A phase II multicenter trial of paclitaxel and carboplatin in women with advanced or recurrent malignant mixed müllerian tumors (MMMT) of the uterus

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5589-5589 ◽  
Author(s):  
L. M. Ramondetta ◽  
R. A. Lacour ◽  
E. D. Euscher ◽  
R. B. Iyer ◽  
E. N. Atkinson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Median Overall Survival ◽  
Treatment Initiation ◽  
Response Rate ◽  
Multicenter Trial ◽  
Study Entry ◽  
Free Interval ◽  
Grade 3

5589 Background: Systemic therapy for advanced malignant mixed müllerian tumor of the uterus (MMMT) after surgery has been disappointing. Currently, the most common treatment regimen is ifosfamide and platinum. Moderate success has been documented using paclitaxel in MMMT of the ovary. The purpose of this study is to evaluate carboplatin and paclitaxel in patients with advanced (IIIb-IVb) and recurrent MMMT of the uterus. Methods: A single arm, prospective, non-randomized phase II trial opened in October 2001. The planned sample size is 37 evaluable patients, with time to progression and response rate as the primary endpoints. Patients receive carboplatin (AUC 5) and paclitaxel (175 mg/m2) every 21 days. Patients treated adjuvantly receive a total of 6 cycles or until progression or toxicity. Patients with disease present at study entry are treated until progression or toxicity. Results: To date, 18 patients have been enrolled. Seven patients received adjuvant treatment and 11 patients had documented disease at study entry. In the adjuvant group, the median progression-free interval was 15.8 months and median overall survival from treatment initiation was 20.2 months. Four of these 7 patients (57%) continue to be followed with a median follow-up of 19.2 months. In the patients with documented disease, the median progression- free interval was 7.8 months and the median overall survival from treatment initiation was 12.4 months. In this group, there were 3 complete and 4 partial responses (63.6% response rate). Over 45% of patients with disease at study entry are alive with a median follow-up of 14.0 months. Four patients experienced grade 4 granulocytopenia. Only two (11%) had treatment-limiting toxicity, one with grade 3 neuropathy and one with grade 3 fatigue. Conclusions: Carboplatin and paclitaxel appear to have improved tolerability and response rate (63.6%) compared to previous reports of ifosfamide and cisplatin (33% RR) in treating MMMT of the uterus. This regimen seems extremely promising and we are awaiting the final results of this trial. No significant financial relationships to disclose.

scholarly journals ATIM-37. PHASE II, OPEN-LABEL, SINGLE ARM, MULTICENTER STUDY OF AVELUMAB WITH HYPOFRACTIONATED RADIATION (HFRT) FOR ADULT PATIENTS WITH SECONDARILY TRANSFORMED IDH-MUTANT GLIOBLASTOMA (GBM)

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi9-vi10
Author(s):  
Sylvia Kurz ◽  
Joshua S Silverman ◽  
Tsivia Hochman ◽  
Lakshmi Nayak ◽  
Isabel Arrillaga-Romany ◽  
...  
Keyword(s):  
Phase Ii ◽  
Multicenter Study ◽  
Somatic Mutations ◽  
Treatment Initiation ◽  
Adult Patients ◽  
Open Label ◽  
Grade 3 ◽  
Hypofractionated Radiation ◽  
Dose Limiting Toxicity

Abstract BACKGROUND There is no effective therapy for patients (pts) with IDH-mutant gliomas that progress after RT and chemotherapy. At time of progression, these tumors have often transformed to glioblastoma (GBM) and have increased numbers of somatic mutations, i.e. have a “hypermutator phenotype”. We hypothesized that there is synergistic efficacy of Avelumab (anti-PD-L1) combined with HFRT in pts with secondarily transformed IDH-mutant GBMs. Safety-lead-in results will be presented. METHODS This is a phase II, open-label, single-arm, multicenter study of Avelumab with HFRT in adults with transformed IDH-mutant GBM who previously received RT and TMZ and/or PCV. All pts received Avelumab 10 mg/kg IV followed at Day 8 by HFRT (25 Gy in 5 daily 5-Gy fractions) and then Avelumab 10 mg/kg IV every 2 weeks. A 3 + 3 design was used for a 6-patient safety-lead-in cohort. Adverse events were recorded according to CTCAE. RESULTS Six pts (F=4, M=2) with a median age= 45.5 yrs (range 31.5–54.4 yrs) were enrolled in the safety-lead-in cohort. No DLT was observed. Grade ≥ 3 AEs included increased cerebral edema (3 pts), hyponatremia (1 pt) and worsening hemiparesis (3 pts). Grade ≤ 2 AEs included nausea, hypothyroidism, lymphopenia, thrombocytopenia, transaminase elevation, and fever/chills. Median follow-up time was 8.9 mo. Best treatment response was SD in 1 patient. At time of last follow-up all pts have discontinued treatment for PD. Median PFS was 4.2 mo (range 1.4–5.7). Median OS was 10.1 (range 6.8–21+) mo. 4 pts (67%) died, 2 pts remain alive in follow-up at 6.9 and 21.6 months after treatment initiation. The study was closed after the safety lead-in completed enrollment due to slow accrual. CONCLUSIONS Avelumab combined with HFRT was tolerable without dose-limiting toxicity in this safety-lead-in cohort of adult patients with transformed IDH-mutant GBM. Further studies are necessary to determine efficacy of this treatment regimen.

scholarly journals Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma

2020 ◽  
pp. JCO.20.02259
Author(s):  
Paul G. Richardson ◽  
Albert Oriol ◽  
Alessandra Larocca ◽  
Joan Bladé ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Free Survival ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.

The VcR-CVAD Regimen Produces a High Complete Response Rate in Untreated Mantle Cell Lymphoma (MCL): First Analysis of E1405 – A Phase II Study of VcR-CVAD with Maintenance Rituximab for MCL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1661-1661 ◽  
Author(s):  
Brad S Kahl ◽  
Hailun Li ◽  
Mitchell R Smith ◽  
Randy D. Gascoyne ◽  
Elisabeth Paietta ◽  
...  
Keyword(s):  
Phase Ii ◽  
Research Funding ◽  
Response Rate ◽  
Complete Response Rate ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Complete Response ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 1661 Poster Board I-687 Introduction One approach to improving outcomes in Mantle Cell Lymphoma (MCL) is to incorporate newer targeted agents into standard chemotherapy regimens. As the proteasome inhibitor bortezomib (Velcade‘) achieved a 33% response rate in relapsed MCL, we hypothesized that the incorporation of Velcade (Vc) into a modified R-hyperCVAD chemotherapy backbone would result in a high complete response rate (CR). The new regimen, VcR-CVAD, was tested for safety and efficacy in a phase II study within the Wisconsin Oncology Network (UW) and demonstrated a CR rate of 77% (Kahl, ASH 2008). To determine the safety and efficacy of this regimen in a cooperative group setting, we initiated E1405: a phase II study of VcR-CVAD with maintenance rituximab (MR) for untreated MCL. Methods Eligible patients had histologically confirmed, previously untreated MCL, PS 0-2, and adequate end organ function. The treatment plan included: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1-3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1-2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1-4. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF support. Patients achieving SD, PR, or CR received MR administered as 4 weekly treatments every 6 months for 2 years (protocol therapy). Patients had an option to receive high dose chemotherapy and autologous stem cell transplantation (off protocol) rather than MR. The primary endpoint of the trial was the CR rate, incorporating PET imaging, to VcR-CVAD induction therapy. Results Seventy-six eligible patients were enrolled between 5/07 and 10/08. Baseline characteristics include median age 62 (40-76), 59M:17F, 91% stage III/IV, and 39% with elevated LDH. Sixty-four patients (84%) completed VcR-CVAD induction therapy. Reasons for treatment discontinuation included PD (1), toxicity (4), patient preference (2), and other/unknown (5). Response information is available on 74 patients while data is outstanding on 2 patients. The ORR was 96% (73/76; 95% CI, 89%-99%), CR rate 75% (57/76; 95% CI, 64%-84%) and the PR rate 21% (16/76; 95% CI, 13%-32%). Six of the PR patients were coded as such because of protocol violations in which a post-treatment bone marrow biopsy or PET scan was not obtained. The CR rate in the 68 completely restaged patients was 84%. Forty-four patients proceeded to planned MR while 21 patients went off protocol to SCT consolidation. Median follow up is currently too short (9 months) to assess PFS and OS. The major toxicity of the treatment regimen was expected myelosuppression. Grade 3-4 non hematologic toxicities were rare. No patients developed grade 3-4 neuropathy. There were no treatment related deaths. Conclusion The VcR-CVAD induction produced high overall response (96%) and CR rate (75%) in a representative MCL patient population treated on a cooperative group protocol. The CR rate was high and comparable to the UW pilot study (77%). No episodes of severe painful peripheral neuropathy were reported using the reduced vincristine dosage and the overall toxicity profile was very acceptable. Longer follow up is needed to determine if the high CR rate will translate into improved PFS and OS. Disclosures Kahl: Genentech: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Off Label Use: Bortezomib as front line treatment in MCL. Smith:Genentech: Research Funding; Millennium: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding. Horning:Genentech: Honoraria, Research Funding.

NCCTG phase I/II trial (N9943) of gemcitabine and pemetrexed in patients with biliary tract or gallbladder carcinoma: Phase II results

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4578-4578 ◽  
Author(s):  
R. R. McWilliams ◽  
N. R. Foster ◽  
F. J. Quevedo ◽  
R. F. Marschke ◽  
J. W. Kugler ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Median Overall Survival ◽  
Hepatic Dysfunction ◽  
Response Rate ◽  
Time To Progression ◽  
Medical Problems ◽  
Folate Supplementation ◽  
Stopping Treatment ◽  
Grade 3

4578 Background: Gemcitabine is commonly used in patients with cholangiocarcinoma with a response rate of 20–30% and median overall survival of 6–10 months. Pemetrexed’s mechanism of action and tolerability in patients with hepatic dysfunction makes it a potential agent for cholangiocarcinoma. Methods: Patients with unresectable, previously untreated biliary tract cancers were eligible for participation. Patients received pemetrexed 500 mg/m2 IV over 10 minutes and gemcitabine 800 mg/m2 IV at 10 mg/m2/minute on days 1 and 15 of an every 4 week schedule with vitamin B12 and folate supplementation. The primary end-point is 6-month survival with a planned accrual of 59 patients. Results: 58 eligible patients are included in this analysis. 93% had metastatic disease. Median age was 61 (range: 40 - 81). Median follow-up was 6.5 months (range: 3.3 - 23.2). Median of 3 cycles of treatment was given (range: 1 - 10). Reasons for stopping treatment included disease progression (57%), adverse events (20%), refusal (17%), death on- study (4%), and other medical problems (2%). 6-month survival was 52% (95% CI: 40 - 68%). Median survival was 6.3 months (95% CI: 5.4 - 8.0 months) and median time-to-progression was 3.8 months (2.4 - 5.0). 46 of 58 patients (79%) experienced at least one grade 3+ AE (at least possible attribution), and 26 patients (45%) experienced at least one grade 4 AE (at least possible attribution), most of which were due to grade 4 neutropenia. Conclusions: This study shows similar results to what would be expected with gemcitabine alone. The addition of pemetrexed, as with other agents, has not significantly enhanced the activity of gemcitabine. Supported by NIH Grant CA25224- 18. [Table: see text] No significant financial relationships to disclose.

Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: Updated Follow-Up and Improved Survival

2014 ◽  
Vol 32 (7) ◽  
pp. 634-640 ◽  
Author(s):  
Antonio Palumbo ◽  
Sara Bringhen ◽  
Alessandra Larocca ◽  
Davide Rossi ◽  
Francesco Di Raimondo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Response Rate ◽  
Complete Response Rate ◽  
Progression Free Survival ◽  
Complete Response ◽  
Free Survival ◽  
Grade 3 ◽  
To Receive

Purpose Bortezomib-melphalan-prednisone (VMP) has improved overall survival in multiple myeloma. This randomized trial compared VMP plus thalidomide (VMPT) induction followed by bortezomib-thalidomide maintenance (VMPT-VT) with VMP in patients with newly diagnosed multiple myeloma. Patients and Methods We randomly assigned 511 patients who were not eligible for transplantation to receive VMPT-VT (nine 5-week cycles of VMPT followed by 2 years of VT maintenance) or VMP (nine 5-week cycles without maintenance). Results In the initial analysis with a median follow-up of 23 months, VMPT-VT improved complete response rate from 24% to 38% and 3-year progression-free-survival (PFS) from 41% to 56% compared with VMP. In this analysis, median follow-up was 54 months. The median PFS was significantly longer with VMPT-VT (35.3 months) than with VMP (24.8 months; hazard ratio [HR], 0.58; P < .001). The time to next therapy was 46.6 months in the VMPT-VT group and 27.8 months in the VMP group (HR, 0.52; P < .001). The 5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P = .01). Survival from relapse was identical in both groups (HR, 0.92; P = .63). In the VMPT-VT group, the most frequent grade 3 to 4 adverse events included neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). All of these, except for thrombocytopenia, were significantly more frequent in the VMPT-VT patients. Conclusion Bortezomib and thalidomide significantly improved OS in multiple myeloma patients not eligible for transplantation.

Phase II study of topotecan and carboplatin in the treatment of platinum-sensitive recurrent ovarian and peritoneal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 15001-15001
Author(s):  
P. Hanjani ◽  
M. S. Shahin
Keyword(s):  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Hematologic Toxicity ◽  
Peritoneal Cancer ◽  
Platinum Sensitive ◽  
Free Interval ◽  
Alive With Disease ◽  
Grade 3

15001 Background: The aim of this trial was to investigate the efficacy and toxicity of the combination of Topotecan (T) and Carboplatinum (C) in the management of recurrent platinum sensitive ovarian and peritoneal cancer. Methods: T (1 mg/m2) was given as a 30-minute infusion daily × 3 days and C (AUC 5) was given as a 30-minute infusion following T on day 3 on a 21-day cycle. Results: Thirty patients (pts) were enrolled and all pts were evaluable for response and toxicity. Mean age was 63.2 (range = 44–84). One hundred eighty five cycles (mean/pt = 6, range 2–10) were evaluable for toxicity. Dose escalation (T = 1.25 mg/m2) was possible in 25 (83.3%) pts. Hematologic toxicity grade 3 and 4 neutropenia was seen in 60 (32.4%) and 10 (5.4%) cycles, respectively. Grade 3 thrombocytopenia was encountered in 24 (13%) cycles. Grade 3 Hgb was observed in 4 (2.2%) cycles. No grade 4 thrombocytopenia/Hgb or neutropenic fever was encountered. Blood transfusions were required in 9 (4.9%) cycles. Bone marrow support with erythropoiten (40% pts), and filgrastim (43.3% pts) were utilized. No neuropathy > grade 1 was encountered. Fourteen pts (46.6%) pts had a hypersensitivity reaction to C and successful desensitization was carried out in 8 (57.1%). Mean follow-up interval was 16.9 months (mos) (Range 1.7–43). To date, 6 (20%) pts are alive without disease, 16 (53.3%) are alive with disease, and 8 (26.7) have died of disease. The overall response rate was 83.3% (5 CR and 20 PR). Five (16.6%) pts had SD. Median progression-free interval was 8.2 mos. Overall mean survival for the cohort was 31.2 mos (95% CI: 24.47–37.71). Conclusions: Given the ICON-4 data, supporting combination therapy in recurrent platinum-sensitive patients, this regimen provides an effective and tolerable alternative to Taxane-platinum combination with no significant neuropathy. This regimen is especially attractive in patients who have significant residual neuropathy after initial treatment. Carboplatinum desensitization was feasible in previously pre-treated patients. No significant financial relationships to disclose.

Cladribine (2-CDA) Plus Sequential Rituximab in Newly Diagnosed Disseminated Extranodal Marginal Zone B-Cell Lymphomas. A Phase II Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2761-2761
Author(s):  
Gaetano Corazzelli ◽  
Gaetana Capobianco ◽  
Filippo Russo ◽  
Oreste Villani ◽  
Patrizia Vassallo ◽  
...  
Keyword(s):  
Phase Ii ◽  
Marginal Zone ◽  
Response Rate ◽  
Single Agent ◽  
Lymphoid Cells ◽  
Outpatient Basis ◽  
Minor Response ◽  
Free Survival ◽  
Grade 3

Abstract Background: Multiple extranodal localizations, nodal spreading and bone marrow (BM) involvement have been associated with shorter overall and event-free survival in Extranodal Marginal Zone Lymphoma (EMZL). No optimal treatment has yet been defined and, in this setting, Rituximab has demonstrated only moderate single agent activity while the role of purine analogs is still controversial, although promising in terms of objective response rate. In order to verify a potential synergy of these agents we conducted a prospective phase II trial evaluating a sequential treatment with 2-CDA, a purine nucleoside analog with proapoptotic and cytotoxic activity on both proliferating and quiescent lymphoid cells, and Rituximab in patients (pts) with untreated disseminated EMZL. Patients and methods: Pts with histologically confirmed MZL, ECOG < 2 and Stage IV disease were enrolled. 2-CDA was administered at a dose of 0.12 mg/kg on 5 consecutive days as a 2-hour infusion, every 4 weeks for 6 courses on outpatient basis. Thereafter, 4 doses of Rituximab (375 mg/m2, i.v., every 2 weeks) were delivered. Prophylaxis with TMP-SMX was required and filgrastim introduced if grade 3–4 neutropenia had occurred. Responses were evaluated after the 4th course of 2-CDA and at the end of the entire program. Results: Twenty-three pts (median age 67 yrs; r 34–81) with advanced [multiple extranodal site (n=16), BM (n=15), distant/diffuse nodal involvement (n=14), orbit (n=8), multicentric skin (n=3), gastric (n=4), leukemic (n=2), lung and pleura (n=3), salivary glands (n=3), Waldeyer’s ring (n= 1), breast (n=1)] EMZL were accrued. B symptoms were present in 4 pts, abnormal LDH in 6. No pts had been irradiated and only 2 had received surgical resection due to emergency (ileum) and diagnostic (lung) procedures. All pts completed treatment program and were evaluable for response. The median number of delivered courses of 2-CDA was 6 (r 3–6). The overall response rate was 91 % [after the 4th course: CR=4, CRu=11, PR=6; at the end of treatment (i.e. including Rituximab): CR= 18 (78%), PR=3 (13%)]. Interestingly, a histological CR was achieved in 13 out of 15 pts with BM involvement (81%). Only 2 pts, with B symptoms at presentation, had a therapeutical diversion at the 3rd and 4th course due to minor response and persisting symptomatic disease. Extrahematological toxicity was negligible. CTCAE Grade 3 and 4 neutropenia occurred in 9 and 5 (22%) pts, respectively and febrile neutropenia occurred in 6 pts (26%). Grade 4 Thrombocytopenia and lymphocytopenia developed in 4 (17%) and 3 (13%) patients, respectively. Delayed grade 3 leuko- and thrombocytopenia occurred two months after 2-CDA withdrawal in three pts and slowly recovered in the following 6–8 weeks. No late opportunistic infection, nor disease recurrence have to date occurred. Failure free survival was 86 % at median follow up of 18 months (range, 4–34). Conclusions: Our prospective study shows that 2-CDA plus sequential Rituximab represents an effective strategy for the upfront treatment of disseminated EMZL. It is feasible in outpatient setting, and associated with favorable early and late toxicity profiles. While a longer follow-up will assess its impact on disease natural history, our results show for the first time that 2-CDA plus sequential rituximab may achieve very high CR rates even in poor prognosis pts with extragastric and widespread EMZL.

Bendamustine, Bortezomib and Dexamethasone (BVD) in Patients with Relapsed-Refractory Multiple Myeloma (MM): Updated Results of a Multicenter Phase II Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4734-4734
Author(s):  
Massimo Offidani ◽  
Laura Maracci ◽  
Laura Corvatta ◽  
Liberati Anna Marina ◽  
Stelvio Ballanti ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Prior Treatment ◽  
New Drugs ◽  
Induction Phase ◽  
Grade 3 ◽  
Therapy Reduction

Abstract Introduction: Bendamustine, a bifunctional alkylating agent, exerts a mechanism of action different from that of other conventional alkylators despite it remains mostly unknown. In patients with newly diagnosed or relapsed-refractory MM bendamustine has proven to be active either as monotherapy or in combination with new drugs, particularly bortezomib and immunomodulatory agents. Methods: The preliminary results of this prospective, phase II study conducted in 22 Italian centres are recently published (Blood Cancer J. 2013, 3: e162). Here we present the conclusive results of the combination Bendamustine (70 mg/m2 days 1, 8), Bortezomib (1.3 mg/ m2 days 1, 4, 8, 11) and Dexamethasone (20 mg days 1-2, 4-5, 8-9, 11-12) (BVD) administered every 4 weeks in patients with relapsed-refractory MM of any age, with adequate cardiac, liver and hematological function, not refractory to bortezomib and treated with no more than four previous lines of therapy. The primary endpoint of this study was achievement of a response at least PR, as to IMWG criteria, after four cycles of BVD. Patients achieving a response less than a PR were taken off-study. Patients obtaining at least a PR received two additional treatment cycles followed by a 12-months consolidation phase with cycles repeated every 2 months. Therefore, patients with a PR after the induction phase could receive up to 18 months of treatment and up to 12 cycles of BVD. Results: 75 patients were included in the study. Median age was 68 years (range 41-85 years), 26.5% had ISS stage 3, 19% IgA myeloma and 9% renal failure. Eight of 36 evaluable patients (22%) had high-risk cytogenetics. Patients had received a median of one prior line of therapy (range 1-4). All patients had received prior treatment with new drugs, such as thalidomide (57%), lenalidomide (54.5%), bortezomib (46.5%) or both (20%). Twenty-four patients (32%) were refractory to IMIDs. Best response rate was 75%, including 14 CRs (20%), 22 VGPRs (24%) and 27 PRs (31%). Five patients (6.5%) died early. Only prior treatment with bortezomib significantly reduced the response rate ≥ PR (48.5% vs 80%; P = 0.004). At a median follow-up of 27 months (range 18-38), 45 patients had progressed and 43 had died. Median TTP and PFS were 17 and 12.5 months, respectively while median OS was 24 months (40% at 3 years). After longer follow-up, prior therapy with bortezomib plus lenalidomide was confirmed as the only factor that significantly reduced TTP (9 vs 19 months; HR = 2.7; 95% CI = 1.3-5.8; P = 0.009), PFS (9 vs 15 months; HR = 2.1; 95% CI = 1.2-3.8; P = 0.020) and OS (17 vs 32 months; HR = 2.1; 95% CI = 1.2-3.9; P = 0.043). Grade 3-4 adverse events occurred in 55% of patients leading to therapy reduction in 24% and to protocol discontinuation in 11% of patients. The most frequent severe adverse events were thrombocytopenia (28%), neutropenia (20%), infections (12%), peripheral neuropathy (9%), gastrointestinal (5%) and cardiovascular events (4%). Compared with younger, patients aged > 70 years had a significantly higher incidence of grade 3-4 side effects particularly thrombocytopenia and infections with, consequently, a higher rate of therapy reduction and discontinuation. Moreover, 4/5 early deaths occurred in patients aged more than 70 years. Conclusions: BVD combination is an effective and well tolerated regimen in relapsed-refractory MM. Data suggest that the optimal target of BVD maybe patients younger than 70 years who has not previously received both bortezomib and lenalidomide. Disclosures Offidani: Mundipharma, Janssen: Honoraria. Off Label Use: Bendamustine. Corvatta:Janssen: Honoraria. Ballanti:Janssen: Honoraria. Brunori:Janssen: Honoraria.

scholarly journals Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial

2019 ◽  
Vol 37 (11) ◽  
pp. 867-875 ◽  
Author(s):  
Celeste Lebbé ◽  
Nicolas Meyer ◽  
Laurent Mortier ◽  
Ivan Marquez-Rodas ◽  
Caroline Robert ◽  
...  
Keyword(s):  
Overall Survival ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Free Survival ◽  
End Point ◽  
Phase Iiib ◽  
Grade 3

PURPOSE Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1+IPI3) is approved for first-line treatment of patients with advanced melanoma in several countries. We conducted a phase IIIb/IV study (CheckMate 511) to determine if nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (NIVO3+IPI1) improves the safety profile of the combination. PATIENTS AND METHODS Patients (N = 360) age 18 years or older with previously untreated, unresectable stage III or IV melanoma were randomly assigned 1:1 to NIVO3+IPI1 or NIVO1+IPI3 once every 3 weeks for four doses. After 6 weeks, all patients received NIVO 480 mg once every 4 weeks until disease progression or unacceptable toxicity. The primary end point was a comparison of the incidence of treatment-related grade 3 to 5 adverse events (AEs) between groups. Secondary end points included descriptive analyses of objective response rate, progression-free survival, and overall survival. The study was not designed to formally demonstrate noninferiority of NIVO3+IPI1 to NIVO1+IPI3 for efficacy end points. RESULTS At a minimum follow-up of 12 months, incidence of treatment-related grade 3 to 5 AEs was 34% with NIVO3+IPI1 versus 48% with NIVO1+IPI3 ( P = .006). In descriptive analyses, objective response rate was 45.6% in the NIVO3+IPI1 group and 50.6% in the NIVO1+IPI3 group, with complete responses in 15.0% and 13.5% of patients, respectively. Median progression-free survival was 9.9 months in the NIVO3+IPI1 group and 8.9 months in the NIVO1+IPI3 group. Median overall survival was not reached in either group. CONCLUSION The CheckMate 511 study met its primary end point, demonstrating a significantly lower incidence of treatment-related grade 3-5 AEs with NIVO3+IPI1 versus NIVO1+IPI3. Descriptive analyses showed that there were no meaningful differences between the groups for any efficacy end point, although longer follow up may help to better characterize efficacy outcomes.

Australasian Gastro-Intestinal Trials Group (AGITG) MASTERPLAN: Randomized phase II study of modified neoadjuvant FOLFIRINOX alone or in combination with stereotactic radiotherapy (SBRT) for patients with high-risk and locally advanced pancreatic cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS4172-TPS4172
Author(s):  
Andrew Oar ◽  
Andrew Kneebone ◽  
Mark Lee ◽  
David Goldstein ◽  
Katrin Marie Sjoquist ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
High Risk ◽  
Phase Ii ◽  
Response Rate ◽  
Locally Advanced ◽  
Resection Rate ◽  
Free Survival ◽  
Randomized Phase Ii

TPS4172 Background: Eighty per cent of patients with non-metastatic pancreatic cancer have high-risk, borderline resectable (BRPC) or locally advanced pancreas cancer (LAPC), conferring a 5-year overall survival of only 12%. MASTERPLAN evaluates the safety and activity of stereotactic body radiotherapy (SBRT) added to neoadjuvant chemotherapy in these patient cohorts. Methods: MASTERPLAN is an investigator-initiated prospective multi-centre randomized phase II trial. Inclusion criteria include histologically confirmed high-risk, BRPC or LAPC. High risk is defined as tumour > 4cm, extrapancreatic extension or node positive. Randomisation is 2:1 to chemotherapy + SBRT (investigational arm) or chemotherapy (control arm) by minimisation with stratification by operability (potentially operable - high risk; BRPC versus inoperable – LAPC; medically inoperable), planned chemotherapy and institution. Both treatment arms receive 6 x 2 weekly cycles of modified FOLFIRINOX (mFOLFIRINOX). Gemcitabine and nab-paclitaxel is permitted if mFOLFIRINOX is unsuitable. The investigational arm receives SBRT (40Gy in 5 fractions) with real time quality assurance. Resectability will be evaluated following initial chemotherapy +/- SBRT. Adjuvant chemotherapy is 6 cycles (12 weeks) of mFOLFIRINOX, or the same duration of gemcitabine and capecitabine (GEMCAP) if neoadjuvant gemcitabine/ nab-paclitaxel given. SBRT adverse events (AEs) will be recorded until study cessation. The primary endpoint is 12-month locoregional control. Secondary endpoints: safety, surgical morbidity and mortality, radiological response rate, progression free survival, pathological response rate, surgical resection rate, R0 resection rate, quality of life, deterioration free survival and overall survival. Biospecimens are collected for translational research for potential prognostic/predictive biomarkers of clinical endpoints and include serial tumour tissue collection from patients undergoing fiducial marker insertion and/or surgery, biopsy at disease progression, serial blood collection and serial buccal and faecal sample collection. An interim analysis will review locoregional failure, distant metastasis and rate of death on the first 40 patients after completion of 12 months follow up. The sample size is 120 patients (80 intervention:40 control), balanced for BRPC/LAPC (60 in each cohort). The minimum follow up is 12 months. The first site opened in October 2019 and 10 patients have been recruited from five sites at 17 Feb 2021. Overall 15 sites in Australia and New Zealand are planned to open to recruitment. Australian Clinical Trials Registry Number: ACTRN12619000409178. Clinical trial information: ACTRN12619000409178.

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