excluding Burkitt lymphoma or lymphoblastic lymphoma that have relapsed or been refractory after at least one treatment regimen, have no curative option available and have adequate organ functions. MK-2206 (200 mg) was given orally, once per week, in 28-day cycles for a maximum of 12 cycles. In the absences of limiting toxicity, MK2206 dose could be increased to 300 mg. Serum cytokines levels are measured in consenting patients on days 1, 8 and 22 of the first cycle. A total of 59 patients were enrolled including 25 patients with classical Hodgkin lymphoma. The median number of prior treatment regimen was 4 (range, 1-10). Based on intent-to-treat analysis, objective responses were observed in 8 (14%) patients, with 29 (49%) patients demonstrating reduction in their tumor measurements (Figure). The median response duration was 5.8 months. In the 25 patients with classical Hodgkin lymphoma, the response rate was 20%. Treatment was well tolerated, with skin rash being the most common toxicity (Any grade: 53%, Grade 3: 15%). Grade 3 or 4 hyperglycemia was observed in 5%, and neutropenia in 2%. There was no grade 3 or 4 thrombocytopenia. Collectively, the study showed that the AKT inhibitor MK2206 can induce responses in classical Hodgkin lymphoma and indolent lymphoma. The single agent activity, however, seems to be low against large B-cell lymphoma, T-cell lymphoma or mantle cell lymphoma. The possible mechanism of resistance to the treatment with AKT inhibitors may include suboptimal inhibition of AKT phosphorylation at low concentrations or development of alternative survival pathway. Future studies should aim at optimizing the dose and schedule of MK2206, and exploring mechanism-based combination strategies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Preliminary Results of a Phase 1b Dose Escalation and Dose Expansion Study of GS-4059 in Combination with Idelalisib in Subjects with B-Cell Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2961-2961 ◽  
Author(s):  
Gilles A. Salles ◽  
Franck Morschhauser ◽  
Bruce Cheson ◽  
Simon A. Rule ◽  
Christopher Fegan ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Employment Equity ◽  
Advisory Committees ◽  
Phase 1B ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Inhibitors of signaling downstream of the B-cell receptor have a demonstrated clinical benefit in a number of lymphoid malignancies but generally require chronic therapy with the potential for single mutations to lead to resistance. GS-4059 (ONO-4059) is a Bruton's tyrosine kinase (BTK) inhibitor. GS-4059 is safe and tolerable as a single agent at doses up to 480 mg in non-Hodgkin lymphoma and up to 600 mg in chronic lymphocytic leukemia (CLL). Idelalisib, a phosphatidylinositol-3-kinase delta (PI3Kd) inhibitor, is approved for the treatment of CLL. Single-agent therapy leads to durable responses, but with limited depth of response; treatment with a combination of GS-4059 and idelalisib has the potential to lead to deeper and more durable responses at lower doses of individual agents than needed as monotherapy. Methods:This ongoing, phase 1b study (NCT02457598) is evaluating the safety and tolerability of GS-4059 in combination with idelalisib. Patients with previously treated CLL, FL, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM), or non-germinal-center B-cell type (non-GCB) diffuse large B-cell lymphoma (DLBCL) and no prior exposure to BTK or PI3Kd inhibitors eligible for enrollment. Patients are enrolled using a 3+3 dose escalation design with a fixed dose of idelalisib (50 mg BID) and increasing doses of GS-4059. Optional dose expansion cohorts of up to 30 patients can be enrolled to generate disease-specific data. Patients were observed for a 28-day period to identify dose-limiting toxicities (DLTs). Efficacy evaluation was performed at 6-week intervals for DLBCL, 24-week intervals for CLL, and 12-week intervals for all other indications. Results: As of June 1, 2016, 20 patients have enrolled; the median age was 64 (37-79) years and 65% were men. The disease subtypes enrolled were CLL (n = 8), FL (5), MZL (2), SLL (2), and 1 each with DLBCL, MCL, and WM. The median number of prior therapies is 2.5 (range 1-4). The median duration of treatment is 113 days (range 29-310) with 17 patients still on-treatment. Three patients discontinued all study treatment due to disease progression (FL, MZL, DLBCL). There has been 1 death on study following progressive disease. Two DLTs of neutropenia were observed at dose level 2B (GS-4059 20 mg BID/idelalisib 50 mg BID), prompting the decision to discontinue the evaluation of twice-daily administration of GS-4059 when combined with idelalisib. The maximum tolerated dose (MTD) was not reached in Arm A of the study (Table 1). Of the 20 patients enrolled, 95% reported a treatment-emergent AE (TEAE), of which 55.0% were ≥grade 3. The only ≥grade 3 TEAE that was present in more than 1 patient was neutropenia. The most common TEAEs are listed in Table 2. Grade 3 liver laboratory test abnormalities were observed in 1 patient after approximately 5 months of treatment; a liver biopsy revealed a lymphocytic infiltrate consistent with CLL. Dose interruption due to an AE was reported in 45% of patients. Aside from 2 patients who discontinued idelalisib due to neutropenia and restarted therapy on GS-4059 alone, all patients successfully re-initiated therapy with both agents after treatment interruption. Nine patients have been on study for ≥24 weeks with 7 patients evaluable for radiographic response; 3 patients have had a >50% decrease in lymphadenopathy (CLL, SLL, FL). Preliminary pharmacokinetic (PK) results indicate that idelalisib at the evaluated dose levels does not significantly alter the PK of GS-4059. Conclusion: Once-daily dosing of GS-4059 up to 80 mg in combination with idelalisib 50 mg BID was generally safe and well tolerated. Early results show efficacy at combination doses significantly below the MTD for either single agent. This data supports continued clinical evaluation of the combination of GS-4059 and idelalisib for the treatment of B-cell malignancies. Disclosures Salles: Mundipharma: Honoraria; Novartis: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Cheson:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding. Fegan:AbbVie: Honoraria; Roche: Honoraria; Gilead Sciences: Honoraria. Nelson:Gilead Sciences: Employment, Equity Ownership. Yang:Gilead Sciences: Employment, Equity Ownership. Mitra:Gilead Sciences: Employment, Equity Ownership. Starodub:Bayer: Consultancy; BMS: Speakers Bureau; Sandoz: Consultancy. Dyer:Roche: Consultancy, Speakers Bureau; ONO Pharmaceuticals: Research Funding; Gilead Sciences: Consultancy, Other: Travel funding, Research Funding, Speakers Bureau.

Phase I/II Trial of the MEK1/2 Inhibitor Trametinib (GSK1120212) in Relapsed/Refractory Myeloid Malignancies: Evidence of Activity in Patients with RAS Mutation-Positive Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 677-677 ◽  
Author(s):  
Gautam Borthakur ◽  
Leslie Popplewell ◽  
Michael Boyiadzis ◽  
James M. Foran ◽  
Uwe Platzbecker ◽  
...  
Keyword(s):  
Amino Acids ◽  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Employment Equity ◽  
Ras Mutation ◽  
Myeloid Malignancies ◽  
Ras Mutations ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 677 Background: Activating mutations of NRAS and KRAS (‘RAS’) are found in 10–30% of myeloid malignancies. Evidence of constitutive activation of the RAS-RAF-MEK-ERK pathway, however, is more ubiquitous. Trametinib is a potent, selective, allosteric inhibitor of MEK1/2 that inhibits proliferation of myeloid cell lines in vitro. A Phase I/II study of single, daily, oral dosing of trametinib in myeloid malignancies is ongoing. Here we report the results from Phase I/II patients receiving the recommended Phase II dose (RP2D) of 2 mg. Methods: Patient eligibility was limited to patients with relapsed/refractory myeloid malignancies and adequate hepatic, renal and cardiac function. There were no hematologic eligibility criteria. Patients were prospectively screened for KRAS mutations at amino acids 12, 13 and for NRAS mutations at amino acids 12, 13 and 61. Clinical response was assessed using International Working Group (2003 and 2006) criteria for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), respectively. Pharmacodynamic marker (pERK) analysis was conducted in phase II patients with patient paired (pre/during treatment) blood and bone marrow samples. Results: Eighty-seven (9 in Phase I and 78 in Phase II) patients received 2 mg of trametinib daily: AML (n=66), MDS (n=11), chronic myelomonocytic leukemia (CMML) (n=7) or other (n=3) (RAS mutations, n=57; RAS wild type, n=15 and RAS unknown, n=15). Median age was 68 years (range 21–87) and for close to half of the patients, trametinib was 3 3rd line of therapy. Trametinib exhibited a long effective half-life with small peak/trough ratios, and the exposure profile maintained time above preclinical target threshold for the 24-hour dosing period. Results of the pharmacodynamic analysis indicated an on-target effect of trametinib. Responses by RAS mutation status for Phase I/II subjects are summarized in Table 1. Responding patients have continued therapy for median of 16.9 weeks (range, 10.9 – 36.7). Drug-related grade 3/4 adverse events (AEs) were encountered in 31/87 (36%) of the Phase I/II patients and there was one grade 5 drug-related AE,cerebrovascular accident. Hepatic toxicities (9%), gastrointestinal disorders (7%) and rash (5%) were the most frequent grade 3/4 AEs. AEs possibly related to inhibition of MEK signaling were blurred vision (total,13%; grade 3, 1%) and decreased cardiac ejection fraction (total, 9%; grade 3, 6%); events were generally reversible. Conclusion: At the RP2D of trametinib (2 mg orally daily), trametinib has shown promising clinical activity and responses (CR/CRp/Marrow CR/MLFS/PR) were almost exclusively seen in patients with refractory myeloid malignancies characterized by somatic RAS mutations. Expansion of the CMML cohort for RAS positive subjects is ongoing. Disclosures: Borthakur: GlaxoSmithKline, Sigma-Tau, Eisai, XBiotech: Research Funding. Off Label Use: Trametinib, to report outcome of clinicla trial to audience at ASH meeting. Foran:GlaxoSmithKline: Research Funding. Platzbecker:GlaxoSmithKline: Honoraria, Research Funding. Giagounidis:GlaxoSmithKline: Honoraria. Ottmann:GlaxoSmithKline: Clinical trial participation Other. Kadia:GlaxoSmithKline: Research Funding. Bauman:GlaxoSmithKline: Employment, Equity Ownership. Wu:GlaxoSmithKline: Employment. Liu:GlaxoSmithKline: Employment. Schramek:GlaxoSmithKline: Employment. Zhu:GlaxoSmithKline: Employment. Wissel:GlaxoSmithKline: Employment, Equity Ownership.

Phase I/II Multicenter Study of Romidepsin in Japanese Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3012-3012
Author(s):  
Michinori Ogura ◽  
Dai Maruyama ◽  
Kensei Tobinai ◽  
Toshiki Uchida ◽  
Kiyohiko Hatake ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Japanese Patients ◽  
T Cell Lymphoma ◽  
Employment Equity ◽  
Equity Ownership ◽  
The Common

Abstract Introduction: Peripheral T-cell lymphoma (PTCL) is an aggressive lymphoma associated with poor prognosis. There is no consensus on standard therapy, and options are limited for patients with relapsed/refractory (R/R) disease. Romidepsin, a potent histone deacetylase inhibitor, has US FDA approval for patients with >=1 prior treatment for PTCL based on 25%-38% overall response rates (ORR) and durable responses (Piekarz et al, Blood. 2011;117:5827; Coiffier et al, J Clin Oncol. 2012;30:631). Here we report results from the phase I/II, multicenter, open-label study of romidepsin in Japanese patients with R/R PTCL or cutaneous T-cell lymphoma (CTCL) (TCL-001; NCT01456039). Methods: Patients aged >=20 years with R/R PTCL or CTCL received romidepsin via a 4-hour IV infusion on days 1, 8, and 15 of each 28-day cycle until progressive disease or unacceptable toxicity. The phase I portion of the study used a 3+3 design to identify any dose-limiting toxicity (DLT; phase I primary endpoint) with romidepsin 9 mg/m2 (cohort 1) and 14 mg/m2 (cohort 2). The phase II dose was based on the highest dose where <=2 of 6 patients experienced a DLT in phase I. The primary endpoint for phase II was ORR; secondary endpoints included time to response (TTR), duration of response (DOR), time to progression (TTP), and toxicity. Toxicity was assessed per NCI CTCAE version 3.0. Efficacy was assessed per modified 1999 IWG response criteria for non-Hodgkin lymphoma, descriptive statistics, and Kaplan-Meier method. Pharmacokinetic (PK) assessments included all patients in phase I with concentration-time data to enable PK parameter calculations for >=1 day. Assessments of the intent-to-treat (ITT) population included all patients receiving at least 1 dose of romidepsin. Results: The ITT population comprised 48 patients with PTCL and 2 with CTCL (1 each in the 9 and 14 mg/m2 cohorts). The common PTCL subtypes were angioimmunoblastic T-cell lymphoma (AITL, n=21, 44%), PTCL not otherwise specified (PTCL-NOS, n=20, 42%), and anaplastic large-cell lymphoma (ALCL ALK-1 negative, n=3, 6%). Most patients had a favorable ECOG performance status (86% 0-1) and 72% were >=65 years of age. Patients had received a median of 2 prior therapies (range, 1-9). Of 9 patients assessable in phase I (n=3 at 9 mg/m2 and n=6 at 14 mg/m2), none experienced a DLT. The recommended phase II dose was 14 mg/m2 in 40 subsequently treated patients. The overall population received a median of 10 doses (range, 1-135) for a median treatment duration of 12.9 weeks (range, 0.1-184.3; 8 patients were treated for >=36 weeks). The common all-grade adverse events (AEs) were thrombocytopenia (n=49, 98%), lymphopenia (n=44, 88%), leukopenia (n=42, 84%), neutropenia (n=40, 80%), pyrexia (n=33, 66%), dysgeusia (n=31, 62%), decreased appetite (n=28, 56%), and nausea (n=27, 54%). The common grade >=3 AEs were lymphopenia (n=37, 74%), neutropenia (n=27, 54%), leukopenia (n=23, 46%), and thrombocytopenia (n=19, 38%). Of the 39 patients whose CD4+ T-cell counts were monitored, while decreased CD4+ T-cell counts (<200 uL) were observed in 82% of patients, opportunistic infection occurred only in 1 patient (3%). Among the 40 patients with PTCL (phase II), the ORR was 43% (95% CI, 27%-58%), including 10 patients (25%) with complete response (CR) or CR unconfirmed (CRu) and 7 (17%) with partial responses (PR) (Table 1). The obtained ORR was significantly higher compared with the threshold ORR of 10% (P<0.0001, one sample binomial test, H0: P<=0.1). The ORR was not different across PTCL subtypes: 44% (8/18) AITL, 41% (7/17) PTCL-NOS, and 100% (2/2) ALCL. In 17 responding patients, the median TTR was 1.8 months (range, 1.6-2.3) and median DOR was 11.1 months (95% CI, 1.6 to not reached). Median TTP was 5.6 months (95% CI, 3.3-12.9; n=40). For 2 patients with CTCL in phase I, best responses (investigator assessment) were 1 PR (9 mg/m2 cohort) and 1 stable disease (14 mg/m2 cohort). Pharmacokinetic analysis indicated a dose-proportional relationship, with no accumulation following multiple doses; results were similar to data reported for non-Japanese patients. Conclusions: Results from this phase I/II study identified a tolerable dose of romidepsin and indicated that romidepsin has an acceptable toxicity profile with clinically meaningful, efficacy in Japanese patients with R/R PTCL. The efficacy and safety data were comparable with results from other romidepsin phase II studies. Disclosures Ogura: Celltrion, Inc.: Consultancy, Honoraria; SymBio Pharmaceuticals: Consultancy, Honoraria. Maruyama:Janssen: Honoraria; Takeda: Honoraria. Tobinai:Chugai Pharma: Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy; Mundipharma KK: Honoraria, Research Funding; SERVIER: Research Funding; HUYA Bioscience: Honoraria; Celgene: Research Funding; Kyowa Hakko Kirin: Research Funding; GlaxoSmithKline: Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Research Funding. Uchida:SymBio Pharmaceuticals: Research Funding. Hatake:Chugai: Research Funding; Meiji-Seika: Consultancy; Otsuka: Consultancy; Kyowa Kirin: Honoraria, Research Funding. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding. Ishida:Celgene KK: Research Funding; Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Bayer Pharma AG: Research Funding. Ishizawa:SymBio Pharmaceuticals: Research Funding. Laille:Celgene: Employment, Equity Ownership. Ro:Celgene: Employment, Equity Ownership. Tamakoshi:Celgene: Employment, Equity Ownership. Sakurai:Celgene: Employment. Ohtsu:Celgene: Employment, Equity Ownership.

scholarly journals Daratumumab (DARA) Maintenance Therapy Improves Depth of Response and Results in Durable Progression-Free Survival (PFS) Following Dara Plus Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) Induction Therapy in Multiple Myeloma (MM): Update of the Lyra Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 863-863 ◽  
Author(s):  
Robert M. Rifkin ◽  
Jason M. Melear ◽  
Edward Faber ◽  
William I. Bensinger ◽  
John M Burke ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Safety Profile ◽  
Employment Equity ◽  
Advisory Committees ◽  
Depth Of Response ◽  
Equity Ownership ◽  
Grade 3

Background: DARA, a human IgGκ monoclonal antibody targeting CD38, is approved in combination with bortezomib, melphalan, and prednisone (VMP) and bortezomib and dexamethasone (Vd) for newly diagnosed MM (NDMM) and relapsed MM (RMM), respectively. CyBorD is a commonly used immunomodulatory drug-sparing regimen for MM. In the LYRA (NCT02951819) study, DARA plus CyBorD (DARA-CyBorD) demonstrated efficacy and a tolerable safety profile at the end of induction. Here, we present updated findings examining the effect of monthly DARA maintenance on the efficacy and safety of DARA-CyBorD in NDMM and RMM. Methods: LYRA is an ongoing, single-arm, open-label, phase 2 study conducted at US community oncology centers. Patients (pts) were aged ≥18 years with documented MM per IMWG criteria, an ECOG performance score (PS) of 0-2, and ≤1 prior line of therapy. Pts received 4-8 induction cycles of DARA-CyBorD (cyclophosphamide 300 mg/m2 PO on Days 1, 8, 15, and 22; bortezomib 1.5 mg/m2 SC on Days 1, 8, and 15; and dexamethasone 40 mg PO or IV weekly [qw]) every 28 days. DARA was given at 8 mg/kg IV on Days 1 and 2 of C1, 16 mg/kg qw from C1D8 through C2, 16 mg/kg q2w for C3-6, and 16 mg/kg q4w for C7-8. After induction, eligible pts could undergo autologous stem cell transplantation (ASCT). All pts received up to 12 maintenance cycles with DARA 16 mg/kg IV q4w. Results: A total of 101 (87 NDMM, 14 RMM) pts were enrolled; 100 (86 NDMM, 14 RMM) pts received ≥1 treatment dose. Median age was 63 years; most pts were white (81%), male (64%), had ECOG PS 0-1 (94%) and had IgG (57%) MM; 36% of pts had high cytogenetic risk, defined as a del(17p), t(4:14) or t(14;16) abnormality. NDMM and RMM pts received a median of 6 and 8 cycles, respectively, of induction therapy. Thirty-nine NDMM pts and 1 RMM pt underwent ASCT. Fifty percent of pts received plerixafor; median stem cell yield for NDMM pts was 6.2 x 106 (range 2-15 x 106) CD34+ cells/kg. A total of 85 (75 NDMM, 10 RMM) pts received ≥1 dose of maintenance treatment; 63 (56 NDMM, 7 RMM) pts have received all 12 maintenance cycles. In NDMM pts, ORR was 87%, with 64% ≥VGPR and 12% ≥CR, by the end of induction. By the end of maintenance, ORR, ≥VGPR and ≥CR rates were 97%, 82% and 51% in NDMM pts who underwent ASCT and 83%, 70% and 30% in NDMM pts who did not receive ASCT. In RMM pts, ORR, ≥VGPR and ≥CR rates were 79%, 71% and 29% by the end of induction and 86%, 71% and 64% by the end of maintenance. At a median follow up of 24.8 mo in NDMM pts and 26.6 mo in RMM pts, median duration of response was not reached (NR). Median PFS (Figure) was NR in NDMM pts, regardless of transplant status, and was 21.7 mo in RMM pts; median OS was NR in NDMM pts and was 30.1 mo in RMM pts. In NDMM pts the 24-mo PFS rate was 89% in pts who underwent ASCT and 72% in pts who did not receive ASCT. The 24-mo OS rate was 90% for NDMM pts. In RMM pts, the 24-mo PFS and OS rates were 48% and 64%, respectively. All treated pts had ≥1 TEAE. Common TEAEs (≥25%) included fatigue, nausea, cough, diarrhea, upper respiratory tract infection, back pain, vomiting, insomnia, dyspnea, constipation, and headache. Grade 3/4 TEAEs were reported in 62% of pts; the most common (≥10%) was neutropenia (14%). Serious TEAEs occurred in 33% of pts; the most common (&gt;2%) were pneumonia, atrial fibrillation and pulmonary embolism. TEAEs led to permanent treatment discontinuation in 7% of pts, with 2% related to treatment. TEAEs resulted in death in 2 pts (nephrotic syndrome, sudden death); both unrelated to treatment. Infusion reactions (IRs) occurred in 56% of pts including grades 1-2 in 52% of pts, grade 3 in 3% of pts and grade 4 in 1% of pts. Most common (&gt;5%) IRs were chills, cough, dyspnea, nausea, pruritus, flushing and nasal congestion. Conclusion: Maintenance with DARA monotherapy for 12 mo increased the &gt;CR rate in NDMM and RMM pts, consistent with observations in prior studies that longer DARA treatment improves depth of response. Importantly, the increase in ≥CR rate was associated with durable PFS and OS. The 24-mo PFS rates in NDMM and RMM pts compare favorably with results for DARA-VMP and DARA-Vd in NDMM and RRMM, respectively. Safety profile was consistent with previous reports of DARA, with no new safety concerns observed with longer follow-up. These data indicate that DARA-CyBorD is a safe, effective MM treatment and that DARA maintenance increases depth of response and achieves durable remissions. Disclosures Rifkin: Amgen: 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. Melear:Texas Oncology: Employment; DARA: Speakers Bureau. Faber:Cardinal Health: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Burke:Gilead: Consultancy; Celgene: Consultancy; Roche/Genentech: Consultancy. Narang:Celgene: Speakers Bureau. Stevens:Astellas: Consultancy. Gunawardena:Janssen: Employment, Equity Ownership. Lutska:Janssen: Employment. Qi:Janssen: Employment. Ukropec:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Lin:Janssen: Employment, Equity Ownership. Yimer:Amgen: Consultancy; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Celgene: Honoraria; Seattle Genetics: Honoraria; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau.

A Phase II Study of Temsirolimus (CCI-779) in Patients with Advanced Leukemias.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4523-4523 ◽  
Author(s):  
Karen W.L. Yee ◽  
Guillermo Garcia-Manero ◽  
Deborah Thomas ◽  
Farhad Ravandi-Kashani ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Blast Crisis ◽  
Single Agent ◽  
Mammalian Target Of Rapamycin ◽  
Median Number ◽  
Prior Therapy ◽  
Flat Dose ◽  
Grade 3

Abstract Temsirolimus (CCI-779, Wyeth Pharmaceuticals) has been shown to inhibit proliferation of a variety of tumors and induce G1 cell cycle arrest by preventing activation of the serine/threonine kinase, mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/Akt pathway. Several lines of evidence implicate the PI3K/Akt/mTOR pathway in hematological malignancies. Interim results of a phase II study evaluating the efficacy and toxicity of single-agent temsirolimus in patients with advanced malignancies are presented. Temsirolimus was administered weekly, at a flat dose of 25 mg, as a 30-minute intravenous infusion. Treatment was continued until evidence of disease progression or unacceptable toxicity. To date, 8 patients have been enrolled and 7 are evaluable for efficacy and toxicity (one patient did not receive temsirolimus). Of these 7 patients, 5 had AML, 1 CML-myeloid blast crisis, and 1 ALL. Median age was 68 years (range, 21 to 87 years) and 5 were male. All patients had received prior therapy, median 2 regimens (range, 1 to 3 regimens). The median number of temsirolimus doses administered was 3 (range, 1 to 10) with a median time on study of 18 days (range, 3 to 89+ days). The most common temsirolimus-related adverse events were grade ≤ 2 and consisted of anorexia, nausea and/or vomiting and diarrhea, mucositis, dermatitis, hypertriglyceridemia, hyperglycemia, hypomagnesemia, hypocalcemia, hypokalemia, hypophosphatemia, and fatigue/asthenia. No patient developed nonspecific pneumonitis. Grade 3 toxicities included fatigue/asthenia (2), hyperglycemia (1), painful mucositis with dehydration and electrolyte abnormalities (1), diarrhea with hypokalemia (1), and hypophosphatemia (1). No patient experienced grade 4 toxicities or death from temsirolimus. No patient required dose reductions, but 2 did have dose delays due to grade 3 mucositis (1) and out-of-state hospitalization for pneumonia and atrial fibrillation (1). No patient achieved a complete remission. One patient with heavily pre-treated Philadelphia-negative precursor B-cell ALL had a transient 79% to 91% reduction in peripheral blood blasts 4 days after the first dose of temsirolimus that was maintained for 12 days prior to disease progression with involvement of the synovial fluid in bilateral knees. At the time of analysis, 6 of the 7 patients have discontinued treatment due to disease progression (4), patient refusal (1), or physician decision (1). Preliminary findings indicate that temsirolimus is relatively well-tolerated at a dose of 25 mg per week and may have biologic activity in ALL. Accrual onto the study is currently ongoing.

Phase I-II Study of Clofarabine-Melphalan-Alemtuzumab (CMA) Conditioning for Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients with Advanced Hematologic Malignancies: Determination of MTD and Outcomes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 197-197 ◽  
Author(s):  
Koen van Besien ◽  
Justin Kline ◽  
Lucy A Godley ◽  
Richard A. Larson ◽  
Vu H. Nguyen ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Level ◽  
Phase Ii ◽  
Renal Toxicity ◽  
Phase Ii Study ◽  
Hematologic Malignancies ◽  
Advisory Committees ◽  
Grade 3 ◽  
One Year

Abstract Abstract 197 Supported by an unrestricted grant from Genzyme Corporation. Fludarabine (Flu) melphalan-alemtuzumab is a well tolerated, reduced intensity conditioning regimen for HCT. Clofarabine (Clo), a second generation nucleoside analog with excellent activity in acute leukemia, might enhance disease control over Flu. We report outcomes of a completed phase I and ongoing phase II study of CMA conditioning for allogeneic peripheral blood HCT. Tacrolimus was administered as GVHD prophylaxis. For the phase I cohort, one pt was enrolled per dose level, until the first DLT or until 2 had grade 3 toxicity. Dose level 1 consisted of: clo 10 mg/m2/day on d −7 to −3 and melphalan 100 mg/m2 on day −2. Clo was increased by 10 mg/m2/day per cohort until 40 mg/m2/day. Then, melphalan was increased by 20 mg/m2 until 140 mg/m2. Alemtuzumab was given at a fixed dose of 20 mg/day on d −7 to −3. Twelve pts were accrued in the phase I portion of whom three remain in remission at 26, 22 and 21 months. Forty pts, median age 53 (24–69), have been accrued in the phase II study of whom 16 had related and 24 unrelated donors. 20 had AML/MDS (6 refractory, 4 CR2, 9 CR1, 1 untreated MDS), 16 NHL (6 refractory, 9 chemosensitive relapse, 1 CR1) 2 CLL, 2 MPD. ASBMT risk score was high in 14, intermediate in 14, and low in 12. Performance score was 0 in 19, 1 in 17, 2 in 2, and not documented in 2 patients. The phase II dose was initiated at Clo 40 mg/m2/day x 5 days and melphalan 140 mg/m2. Twenty-four pts received this dose. Grade 3 renal toxicity occurred between day −7 and day +7 in 4 of 24 (17%) pts receiving this dose. The phase II dose was then reduced to Clo 30 mg/m2/day x 5 days and melphalan 140 mg/m2, and used to treat 16 pts. One pt with preexisting cardiomyopathy and refractory AML died during conditioning from cardiovascular failure. No grade 3 renal toxicity has been observed in this cohort and 3 pts had reversible grade 2 renal failure. Other toxicities included: gr 2–3 reversible ALT elevation between day −2 and day +5 in 8 pts; gr 2 reversible bilirubin elevation in 1 pt. No grade 3–4 hand foot syndrome or VOD occurred in this cohort. All evaluable pts engrafted. Twenty of 24 pts had full donor CD3 chimerism on day 30 and 2 had mixed donor chimerism. 11 pts had gr II aGVHD, and 3 had gr IIII/IV aGVHD. 7 have cGVHD.With a median follow-up of 313 days (19–607), 24 of 40 pts (60%) in the phase II portion of the study remain in remission. Eight have relapsed, 4 of whom have died. Eight others have died of treatment-related causes (7 after Clo 40 and 1 after Clo 30). Estimated one year survival is 72% (95%CI, 56–88) and PFS is 63% (45–81%). Neither dose of Clo (40 vs 30), donor type (MUD vs related), age (< 50 vs >50) affected outcomes. One year PFS was 56% (28–84) for NHL and 68% (46–90) for AML/MDS (P=NS). One year PFS was 43% (15–71%) for ASBMT high risk pts vs 70% (50–90%) for ASBMT low/intermediate risk pts (P=0.01; Figure 1). Conclusions: Clofarabine - melphalan - alemtuzumab conditioning induces durable remissions in a substantial fraction of patients with advanced hematologic malignancies. Clo 30/Mel 140 has an excellent safety profile. Disclosures: Off Label Use: clofarabine for transplant conditioning. Kline:Genzyme corporation: Membership on an entity's Board of Directors or advisory committees. Odenike:Genzyme corporation: Membership on an entity's Board of Directors or advisory committees. Stock:Genzyme: Research Funding.

Safety and Tolerability of Conatumumab in Combination with Bortezomib or Vorinostat in Patients with Relapsed or Refractory Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1708-1708 ◽  
Author(s):  
Anas Younes ◽  
Mark Kirschbaum ◽  
Lubomir Sokol ◽  
Lorrin Yee ◽  
Jorge Romaguera ◽  
...  
Keyword(s):  
Research Funding ◽  
Cell Lymphoma ◽  
Death Receptor ◽  
Large Cell ◽  
Employment Equity ◽  
Expansion Phase ◽  
Mantle Cell ◽  
Equity Ownership ◽  
Refractory Lymphoma ◽  
Grade 3

Abstract Abstract 1708 Poster Board I-734 Conatumumab is an investigational, fully human, monoclonal antibody agonist of human death receptor 5 (DR5 [TRAIL receptor 2]) that activates caspases and triggers apoptosis in sensitive tumor cells. DR5 is expressed by a variety of lymphoma cell lines, and TRAIL receptor agonists have been shown to induce apoptosis in lymphoma cells and lymphoma xenografts. Bortezomib and vorinostat are active and approved agents in certain lymphoma subtypes. In addition, they enhance death receptor-mediated apoptosis in multiple tumor models. In this 2-part study, we evaluated conatumumab in combination with bortezomib or vorinostat to treat patients (pts) with relapsed or refractory lymphoma. The dose-escalation phase evaluated the safety and tolerability of escalating doses of conatumumab in combination with bortezomib or vorinostat; the dose-expansion phase was designed to estimate the efficacy of conatumumab plus bortezomib in pts with mantle cell lymphoma (MCL). Here we present data from the dose-escalation phase. Eligibility criteria included: relapsed or refractory low-grade lymphoma, mantle cell lymphoma (MCL), diffuse large cell lymphoma, or Hodgkin lymphoma; age ≥ 18 years; informed consent; ECOG performance status of 0 or 1; life expectancy of > 3 months; adequate organ function; no prior treatment with bortezomib or vorinostat; no evidence of CNS involvement by lymphoma; and no primary CNS lymphoma. Three to 6 pts were enrolled into 1 of 3 sequential dose cohorts (1.5, 5, or 15 mg/kg) of conatumumab administered intravenously every 3 weeks (on day 1 of every 21-day cycle) in combination with either bortezomib (1.3 mg/m2 IV twice weekly for 2 weeks followed by a 10-day rest period) or vorinostat (400 mg orally daily). Endpoints included safety, maximum tolerated dose (MTD) of conatumumab, pharmacokinetics (PK) of conatumumab, incidence of anti-conatumumab antibodies, and best tumor response (complete response [CR] and partial response [PR]). CRs were confirmed by FDG-PET and bone marrow biopsy per Cheson criteria (2007). Monocyte DR5 occupancy by conatumumab was determined as an exploratory endpoint. As of July 9, 2009, 27 pts were enrolled and 23 received ≥1 dose of conatumumab: 3, 3, and 6 pts at 1.5, 5, and 15 mg/kg conatumumab + bortezomib; 7, 3, and 1 pt at 1.5, 5, and 15 mg/kg conatumumab + vorinostat. 15 pts were men; median (range) age was 53 (23 to 81) years; ECOG PS 0 = 65%, 1 = 26%, unknown = 9%; disease stage I = 4%, II = 4%, III = 39%, IV = 48%, unknown = 4%. Nine pts are still receiving treatment. The most common treatment-emergent adverse events (AE) were: fatigue (13 pts), diarrhea (9 pts), constipation (8 pts), nausea (8 pts), thrombocytopenia (8 pts), headache (7 pts), anemia (5 pts), dizziness (5 pts), and peripheral neuropathy (5 pts). A total of 6 and 3 pts reported worst grade 3 and 4 AEs, respectively, with no apparent differences between the 2 drug combinations. There were 2 DLTs: grade 3 prolonged Qt at 1.5 mg/kg conatumumab + vorinostat and grade 4 pulmonary embolism at 15 mg/kg conatumumab + bortezomib. An MTD has not been reached. Anti-conatumumb antibodies have not been detected in any pt. After one dose of conatumumab at 1.5, 5, or 15 mg/kg after bortezomib or vorinostat, conatumumab exposures were slightly higher (< 2-fold) than those in the first-in-human monotherapy study, indicating minimal effect of bortezomib or vorinostat on PK of conatumumab. Two pts had a confirmed CR: 1 pt with diffuse large cell lymphoma (1.5 mg/kg vorinostat cohort) at day 97 and 1 pt with nodular sclerosis Hodgkin lymphoma (5 mg/kg vorinostat cohort) at day 169. Thirteen pts had stable disease as their best objective response, 10 of whom had tumor shrinkage (range [based on sum of nodal and extra-nodal at each visit], -1.74% to -68.24%]). Receptor occupancy data will be presented. The combination of conatumumab with either bortezomib or vorinostat did not result in an unacceptable rate of dose-limiting toxicities and showed preliminary evidence of anti-tumor activity in pts with relapsed or refractory lymphoma. The expansion phase in pts with MCL treated with conatumumab plus bortezomib is currently enrolling. Disclosures Younes: Seattle Genetics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Abbott Oncology: Consultancy; Genentech: Consultancy, Honoraria, Research Funding; Allos Therapeutics : Consultancy; Gloucester Pharm: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Tiba Oncology: Consultancy; Trubion Pharmaceuticals: Consultancy; Sanofi-Aventis: Honoraria, Research Funding; Methylgene: Honoraria, Research Funding; Pharmion: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Biogen Idec: Honoraria, Research Funding. Kirschbaum:Merck: Research Funding, Speakers Bureau. Romaguera:Wyeth: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Goyal:Amgen Inc.: Employment, Equity Ownership. Hsu:Amgen Inc.: Employment, Equity Ownership. Hwang:Amgen Inc.: Employment, Equity Ownership. Gorski:Amgen Inc.: Employment, Equity Ownership. Wong:Amgen Inc.: Employment, Equity Ownership. Beaupre:Amgen Inc.: Employment, Equity Ownership.

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