Phase 1/2 Study Of Brentuximab Vedotin In Pediatric Patients With Relapsed Or Refractory (R/R) Hodgkin Lymphoma (HL) Or Systemic Anaplastic Large-Cell Lymphoma (sALCL): Preliminary Phase 2 Data For Brentuximab Vedotin 1.8 Mg/Kg In The HL Study Arm

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4378-4378 ◽  
Author(s):  
Franco Locatelli ◽  
Kathleen A Neville ◽  
Angelo Rosolen ◽  
Judith Landman-Parker ◽  
Nathalie Aladjidi ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Brentuximab Vedotin ◽  
Phase 2 ◽  
Free Survival ◽  
Grade 3 ◽  
Preliminary Phase

Abstract Background Brentuximab vedotin is a CD30-targeted antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Pivotal phase 2 studies reported the efficacy and manageable toxicities of the drug, leading to its approval by the US FDA for use in adult patients with R/R HL and R/R sALCL in 2011. Data for brentuximab vedotin in children with these lymphomas are currently limited but promising. This ongoing phase 1/2 prospective, open-label, multicenter study is the first clinical trial of brentuximab vedotin conducted exclusively in pediatric patients with R/R HL or R/R sALCL (NCT01492088). The phase 1 portion established the recommended phase 2 dose (RP2D) of brentuximab vedotin in pediatric patients with R/R HL or R/R sALCL as 1.8 mg/kg every 3 weeks (Q3wk), and complete response (CR) and partial response (PR) were reported in 88% of patients at the RP2D. Here, we report preliminary phase 2 response, safety and PK findings for the HL patients receiving the RP2D. Methods The phase 2 portion aimed to enroll 15 response-evaluable HL patients at the RP2D, including those R/R HL patients treated at the RP2D in phase 1 (phase 2 data for the sALCL patients are not reported here). The phase 2 primary objective was overall response rate (ORR; CR + PR) at the RP2D; secondary objectives were time to progression, time to response, duration of response, event-free survival, progression-free survival, overall survival, to characterize PK, to further evaluate safety, and to determine immunogenicity of brentuximab vedotin. Patients with R/R HL aged 5 to<18 years, with measurable disease, who were in their second or later relapse, had failed chemotherapy, and were ineligible for, refused, or previously received stem cell transplant, received brentuximab vedotin 1.8 mg/kg by IV infusion Q3wk for up to 16 cycles until progression or unacceptable toxicity. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Responses will be assessed both by the investigators and independent review facility per IWG revised response criteria for malignant lymphoma; investigator responses are reported here. Blood samples for PK analysis were collected on day 1 (all cycles) immediately before and 5 minutes after the infusion and on prespecified days during cycles 1, 2, and 8. Results 16 patients with R/R HL received at least 1 dose of brentuximab vedotin at the RP2D; median age was 15 years (range, 8–18); 56% were male; Ann Arbor stage at initial diagnosis was 44% stage II, 6% stage III, 44% stage IV, and 6% unknown; median time from initial diagnosis was 16.7 months (range, 0–38) and 50% had B symptoms at baseline. At data cut-off (June 20, 2013), patients had received a median of 3 cycles of treatment (range, 1–16); 10 (63%) patients had discontinued treatment due to: progressive disease (n=7), AEs (n=2), and allogeneic transplant (n=1). Response data were available for 14 patients at data cut-off. The ORR was 64% (95% confidence interval [CI]: 35, 87); 3 (21%; 95% CI: 5, 51) patients achieved CR and 6 (43%; 95% CI: 18, 71) achieved PR. Reponses were typically observed at C2. 12 of 16 (75%) patients had ≥1 AE, and 7 (44%) had grade ≥3 AEs. The most common (>1 patient) AEs were nausea (38%), pyrexia (31%), neutropenia, paresthesia (each 19%), abdominal pain, upper abdominal pain, constipation, decreased appetite, diarrhea, hepatotoxicity, hypokalemia, leukopenia, myalgia, pharyngitis, and vomiting (each 13%). 7 serious AEs (SAEs) occurred in 5 patients; 4 SAEs in 3 patients were considered related to brentuximab vedotin: grade 3 hepatotoxicity and grade 3 febrile neutropenia (n=1); grade 3 anaphylaxis (n=1); and grade 3 pneumonia (n=1). One patient died on C2D4 of unrelated cardiac arrest due to progressive mediastinum enlargement (disease progression). 2 (13%) patients discontinued, 1 due to grade 3 hepatotoxicity on C1D13 and 1 due to grade 3 peripheral neuropathy on C8D4. Preliminary PK data show that brentuximab vedotin remained detectable in the blood just prior to the next infusion over the treatment period; thus, patients remain exposed to brentuximab vedotin from cycle to cycle. Conclusions Brentuximab vedotin 1.8 mg/kg Q3wk (RP2D) was generally well tolerated in pediatric patients with R/R HL and demonstrated preliminary evidence of activity, with an ORR to date of 64%, including 21% CR. The phase 2 portion is ongoing in pediatric patients with R/R HL and R/R sALCL. Disclosures: Off Label Use: Brentuximab vedotin for the treatment of pediatric patients with relapsed or refractory Hodgkin lymphoma. Franklin:Millennium: The Takeda Oncology Company: Research Funding. Fasanmade:Millennium: The Takeda Oncology Company: Employment, Equity Ownership, Research Funding. Wang:Millennium: The Takeda Oncology Company: Employment. Sachs:Millennium: The Takeda Oncology Company: Employment. Mauz-Koerholz:Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees.

Brentuximab Vedotin in Combination with Dacarbazine or Bendamustine for Frontline Treatment of Hodgkin Lymphoma in Patients Aged 60 Years and Above: Interim Results of a Multi-Cohort Phase 2 Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 587-587 ◽  
Author(s):  
Christopher A. Yasenchak ◽  
Andres Forero-Torres ◽  
Vivian Jean Mikao Cline-Burkhardt ◽  
Rodolfo E Bordoni ◽  
Dipti Patel-Donnelly ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Older Patients ◽  
Research Funding ◽  
Brentuximab Vedotin ◽  
Observation Time ◽  
Cell Transplant ◽  
Phase 2 ◽  
Frontline Treatment ◽  
Grade 3

Abstract Introduction Older patients (pts) with Hodgkin lymphoma (HL) have inferior outcomes compared to younger pts treated with standard chemotherapy regimens, and tolerate therapy poorly. New therapeutic options that improve both efficacy and tolerability are needed for these pts. Brentuximab vedotin (ADCETRIS®), an anti-CD30 antibody-drug conjugate, has durable activity as monotherapy in relapsed HL with a manageable safety profile. For frontline single agent treatment of HL pts aged ≥60 yrs, the objective response rate (ORR) was 92% (73% complete remission [CR]) and the median progression-free survival (PFS) was 10.5 months (mo) (Forero-Torres 2015). Brentuximab vedotin + dacarbazine (DTIC) demonstrated compelling activity in preclinical models (McEarchern 2010), and brentuximab vedotin + bendamustine (benda) provided an 82% CR rate in pts with relapsed HL (LaCasce 2014). This phase 2, frontline, open-label study examines the efficacy and durability of response of brentuximab vedotin as monotherapy and in combination with DTIC or benda in HL pts aged ≥60 yrs (NCT01716806). Methods Approximately 70 treatment-naïve pts aged ≥60 yrs with HL (30 monotherapy; 20 for each combination) are to be enrolled. Eligible pts have ECOG ≤3 and are ineligible for or have declined conventional treatment. Brentuximab vedotin 1.8 mg/kg is administered every 3 weeks for up to 12 cycles with DTIC (375 mg/m2) and up to 6 cycles with benda (90 or 70 mg/m2). Pts with clinical benefit may receive additional cycles of brentuximab vedotin. Response is assessed after Cycles 2, 4, 8, 12, 16 and every 6 cycles thereafter. The primary endpoint is ORR per the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results Thus far, 60 pts have been treated (n=27 monotherapy; 22 DTIC combo; 11 benda combo). Median age for all pts was 76 yrs (range, 62-92), 55% were male, 65% had stage III-IV disease, 40% had B symptoms, 28% had ECOG 2-3, and 70% were deemed ineligible for conventional chemotherapy. To date, a median of 11.5 treatment cycles have been received by DTIC combo pts, compared to 8 cycles by monotherapy pts. Duration of treatment for the benda combo pts will be more clearly defined with additional follow-up time. A total of 45 pts have discontinued therapy. Discontinuations were due to adverse event (AE; n=18, including 15 for Grade 2 or 3 peripheral neuropathy), progressive disease (PD) after complete or partial remission (CR or PR; n=13), or other reasons (see table; n=14). Fifteen pts remain on therapy. For pts treated with the DTIC combo, the ORR was 100% (62% CR). The median PFS has not been reached (median observation time 9.8 mo) and 18/21 pts remain alive without PD. For pts treated with the benda combo, the starting dose of benda was reduced from 90 to 70 mg/m2 to improve tolerability after the first 10 pts were enrolled. The ORR was 100% (78% CR) in the first 9 pts; with limited observation time (median 3.6 mo), 8/9 pts remain alive without PD. Treatment-related AEs ≥ Grade 3 occurred in 43% of pts overall, SAEs were reported for 22% overall, and no pt died within 30 days of last dose. Conclusions This planned analysis demonstrated 100% ORRs for both the DTIC combo and benda combo with acceptable tolerability. Based upon these data, combinations including brentuximab vedotin appear to have promise as frontline therapy in this vulnerable patient population. Ongoing follow-up will define durability, and ultimately the potential role of these combinations as standard options for elderly patients with HL. Table. Monotherapy (N=27) DTIC Combo (N=22) Benda Combo a (N=11) Median treatment cycles (range) Brentuximab vedotin 8 (3, 23) b 11.5 (2, 16) 4 (2, 8) DTIC or benda - 11.5 (1, 12) 4 (1, 6) Pts remaining on therapy, n (%) 0 b 6 (27) 9 (82) Reason for treatment discontinuation, n (%) AE 11 (41) b 7 (32) 0 PD after CR or PR, n (%) 11 (41) b 2 (9) 0 Investigator decision 1 (4) b 4 (18) 1 (9) Pt decision 3 (11) b 2 (9) 1 (9) Completed treatment 0 b 1 (5) 0 Other non-AE reason 1 (4) b 0 0 Efficacy evaluable pts (N) 26 b 21 9 ORR, n (%) 24 (92) b 21 (100) 9 (100) CR rate, n (%) 19 (73) b 13 (62) 7 (78) PFS, median mo (range) 10.5 (2.6+, 22.3+) b - (4.2+, 14.3+) - (1.2+, 6.2+) Median observation time, mo (range) 20.4 (4.6, 30.4) 9.8 (4.9, 14.3) 3.6 (2.3, 7.0) Pts with progression or death, n (%) 16 (62) 3 (14) 1 (11) Treatment-related AE ≥ Grade 3, n (%) 13 (48) b 8 (36) 5 (45) Any SAE, n (%) 6 (22) b 2 (9) 5 (45) aEnrollment is ongoing bForero-Torres 2015 Disclosures Yasenchak: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is indicated in the US 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. This study evaluates brentuximab vedotin as frontline treatment, both as monotherapy and in combination therapy, in older patients with HL.. Forero-Torres:Seattle Genetics, Inc.: Research Funding. Cline-Burkhardt:Seattle Genetics, Inc.: Research Funding. Bordoni:Seattle Genetics, Inc.: Research Funding. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Flynn:Seattle Genetics, Inc.: Research Funding. Chen:Genentech: Consultancy, Speakers Bureau; Seattle Genetics, Inc.: Consultancy, Other: Travel expenses, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau. Fong:Seattle Genetics, Inc.: Employment, Equity Ownership.

scholarly journals Outcome of Hodgkin Lymphoma after Progression Following Autologous Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2994-2994
Author(s):  
Joseph M. Connors ◽  
Alina S Gerrie ◽  
Maryse M Power ◽  
Kerry J Savage
Keyword(s):  
Stem Cell ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Single Agent ◽  
Progression Free Survival ◽  
Brentuximab Vedotin ◽  
Primary Objective ◽  
Initial Diagnosis ◽  
Cell Transplant ◽  
Free Survival

Abstract Background Clinical trials have demonstrated a high level of effectiveness for brentuximab vedotin (BV) for patients with relapsed or refractory classical Hodgkin lymphoma (HL); however, how patients fare in routine clinical practice if their HL recurs after autologous stem cell transplant (ASCT) is less clear. Our primary objective was to characterize overall survival (OS) and progression-free survival (PFS) among a cohort of real-world patients treated with BV after ASCT. The secondary objective was to characterize the outcome of treatment after failure of ASCT or ASCT and BV. Methods We screened the population-based British Columbia Cancer Agency (BCCA) Lymphoid Cancer Database to identify patients with classical HL (excluding lymphocyte predominant HL) who were aged >16 years at initial diagnosis, staged and treated in BC, had primary treatment with ABVD or equivalent chemotherapy, underwent ASCT as part of first treatment for refractory or relapsed disease and relapsed again after ASCT. We excluded patients who have been treated at any time with a checkpoint inhibitor. We determined Kaplan-Meier estimates of overall (OS) and progression free survival (PFS) from the date of the progression that occurred after ASCT and, for those treated with the agent, after subsequent BV. Therapies given in sequence without a pause between therapies were considered part of the same line of therapy. Results Between 1986 and 2015 93 patients experienced recurrence of HL after ASCT. Their median age at initial diagnosis was 30 years and 51% were male. After failure of ASCT 23 (25%) received radiation monotherapy and 61 received chemotherapy (66%), either as a single agent or in various combinations and of these 9 (10%) also received radiation; 6 (6%) received a second transplant (5 allogeneic and 1 repeat ASCT); and 5 refused or were too frail for treatment other than with corticosteroids. The median PFS and OS from the time of relapse after ASCT for these 93 patients were 7.1 (range 0.2-352) and 16.2 months (range 0.2-352), respectively. Of those 93, 17 patients received BV alone or BV+bendamustine at some point following ASCT. The median age of BV-treated patients was 33 years at the time of their original diagnosis and 29% were male. Among those 17 patients, 9 received single agent BV and 8, BV+bendamustine as part of a clinical trial. The median time from ASCT to the start of BV was 27.5 months. Counting ASCT as 2nd line treatment, 10 individuals received BV as 3rd line, 6 as 4th line and 1 as 5th line therapy. For all 17 patients the subsequent median PFS and OS from the time of BV initiation were 5.1 (range 1.5-34.6) and 18.8 months (range 2.4-40.5), respectively. 12 of these patients relapsed again and their subsequent median PFS and OS were 0.6 (range 0.5-29) and 3 (range 0.5-30) months, respectively. All 9 patients who received single agent BV relapsed again at a median of 2 months (range 1.2-9.7); 5 of the 8 patients treated with BV+bendamustine remain in remission 6 to 36 months later. Conclusions These data highlight the poor prognosis for patients with relapsed or refractory cHL, particularly for those whose lymphoma recurs after brentuximab vedotin as well as the highly individualized management of patients whose lymphoma has recurred after ASCT. Future therapies that prevent or significantly delay relapse will help in alleviate the substantial clinical burden due to relapsed and refractory Hodgkin lymphoma. Disclosures Connors: Millennium Takeda: Research Funding; Seattle Genetics: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Bristol Myers Squib: Research Funding.

A Phase I/II Study of Lenalidomide in Combination with Rituximab in Relapsed/Refractory Mantle Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2719-2719 ◽  
Author(s):  
Luhua Wang ◽  
Luis Fayad ◽  
Fredrick B. Hagemeister ◽  
Sattva Neelapu ◽  
Felipe Samaniego ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Employment Equity ◽  
Mantle Cell ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 2719 Poster Board II-695 Background: Rituximab directly targets CD20 positive lymphoma cells while lenalidomide targets the microenvironment. This combination was proven effective in vitro and in vivo in mantle cell lymphoma (Wu et al, Clin Cancer Res 2008; Zhang et al, Am J Hematol 2009). Clinically, lenalidomide (Habermann et al, Br J Haematol 2009) and rituximab have single-agent activity in mantle cell lymphoma (MCL) and may be an effective combination. The goal of our study was to determine the maximum tolerated dose (MTD) in phase 1 and evaluate the efficacy and safety of lenalidomide plus rituximab in patients with relapsed/refractory MCL in phase 2. Methods: Patients with relapsed/refractory MCL received lenalidomide on days 1–21 of every 28-day cycle, and rituximab (375 mg/m2) weekly during cycle 1. Dose escalation was used to determine the MTD with lenalidomide (10 mg, 15 mg, 20 mg, and 25 mg). Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic, or grade 4 hematologic adverse events in cycle 1. Phase 2 has reached targeted enrolment with 45 patients treated at MTD. Kaplan-Meier method was used to estimate progression free survival rate and response duration. Median time to event in months with 95% confidence interval was calculated. Of 45 patients treated at the MTD, the median age was 66 (46–85), 91% were males. All patients had received prior rituximab and were enrolled regardless of prior rituximab sensitivity or resistance. Results: The median follow-up time for the censored observations was 11.4 months. Two DLTs occurred at 25 mg in phase 1 (hypercalcemia, non-neutropenic fever); therefore, the MTD was 20 mg. The grade 3–4 non-hematologic events included elevated AST, elevated ALT, fatigue, myalgia, tremors, ataxia, cough, deep vein thrombosis, dyspnea, edema (facial), infection, neuropathy sensory, rash, and respiratory failure. Grade 3–4 hematologic adverse events included neutropenia (37 events), neutropenic fever (4 events), and thrombocytopenia (16 events). There were no responses in patients treated at 10 mg or 15 mg. Thirty six patients (36) were evaluable for response. Nine (9) patients are too early in their treatment and are not yet eligible for response evaluation. Among the 36 evaluable patients, 11 (31%) patients achieved CR, 8 (22%) patients achieved PR, 3 (8%) patients had minor response, 6 (17%) patients had stable disease and 8 (22%) patients had progressive mantle cell lymphoma. The overall response rate (CR + PR) was 53%. Seventy eight (78%) patients achieved stable disease or better and benefited from oral Lenalidomide plus 4 doses of rituximab. The median time to response was 2 months (2–8), and the median duration of response for the 19 patients with CR or PR was 18 months (95% CI: 10.6, NA) (range1–30 months). The median progression free survival for all patients on phase 2 was 14 months (95% CI: 9.8, NA) (ranging from 1–32 months). Conclusion: Oral lenalidomide plus rituximab resulted in durable responses in relapsed/refractory MCL with a favourable toxicity profile. Disclosures: Wang: Celgene: Honoraria, Research Funding. Hagemeister:Celgene Corporation: Consultancy. Samaniego:Celgene Corporation: Research Funding. Yi:Celgene Corporation: Research Funding. Shah:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Elan: Consultancy; Millennium: Research Funding, Speakers Bureau. Bell:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Zeldis:Celgene: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Phase 1/2 Trial Of Lenalidomide In Combination With Cyclophosphamide and Prednisone (REP) In Patients With Lenalidomide-Refractory Multiple Myeloma (REPEAT-study)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 287-287 ◽  
Author(s):  
Inger S. Nijhof ◽  
Sonja Zweegman ◽  
Mark-David Levin ◽  
Harry R. Koene ◽  
Aart Beeker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Dose Level ◽  
Research Funding ◽  
Phase 1 ◽  
Oral Cyclophosphamide ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Grade 3 ◽  
Dose Levels

Abstract Background The outcome of multiple myeloma (MM) patients who are no longer responding to thalidomide, lenalidomide (LEN) and bortezomib (BORT) is very poor, with a median event-free survival of 5 months and median overall survival (OS) of 9 months (Kumar SK et al, Leukemia 2012; 26;149-157). We have previously shown in a small retrospective study that the combination of continuous low dose oral cyclophosphamide (endoxan) and prednisone combined with lenalidomide (REP) had remarkable activity in heavily pretreated LEN-refractory multiple myeloma patients (median 6 lines of previous chemotherapy) (vd Donk et al; Br J Haematol 2010;148(2):335-7). To determine the optimal dose of lenalidomide with continuous cyclophosphamide and prednisone, we initiated a prospective study to evaluate the maximum tolerated dose (MTD) of the REP regimen and to assess its efficacy and safety in LEN-refractory MM patients. Here we report safety and efficacy data from the phase 1 dose-escalation part of the REPEAT-study (NCT01352338). Patients and Methods Patients aged ≥ 18 years with LEN-refractory MM, ECOG-performance status 0-3 and adequate kidney, liver and hematologic function were included. Five dose levels were evaluated using a standard 3+3 design, based on dose-limiting toxicities (DLTs) occurring in cycle 1. Patients received LEN in doses ranging from 10-25 mg/day on days 1-21 of 28-day cycle, while oral cyclophosphamide (50 or 100 mg) and prednisone (20 mg) were given continuously. Therapy was continued until progression. The MTD for the phase 2 part is defined as the highest dose level with 0 or 1 DLT's observed in 6 patients. Results Up till now, 35 patients were enrolled (22 in phase 1 and 13 in phase 2) from August 2011 to June 2013. The phase 2 part is still recruiting and data are not evaluable yet. One patient in phase 1 was excluded because of study violation and is not included in the analysis. The median age of the 21 evaluable patients in phase 1 was 69 years (range 41-73); 76% were male. The median duration of the disease from diagnosis was 41 months (range 18-96), median number of prior therapies was 3 (range 2-6), and 12 patients (57%) had previously received autologous SCT. All patients were LEN-refractory, 19 (90%) had prior BORT treatment, and 16 (76%) had BORT-refractory MM. Fifty-five % of the patients were considered high risk by FISH. At the time of analysis, 16 of 21 patients in phase 1 have discontinued treatment because of disease progression (13), alternative treatment (allo-SCT) (1), or adverse events (2). The MTD was defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously (dose level 4), based on three patients experiencing a DLT: two developed pneumonia (in dose levels 4 and 5; CTC grade 3), and one patient at dose level 5 experienced CTC grade 3 dyspnea. Neutropenia (18%) and thrombocytopenia (18%) were the most common grade 3 hematological adverse events (AEs), which were managed with growth factor support and/or dose modification. There were no grade 4 hematologic AEs. Grade 3 respiratory tract infections (29%) and grade 2 fatigue (19%) were the most common non-hematological AEs. Venous thromboembolism occurred in 1 patient. Figure 1 shows a waterfall plot of the responses of the patients that participated in the phase 1 part of the study. Overall response rate (≥ PR) was 67% with 6 out of 21 (29%) patients achieving at least VGPR. In addition 2 patients achieved MR (≥ MR: 76%). Median PFS and OS were 6.3 and 15.5 months respectively. Similar results were achieved in the subset of patients with LEN- and BORT-refractory disease. Interestingly, laboratory experiments with purified myeloma cells from these patients suggest synergism between LEN and cyclophosphamide. Conclusions The REP regimen induces high response rates and prolonged PFS and OS in LEN-refractory patients with acceptable toxicity. The MTD is defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously. Phase 2 is enrolling patients and evaluates efficacy and safety of the REP regimen at the MTD. REP should be considered a valuable salvage option for LEN-refractory MM patients. We will present an updated follow-up at ASH. Disclosures: Sonneveld: Onyx: Research Funding; Millenium: Research Funding; Janssen-Cilag: Research Funding; Onyx: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Celgene: Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. van de Donk:Celgene: Research Funding.

A Phase 2 Study Of Single-Agent Brentuximab Vedotin For Front-Line Therapy Of Hodgkin Lymphoma In Patients Age 60 Years and Above: Interim Results

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4389-4389 ◽  
Author(s):  
Christopher A. Yasenchak ◽  
Robert Chen ◽  
Jeff P. Sharman ◽  
Ralph V. Boccia ◽  
Beata Holkova ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Single Agent ◽  
Autologous Stem Cell Transplant ◽  
Brentuximab Vedotin ◽  
Cell Transplant ◽  
Treatment Naïve ◽  
Multi Agent ◽  
Grade 3

Abstract Introduction Hodgkin lymphoma (HL) in patients aged ≥60 years has disproportionately inferior outcomes as compared to HL in younger patients. This can be mostly attributed to treatment-related factors that compromise cure rates. Comorbidities in older patients are associated with higher rates of treatment-related toxicities and can prevent delivery of standard intensity and/or duration of chemotherapy. A retrospective multicenter analysis showed an increased incidence of bleomycin-associated pulmonary toxicity (32%; with a mortality rate of 25%) in HL patients aged ≥ 60 who received ABVD for frontline therapy (Evens 2012). Novel therapeutic approaches with improved efficacy and tolerability are needed for this population. Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate that comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Robust antitumor activity and acceptable toxicity has been demonstrated in HL patients who relapse after conventional chemotherapy or autologous stem cell transplant. A retrospective analysis of patients aged ≥60 years with relapsed/refractory CD30+ lymphomas across 7 single-agent brentuximab vedotin studies showed antitumor activity and clinical response duration consistent with those observed in younger patients (Fanale 2012). Thus, this ongoing phase 2, single-arm, open-label study was initiated to evaluate the efficacy, safety, and tolerability of brentuximab vedotin as frontline monotherapy for HL patients aged ≥60 years (NCT01716806). Methods The population to be enrolled includes ∼30 treatment-naïve patients with classical HL (Stages I–IV). Eligible patients must be aged ≥60 years, have an ECOG status ≤3, and be ineligible for or have declined conventional chemotherapy. Brentuximab vedotin 1.8 mg/kg is administered every 3 weeks by IV infusion. Patients achieving stable disease (SD) or better can receive up to 16 cycles of treatment, after which therapy can be continued for those experiencing clinical benefit. The primary endpoint is objective response rate (ORR) as assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Response assessments are performed at Cycles 2, 4, 8, 12, and EOT (including PET at Cycles 2, 8, and EOT). Results Thirteen patients with treatment-naïve classical HL have been enrolled to date. Median age was 75 years (range, 64 to 92) and approximately half of the patients were male (54%). Seven patients (54%) had moderate age-related renal insufficiency at baseline (creatinine clearance ≥30 and<60). Thus far, patients have received a median of 5 cycles of brentuximab vedotin treatment (range, 1 to 11). Four patients discontinued treatment, 2 due to progressive disease, 1 due to a serious adverse event (Grade 3 orthostatic hypotension), and 1 due to patient decision. Of the 11 patients with a response assessment (see table), the ORR was 82% (n=9) and the complete remission (CR) rate was 64% (n=7). For the 10 patients who had interim PET scans after 2 cycles of therapy, the mean decrease in maximum standardized uptake value (SUVmax) between baseline and Cycle 2 was 83%. Cycle 2 PET scans were negative (Deauville Score 1-3) in 36% of patients, and the range of duration of response was 0.1+ to 20.6+ weeks thus far. Treatment-related adverse events (AEs) occurring in ≥15% of patients included neutrophil count decreased, peripheral sensory neuropathy, pruritus, and rash (n=2 each); most events were Grade 1 or 2. Grade 3 treatment-related AEs included neutrophil count decreased, rash, and orthostatic hypotension (n=1 each). No Grade 4 or 5 events have been observed to date. Conclusions In this interim analysis of patients aged ≥60 years with newly diagnosed HL, compelling antitumor activity with single-agent brentuximab vedotin has been demonstrated. To date, a response rate of 82% has been shown in this historically challenging population of patients who either declined or were not eligible for standard chemotherapy. Preliminary safety data demonstrate tolerability in this patient population and the data are consistent with the current safety profile of brentuximab vedotin. Disclosures: Yasenchak: 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. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel expenses Other. Sharman:Seattle Genetics, Inc.: Research Funding, Travel expenses Other; Genentech: Research Funding; Gilead: Research Funding. Boccia:Seattle Genetics, Inc.: Honoraria, Research Funding. Holkova:Seattle Genetics, Inc.: Research Funding. Rosen:Seattle Genetics, Inc.: Advisory/scientific board membership Other, Honoraria, Research Funding. Friedberg:Seattle Genetics, Inc.: Research Funding. O'Meara:Seattle Genetics, Inc.: Employment, Equity Ownership. Forero-Torres:Seattle Genetics, Inc.: Research Funding, Speakers Bureau.

Brentuximab Vedotin Combined with ABVD or AVD for Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma: Long Term Outcomes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 292-292 ◽  
Author(s):  
Joseph M Connors ◽  
Stephen Ansell ◽  
Steven I. Park ◽  
Michelle A. Fanale ◽  
Anas Younes
Keyword(s):  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Response Rate ◽  
Phase 1 ◽  
Brentuximab Vedotin ◽  
Advanced Stage ◽  
Newly Diagnosed ◽  
Genetics Research

Background: The ABVD regimen containing doxorubicin, bleomycin, vinblastine, and dacarbazine is a common standard of care for the frontline treatment of advanced stage Hodgkin lymphoma (Santoro 1987; Duggan 2003) and is curative for the majority of patients; however, up to 30% of patients require a secondary therapy. Hodgkin Reed-Sternberg cells of classical HL (cHL) typically express CD30. In a pivotal phase 2 trial brentuximab vedotin (A, ADCETRIS®), comprised of an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE) induced an objective response rate (ORR) of 75% and complete response rate (CR) of 34% in highly treatment-refractory patients with cHL (Younes 2012). Methods: We conducted a phase 1, open-label, multicenter study to evaluate the safety and efficacy of A when administered in combination with standard therapy (ABVD) or the same regimen without bleomycin (AVD) (Younes 2013). Adult patients with newly diagnosed advanced stage (II bulky, II B, III or IV; 80% stage III or IV) received doses of 0.6, 0.9, or 1.2 mg/kg A with standard doses of ABVD or 1.2 mg/kg with AVD, depending on cohort assignment on Days 1 and 15 of each 28-day cycle for up to 6 cycles of therapy. Previously we reported that among patients assessable for response 95% of patients given ABVD+A achieved a CR, as did 96% of patients given AVD+A. None of 26 patients given AVD+A but 11 of 25 (44%) given ABVD+A experienced pulmonary toxicity, including 2 deaths, establishing that A cannot be safely combined with bleomycin. In this current study we provide the long term survival and safety data on patients enrolled in the phase 1 trial. Results: In total 51 patients were assigned to either ABVD+A (n=25) or AVD+A (n=26). 1 patient who withdrew from the trial during the first cycle of ABVD+A is excluded from this analysis and 1 patient who received 3 cycles of ABVD+A, then withdrew, then received 3 cycles of ABVD alone and 2 patients who died during treatment (pulmonary toxicity) are included (total n=50). Median follow-up from diagnosis for the 24 patients treated with ABVD+A is 41 months (range 9-51 months) and for the 26 patients treated with AVD+A, 31 months (range 9-35 months). All 26 patients treated with AVD+A have been followed longer than the longest time to relapse (7 months). 45 patients remain in first CR and 5 treatment failures have occurred: 4 in the ABVD+A cohort (2 toxic deaths; 2 relapses (9 and 23 months from diagnosis)) and 1 after AVD+A (7 months from diagnosis). 3y-failure-free survival (3y-FFS) is 83% and 96% for ABVD+A and AVD+A, respectively, and 3y-overall survival (3y-OS), is 92% and 100%. No additional toxic deaths have occurred in follow-up. Conclusions: These updated outcomes reflecting the impact of adding brentuximab vedotin (1.2 mg/kg) to standard doses of AVD for classical Hodgkin lymphoma, demonstrating 96% 3y-FFS and 100% 3y-OS with no major unexpected toxicity, strongly support the current large international trial comparing AVD-A (AVD+1.2mg/kg brentuximab vedotin) to standard ABVD (ECHELON-1, clinicaltrials.gov NCT01712490), which may identify a new, less toxic gold standard treatment for advanced stage classical Hodgkin lymphoma. Disclosures Connors: Seattle Genetics: Research Funding. Off Label Use: brentuximab vedotin in phase 1 trial. Ansell:Seattle Genetics: Research Funding. Park:Seattle Genetics: Research Funding; Millennium/Takeda: Research Funding. Fanale:Seattle Genetics: Research Funding. Younes:Seattle Genetics: Research Funding; Millennium/Takeda: Research Funding.

Efficacy and safety of epacadostat plus pembrolizumab treatment of NSCLC: Preliminary phase I/II results of ECHO-202/KEYNOTE-037.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9014-9014 ◽  
Author(s):  
Tara C. Gangadhar ◽  
Bryan J. Schneider ◽  
Todd Michael Bauer ◽  
Jeffrey S. Wasser ◽  
Alexander I. Spira ◽  
...  
Keyword(s):  
Phase 1 ◽  
Phase 2 ◽  
Test Results ◽  
Efficacy And Safety ◽  
Open Label ◽  
Open Label Phase ◽  
History Of ◽  
Grade 3 ◽  
Preliminary Phase ◽  
Clinical Trial Information

9014 Background: ECHO-202/KEYNOTE-037 is an open-label, phase 1/2 study of epacadostat (a potent and selective oral inhibitor of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1) plus pembrolizumab (E + P) in patients (pts) with advanced tumors. We report preliminary efficacy and safety outcomes for the phase 1/2 NSCLC cohort. Methods: Adult pts with prior platinum-based therapy (tx) and no prior checkpoint inhibitor tx were eligible. Phase 1 dose-escalation tx was E (25, 50, 100, 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) tx doses were selected for phase 2 cohort expansion. Efficacy was evaluated by tumor proportion score (TPS [% viable tumor cells, PD-L1 staining]: < 50% and ≥50%) and by prior lines of tx in RECIST 1.1 evaluable pts. Safety was assessed in pts receiving ≥1 E + P dose. Results: As of 29OCT2016,43 pts (phase 1, n = 12; phase 2, n = 31) were evaluated. Median age was 65 years, 58% of pts were women, 12% were EGFR-positive, and 23% were KRAS-positive. Most pts had a history of smoking (84%), ≤2 prior lines of tx (84%), and no prior TKI tx (93%). For the 40 efficacy-evaluable pts, ORR (CR+PR) and DCR (CR+PR+SD) were 35% (14/40; 14 PR) and 60% (24/40; 10 SD), respectively. PD-L1 TPS test results were available in 28/40 efficacy-evaluable pts. ORR and DCR for pts with TPS ≥50% and ≤2 prior tx were 43% (3/7; all PR) and 57% (4/7; 1 SD), respectively; for pts with TPS < 50% and ≤2 prior tx, ORR and DCR were 35% (6/17; all PR) and 53% (9/17; 3 SD). Among the 40 efficacy-evaluable pts, 12/14 responses were ongoing (range, 1+ to 519 days) at data cutoff. PFS and biomarker analyses are ongoing. Across all 43 pts, most frequent TRAEs were fatigue (19%), arthralgia (9%), and increased AST (9%); 16% of pts had grade ≥3 TRAEs, and increased lipase (asymptomatic) was the only grade ≥3 TRAE that occurred in > 1 pt (n = 2). Two pts discontinued due to TRAEs (grade 3 increased AST, grade 2 increased ALT [n = 1]; grade 2 brain edema [n = 1]). Conclusions: E + P was generally well tolerated and associated with promising responses in pts with NSCLC. A phase 3 NSCLC study is planned. Clinical trial information: NCT02178722.

scholarly journals PET-Based Response after 2 Cycles of Brentuximab Vedotin in Combination with AVD for First-Line Treatment of Unfavorable Early-Stage Hodgkin Lymphoma: First Analysis of the Primary Endpoint of Breach, a Randomized Phase II Trial of Lysa-FIL-EORTC Intergroup

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 736-736
Author(s):  
Luc-Matthieu Fornecker ◽  
Julien Lazarovici ◽  
Igor Aurer ◽  
Rene-Olivier Casasnovas ◽  
Anne-Claire Gac ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Early Stage ◽  
Brentuximab Vedotin ◽  
Primary Objective ◽  
Advisory Board ◽  
Advisory Committees ◽  
Grade 3

Abstract Background: About 15-20% of patients with early-stage unfavorable Hodgkin lymphoma (HL) relapse or are refractory to first-line treatment with combined modality therapies. Early assessment of metabolic response after 2 cycles of ABVD has been shown to be an accurate predictor of progression-free survival and overall survival. Brentuximab vedotin (BV) in combination with AVD chemotherapy (BV-AVD) has demonstrated a promising efficacy with a favorable safety profile in a phase I trial for treatment-naive patients (Younes A. et al, Lancet Oncol 2013). Based on these results, we conducted a randomized, multicentric, phase II trial in order to improve the PET response rate after 2 cycles with BV-AVD regimen for previously untreated, early-stage unfavorable Hodgkin lymphoma. Methods: Patients with previously untreated, stage I/II, HL and unfavorable EORTC/LYSA criteria (defined with at least one of the following: age ≥ 50 y, bulky mediastinal mass with mediastinum / thorax ratio ≥ 0.35, number of involved nodal areas ≥ 4, ESR ≥ 50mm/h or ≥ 30mm/h with B symptoms) were enrolled at the time of diagnosis. Patients were randomly assigned in a 2:1 ratio to receive 4 cycles of BV-AVD (experimental arm) or ABVD (standard arm), followed by 30Gy involved node radiation therapy (INRT). The primary objective was to evaluate the efficacy of the BV-AVD regimen, as measured by negative-PET rate after 2 cycles based on central review. PET was interpreted according to the Deauville 5-point scale with negative PET defined as Deauville 1-3. Patients with missing PET evaluation, whatever the reason, were considered as non-responders. The statistical hypothesis was based on an increase of 10% (from 75% to 85%) of the PET negativity rate after 2 cycles in the experimental arm. The standard arm was added in order to ensure that the hypothesis taken in the sample size evaluation (negative-PET rate after 2 cycles of ABVD ≤ 75%) was verified. If ≥ 93 patients out of 113 evaluable patients had negative-PET, the hypothesis that the negative-PET rate ≤ 75% in the experimental arm would be rejected. This planned analysis of the primary endpoint was performed by intention to treat (ClinicalTrials.gov registration: NCT02292979). Results: From March 2015 to October 2016, 170 patients were included, 113 were randomized in the BV-AVD arm and 57 in the ABVD arm. Median age at randomization was 29 y (range 18-60) and 51% were female. The median number of involved nodal areas was 3 and 92% of the patients were Ann Arbor stage II, 57% had a bulky disease and 40% had B symptoms. After 2 cycles of treatment, 93/113 patients (82.3%, 95% CI 75.3-88.0) and 43/57 (75.4%, 95% CI 64.3-84.5) achieved a negative-PET based on central review in the experimental and standard arms, respectively. With the lower bound of the 95% confidence interval superior to 75% in the experimental arm, the primary objective can be considered to be met. During the first 2 cycles, grade 3-4 adverse events (AEs) were documented in 74% of the patients in the BV-AVD arm and 56% in the ABVD arm. The most frequent grade 3-4 AEs in the experimental arm were neutropenia (64%), leucopenia (31%), gastro-intestinal disorders (8%), febrile neutropenia (7%), transaminases increased (4%) and infections (4%). Only 2 patients (2%) have developed a grade 3-4 peripheral neuropathy after the first 2 cycles of BV-AVD. No pulmonary toxicity has been observed. Grade 3-4 serious AEs (SAEs) were documented in 19% of the patients in the experimental arm (treatment-related SAEs in 17%) and 7% in the standard arm. SAEs have led to permanent BV discontinuation in 7/113 (6%) patients during the first 2 cycles. Reasons for permanent BV discontinuation were loss of weight, hyponatremia, febrile neutropenia, epileptic seizure, peripheral neuropathy, hepatitis and cutaneous rash. Conclusion: This randomized, multicentric, open-label phase II trial aimed to evaluate the efficacy of BV in combination with AVD chemotherapy based on PET response after 2 cycles for previously untreated, unfavorable early-stage HL. The primary objective was met with an improvement of the negative-PET rate with BV-AVD regimen. This first analysis highlighted an increased toxicity with BV-AVD regimen compared to ABVD, with a higher rate of grade 3-4 AEs and SAEs during the first 2 cycles of treatment. Disclosures Fornecker: BMS: Honoraria; Servier: Honoraria; Gilead: Honoraria; Roche: Honoraria; Takeda: Honoraria. Aurer: takeda: Honoraria, Research Funding. Bonnet: Takeda: Other: advisory board. Perrot: Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: 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; Sanofi: Honoraria; Amgen: Honoraria. Specht: Takeda: Other: advisory board. Touati: Takeda: Honoraria. Stamatoullas: Takeda: Consultancy; Celgene Corporation: Honoraria. Lugtenburg: Takeda: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Servier: Honoraria; Celgene: Honoraria; BMS: Honoraria; Sandoz: Honoraria. Federico: takeda: Honoraria, Research Funding. Andre: Takeda: Honoraria, Other: Advisory board, Research Funding.

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