A Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2746-2746 ◽  
Author(s):  
Eric D. Jacobsen ◽  
Ranjana H. Advani ◽  
Yasuhiro Oki ◽  
Jeff Sharman ◽  
Steven M. Horwitz ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
Objective Response ◽  
Brentuximab Vedotin ◽  
Grey Zone ◽  
Advisory Committees

Abstract Abstract 2746 Background: Brentuximab vedotin (ADCETRIS®) is a CD30-directed antibody-drug conjugate approved for the treatment of relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL). Several non-Hodgkin lymphoma (NHL) subtypes such as diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphomas (PTCL) have variable quantitative and qualitative expression of CD30. As a result of the high objective response rate (86%) and durable complete remissions (CR) observed in a pivotal phase 2 study in ALCL, a study was initiated to investigate the efficacy and safety of brentuximab vedotin in other NHLs that express the CD30 antigen. Methods: A phase 2, open-label, single-arm, multicenter study is currently ongoing to evaluate the antitumor activity of brentuximab vedotin in approximately 75 patients with relapsed or refractory CD30-positive NHL (ClinicalTrials.gov NCT01421667). Brentuximab vedotin, 1.8 mg/kg, is administered every 3 weeks by IV infusion. Patients who achieve at least stable disease are eligible to receive continued treatment until disease progression or unacceptable toxicity. The primary efficacy endpoint is objective response rate (ORR) as assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Efficacy variables will be analyzed by total patients, WHO NHL classification, DLBCL (excluding peripheral mediastinal large B-cell lymphoma [PMBL] due to differing treatment paradigms and outcomes for this DLBCL subtype), and by each individual disease. The correlation between antitumor activity and quantitative CD30 expression is also being explored. Results: Fifty-three patients with various CD30-positive NHLs have been enrolled to date (35 with B-cell neoplasms and 18 with mature T-/NK-cell neoplasms). Twenty-nine (55%) patients had refractory disease, 19 (36%) had relapsed since their most recent prior therapy, and 5 (9%) had primary refractory disease (did not achieve a CR with frontline therapy or relapsed within 3 months of completing frontline therapy). Diagnoses include DLBCL (assorted disease subtypes, n=22), angioimmunoblastic T-cell lymphoma (AITL, n=9), PTCL-NOS (n=8), grey zone lymphoma (n=5), PMBL (n=4), follicular lymphoma (n=3), post-transplant lymphoproliferative disorder (n=1), and cutaneous T-cell lymphoma (n=1). The median age is 64 years (range 16–83) and 30 patients (57%) are male. Patients have received a median of 3 prior systemic therapies and 6 patients have received prior stem cell transplants. Of the 36 patients who have had a response assessment to date, 12 (33%) have achieved an objective response (5 CR, 7 partial remissions [PR]). The ORR for B-cell NHLs is 36% (9/25), and 27% (3/11) for mature T-/NK-cell NHLs. Thus far, responses are particularly noteworthy in DLBCL (excluding PMBL) where 7 of 15 patients (47%) have responded (3 CR, 4 PR), in AITL where 3 of 5 patients (60%) have responded (2 CR, 1 PR), and in grey zone lymphoma where 2 of 5 patients (40%) have achieved a PR. Median duration of response has not been reached. Of the 12 responding patients, 7 remain on treatment, 3 discontinued due to a patient decision (non-adverse event), and 2 due to adverse events of neutropenia (related) and pneumocystis jiroveci pneumonia (unrelated). CD30 expression levels for patients with a CR or PR were widely variable and ranged from <1% to 90%. Treatment-emergent adverse events (TEAEs) occurring in ≥10% of patients include fatigue (26%), diarrhea (16%), nausea (16%), pyrexia (16%), neutropenia (14%), dyspnea (12%), and abdominal pain (10%), and TEAEs considered related to study drug include fatigue (16%) and neutropenia (14%). Most AEs have been Grade 1 or 2. Grade 3 dyspnea, hyponatremia, and decreased white blood cell count have occurred in 2 patients each, while Grade 3 neutropenia has occurred in 3 patients. Two patients have experienced Grade 4 neutropenia. Peripheral neuropathy events have been Grade 1 or 2. Conclusions: In this interim analysis of 53 patients (36 with response evaluations), compelling antitumor activity has been demonstrated in both B-cell and mature T-/NK-cell NHLs, in particular DLBCL, AITL, and grey zone lymphoma. Due to the range of CD30 expression in patients achieving an objective response, more data are needed to determine if there is a correlation between CD30 expression and antitumor activity. Preliminary safety data are consistent with the safety profile of brentuximab vedotin. Disclosures: Jacobsen: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is indicated for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with brentuximab vedotin. Advani:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbott: Research Funding. Oki:Seattle Genetics, Inc.: Research Funding. Sharman:Seattle Genetics, Inc.: Research Funding. Horwitz:Seattle Genetics, Inc.: Consultancy, Research Funding; Novartis: Consultancy; Millennium: Consultancy; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Allos Therapeutics: Consultancy, Research Funding; Merck: Honoraria; Genzyme: Research Funding; Infinity Pharmaceuticals: Research Funding. Forero-Torres:Seattle Geentics, Inc.: Research Funding, Speakers Bureau. O'Connor:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Shustov:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Siddiqi:Seattle Genetics, Inc.: Consultancy, Research Funding. Grove:Seattle Genetics, Inc.: Employment, Equity Ownership. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other.

A Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results In Patients With DLBCL and Other B-Cell Lymphomas

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 848-848 ◽  
Author(s):  
Nancy L. Bartlett ◽  
Jeff P. Sharman ◽  
Yasuhiro Oki ◽  
Ranjana H. Advani ◽  
Celeste M. Bello ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Brentuximab Vedotin ◽  
Advisory Committees ◽  
Board Membership

Abstract Background Brentuximab vedotin (ADCETRIS®) is an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Variable CD30 expression has been demonstrated in several B-cell non-Hodgkin lymphoma (NHL) subtypes such as diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBL). Methods A phase 2, open-label, single-arm study is ongoing to evaluate the antitumor activity of brentuximab vedotin in relapsed or refractory CD30-positive NHL, including B-cell neoplasms (Clinical Trials.gov NCT01421667). CD30 expression is determined by immunohistochemistry per local laboratory; any level of CD30-positive expression is permitted for enrollment. Brentuximab vedotin, 1.8 mg/kg, is administered every 3 weeks by IV infusion. Patients who achieve at least stable disease are eligible to receive continued treatment until disease progression or unacceptable toxicity. The primary efficacy endpoint is objective response rate (ORR) as assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Correlation between antitumor activity and quantitative CD30 expression is also being explored. This subset analysis presents interim data for patients with relapsed/refractory Bcell neoplasms. Results Sixty-two B-cell lymphoma patients with variable CD30 expression by central review (range 0–100%) have been enrolled to date. Diagnoses include DLBCL (n=44) and other B-cell neoplasms (n=18) [grey zone lymphoma (n=6), PMBL (n=6), follicular lymphoma (n=3), and post-transplant lymphoproliferative disorder (n=3)]. The median age of all patients was 55 years (range, 16–85 years), and the majority had an ECOG performance status of 0/1 (92%). Patients had received a median of 2 prior therapies (range, 1 to 19); 11 (18%) had received prior stem cell transplant. Forty patients (65%) had primary refractory disease, and 47 patients (76%) were refractory to their most recent prior therapy. Fourteen patients (23%) had never responded to any prior therapy. At the time of this analysis, patients had received a median of 3 cycles of treatment (range, 1–17 cycles), with a median duration of treatment of 10.5 weeks (range, 2.4 to 57.1 weeks). Twelve (19%) patients remain on treatment. Of the 43 efficacy evaluable DLBCL patients, 40% achieved an objective response [7 complete remission (CR), 10 partial remission (PR)]; the median duration of objective response was 36 weeks (range, 0.1+ to 62.3+ weeks). Of the 18 efficacy evaluable patients with other Bcell neoplasms, 22% achieved an objective response: PMBL (1 CR), PTLD (1 CR), and grey zone lymphoma (2 PRs). The median duration of objective response was 21.7 weeks (range, 6.1 to 37.1 weeks). CD30 expression levels for patients with a CR or PR were variable and ranged from <1% to 90%. There was no statistical correlation between CD30 expression and response rate. Treatment-emergent adverse events (AEs) occurring in >20% of patients included fatigue (40%), nausea and neutropenia (37% each), pyrexia (32%), diarrhea (31%), peripheral sensory neuropathy (26%), vomiting (23%), and anemia and constipation (21% each). Peripheral neuropathy events have been primarily Grade 1 or 2. Neutropenia (29%) was the only Grade 3/4 related AE observed in >10% of patients. AEs led to treatment discontinuation in 6 patients; the most common reason was peripheral sensory neuropathy (2 patients). Conclusions In this interim analysis of 62 patients with highly refractory B-cell lymphomas, compelling antitumor activity has been observed with brentuximab vedotin. Forty percent of DLBCL patients achieved an objective response, with median remission duration of >8 months and a notable proportion of complete remissions. No correlation between CD30 expression and response rate has been observed to date. Safety data are consistent with the profile of brentuximab vedotin. This study continues to enroll patients and updated results will be presented at the meeting. Disclosures: Bartlett: Seattle Genetics, Inc.: Advisory/scientific board membership and travel expenses Other, Research Funding. Off Label Use: Brentuximab vedotin is indicated for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. Sharman:Seattle Genetics, Inc.: Research Funding, Travel expenses Other; Genentech: Research Funding; Gilead: Research Funding. Oki:Seattle Genetics, Inc.: Research Funding. Advani:Millennium: Advisory/scientific board membership, Advisory/scientific board membership Other, Research Funding; Seattle Genetics, Inc.: Advisory/scientific board membership Other, Research Funding; Genentech: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pharmacyclics, Inc.: Research Funding; Janssen R&D: Research Funding; Allos Therapeutics: Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees; Abbott: Research Funding. Bello:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees; Spectrum pharmaceuticals: Speakers Bureau. Winter:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Jacobsen:Seattle Genetics, Inc.: Advisory/scientific board membership Other, Research Funding.

scholarly journals Mutational Landscape of Grey Zone Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 21-21
Author(s):  
Clementine Sarkozy ◽  
Stacy Hung ◽  
Katsuyoshi Takata ◽  
Elizabeth Chavez ◽  
Tomohiro Aoki ◽  
...  
Keyword(s):  
B Cell ◽  
Exome Sequencing ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Grey Zone ◽  
Advisory Committees ◽  
Mutational Landscape ◽  
Intermediate Morphology

Introduction: Grey zone lymphoma (GZL), a B-cell lymphoma with features intermediate between large B-cell lymphoma (LBCL) and classical Hodgkin lymphoma (cHL), is a rare and poorly defined entity. To decipher its mutational landscape and discover new therapeutic targets, we performed exome sequencing of 31 GZL cases. Methods: GZL cases from the LYSA group (N=139) and BC Cancer (N=30) were centrally reviewed and classified as previously published (Sarkozy et al, Am J Surg Pathol 2019). Whole-exome sequencing was performed on 31 cases with available fresh frozen tissue, using laser micro-dissection (LMD, MMI technology) to enrich for tumor cells and obtain matching normal DNA from microenvironment cells. DNA was extracted (Agencourt® DNAdvance kit) and genomic libraries were constructed with the Ovation ultra-low kit (Nugen®). Exome capture was performed using Agilent SureSelectXT V6+UTR followed by paired-end sequencing (NextSeq®). Somatic nucleotide variants (SNVs) and indels were identified using VarScan, Strelka and Mutect. Parameters affecting the sensitivity and specificity of variant calling were optimized using 7 "gold standard" cases for which DNA from peripheral blood cells was additionally available. Possible oncogenic drivers were identified based on rate of recurrence, MutSigCV and literature review. Results: Among the 31 GZL cases, the median age was 41 y (14-83) with a sex ratio of 15M:16F; 21 cases had mediastinal involvement, including 15 within the thymic area; EBER in-situ hybridization (ISH) was positive in 8 cases. Seven (23%) cases were classified as group-0 (cHL morphology with 100% CD20 expression), 22 (71%) with an intermediate morphology as group-1 (N=9, cHL-like morphology) or group-2 (N=13, LBCL-like morphology) and 2 (6%) as group-3 (LBCL with 100% of CD30 expression). The mean coverage was 96X (42-203) for tumor samples. One case was excluded due to failure in the LMD process. Among the 30 cases, 6628 variants across 4826 genes were found, including 2903 coding mutations (325 indels and 2808 SNVs, mean of 104/sample, range: 15-678), 721 affecting the 5' UTR and 2774 the 3' UTR. A total of 152 genes were identified as being potential oncogenic drivers, with a mean of 11 mutated genes per case (range 2-36). The most recurrently mutated genes were SOCS1 (33%), B2M (23%), GNA13 (20%), LRRN3 (17%), and ZNF217, NCOR1, ITPKB, IRF2BP2, CSF2RB, and CSMD3 (13% each). The epigenetic SWI/SNF and transcription regulation pathway (including NCOR1/2, ARID1A, KMT2D, KMT2A) was affected in 73% of the cases, JAK/STAT in 70% and NF-kB in 19%. As assessed by CNVkit and GISTIC, the most recurrent gains/amplifications identified were in 9p24.1 (JAK2, CD274, PDCD2LG2; 69%) and 2p16.1 (REL, BCL11A; 62%), and losses in 11q14.3 (ATM; 48%) and 12q24.33 (NCOR2; 48%). Based on mutational signature analysis, individual base substitutions were linked to mutagenic processes, with the highest contributions associated with aging (29%) and defective DNA mismatch repair (27%); moreover, mutations attributable to AID/APOBEC activity (5%), were found to be significantly enriched in EBV- vs. EBV+ cases (p = 0.013). EBV+ cases had fewer total variants (mean 98 vs 258, p=0.08) and potential oncogenic variants (mean 7 vs 15, p=0.03) compared to EBV- cases. EBV+ cases also lacked mutations in the NF-kB pathway and MHC-class I components (B2M and HLA-B: 0% vs 43% in EBV-, p=0.06) but had mutations in STAT3, DHX58, ACTB and ATP13A4 (6/7 cases) not present in the 23 EBV- cases. LRRN3 and GNA13 mutations were significantly associated with thymic area involvement (40% vs 0%, p=0.01). Furthermore, fluorescence-ISH indicated that 20% (1/5) of EBV+ cases had a rearrangement in the CIITA locus (16p13.13) vs 53% (9/17) in EBV- cases. Patients with an intermediate morphology had more oncogenic variants than those in group 0 and 3 (mean of 15 vs 6 variants/case, p=0.01 affecting 12 vs 5 genes, p=0.004). Finally, NCOR1 (N=4) and NCOR2 (N=2) mutations were exclusively found in cases with intermediate morphology (23% vs 0% for those with group 0 or 3 morphology). Conclusion: These data suggest that GZL is a highly heterogenous disease harboring somatic driver events shared with PMBCL and HL. We also discovered novel gene mutations pointing to the importance of previously unrecognized pathways in the pathogenesis of GZL. The distinct mutational pattern in EBV+ GZL suggests divergent evolutionary trajectories. Disclosures Sarkozy: Takeda: Research Funding. Salles:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; BMS: Honoraria; Amgen: Honoraria, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events. Savage:BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria; Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Scott:Celgene: Consultancy; Roche/Genentech: Research Funding; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Steidl:Juno Therapeutics: Consultancy; Tioma: Research Funding; Roche: Consultancy; Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: Filed patent on behalf of BC Cancer; Seattle Genetics: Consultancy; Bayer: Consultancy.

Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma: A Phase 2 Study Update

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 443-443 ◽  
Author(s):  
Ranjana H. Advani ◽  
Andrei R. Shustov ◽  
Pauline Brice ◽  
Nancy L. Bartlett ◽  
Joseph D. Rosenblatt ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Objective Response ◽  
Large Cell ◽  
Brentuximab Vedotin ◽  
Employment Equity ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Equity Ownership

Abstract Abstract 443 Background: Systemic anaplastic large cell lymphoma (sALCL) is a T-cell non-Hodgkin lymphoma (NHL) characterized by the uniform expression of CD30. sALCL accounts for 2–5% of all cases of NHL; approximately 40–65% of patients experience recurrent disease after frontline treatment with few effective treatment options. Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). A phase 2 study was conducted to determine the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047); updated results of this trial are presented. Methods: Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. Determination of efficacy was based on objective response assessments per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Patients were enrolled between June 2009 and May 2010 at 22 clinical sites in the US, Canada, and Europe. Results: 58 patients with a median of 2 prior therapies (range 1–6) were treated; 57% were male and the median age was 52 years (range 14–76). Seventy-two percent of patients had ALK-negative disease, 62% had primary refractory disease (defined as no complete remission (CR) or relapse within 3 months of frontline therapy), and 26% had failed a prior autologous stem cell transplant (SCT). As previously reported, the objective response rate (ORR) was 86%, the CR rate was 57%, and 97% of patients had a reduction in tumor volume postbaseline. At the time of this updated analysis (data cut May 2011), all but 2 patients had discontinued treatment with brentuximab vedotin; the median number of treatment cycles was 7 (range 1–16). The median duration of objective response was 13.0 months (range 0.1–19.1+) and the median duration of response for patients achieving a CR was 17.1 months (range 0.7–19.1+). Median progression-free survival (PFS) was 14.6 months and median overall survival was not yet reached. Per investigator assessment, the median PFS with brentuximab vedotin was significantly longer than the median PFS achieved with the most recent prior therapy (20.0 months vs. 5.9 months; P value <0.001). All subgroups of patients analyzed in the study achieved a similar level of antitumor activity, regardless of baseline disease characteristics, tumor burden, or prior treatment history. Responses were particularly noteworthy in patients who had never responded to any previous therapy (n=13); in this subgroup of patients, 10 achieved an objective response (77%) and 4 a CR (31%). After discontinuing treatment in the study, 16 patients (28%) received a hematopoietic SCT (8 allogeneic, 8 autologous). The most common adverse events observed in the study were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). Most AEs in the study were Grade 1 or 2 in severity. Ten patients (17%) experienced Grade 3 events of peripheral neuropathy as defined in a Standardised MedDRA Query; no Grade 4 events were observed. In patients with neuropathy, 79% (26 of 33) have experienced resolution or some improvement and the median time to resolution or improvement was 13.3 weeks (range 0.3–48.7). Conclusions: Durable complete remissions were achieved with brentuximab vedotin, and treatment was associated with manageable toxicity, in patients with relapsed or refractory sALCL. Approximately half of the responding patients (24 of 50) continued in remission at the time of this analysis; updated results of efficacy and long term safety will be presented at the meeting. Based on the results from this study, a trial evaluating the safety of brentuximab vedotin administered in sequence and in combination with multiagent chemotherapy was initiated and is currently ongoing in frontline sALCL. Disclosures: Advani: Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). It is an investigational agent that is being studied in CD30+ malignancies. Shustov:Millennium: Honoraria; Seattle Genetics, Inc.: Consultancy, Research Funding. Brice:Roche: Honoraria; Seattle Genetics, Inc.: Honoraria, Research Funding. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel Expenses. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Matous:Cephalon: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics, Inc.: Research Funding; Millennium: Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding. Fanale:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Connors:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Pro:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals A Phase 2 Study of Panobinostat (PAN) in Combination with Bortezomib (BTZ) in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma (PTCL) or NK/T-Cell Lymphoma (NKL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 503-503 ◽  
Author(s):  
Yeow-Tee Goh ◽  
William YK Hwang ◽  
Colin Phipps Diong ◽  
Yap chun Hsien ◽  
Kevin Tay ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
Performance Status ◽  
Objective Response ◽  
T Cell Lymphoma ◽  
Conventional Chemotherapy ◽  
Advisory Committees

Abstract Background Relapsed/refractory PTCL and NKL after conventional chemotherapy carry a poor prognosis and there is currently no proven salvage treatment available. Numerous preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors. PAN inhibits the aggresome pathway of protein degradation, which is upregulated when the proteasome pathway is inhibited by BTZ. Primary end point of this phase II multi-center open-label clinical study (NCT00901147) is the objective response rate (ORR) according to the Revised Response Criteria (Cheson 2007) among eligible patients (pts) treated with this novel combination of BTZ and PAN. Secondary end points include the evaluation of the progression-free survival (PFS) and the assessment of the safety and tolerability of the combination. We report the final clinical results of our study exploring this novel combination. Methods Pts with histologically confirmed PTCL or NKL who failed or were refractory to 1 or more prior systemic therapy, and had measurable disease and ECOG performance status 0–2 were eligible. Pts were accrued according to a 2-stage Gehan design. Pts receive thrice weekly oral PAN (20 mg) and twice weekly BTZ (IV 1.3 mg/m2), both for 2 of 3 weeks for up to 8 cycles. CT scanning and/or FDG-PET were performed after every two cycles. Results: Among 25 pts enrolled, histologies included: angioimmunoblastic T-cell lymphoma (AITL) n=8, PTCL (unspecified) n=11, Anaplastic large cell lymphoma, ALK+ and ALK- n=1 and 2 respectively, NKL, nasal type n=2 and subcutaneous panniculitis-like T-cell lymphoma n=1. The median age was 59 (35-79) years, and 64% were male. Outcomes are available on 23 patients as 2 patients withdrew consent before any response assessment could be made. The ORR (CR+PR) was 43% (10/23) with 22% (5/23) attaining a CR. Median time to response was 6 weeks. Five pts (22%) had stable disease while 8 pts developed progressive disease (35%) while on study. Pts received a median of 2 prior therapies (range 1-4); 28% had prior autologous stem cell transplantation (SCT). Common treatment-related grade 3/4 adverse events included thrombocytopenia (68%), neutropenia (36%), diarrhoea (28%) and asthenia/fatigue (16%). Peripheral neuropathy of any grade was observed in 40%. 5 pts successfully underwent subsequent allogeneic SCT. Updated survival analysis will be presented. Conclusions The study regimen is generally well tolerated and shows encouraging activity across different T/NK-cell lymphomas. The novel combination could successfully serve as a bridge to allogeneic SCT for many transplant-eligible patients who have failed conventional chemotherapy. These results form the basis for further validation studies on proteasome and HDAC inhibition in PTCL or NKL. Ongoing correlative studies are designed to determine if the study regimen is more active in diseases with up-regulation of NF-kappa B activity or transcription factors/ co-regulators known to be modified by acetylation. Disclosures Goh: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jannsen Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Kim:Novartis, Celgene, Takeda: Research Funding. Tan:JANSEN: Honoraria, Research Funding; NOVARTIS: Research Funding.

scholarly journals Parsaclisib in Combination with R-CHOP for Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma: Preliminary Results of a Phase 1/1b Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1415-1415
Author(s):  
Yucai Wang ◽  
Betsy Laplant ◽  
Rebecca L. King ◽  
Ivana N. Micallef ◽  
Stephen M. Ansell ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Phase 1B

Abstract Introduction: Novel genetic classifications of diffuse large B-cell lymphoma (DLBCL) highlight the molecular complexity beyond cell of origin and provide new therapeutic implications. Next generation trials may incorporate novel agents for different genetic subtypes based on the pathogenesis mechanisms. For example, with the LymphGen classification, the MCD, BN2, ST2, and EZB subtypes are predicted to be susceptive to PI3K/mTOR targeting (Wright 2020). However, PI3K inhibitors have not been tested in the frontline, although data on the mTOR inhibitor everolimus were encouraging (Alliance 1085). We launched a phase 1/1b trial (NCT04323956) to investigate the feasibility of combining a novel PI3K inhibitor parsaclisib with standard R-CHOP immunochemotherapy and to seek an efficacy signal. Methods: Adult patients with newly diagnosed DLBCL were eligible if any of the following was present: 1) non-GCB subtype per the Hans algorithm; 2) expression of either Myc (≥40%) or Bcl2 (≥50%) by immunohistochemistry; or 3) MYC rearrangement by FISH. High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, regardless of morphology, was also eligible. All patients received parsaclisib plus R-CHOP. Phase 1 followed a 3+3 design and the primary endpoint was maximum tolerated dose (MTD) of parsaclisib. Dose levels tested were level 1 (20 mg QD, d1-10; starting level) and level 2 (20 mg QD, d1-14). MTD was defined as the dose level below the lowest dose that induced dose limiting toxicity (DLT) in at least one-third of patients. The primary endpoint in phase 1b is complete response (CR) rate by PET. Results: From July 2020 to June 2021, 15 patients were enrolled, 9 in phase 1 and 6 in phase 1b. The median age at diagnosis was 56 years (range 20-79), and 7 (47%) were female. One patient (7%) had ECOG PS ≥2, 7 (47%) had elevated LDH, 7 (47%) had &gt;1 extranodal site, 13 (87%) had stage III/IV, and 7 (47%) had high-intermediate or high risk International Prognostic Index. Pathology was DLBCL in 13 patients (2 with concurrent follicular lymphoma) and high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements in 2 patients. Four (27%) had non-GCB subtype, 7 (47%) had Myc or Bcl2 single expression, 8 (53%) had Myc/Bcl2 double expression, and 5 (33%) had MYC rearrangement (2 with concurrent BCL2 and/or BCL6 rearrangements). In phase 1, 3 patients were enrolled at dose level 1 and 6 patients were enrolled at dose level 2. No DLT was observed. Therefore, MTD was not reached, and dose level 2 was selected for phase 1b dose expansion. Six patients were enrolled in phase 1b to date. At the data cutoff date of 7/22/2021, 8 patients completed all 6 cycles of treatment, 1 competed 5 cycles, 3 completed 3 cycles, 2 completed 2 cycles, and 1 completed 1 cycle. Treatment-related adverse events (AE) are summarized in Table 1. The most common hematological AE included lymphopenia (60%), anemia (53%), neutropenia (53%), and thrombocytopenia (27%), and the most common non-hematological AE included nausea (67%), alopecia (40%), constipation (33%), fatigue (33%), dyspepsia (20%), and peripheral sensory neuropathy (20%). The most common grade 3 or 4 AE included lymphopenia (47%), neutropenia (33%), and anemia (13%). One 80-year-old female required parsaclisib dose reduction in cycle 3 and subsequent parsaclisib discontinuation as well as cyclophosphamide and doxorubicin dose reductions due to febrile neutropenia (no source of infection was identified). No other patients required dose reductions. The median follow-up was 3.7 months (range 0.8-10.7). Thirteen patients were evaluable for interim response by PET. The objective response rate was 92%, with 8 (62%) CR and 4 (31%) partial response (PR). One (8%) patient progressed before cycle 2 following a transient clinical response (shrinking palpable mass). Among those who achieved an objective response at interim, 7 patients were evaluable for end of treatment response and all 7 maintained a response, with 6 (86%) CR and 1 (14%) PR. Conclusions: Parsaclisib and R-CHOP combination therapy was generally well tolerated, with no DLT observed in phase 1 and no major safety concerns in both phase 1 and the ongoing phase 1b expansion. The preliminary efficacy signal of objective response appears encouraging in a small cohort of high risk patients. Parsaclisib plus R-CHOP can be an experimental arm for future frontline DLBCL trials investigating genetic subtype-driven novel therapies. Figure 1 Figure 1. Disclosures Wang: Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genentech: Research Funding; MorphoSys: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. King: Celgene/BMS: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Tun: Gossamer Bio, Acrotech: Consultancy; Mundipharma, Celgene, BMS, Acrotech, TG therapeutics, Curis, DTRM: Research Funding. Habermann: Seagen: Other: Data Monitoring Committee; Incyte: Other: Scientific Advisory Board; Tess Therapeutics: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Parsaclisib is an investigational agent used in this clinical trial.

Retrospective Analysis of the Safety and Efficacy of Brentuximab Vedotin in Patients Aged 60 Years or Older with Relapsed or Refractory CD30+ Hematologic Malignancies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3687-3687 ◽  
Author(s):  
Michelle A. Fanale ◽  
Nancy L. Bartlett ◽  
Andres Forero-Torres ◽  
Anas Younes ◽  
Robert W. Chen ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Board Of Directors ◽  
Research Funding ◽  
Objective Response ◽  
Sensory Neuropathy ◽  
Hematologic Malignancies ◽  
Brentuximab Vedotin ◽  
Phase 2 ◽  
Advisory Committees ◽  
Grade 3

Abstract Abstract 3687 Background Patients ≥60 years of age comprise a significant portion of the population with hematologic malignancies. In addition, advanced age is a known negative prognostic indicator in many cancers including CD30+ malignancies such as Hodgkin lymphoma (HL) and systemic anaplastic large-cell lymphoma (sALCL). Novel treatments with significant antitumor activity and increased tolerability are needed in this patient population that is often underrepresented in clinical trials. Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate (ADC) comprised of the microtubule-disrupting agent monomethyl auristatin E (MMAE) conjugated to an antibody that binds human CD30. This ADC has been studied in 2 phase 2 single-arm studies of patients aged ≥12 years with relapsed or refractory CD30+ lymphomas (median age 36.5, 13% ≥60). Brentuximab vedotin (1.8 mg/kg) administered once per 3-week cycle demonstrated objective response rates (ORRs) of 75% and 86% and complete remission (CR) rates of 34% and 57%, in HL and sALCL patients respectively. These objective responses were durable with a median duration of 6.7 and 13.0 months, respectively. The 3 most common adverse events (AEs) in HL and sALCL patients were peripheral sensory neuropathy (42% HL, 41% sALCL), nausea (35% HL, 40% sALCL), and fatigue (34% HL, 38% sALCL). Grade ≥3 neutropenia was observed in 20% of HL patients and 21% of sALCL patients. Methods This study presents a retrospective analysis of a subset of 40 patients aged 60 years or older with relapsed or refractory CD30+ lymphomas who received brentuximab vedotin in 1 or more of 7 clinical studies. Patients enrolled in the hepatic/renal impairment arm of a brentuximab vedotin pharmacokinetics study were excluded. The dosing schedule was either weekly (range 0.6–1.0 mg/kg) or every 3 weeks (range 1.2–2.7 mg/kg) with most patients receiving 1.8 mg/kg IV every 3 weeks. Antitumor activity was assessed by best response according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). AEs were continually monitored in all studies from the start of dosing to 30 days after the last dose. Results The median age of patients was 66 years (range 60–82). There were 22 sALCL patients and 15 HL patients (median age 66.5 and 68.0 years, respectively) in the analysis set. Three patients (8%) were diagnosed with other CD30+ lymphomas and had a median age of 62.0 years. The majority of patients were male (65%). Patients had received a median of 2.0 prior cancer-related systemic therapies (range 1–6) and 34 of 40 had received a prior stem cell transplant. Baseline B symptoms were reported in 8 patients (20%). Patients received a median of 7.5 cycles (range 1–22) of single-agent brentuximab vedotin treatment with a median dose intensity of 0.56 mg/kg/week (range 0.3–0.9). All sALCL patients and 53% of HL patients achieved an objective response (CR rate, 50% and 40%, respectively). Across diagnoses, the ORR was 78% with 43% of patients achieving a CR. The median duration of response was 13.0 months for sALCL patients and was not reached in HL patients at the time of analysis. Resolution of B symptoms was observed in half of the patients (4 of 8) who presented with baseline B symptoms. Treatment-emergent AEs of any grade (incidence ≥30%) included fatigue (58%), peripheral sensory neuropathy (58%), and nausea (38%). Treatment-emergent AEs ≥ Grade 3 in severity (incidence ≥20%) included neutropenia (25%) and anemia (20%). Serious adverse events (SAEs) were reported in 53% of patients with the most common (≥10%) being mental status changes (10%). AEs leading to treatment discontinuation occurred in 30% of patients. Death occurred within 30 days of the last dose in 1 patient with the cause of death considered unrelated to brentuximab vedotin or disease. Overall, 30% of patients received growth-factor support. Conclusions Brentuximab vedotin showed substantial antitumor activity and evidence of B-symptom resolution in these patients ≥60 years of age. Antitumor activity and the durability of clinical responses were consistent with those observed in the phase 2 studies of patients aged ≥12 years. AEs of fatigue and sensory neuropathy were more frequent in the older population, while other AEs such as nausea and neutropenia occurred with a similar incidence as in the phase 2 studies. Future studies will explore the safety and efficacy of brentuximab vedotin in earlier lines of therapy for this underserved population. Disclosures: Fanale: Seattle Genetics, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel expenses Other. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other. Forero-Torres:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Younes:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Affimed: Research Funding; Gilead: Research Funding; Johnson & Johnson: Research Funding. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel Expenses Other. Friedberg:Seattle Genetics, Inc.: Consultancy, Research Funding. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Shustov:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Smith:Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Zain:Seattle Genetics, Inc.: Honoraria, Research Funding. O'Meara:Seattle Genetics, Inc.: Employment, Equity Ownership. Gopal:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding.

scholarly journals Impact of Interim FDG-PET (iPET) in the Outcomes of Patients with Aggressive B-Cell Lymphomas Receiving DA-EPOCH-R

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2898-2898
Author(s):  
Vania Phuoc ◽  
Leidy Isenalumhe ◽  
Hayder Saeed ◽  
Celeste Bello ◽  
Bijal Shah ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Fdg Pet ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
End Of Treatment

Introduction: 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) remains the standard of care for baseline and end of treatment scans for aggressive non-Hodgkin lymphomas (NHLs). However, the role of interim FDG-PET remains not as well defined across aggressive NHLs, especially in the era of high-intensity chemoimmunotherapy. Interim FDG-PET (iPET) can serve as an early prognostic tool, and prior studies evaluating the utility of iPET-guided treatment strategies primarily focused on diffuse large B-cell lymphomas (DLBCL) and frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Classification criteria systems assessing response also differ between studies with no clear consensus between use of Deauville criteria (DC), International Harmonization Project (IHP), and the ΔSUVmax method. Methods: This study evaluates our institutional experience with iPET during treatment with DA-EPOCH ± R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with or without Rituximab) in aggressive NHLs. We retrospectively evaluated 70 patients at Moffitt Cancer Center who started on DA-EPOCH ± R between 1/1/2014 to 12/31/2018 for aggressive NHLs. Response on interim and end-of-treatment (EOT) scans were graded per DC, IHP, and ΔSUVmax methods, and progression free survival (PFS) probability estimates were calculated with chi-square testing and Kaplan Meier method. PFS outcomes were compared between interim negative and positive scans based on each scoring method. Outcomes were also compared between groups based on interim versus EOT positive or negative scans. Results: We identified 70 patients with aggressive NHLs who received DA-EPOCH ± R at our institute. The most common diagnoses were DLBCL (61%) followed by Burkitt's lymphoma (10%), primary mediastinal B-cell lymphoma (9%), plasmablastic lymphoma (7%), gray zone lymphoma (6%), primary cutaneous large B-cell lymphoma (1%), primary effusion lymphoma (1%), and other high-grade NHL not otherwise specified (3%). Of the 43 patients with DLBCL, 21/43 (49%) had double hit lymphoma (DHL) while 7/43 (16%) had triple hit lymphoma (THL), and 3/43 (7%) had MYC-rearranged DLBCL while 2/43 (5%) had double expressor DLBCL. Thirty nine out of 70 (56%) were female, and median age at diagnosis was 58.39 years (range 22.99 - 86.86 years). Most patients had stage IV disease (49/70, 70%), and 43/70 (61%) had more than one extranodal site while 45/70 (64%) had IPI score ≥ 3. Forty-six out of 70 (66%) received central nervous system prophylaxis, most with intrathecal chemotherapy (44/70, 63%). Fifty-five out of 70 (79%) had iPET available while 6/70 (9%) had interim computerized tomography (CT) scans. Fifty-six out of 70 (80%) had EOT PET, and 4/70 (6%) had EOT CT scans. Sustained complete remission occurred in 46/70 (66%) after frontline DA-EPOCH ± R (CR1), and 12/70 (17%) were primary refractory while 5/70 (7%) had relapse after CR1. Four of 70 (6%) died before cycle 3, and 3/70 (4%) did not have long-term follow-up due to transition of care elsewhere. Median follow-up was 15.29 months (range 0.85 - 60.09 months). There was significantly better PFS observed if iPET showed DC 1-3 compared to DC 4-5 (Χ2=5.707, p=0.0169), and PFS was better if iPET was negative by IHP criteria (Χ2=4.254, p=0.0392) or ΔSUVmax method (Χ2=6.411, p=0.0113). Comparing iPET to EOT PET, there was significantly better PFS if iPET was negative with EOT PET negative (iPET-/EOT-) compared to iPET positive with EOT negative (iPET+/EOT-), and iPET+/EOT+ and iPET-/EOT+ had worse PFS after iPET-/EOT- and iPET+/EOT- respectively. This pattern in iPET/EOT PFS probability remained consistent when comparing DC (Χ2=30.041, p<0.0001), IHP (Χ2=49.078, p<0.0001), and ΔSUVmax method (Χ2=9.126, p=0.0104). These findings fit clinical expectations with positive EOT scans indicating primary refractory disease. There was no significant difference in PFS when comparing DLBCL versus non-DLBCL (Χ2=3.461, p=0.0628) or DHL/THL versus non-DHL/THL diagnoses (Χ2=2.850, p=0.0914). Conclusion: Our findings indicate a prognostic role of iPET during treatment with DA-EPOCH ± R for aggressive NHLs. Significant differences in PFS were seen when graded by DC, IHP, and ΔSUVmax methods used in prior studies and when comparing interim versus EOT response. Larger studies are needed to confirm these findings. Disclosures Bello: Celgene: Speakers Bureau. Shah:Novartis: Honoraria; AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Sokol:EUSA: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE): First Detailed Report of Primary Treatment

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1614-1614 ◽  
Author(s):  
Francine M. Foss ◽  
Kenneth R. Carson ◽  
Lauren Pinter-Brown ◽  
Steven M. Horwitz ◽  
Steven T. Rosen ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Board Of Directors ◽  
Initial Treatment ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Primary Treatment ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Advisory Committees

Abstract 1614 Background: Registries can be invaluable for describing patterns of care for a population of patients. COMPLETE is a registry of peripheral T-cell lymphoma (PTCL) patients designed to identify the lymphoma-directed treatments and supportive care measures that PTCL patients receive. We report here the first detailed findings of initial therapy. Methods: This is a prospective, longitudinal, observational registry that is led by a global steering committee. Patients with newly diagnosed PTCL and providing written informed consent are eligible. Patients are entered into the registry from time of initial diagnosis and followed for up to 5 years. Only locked records are reported. Results: As of July 2012, 330 patients have been enrolled from the United States. The first patient was enrolled in February 2010. Locked baseline and treatment records are available for 124 and 81 patients, respectively. Of the 124 patients with locked baseline records, 67 patients (54%) were male, the mean age was 59 (range: 19–89), and race/ethnicity was recorded as: White (87 patients; 70%), Black (19; 15%), Asian (5; 4%) and other/unknown (13; 11%). Histology was reported as follows: PTCL-not otherwise specified (27%), anaplastic large cell lymphoma-primary systemic type (18%), angioimmunoblastic T-cell lymphoma (17%), transformed mycosis fungoides (7%), T/NK-cell lymphoma-nasal and nasal type (6%), adult T-cell leukemia/lymphoma, HTLV 1+ (6%) and other (19%). 25 patients (20%) had received another diagnosis, including B-cell lymphoma, Hodgkin's disease and other T-cell lymphomas, prior to their current diagnosis of PTCL. 49 patients (40%) had B symptoms, 102 patients (82%) had an Ann Arbor stage of III/IV, 116 patients (94%) had ECOG performance status of 0–1, and international prognostic index (IPI) score was distributed as follows: IPI 0 (7% of patients), 1 (15%), 2 (43%), 3 (26%), and 4 (9%). Of the 81 patients with locked treatment records, details on initial treatment can be found in table below. Conclusions: This first detailed analysis of primary treatment of PTCL indicates that this disease is still largely being treated with regimens derived primarily from studies of B-cell lymphomas and that a single standard of care does not exist. The fact that a meaningful proportion of patients were initially diagnosed with something other than their current diagnosis of PTCL points out the challenges of diagnosing the disease. While the intent of initial treatment for most patients is to affect a cure, more than 20% of patients were noted as deceased at the end of initial treatment, underscoring the need for more effective, disease-specific therapy. Disclosures: Foss: Merck: Study Grant, Study Grant Other; Celgene: Study Grant, Study Grant Other; Eisai: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Allos: Consultancy. Carson:Allos: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Pinter-Brown:Allos: Consultancy, Membership on an entity's Board of Directors or advisory committees. Horwitz:Allos: Consultancy, Research Funding. Rosen:Allos: Consultancy, Honoraria. Pro:Celgene: Honoraria, Research Funding; Spectrum: Honoraria; Allos: Honoraria; Seattle Genetics: Research Funding. Gisselbrecht:Allos: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hsi:Allos: Research Funding; Eli Lilly: Research Funding; Abbott: Research Funding; Cellerant Therapeutics: Research Funding; BD Biosciences: Research Funding; Millenium: Research Funding.

Phase II Study Of Anti-CD19 Antibody Drug Conjugate (SAR3419) In Combination With Rituximab: Clinical Activity and Safety In Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (NCT01470456)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4395-4395 ◽  
Author(s):  
Bertrand Coiffier ◽  
Catherine Thieblemont ◽  
Sophie de Guibert ◽  
Jehan Dupuis ◽  
Vincent Ribrag ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Duration Of Response ◽  
Grade 3

Abstract Background SAR3419 is a humanized anti-CD19 antibody conjugated to maytansin DM4, a potent cytotoxic agent. SAR3419 targets CD19, an antigen expressed in the majority of B cell non-Hodgkin lymphomas (NHL). The recommended dose for single agent SAR3419 was previously determined to be 55 mg/m2 administered IV every week for 4 weeks, then bi-weekly. In phase I, clinical activity was shown mainly in patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). (Trial funded by Sanofi). Methods Patients (pts) with a CD20+ and CD19+ DLBCL relapsing or refractory (R/R) after at least 1 standard treatment including rituximab and not candidate for or who already underwent transplantation, were eligible. Refractory disease was defined as unresponsive to or progressing within 6 months of regimen completion. Fresh (or recent formalin-fixed, paraffin-embedded) biopsy was required before SAR3419 start. Pts received 375 mg/m2 of rituximab (R) IV and 55 mg/m² of SAR3419 on day 1, 8, 15, 22 (35-day cycle 1), followed by bi-weekly R and SAR3419 at the same doses for 2 additional 28-day cycles, provided there was no disease progression or other study discontinuation criteria met. The primary objective was the overall response rate (ORR) following Cheson 2007 criteria, with the first tumor assessment being done 42 days after the last study treatment administration. Secondary objectives were: safety, pharmacokinetics (PK), duration of response (DOR), progression free survival (PFS), overall survival (OS) and correlation of the antitumor and biological activity of the combination with tumor biomarker status. Results Fifty-three pts were enrolled, 52 treated. Median age was 66.5 years (range 38-85), 50% were male; 23%, 33% and 40% of patients had received 1, 2 or ≥3 prior chemo/immunotherapy regimens for DLBCL, respectively. Of the enrolled patients, 3.8% had received no prior regimen for DLBCL and therefore were excluded from primary analysis for efficacy. Seventy-three percent had stage III/IV disease, 59% had elevated lactate dehydrogenase (LDH), and 63% had bulky disease. Sixty percent were refractory to first regimen (primary refractory), 16% were refractory to last regimen and 24% were relapsed pts. The ORR in the per-protocol population (n=45) was 31.1% (80% confidence interval (CI): 22.0% to 41.6%). Among the 14 responders, 5 had progressed at the time of analysis, with duration of response beyond 6 months for 3 of them. The ORR was 58.3% (80% CI: 36.2% to 78.1%) for patients with relapsed DLBCL (n=12), 42.9% (80% CI: 17.0% to 72.1%) for pts refractory to last regimen (n=7) and 15.4% (80% CI: 6.9% to 28.4%) for primary refractory pts (n=26). Overall survival and PFS data are not yet mature. Biomarkers and PK data will be presented at the meeting. The most common (≥10%) all grades non-hematologic treatment-emergent adverse events (TEAEs) were asthenia (25.0%), nausea (21.2%), cough (19.2%), diarrhea (17.3%), weight decrease (17.3%), vomiting (15.4%), dyspnea (15.4%), abdominal pain (13.5%), back pain (13.5%), pyrexia (13.5%) and constipation (11.5%). Related grade 3-4 TEAEs were: 1 syncope, 1 bronchospasm, 2 neutropenia and 1 anemia. No TEAEs led to treatment discontinuation, no grade 3-4 peripheral neuropathy or grade 3-4 ocular events were observed. Two pts experienced grade 2 keratitis, both rapidly recovered with local treatment. Hematological toxicity was moderate, with grade 3-4 neutropenia and thrombocytopenia in 15.7% and 9.8% pts, respectively. No complications related to neutropenia were reported. Grade 3 transaminase increase was observed in 1 patient. Conclusions The combination of SAR3419 plus R showed moderate ORR in R/R DLBCL; however the study population was of poor prognosis (60% refractory to first line therapy). In the relapsed DLBCL patients a higher ORR was observed. SAR3419 plus R presented with a favorable safety profile. Further investigations on biomarker expression are ongoing to identify a sub-group of pts who could have better benefited from this combination. Disclosures: Coiffier: Sanofi: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Phase II of SAR3419. Ribrag:Johnson & Johnson: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cartron:LFB: Honoraria; GSK: Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Casasnovas:Roche: Consultancy, Honoraria, Research Funding. Hatteville:Sanofi: Employment. Zilocchi:Sanofi: Employment. Oprea:Sanofi: Employment. Tilly:Amgen: Research Funding; Janssen: Honoraria; Pfizer: Honoraria; Takeda: Membership on an entity’s Board of Directors or advisory committees; Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Poor Outcomes Among Patients Failing Dose-Adjusted EPOCH in Aggressive Lymphoma: A Collaborative, Retrospective Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1518-1518 ◽  
Author(s):  
Jackie Vandermeer ◽  
Allison M Winter ◽  
Ajay K. Gopal ◽  
Ryan D. Cassaday ◽  
Brian T. Hill ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Salvage Therapy ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
First Line ◽  
Advisory Committees ◽  
First Line Therapy

Abstract Introduction Among patients with aggressive B-NHL who fail RCHOP, about half respond to standard salvage regimens and may proceed to curative-intent, transplant-based therapy. However, whether pts failing more intensive regimens such as dose-adjusted, infusional EPOCH benefit from standard salvage regimens is unclear. We hypothesized that such patients comprise a higher-risk cohort, facing inferior response rates and outcomes using standard salvage regimens. We undertook a collaborative study to assess response rates and survival among pts failing EPOCH for aggressive B-NHL, to inform patient management and design of clinical trials in this setting. Methods Pharmacy records and institutional databases were queried, identifying pts receiving EPOCH over the last 10 years at the University of Washington/SCCA and the Cleveland Clinic Foundation, for combined analysis. Under IRB approval, patient characteristics, histology, outcome with EPOCH, time to EPOCH failure, response to salvage, and overall survival were analyzed. Diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, B-cell-lymphoma unclassifiable, HIV-associated B cell lymphoma, and transformed B cell non-Hodgkin lymphoma were included. Pts receiving <2 cycles EPOCH, or who had inadequate follow-up (<3 months), were excluded. Failure of EPOCH was defined as failure to respond or progression during therapy, need for initiation of salvage therapy, or death during therapy of any cause. Adverse events or treatment change due to toxicity were not included in the definition of failure. JMP 11 was used to generate kaplan-meier survival estimates. Results 124 pts with aggressive B-NHL receiving EPOCH were identified. 54 had not relapsed, and among 70 remaining da-EPOCH failures, 37 met the above inclusion criteria. Median age was 55. 27% were female, and 23 received EPOCH as first-line therapy. All but 3 received rituximab with EPOCH. Histologies were primarily DLBCL in 22/37 (60%) and BCL-U in 12/37 (32%) carrying a MYC translocation; most of these harbored additional translocations in BCL2 and/or BCL6 (10/12). However, data regarding MYC rearrangement was not available for all pts. 2 had HIV-associated B-NHL and 3 had PMBCL. With 18 months follow up, the median time to EPOCH failure was 5 months. Only 3 EPOCH failures occurred late (>12 months). Median OS from the date of EPOCH failure was 10 months (Figure 1). Those receiving EPOCH as first-line therapy (23) had a median OS of 14 months from EPOCH failure, as opposed to 4 months for those receiving EPOCH as salvage therapy (log-rank p=.01). Salvage chemotherapy regimens after EPOCH were diverse, and generally ineffective; 6/28 (21%) regimens produced a response (Table 1). Among patients failing EPOCH within a year, platinum-containing salvage (RICE/RDHAP) was effective in only 2/13 patients (15%). 9 patients did not receive any salvage, most of whom died or proceeded to palliative measures and/or hospice care. Conclusions A relatively low overall response rate (21%) was observed in this retrospective analysis of patients failing EPOCH. Analogous to early RCHOP failure in the CORAL study, those failing EPOCH within a year may face inferior outcomes with platinum-based salvage therapy. While combined from two institutions, our data represent a modest sample size and require confirmation. If verified, examination of mechanisms of resistance to EPOCH, and selecting EPOCH failures for clinical trials of novel targeted therapies and transplant-based approaches, may prove critical. Table 1. Salvage Therapy for REPOCH failures Regimen: response/total number treated Notes Response to any salvage: 6/28 (21%) Some patients received more than 1 chemo salvage; responses were tabulated per regimen. RICE: 4/12 2/3 alive post transplant(1 auto 1 allo; 1 declined transplant and survived; 1 died) RDHAP: 1/6 Gemcitabine-based: 0/5 HyperCVAD (Part A and/or B): 1/5 Survivor had CNS only relapse, received regimen B and transplant 9- received no systemic treatmen; most died or proceeded to palliative measures and/or hospice Figure 1. Figure 1. Disclosures Gopal: Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding; Emergent/Abbott: Research Funding; Sanofi-Aventis: Honoraria; Seattle Genetics: Consultancy, Honoraria; BioMarin: Research Funding; Piramal: Research Funding; Janssen: Consultancy; Millenium: Honoraria, Research Funding; BMS: Research Funding; Merck: Research Funding. Hill:Seattle Genetics: 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; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Till:Roche/Genentech: Research Funding; Pfizer: Research Funding.

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