scholarly journals Tislelizumab (BGB-A317) for Relapsed/Refractory Classical Hodgkin Lymphoma: Preliminary Efficacy and Safety Results from a Phase 2 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 682-682 ◽  
Author(s):  
Yuqin Song ◽  
Quanli Gao ◽  
Huilai Zhang ◽  
Lei Fan ◽  
Jianfeng Zhou ◽  
...  
Keyword(s):  
Response Rate ◽  
Chinese Patients ◽  
Upper Respiratory Tract ◽  
Phase 2 ◽  
Employment Equity ◽  
Cancer Hospital ◽  
Phase 2 Study ◽  
Equity Ownership ◽  
Upper Respiratory ◽  
Grade 3

Abstract Background: Tislelizumab is a humanized IgG4 monoclonal antibody with high affinity/specificity for programmed cell death protein 1 (PD-1). Tislelizumab was specifically engineered to minimize binding to FcɤR on macrophages, thereby abrogating antibody-dependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy (Dahan 2015). Results of tumor growth inhibition studies suggest that tislelizumab had superior antitumor activity compared with nivolumab in mice transplanted with human cancer cells and peripheral blood mononuclear cells. Favorable results with other PD-1 inhibitors in patients with relapsed or refractory (R/R) classical HL (cHL) provide a strong rationale to investigate tislelizumabin this disease. Methods: BGB-A317-203 (clinicaltrials.gov NCT03209973) is a single-arm, open-label, multicenter, phase 2 study of tislelizumab in Chinese patients with R/R cHL; all patients received tislelizumab 200 mg intravenously every 3 weeks until progression or unacceptable toxicity. Patients were eligible if they (a) failed to achieve a response or progressed after autologous stem cell transplant (ASCT) or (b) received ≥2 prior systemic chemotherapy regimens for cHL and were ineligible for ASCT. Diagnosis of cHL was confirmed in all patients by central pathologic review.The primary endpoint was overall response rate (ORR) determined using the Lugano criteria (Cheson, 2014) as assessed by an independent review committee (IRC). Key secondary endpoints included progression-free survival (PFS), duration of response, rate of complete response (CR), time to response, safety, and tolerability. Treatment emergent adverse events (TEAEs) were summarized according to NCI-CTCAE v4.03. Results: In total, 70 patients were enrolled from 11 Chinese centers; patient characteristics are shown in the Table. With a data cutoff date of 25 May 2018, the median follow-up was 7.9 months (range, 3.4 to 12.7). The IRC-assessed ORR was 85.7%, based on PET-CT scans. A total of 43 patients (61.4%) achieved CR, 38 of whom were in CR at the first on-study response assessment. At data cutoff, 53 patients remained on treatment and 17 had discontinued (11 for progressive disease [PD]; 4 for TEAEs; 1 withdrew consent; 1 due to pregnancy). The estimated 6-month PFS rate was 80%. The most frequently reported (≥15%) TEAEs due to any cause were pyrexia (52.9%), hypothyroidism (30.0%), increased weight (28.6%), upper respiratory tract infection (27.1%) and cough (17.1%). Grade ≥3 TEAEs reported in ≥2 patients were upper respiratory tract infection (2.9%) and pneumonitis (2.9%). Immune-related TEAEs were reported in 23 patients (32.9%); Grade ≥3 in 5 patients (7.1%): pneumonitis (n=2), organizing pneumonia, nephritis (focal segmental glomerulosclerosis) and increased creatine phosphokinase (each n=1). There were no Grade 5 TEAEs. TEAEs that led to treatment discontinuation in 4 patients (5.7%) included pneumonitis (n=2), organizing pneumonia (n=1), and focal segmental glomerulosclerosis (n=1). One patient died on study due to PD. Conclusions: In this study, tislelizumab therapy was shown to be highly active resulting in a high CR rate in patients with R/R cHL who had failed or were ineligible for ASCT. Tislelizumab was generally well-tolerated in Chinese patients with R/R cHL. The safety profile was generally consistent with that of other PD-1 inhibitors for the treatment of cHL. Disclosures Song: Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Liu:West China Hospital of Sichuan University: Employment. Guo:BeiGene (Shanghai) Co., LTD: Employment. Yang:BeiGene (Beijing) Co., Ltd.: Employment. Elstrom:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Huang:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Novotny:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Wei:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Zhu:Beijing Cancer Hospital: Employment.

Multicenter Open-Label Phase 2 Study of Ibrutinib in Chronic Graft Versus Host Disease (cGVHD) after Failure of Corticosteroids

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. LBA-3-LBA-3 ◽  
Author(s):  
David Miklos ◽  
Corey S. Cutler ◽  
Mukta Arora ◽  
Edmund K. Waller ◽  
Madan Jagasia ◽  
...  
Keyword(s):  
Research Funding ◽  
Response Rate ◽  
Sustained Response ◽  
Phase 2 ◽  
Employment Equity ◽  
End Points ◽  
Phase 2 Study ◽  
Equity Ownership ◽  
Grade 3 ◽  
Over Time

Abstract Background: Chronic GVHD (cGVHD) is a serious complication of allogeneic stem cell transplantation. Effective therapy for patients (pts) with cGVHD who fail corticosteroids remains an unmet medical need. Both B and T cells play a role in the pathophysiology of cGVHD. In preclinical models, ibrutinib (ibr) reduced the severity of cGVHD through its inhibition of Bruton's tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK) (Dubovsky, J Clin Invest 2014). Ibr has recently been granted a breakthrough therapy designation (BTD) for cGVHD after failure of 1 or more lines of systemic therapy. The request for a BTD was supported by early data from a phase 2 study that evaluated the efficacy and safety of ibr in pts with cGVHD who are in need of additional therapy. The final results of this same study are presented here. Methods: Pts who had received ≤3 prior regimens for cGVHD and had either >25% body surface area erythematous rash or a National Institutes of Health (NIH) mouth score >4 were treated with daily ibr (420 mg) until cGVHD progression or unacceptable toxicity. The primary end point was cGVHD response based on the 2005 NIH consensus response criteria. Secondary end points included rate of sustained response, change in Lee cGVHD symptom scale, changes in corticosteroid requirement over time, and safety end points. The effects of ibr on lymphoid and myeloid cell signaling pathways, and phenotype along with plasma cytokines and chemokines were evaluated. Results: A recommended phase-2 dose of 420 mg was identified in phase 1b (n=6) with no dose-limiting toxicities reported. Of 42 pts treated with ibr, median age was 56 y (range, 19-74). Median duration of cGVHD before study entry was 13.7 mo (range, 1.1-63.2). Median number of prior regimens was 2 (range, 1-3). At a median follow-up of 13.9 mo, overall response rate (ORR) was 67% (28/42 pts; 9 [21%] CR, 19 [45%] PR), with 20/28 (71%) and 12/25 (48%) responders showing a sustained response of ≥20 and ≥32 weeks, respectively (Figure 1). Overall, 21 responders (75%) had corticosteroid doses <0.15 mg/kg/d during the study (Figure 2). Five responders discontinued corticosteroid therapy while in response. Median overall clinician-assessed cGVHD severity score decreased from 7 at baseline (n=41) to 4 at week 25 (n=20) and 3 at week 49 (n=15). A corresponding decrease in median pt-assessed overall cGVHD score from 7 at baseline (n=42) to 5 at week 25 (n=18) and 4 at week 49 (n=14) was reported. Improvement in Lee cGVHD symptom score was reported for 12 (43%) and 17 (61%) of 28 responders by month 6 and overall, respectively, compared with 1 (11%) of 9 nonresponders by month 6 and overall. Of 36 pts with ≥2 involved organs, 20 (56%) showed a response in ≥2 organs; of 12 pts with ≥3 involved organs, 5 (42%) showed a response in ≥3 organs. Analysis of soluble plasma factors associated with inflammation, fibrosis, and cGVHD from all treated pts showed a significant decrease over time with ibr, including soluble CD25 and IP-10 levels, which are implicated in cGVHD-related inflammation (Figure 3). The most common adverse events (AEs) were fatigue (57%), diarrhea (36%), muscle spasms (29%), nausea (26%), and bruising (24%). Grade ≥3 AEs occurring in >3 pts were pneumonia (n=6), fatigue (n=5), and diarrhea (n=4). Serious AEs (SAEs) occurred in 22 pts (52%); grade ≥3 SAEs reported in 17 pts (40%) included pneumonia (n=5), septic shock (n=2), and pyrexia (n=2). Two fatal events (multilobular pneumonia and bronchopulmonary aspergillosis) were reported. Five pts discontinued therapy for progressive cGVHD and 14 for AEs including fatigue (n=3) and pneumonia (n=2). Twelve pts (29%) continued ibr; their treatment duration ranges from 5.6-24.9 mo. Conclusions: With an ORR of 67% and a sustained response rate of ≥20 weeks of 71%, treatment with ibr resulted in clinically meaningful and durable responses in pts who failed at least 1 prior treatment for cGVHD. Most responders were able to reduce steroid dose to an acceptable minimal level. Biomarker changes support an effect of ibr on immune cell subsets in pts with cGVHD. Reported AEs are consistent with those for ibr in B-cell malignancies and pts with cGVHD. Observed response rates in this pretreated, high-risk population support further study of ibr for frontline treatment of cGVHD. Disclosures Miklos: Pharmacyclics, LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, and Expenses, Research Funding; Kite Pharma: Research Funding; Roche: Research Funding; Novartis: Research Funding; Sanofi Oncology: Other: Travel, Accommodations, and Expenses. Cutler:Insys: Consultancy; Seattle Genetics: Consultancy; Regimmunie: Consultancy; Incyte: Consultancy. Arora:Takeda Oncology: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Research Funding. Waller:Cerus: Equity Ownership; Chimerix: Equity Ownership; Cambium Medical Technologies: Equity Ownership, Other: Other relationship indicated, Patents & Royalties; Novartis: Consultancy, Honoraria, Research Funding; Helocyte: Consultancy. Jagasia:Theracos: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Flowers:Pharmacyclics, LLC, an AbbVie Company: Research Funding. Logan:Amgen: Consultancy; Jazz: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; Astellas: Research Funding; Novartis: Research Funding. Nakamura:Seattle Genetics: Consultancy; Amgen: Consultancy. Blazar:Tobira Therapeutics: Consultancy; Vulcan CApital: Consultancy; Idera Pharma: Consultancy; Sidley Austin LLP: Consultancy; Merck Serono: Consultancy; Fate Therapeutics: Consultancy; Merck, Sharpe & Dohme Corp: Consultancy; Bristol-Myers Squibb: Consultancy; Kadmon Pharmaceuticals Inc: Consultancy, Research Funding; Kymab: Consultancy; Five Prime Therapeutics: Consultancy; Vitae Pharmaceuticals, Inc.: Consultancy; Flx Bio: Consultancy; No Company: Patents & Royalties: no company. Li:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Lal:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment; Infinity: Equity Ownership; Clovis: Equity Ownership; Reviva Pharmaceuticals: Equity Ownership; The Permanente Medical Group: Employment, Equity Ownership; Gilead Sciences: Employment, Equity Ownership. Dubovsky:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. James:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Styles:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Jaglowski:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding.

Bortezomib, Thalidomide, and Dexamethasone (VTD) Versus VTD Plus Cyclophosphamide as Induction Therapy in Previously Untreated Multiple Myeloma Patients Eligible for HDT-ASCT: A Randomized Phase 2 Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2312-2312 ◽  
Author(s):  
Heinz Ludwig ◽  
Luisa Viterbo ◽  
Richard Greil ◽  
Tamas Masszi ◽  
Ivan Spicka ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Response Rates ◽  
Phase 2 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 2312 Poster Board II-289 Bortezomib (Velcade®) has shown substantial activity and manageable toxicity in newly diagnosed multiple myeloma (MM) in combination with thalidomide (Thalomid®) and dexamethasone (VTD) in a phase 3 study (Cavo et al, ASH 2008), and with cyclophosphamide and dexamethasone (VCD) in a phase 2 study (Knop et al, ASCO 2009). Four-drug combinations may be more effective than 3-drug regimens, but may also be associated with increased toxicity. This randomized, non-comparative, open-label, multicenter, phase 2 study was designed to evaluate the efficacy and safety of VTD and VTD plus cyclophosphamide (VTDC) as induction therapy prior to high-dose therapy plus autologous stem cell transplant (HDT-ASCT). A total of 98 previously untreated MM patients with measurable disease who were candidates for HDT-ASCT were enrolled. Additional eligibility criteria included: age 18–70 years, Karnofsky Performance Status (KPS) ≥60%, adequate hematologic, hepatic, and renal function, and no grade ≥2 peripheral neuropathy (PN)/neuropathic pain. Patients were randomized (1:1), stratified by International Staging System (ISS) disease stage (I / II / III), to receive four 21-day cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, thalidomide 100 mg daily, and dexamethasone 40 mg on days 1–4 and 9–12 (VTD), or VTD plus cyclophosphamide 400 mg/m2 IV on days 1 and 8, as induction therapy prior to HDT-ASCT. All patients received antithrombotic prophylaxis. Patients who became ineligible for HDT-ASCT or had a complete response (CR) after induction therapy could receive an additional 4 cycles of treatment. Responses were categorized using modified IMWG Uniform Response Criteria (stringent CR [sCR] were unconfirmed by immunohistochemistry) through blinded review by the principal investigator and medical monitor, using central laboratory M-protein data and local bone marrow data. The primary efficacy endpoint was combined CR rate (sCR + CR + near-CR) following induction therapy. Secondary objectives included combined CR rate post-HDT-ASCT, overall response rate (ORR: ≥partial response) post-induction and post-HDT-ASCT, time to progression (TTP), overall survival (OS), and safety. Adverse events (AEs) were graded using NCI CTCAE v3.0. Forty nine patients were randomized to each arm; median age was 57 and 58 years in the VTD and VTDC arms, respectively, 53% and 51% of patients were male, 49% and 43% had KPS ≤80%, and 24 / 45 / 31% and 18 / 47 / 35% had ISS stage I / II / III MM. All but 7 patients completed induction; these patients discontinued due to AEs (3 [6%] each arm) and disease progression (1 [2%] VTDC). Four VTDC patients received additional cycles of treatment. One patient (VTDC arm) was not evaluable for response. Response rates following induction are shown in the table. Median CD34+ stem cell yields were 8.16 (VTD; n=48) and 8.13 (VTDC; n=40) x 106/kg. At data cut-off (April 10, 2009), 47 VTD and 35 VTDC patients had undergone HDT-ASCT; response rates post-HDT-ASCT in 38 and 27 evaluable patients are shown in the table. Time-to-event data are not mature (median follow-up: 9.8 months). The 1-year survival rate was estimated to be 94% in each arm. At least one AE was reported in 98% and 96% of patients on the VTD and VTDC arms, with at least one grade ≥3 AE reported in 47% and 59%, respectively. The most common non-hematologic grade 3/4 AEs included fatigue (2% and 8%) and constipation (6% and 2%); analyses of hematology laboratory values indicated grade 3/4 AEs of lymphopenia (39% and 77%), anemia (8% and 18%), neutropenia (14% and 18%), and thrombocytopenia (6% each). PN was reported in 35% (VTD) and 29% (VTDC) of patients, including 8% grade 3 in each arm and 2% grade 4 in the VTD arm. Two patients (1 [2%] each arm) had deep vein thrombosis; one (VTDC arm) was a grade 3 SAE. At least one serious AE (SAE) was reported in 22% (VTD) and 41% (VTDC) of patients, including 6% and 14% with SAEs of infections (MedDRA SOC), and 2% and 14% with musculoskeletal-related pain. In conclusion, both VTD and VTDC are highly active induction regimens, with CR rates and ORRs among the highest reported; the efficacy profiles were similar between the arms, but there were higher rates of toxicity in the VTDC arm compared with the VTD arm. Table. Response rates following induction and post-HDT-ASCT. Post-induction n=49 n=48 Combined CR*, % 51 44 sCR†, % 27 27 ORR, % 100 96 Post-HDT-ASCT n=38 n=27 Combined CR*, % 76 78 sCR, % 39 33 ORR, % 100 100 * sCR + CR + near-CR † unconfirmed Disclosures: Ludwig: Celgene: Honoraria; Mundipharma: Honoraria; AMGEN: Honoraria; Ortho-Biotech : Honoraria; Janssen-Cilag: Research Funding; Roche: Honoraria. Masszi:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees. Shpilberg:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Hajek:Janssen-Cilag: Honoraria. Dmoszynska:Milllennium: Research Funding. Cakana:Janssen Cilag: Employment, Equity Ownership. Enny:Johnson & Johnson: Employment, Equity Ownership. Feng:Johnson & Johnson: Employment. van de Velde:Johnson & Johnson: Employment, Equity Ownership.

scholarly journals Safety and Activity of the Investigational Bruton Tyrosine Kinase Inhibitor Zanubrutinib (BGB-3111) in Patients with Mantle Cell Lymphoma from a Phase 2 Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 148-148 ◽  
Author(s):  
Yuqin Song ◽  
Keshu Zhou ◽  
Dehui Zou ◽  
Jianfeng Zhou ◽  
Jianda Hu ◽  
...  
Keyword(s):  
Phase 2 ◽  
Employment Equity ◽  
Phase 2 Trial ◽  
Cancer Hospital ◽  
Grade 5 ◽  
Mantle Cell ◽  
Bruton Tyrosine Kinase ◽  
Equity Ownership ◽  
Grade 3 ◽  
Wbc Count

Abstract Background: The Bruton tyrosine kinase (BTK) inhibitor zanubrutinib,has demonstrated greater selectivity for BTK versus other TEC- and EGFR-family kinases in biochemical assays and favorable pharmacokinetic/pharmacodynamic properties in preclinical studies. In a phase 1 clinical trial, zanubrutinib showed complete and sustained 24-hour BTK occupancy in both blood and lymph node biopsies from patients treated at 160 mg twice daily (bid; Tam et al. Blood 2016;128:642), and was associated with durable responses in patients with non-Hodgkin lymphoma (Tam et al. Blood 2017;130:152). Here, we present initial safety and efficacy data from a phase 2 trial of zanubrutinib in patients with relapsed or refractory mantle cell lymphoma (R/R MCL). Methods: Conducted in China, BGB-3111-206 (clinicaltrials.gov NCT03206970) is a pivotal, single-arm, open-label, multicenter phase 2 study. Patients with R/R MCL aged 18-75 years and with 1-4 prior treatment regimens received zanubrutinib 160 mg bid until disease progression (PD) or unacceptable toxicity. The primary objective is to evaluate the efficacy of zanubrutinib as measured by overall response rate (ORR) assessed by an Independent Review Committee (IRC). Response was assessed with PET-CT scans (in subjects with FDG-avid disease) and CT or MRI scans (in subjects with FDG non-avid disease) at each response assessment and for confirmation of complete response (CR) per the International Conference on Malignant Lymphoma (Lugano) criteria (Cheson, 2014). Key secondary endpoints included progression free survival (PFS), time to response (TTR), duration of response (DOR) and safety. Treatment-emergent adverse events (TEAEs) were assessed according to NCI CTCAE v4.03. Results: As of 27 March 2018, 86 patients with R/R MCL were enrolled and treated. Patient characteristics are summarized in the Table. Over one-half (52.3%) of patients were refractory to their last prior therapy. Median follow-up was 36 weeks (range,1-56) at the data cut. Twenty-one patients discontinued zanubrutinib (13 for PD; 6 for TEAEs; 1 withdrew consent; and 1 per investigator's discretion). One patient was not evaluable for response due to a lack of central pathologic confirmation of MCL. Of the 85 evaluable patients, ORR per the IRC was 84% (n=71; Table), with CR reported in 59% of patients (n=50). The estimated event-free rate for responders was 90% at 24 weeks after response. In total, 12 patients have progressed; the estimated PFS rate was 82% at 24 weeks. The most frequent (≥15%) TEAEs due to any cause included decreased neutrophil count (31.4%), upper respiratory tract infection (29.1%), rash (29.1%), decreased platelet count (22.1%), and decreased white blood cell (WBC) count (17.4%). Grade ≥3 TEAEs due to any cause reported in >2 patients included decreased neutrophil count (11.6%), lung infection (5.8%), anemia (4.7%), and decreased WBC count (3.5%). Petechia/purpura/contusion and hematuria were each reported in 4 patients (4.7%, all grade 1/2); major hemorrhage (serious or grade ≥3 bleeding or central nervous system bleeding of any grade)was reported in 1 patient (1.2%); no cases of atrial fibrillation/flutter or tumor lysis syndrome were reported. Six patients died within 30 days of last study treatment, 1 from PD, 4 due to Grade 5 TEAEs and 1 due to a Grade 5 event that was not treatment emergent. TEAEs leading to discontinuation of zanubrutinib included (n=1 each): infection, pneumonia, lung infection, interstitial lung disease, and twoGrade 5 TEAEs (cerebral hemorrhage and road traffic accident). Conclusions: Zanubrutinib was shown to be highly active in patients with R/R MCL, as demonstrated by a high rate of CR documented by PET-based imaging. Zanubrutinib was generally well-tolerated, consistent with previous reports of zanubrutinib treatment in patients with various B-cell malignancies. Disclosures Song: Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Zhou:Affiliated Cancer Hospital of Zhengzhou University: Employment; Health and Family Planning Commission of Henan Province: Patents & Royalties: Scientific and technological innovative talents "51282" Project leaders; Henan Cancer Hospital: Consultancy, Employment; Natural Science Foundation of China: Research Funding. Jin:College of Medicine, Zhejiang University: Employment; The National Natural Science Foundation of China: Research Funding. Guo:BeiGene (Shanghai) Co., LTD: Employment. Wang:BeiGene (Shanghai) Co., LTD: Employment. Hilger:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Huang:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Novotny:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Osman:BeiGene USA: Employment, Equity Ownership. Zhu:Beijing Cancer Hospital: Employment.

scholarly journals Phase 2 study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia

Haematologica ◽  
2021 ◽  
Author(s):  
Kerry A. Rogers ◽  
Philip A. Thompson ◽  
John N. Allan ◽  
Morton Coleman ◽  
Jeff P. Sharman ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Upper Respiratory Tract ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Btk Inhibitor ◽  
Upper Respiratory ◽  
Grade 3

B-cell receptor signalling inhibition by targeting Bruton tyrosine kinase (BTK) is effective in treating chronic lymphocytic leukemia (CLL). The BTK inhibitor ibrutinib may be intolerable for some patients. Acalabrutinib is a more selective BTK inhibitor that may be better tolerated by patients who are intolerant to ibrutinib. A phase 2 study of acalabrutinib was conducted in patients with relapsed/refractory CLL who were ibrutinib-intolerant and had continued disease activity. Intolerance was defined as having discontinued ibrutinib due to persistent grade 3/4 adverse events (AEs) or persistent/recurrent grade 2 AEs despite dose modification/interruption. Patients received oral acalabrutinib 100 mg twice daily until disease progression or intolerance. Sixty patients were treated. Overall response rate to acalabrutinib was 73% and three patients (5%) achieved complete remission. At median follow-up of 35 months, the median progressionfree and overall survival were not reached; 24-month estimates were 72% and 81%, respectively. The most frequent AEs with acalabrutinib were diarrhea (53%), headache (42%), contusion (40%), dizziness (33%), upper respiratory tract infection (33%), and cough (30%). Most common reasons for acalabrutinib discontinuation were progressive disease (23%) and AEs (17%). Most patients with baseline samples (49/52; 94%) and all with on-treatment samples (3/3; 100%) had no detectable BTK and/or PLCG2 mutations. Acalabrutinib is effective and tolerable in most patients with relapsed/refractory CLL who are intolerant of ibrutinib. Acalabrutinib may be useful for patients who may benefit from BTK inhibitor therapy but are ibrutinib intolerant.

scholarly journals Lyra: A Phase 2 Study of Daratumumab (Dara) Plus Cyclophosphamide, Bortezomib, and Dexamethasone (Cybord) in Newly Diagnosed and Relapsed Patients (Pts) with Multiple Myeloma (MM)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 152-152 ◽  
Author(s):  
Habte Yimer ◽  
Jason Melear ◽  
Edward Faber ◽  
William Bensinger ◽  
John M Burke ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Split Dose ◽  
Phase 2 Study ◽  
Equity Ownership ◽  
Grade 3 ◽  
Line Of Therapy

Abstract Background: Dara, a human IgGκ monoclonal antibody that targets CD38, is approved in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of newly diagnosed (ND) MM. CyBorD is another commonly used immunomodulatory drug-sparing regimen for MM. We evaluated the safety and efficacy of dara-CyBorD and administered the first dara infusion as a split dose over 2 days in pts with NDMM or relapsed MM (RMM) after 1 prior line of therapy. Methods: This is an ongoing, multicenter, single-arm, open-label, phase 2 study conducted at US community oncology centers in pts aged ≥18 years with documented MM per IMWG criteria; measurable disease; ECOG performance score (PS) of 0-2; and ≤1 prior line of therapy. Pts received 4-8 cycles (C) of dara-CyBorD (oral cyclophosphamide 300 mg/m2 on Days 1, 8, 15, and 22; subcutaneous bortezomib 1.5 mg/m2 on Days 1, 8, and 15; and oral or IV dexamethasone 40 mg weekly) every 28 days. Dara was administered at 8 mg/kg IV in 500 ml on Days 1 and 2 of C1, 16 mg/kg weekly from C1D8 through C2, 16 mg/kg every 2 weeks (q2w) for C3-6, and 16 mg/kg q4w for C7-8. After induction, pts could undergo autologous stem cell transplantation (ASCT). All pts receive 12 cycles of maintenance dara 16 mg/kg IV q4w. The primary endpoint was the proportion of pts achieving very good partial response or better (VGPR+) after 4 induction cycles using a computer algorithm based upon IMWG response criteria. Results: A total of 101 (87 ND, 14 RMM) pts were enrolled; 100 (86 ND, 14 RMM) pts received at least 1 dose of study treatment. Median age was 63 years (63 ND, 68 RMM); most pts were white (81%), male (64%), had ECOG PS 0-1 (94%), and had IgG (57%) or IgA (17%) MM; 35% of pts had high-risk cytogenetics defined as del(17p), t(4:14), or t(14;16). Eighty-two ND pts completed at least 4 induction cycles, 55 at least 6 cycles, and 26 the maximum of 8 cycles; 28 ND pts underwent ASCT by the data cutoff date. After 4 induction cycles, 44% of ND pts achieved VGPR+ (5% CR) with an overall response rate (ORR) of 79%. The VGPR+ rate (57%), CR rate (14%), and ORR (71%) were similar in RMM pts. At the end of induction (median 6 cycles), the VGPR+ rate, CR rate, and ORR in ND pts were 56%, 9%, and 81%, respectively. With a median follow up of 7.9 months, median PFS and OS were not reached; the 12-month PFS and OS rates were 87% and 99%, respectively, in ND pts. All 100 evaluable pts experienced ≥1 treatment-emergent adverse event (AE). AEs with incidence ≥20% included fatigue, nausea, diarrhea, cough, insomnia, vomiting, constipation, upper respiratory tract infection, dyspnea, headache, and back pain. Grade ≥3 AEs were reported for 56% of pts; the most common (≥10%) was neutropenia. Serious AEs (SAEs) occurred in 21% of pts; the most common (≥2%) were atrial fibrillation, bacteremia, pulmonary embolism, and mental status changes. AEs led to permanent treatment discontinuation in 3% of pts. Infusion reactions (IRs) occurred in 54% of pts, including 49% at C1D1 and 4% at C1D2; 2 Grade 3 IRs (hypertension, anaphylactic reaction) occurred at C1D1; no Grade ≥4 IRs occurred. The most common (≥5%) IRs were chills, cough, dyspnea, nausea, pruritus, and flushing. Median infusion time was 4.5 hours for C1D1, 3.8 hours for C1D2, and 3.5 hours for subsequent doses. Conclusion: Dara-CyBorD was active and well tolerated in pts with ND and RMM, including pts with high-risk cytogenetics. ORR, VGPR+, and CR rates improved with cycles 5-8 of induction, indicating that longer therapy with dara results in deeper response. Preliminary PFS and OS data in ND pts in the first year are comparable to dara-VMP. The safety profile was consistent with that previously reported for dara, with no new safety signals observed. Split first daratumumab dosing was feasible, reduced Day 1 infusion time, and resulted in a similar IR rate as previously described for single-dose administration. These findings indicate that dara-CyBorD, using a split-dose first infusion, can be safely administered in the community setting and may be an effective treatment option for pts with MM. www.clinicaltrials.gov identifier: NCT02951819 Figure 1. Kaplan-Meier estimate of progression-free survival (PFS) among patients with newly diagnosed multiple myeloma. Disclosures Yimer: AstraZeneca: Speakers Bureau; Puma Biotechnology: Equity Ownership; Clovis Oncology: Equity Ownership; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Equity Ownership; Janssen: Speakers Bureau. Melear:Janssen: Speakers Bureau. Faber:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: 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. Bensinger:celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; amgen: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Burke:Gilead: Consultancy; Genentech: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Tempus Labs: Consultancy. Narang:Janssen: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Stevens:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gunawardena:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Lutska:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Qi:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Ukropec:Janssen Scientific Affairs, LLC: Employment. Qi:Janssen Research & Development, LLC: Employment. Lin:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Rifkin:Amgen: Consultancy; McKesson: Equity Ownership; Boehringer Ingelheim: Consultancy; Celgene: Consultancy; EMD Serono: Consultancy; Takeda: Consultancy; Sandoz: Consultancy.

scholarly journals Phase 3 Study of Pomalidomide with Cyclophosphamide and Dexamethasone Versus Pomalidomide and Dexamethasone in Asian Patients with Relapsed/Refractory Myeloma (RRMM) - Interim Analysis of a Trial By the Asian Myeloma Network (AMN)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Wee-Joo Chng ◽  
Xinhua Li ◽  
Cindy Lin ◽  
Jin Seok Kim ◽  
Hiroshi Handa ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Research Funding ◽  
Response Rate ◽  
Prior Exposure ◽  
Phase 2 ◽  
Asian Patients ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Experienced Grade

Background Pomalidomide is an immunomodulatory drug that has been approved for the treatment of relapse refractory myeloma. A previous small randomized phase 2 study in the United States showed that combination of Pomalidomide, cyclophosphamide and dexamethasone induce a greater response rate than pomalidomide and dexamethasone1. In our prior study, AMN0012, we should that in patients with sub-optimal response to pomalidomide and dexamethasone, the addition of cyclophosphamide can increase response resulting in improvement of progression free survival. In the current study, we seek to randomize Asian patients with RRMM between PCD and PD to confirm the benefit of PCD. Method We conducted a prospective randomized trial of pomalidomide (4mg daily for 21 days followed by 7 days rest) plus dexamethasone 40mg once weekly for 4 weeks with or without cyclophosphamide (400mg once a week) in patients with relapse and refractory myeloma that has to be refractory to lenalidomide and has prior exposure to proteasome inhibitors. Each cycle is 4 weeks. Patients from Singapore, Japan and Korea (NCT03143049) were included in this Asian Myeloma Network trial. The trial was started in Sep 2017 and is still ongoing. To date, 53 patients have been recruited so far. This interim report presents data available up till the data cut-off date of 24 June 2020. Results Forty-six patients have available base line information and safety data and is included in this interim analysis. 50% of patients are male and median age of the cohort is 68 years old. 39% and 28% of patients are International Stage System (ISS) stage 2 and 3 respectively. 20% of patients have abnormal creatinine clearance. Median prior line of treatment is 3. All patients are refractory to lenalidomide and 96% have prior exposure to bortezomib. In addition, 12 patients (26%) and 5 (11%) have been treated with Carfilzomib and Ixazomib respectively. 15 (33%) patients had prior high dose melphalan and autologous stem cell transplant. 20 (44%) patients required dose reduction of pomalidomide, cyclophosphamide or dexamethasone. 89% of patients experience adverse events (AEs) of any grade. Of the 297 episodes of AEs, 43% are grade 3 or higher, with 50% of these episodes related to the study drugs. 57% of patients experienced serious AEs (SAEs) of any grade. Of the 74 episodes of SAE, 89% are grade 3 or higher, with 49% of these episodes related to the study drugs. Almost all of these events are related to cytopenias and infections. 20 (44%) of the patients develop grade 3 neutropenic fever and 9 (20%) patients have grade 3 or higher pneumonia. Only 1 patient experienced grade 3 peripheral neuropathy, 1 patient develop grade 3 pulmonary embolism, 1 patient developed grade 3 venous thromboembolism, and 1 patient experienced grade 3 renal impairment. At a median follow-up of 10.9 months, 9 of the 46 patients have died, and 21 have progressed. Three patients withdrew due to toxicity. While the overall response of the study population is not part of this interim analysis, we assessed the response of patients from the National University Cancer Institute, Singapore which has the highest number of patients recruited to get an idea of the therapeutic efficacy. Of the 14 patients recruited at NCIS, 1 patient achieved CR, 3 VGPR, 7 PR, producing a response rate of 79%. Conclusion In this interim analysis of a prospective randomized study of pomalidomide and dexamethasone with or without cyclophosphamide in Asian patients, we demonstrated the feasibility and efficacy of this combination. Longer follow-up and final analysis of the study will be needed to ascertain the therapeutic advantage of PCD over PD in relapse and refractory myeloma that is refractory to lenalidomide. References 1. Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. 2. Soekojo CY, Kim K, Huang SY, Chim CS, Takezako N, Asaoku H, Kimura H, Kosugi H, Sakamoto J, Gopalakrishnan SK, Nagarajan C, Wei Y, Moorakonda R, Lee SL, Lee JJ, Yoon SS, Kim JS, Min CK, Lee JH, Durie B,Chng WJ. 3. Pomalidomide and dexamethasone combination with additional cyclophosphamide in relapsed/refractory multiple myeloma (AMN001)-a trial by the Asian Myeloma Network. Blood Cancer J. 2019 Oct 8;9(10):83. Disclosures Chng: Novartis: Honoraria; Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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.

A Phase I/II Study of CYT387, An Oral JAK-1/2 Inhibitor, In Myelofibrosis: Significant Response Rates In Anemia, Splenomegaly, and Constitutional Symptoms

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 460-460 ◽  
Author(s):  
Animesh Pardanani ◽  
Geeta George ◽  
Terra Lasho ◽  
William J. Hogan ◽  
Mark R. Litzow ◽  
...  
Keyword(s):  
Phase I ◽  
Response Rate ◽  
Red Cell ◽  
Spleen Size ◽  
Jak Inhibitors ◽  
Employment Equity ◽  
Previously Treated ◽  
Equity Ownership ◽  
Red Cell Transfusion ◽  
Grade 3

Abstract Abstract 460 Background: CYT387 is a potent JAK-1/2 inhibitor that suppresses the in vitro growth of cells harboring JAK2V617F (Leukemia 2009;23:1441) and was effective in a murine model of myeloproliferative neoplasms (MPN) (Blood 2010;115:5232). Aims/Methods: To assess the safety, tolerability, and pharmacokinetic behavior of CYT387 in a Phase I dose-escalation study in patients with high- or intermediate-risk primary myelofibrosis (PMF) and post-PV or post-essential thrombocythemia (ET) myelofibrosis. The secondary objective was evaluation of preliminary efficacy. CYT387 was administered orally once daily in 28-day cycles. Once dose-limiting toxicity (DLT) was identified, a dose-confirmation cohort initiated treatment at the maximum tolerated dose (MTD) or lower. Result: Thirty six subjects (median age 64 years) have been enrolled (targeted accrual 120); 18 each in the dose escalation and dose confirmation phases. Twenty-three subjects had PMF, 8 post-PV MF, and 5 post-ET MF; 81% were JAK2V617F-positive. Median palpable spleen size was 18 cm and 20 subjects (56%) were red cell transfusion-dependent at study entry. Prior treatment included JAK inhibitors (9 and 1 subjects with INCB018424 and TG101348, respectively) and pomalidomide in 9 patients. The median treatment duration to date is 15 weeks (range 4–38). Dose-linear plasma exposures were observed up to 300 mg/day, with mean elimination T1/2 at steady state ranging from 3.9 to 5 hours across doses. Toxicity: All 36 subjects were evaluable for toxicity. At 400 mg/day, 2 of 6 subjects experienced DLT (1 each with asymptomatic grade 3 hyperlipasemia and grade 3 headache that were reversible upon holding drug); consequently, the MTD was declared at 300 mg/day. In the dose-confirmation phase, subjects were started at one of 2 dose levels that were deemed clinically effective: 150 mg/day (n=15) and 300 mg/day (n=3). Thirty-five subjects are currently on active therapy: 100 mg/day (n=2), 150 mg/day (n=20), 300 mg/day (n=10), and 400 mg/day (n=3). CYT387 was well tolerated. No grade 4 non-hematological toxicities were observed. Grade 3 non-hematologic adverse events were infrequent and included increased transaminases (n=2), increased alkaline phosphatase (n=2), headache/head pressure (n=2), increased lipase (n=1), and QTc prolongation (n=1). Thirteen (36%) subjects experienced “first-dose effect” characterized by grade 1 lightheadedness and hypotension; this phenomenon was self-limited and generally resolved within 3–4 hours with rare recurrence. Grade 3/4 thrombocytopenia was seen in 8 (22%) subjects, and treatment-emergent grade 3 anemia was seen in 1 subject only (3%). Treatment-emergent grade 3/4 neutropenia was not observed. Efficacy: Thirty two of 36 subjects who completed at least 1 cycle were eligible for response assessment: Anemia: Twenty two subjects were evaluable for anemia response (baseline Hgb <10 g/dL or red cell transfusion-dependent). Of these, 9 subjects (41%) achieved the threshold of response for “Clinical Improvement (CI)” per the International Working Group for MPN Research and Treatment (IWG-MRT) criteria, including 2 of 4 subjects who were previously treated with INCB018424. An additional 5 subjects experienced a >50% reduction in transfusion requirement, thus increasing the total anemia response rate to 63%. Splenomegaly: Thirty of 32 evaluable subjects had splenomegaly at baseline: median 20 cm; range 10–32 cm. Twenty nine subjects (97%) had some degree of spleen size reduction (median 9 cm; range 2–18 cm): 11 (37%) patients have achieved a minimum 50% decrease in palpable spleen size, thus qualifying them for a CI, including 3 of 8 subjects (38%) who were previously treated with INCB018424. Constitutional symptoms: The proportion of patients with the following symptoms at baseline, are: fatigue (97%), pruritus (22%), night sweats (38%), cough (13%), bone pain (28%), and fever (16%). At last follow up, improvement (complete resolution) in these symptoms was reported by 68% (16%), 86% (57%), 83% (75%), 75% (50%), 78% (44%), and 100% (100%), respectively. Conclusion: CYT387 is first-in-class of the JAK inhibitors with a significant response rate in anemia in myelofibrosis patients. The drug also shows substantial activity in reducing spleen size and controlling constitutional symptoms. CYT387 is well tolerated, and treatment responses have been seen both at (300 mg/day) and below (150 mg/day) the MTD. Disclosures: Pardanani: Cytopia Inc.: Research Funding. Off Label Use: Clinical trial data for CYT387 use in Myelofibrosis. Fida:YM Biosciences Australia: Employment, Equity Ownership. Burns:YM Biosciences Australia: Employment, Equity Ownership. Smith: YM Biosciences Australia: Employment, Equity Ownership.

Bortezomib-Dexamethasone Alone or Plus Cyclophosphamide or Lenalidomide As Second-Line Treatment for Patients with Multiple Myeloma: Final Results From a Phase 2 Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1861-1861
Author(s):  
Meletios Athanasios Dimopoulos ◽  
Meral Beksac ◽  
Lotfi Benboubker ◽  
Huw Roddie ◽  
Nathalie Allietta ◽  
...  
Keyword(s):  
Response Rate ◽  
Stage Migration ◽  
Second Line ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Line Of Therapy

Abstract Abstract 1861 Background: Bortezomib plus dexamethasone (VD) has been shown to be effective and well tolerated in patients (pts) with multiple myeloma (MM) as frontline induction therapy and in relapsed pts; however, no studies have prospectively assessed VD as second-line therapy. The addition to VD of cyclophosphamide (VDC) or lenalidomide (VDR) may improve efficacy, but with increased toxicities. This phase 2 study evaluated the efficacy and safety of VD, with the addition of C or R for pts with stable disease (SD) after 4 cycles, in pts with relapsed or refractory MM following 1 prior line of therapy. This is the first prospective study of VD as second-line therapy for MM. Methods: Bortezomib-naïve pts aged ≥18 years with measurable MM and no grade ≥2 peripheral neuropathy (PN) who had relapsed/progressed after 1 previous line of therapy received four 21-day cycles of VD (bortezomib 1.3 mg/m2, days 1, 4, 8, 11; Dex 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12). Pts achieving at least partial response (PR) then received a further 4 cycles of VD. Pts with SD were randomized to a further 4 cycles of VD, or 4 cycles of VDC (VD + C 500 mg, days 1, 8, 15), or VDR (VD + R 10 mg, days 1–14) for Cycles 5–8. Pts with progressive disease (PD) discontinued treatment. The primary end point was response rate; secondary end points included time to response, duration of response (DOR), safety, and improvement in renal function (defined by the Cockcroft-Gault glomerular function rate [GFR], assessed prior to treatment on day 1, Cycles 1–5). Results: A total of 189 pts were enrolled; 26 did not receive therapy and were excluded from the safety/ITT population (N=163). Median age was 63 years (range 34–86), 53% were male, 20% had KPS ≤70; median time from prior therapy was 13.9 months. In the ITT population, 52% of pts (84/163) experienced an OR by Cycle 4 as validated by IDMC. Discontinuations were due to toxicity (N=10), death, PD, and other reasons (6 each). Of 135 remaining pts who started Cycle 4 treatment, 120 pts had a response assessment at Cycle 4; according to investigators, 82% of these pts experienced an overall response (OR) and 2.5% had PD; median time to first and best response was 49 and 85 days, respectively. Nineteen pts had SD and were randomized: 7 to VD, 8 to VDC (1 did not continue treatment), 4 to VDR. Only 11 pts received a third drug, C or R, in addition to VD. Due to the high response rate for the first four cycles, the second randomization arm was not completed. 47% (77/163) had continued treatment up to Cycle 8. Based on IDMC response validation as of June 2011, 122 patients had a Best Confirmed Response: 75% OR, 20% SD, and 4% PD. GFR results at Cycle 8 are shown in the Table. In pts who had baseline and on-study assessments, median GFR was 62.2 mL/min at baseline and increased after Cycles 1, 2, 3, 4, 5, 6, 7, and up to Cycle 8 by 4.5, 5.7, 9.4, 8.7, 6.0, 9.6, 8.9, and 5.5 mL/min, respectively. Of the 26 pts with stage migration from baseline GFR to best GFR at Cycle 4, 12 had a renal response (MR renal). Of the 24 pts with baseline GFR <50 ml/min and renal response with stage migration from baseline GFR to best GFR at Cycle 8, 13 had CR renal, 11 had MR renal. Grade 3/4 adverse events (AEs) occurred in 64% of pts; the most common were thrombocytopenia (17%), anemia (10%), and constipation (6%). 40% of pts had serious AEs, and 46%/29%/12% had AEs resulting in dose reductions/discontinuation/death. Overall rates of sensory PN, polyneuropathy, PN (neuropathy peripheral), and motor PN in Cycles 1–8 were 20%, 18%, 13%,and 1% respectively, including 5%, 5%, 4%, and 1% grade 3/4, respectively; 55% of PN events were reversible, with resolution in 43%. Conclusions: This is the first prospective trial which assessed VD as second-line treatment in MM. VD is effective and well tolerated with less than 10% of pts receiving subsequent C or R added to VD. Overall renal function was shown to improve with treatment. PN was manageable with good reversal rates. VD represents a feasible, active treatment option for pts with relapsed MM. Final efficacy and safety data will be presented. Disclosures: Dimopoulos: Ortho Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc: Consultancy, Honoraria. Beksac:Celgene: Honoraria, Speakers Bureau; Janssen-Cilag: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Allietta:Covance for Janssen-Cilag: Employment. Broer:Janssen-Cilag: Employment. Couturier:Janssen-Cilag: Employment. Angermund:Janssen-Cilag: Employment. Facon:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Update on KEYNOTE-199, cohorts 1-3: Pembrolizumab (pembro) for docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 104-104 ◽  
Author(s):  
Emmanuel S. Antonarakis ◽  
Josep M. Piulats ◽  
Marine Gross-Goupil ◽  
Jeffrey C. Goh ◽  
Ulka N. Vaishampayan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Response Rate ◽  
Phase 2 ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Phase 2 Study ◽  
Previously Treated ◽  
Grade 3 ◽  
Clinical Trial Information

104 Background: The KEYNOTE-199 multicohort phase 2 study (NCT02787005) showed that pembro monotherapy has antitumor activity and acceptable safety in patients (pts) with mCRPC previously treated with a next-generation hormonal agent (NHA) and docetaxel in cohort 1 (C1) (RECIST-measurable, PD-L1+ disease), C2 (RECIST-measurable, PD-L1− disease), and C3 (bone-predominant disease, irrespective of PD-L1). Updated results with additional follow-up for C1-3 are presented. Methods: Pts previously received ≥1 NHAs and 1 or 2 chemotherapies, including docetaxel. Pts received pembro 200 mg Q3W for 35 cycles or until progression or intolerable toxicity. Primary end point was ORR. Key secondary end points were DCR, DOR, PSA (≥50%) response rate, rPFS, OS, and safety. Results: Of 258 pts enrolled (C1=133; C2=67; C3=58), 6 completed (C1=4; C3=2) and 252 discontinued (C1=129; C2=67; C3=56) therapy, primarily due to progression (C1=106; C2=61; C3=45). Median follow-up was 9.6 mo (C1, 9.5; C2, 7.9; C3, 14.2). ORR (95% CI) for pts with measurable disease was 6% (2.6-11.5) in C1 and 3% (0.4-10.4) in C2 (Table; includes other efficacy results). Treatment-related AEs of any grade/grade 3-5 occurred in 57%/16% in C1, 60%/15% in C2, and 71%/17% in C3. 1 pt in each cohort died of a treatment-related AE (C1, sepsis; C2, unknown; C3, immune-related pneumonitis). Conclusions: With additional follow-up, pembro monotherapy continued to show antitumor activity and disease control in pts with RECIST-measurable and bone-predominant mCRPC previously treated with both NHA and docetaxel. Pts experienced durable responses. Safety was consistent with the known safety profile of pembro. Clinical trial information: NCT02787005. [Table: see text]

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