scholarly journals Phase 2 Study of 5 Days Azacytidine Priming Prior to Fludarabine, Cytarabine and G-CSF Combination for Patients with Relapsed or Refractory AML

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5181-5181
Author(s):  
Ibraheem H. Motabi ◽  
Shahid Iqbal ◽  
Syed Ziauddin A. Zaidi ◽  
Belal Albtoosh ◽  
Nawal Faiez Alshehry ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Response Rate ◽  
Response Rate ◽  
Complete Response ◽  
Refractory Disease ◽  
Curative Therapy ◽  
Overall Response ◽  
Remission Status ◽  
The Mean ◽  
Refractory Aml

Abstract Background: Acute Myeloid Leukemia (AML) is a group of heterogeneous clonal disorder of myeloid progenitor cells. Relapsed and refractory AML represent a clinical and therapeutic challenge to hematologist because of chemotherapy resistant disease and are associated with poor outcome. Allo-SCT is the only potentially curative therapy for such patients and is only possible after achieving second remission. FLAG is used more commonly and is associated with around 50%. We hypothesize that pretreatment with azacytidine will improve the overall response rate and remission status. Objectives : The primary objective of this study is to evaluate the overall response rate (ORR) of pretreatment with azacytidine followed by FLAG for the treatment of relapsed/refractory AML. Methods: This is prospective phase II study of patients with diagnosis of refractory/relapse AML at King Fahad Medical City, Riyadh, Saudi Arabia between January 2015 and July 2018. Patient confirmed to be relapse/refractory AML based on bone marrow biopsy results were included. Eligible patients received pretreatment with azacytidine for 5 days (days -5 to -1). The FLAG protocol was started on the next day after the completion of 5-azacytidine. G-CSF was started on day 0 (24 hours after last 5-azacytine dose) and continued for a total of seven days (days 0 to 6). Fludarabine and cytarabine was started on next day after G-CSF start day and continued daily for 5 days (days 1 to 5). Patients were followed up with daily clinical examination and labs until next bone marrow examination at count recovery up to day 35. The bone marrow sample was analyzed for cell cycle and global DNA methylation status before and after azacytidine treatment. The ORR is the proportion of the treated patients who achieved CR or Cri. The toxicity was graded base on the frequency of Adverse Events (the NCI-CTCAE version 4.0 scoring system). Results: Sixteen refractory/relapsed AML patients (5 females; 11 males) admitted to our Center from January 2105 to July 2018 were included in the study. Twelve patients were evaluable after exclusion of three patients from analysis based on exclusion criteria. One patient died during induction. The mean age was 39.38 ± 15.11 years. The mean WBC, hemoglobin, platelets, peripheral blood blasts, bone marrow blasts were 26.44 ± 23.15, 7.43 ± 1.55, 61.81 ± 85.20, 49 ± 30.36, and 57.36 ± 29.23 respectively at diagnosis. The mean bone marrow blasts were 42.09 ± 29.75 at relapse/refractory disease. Seven patient had normal Cytogentics. One patient had BCR (9q43), PML (15q22), RUNX1T1(8q22) & MLL (11q23) genes. Another one had EGR1 (5q31) deletion, while t(8;21) was found in another patient. One patient was positive for 7q31 deletion. Four out of twelve patients had abnormal molecular cytogentics including FLT3 -ITD, CEBPA, FLT3 -TKD mutation and KITD816V. No patient has extramedullary disease at diagnosis or relapse settings. Seven out of twelve patients had primary refractory disease while five patients had relapsed disease with 6 months' median duration of remission (Range 1.25-84). Nine patient received 3+7 induction regimen at diagnosis while three had ICE protocol. Eight out of twelve patients showed complete response (67%). Four out of five relapsed patients achieved complete response (80%) whereas four out of seven (57.14%) achieved complete response in refractory disease. Eight patients were referred for stem cell therapy. The most common toxicity was cytopenia and bacterial infections. One patient has left arm cellulitis whereas one had arthritis with myositis. All patients were successfully treated with antibiotics, one patient died during study period because of severe invasive fungal infection. Conclusion Our phase II study preliminary results indicate that the addition of Azacitidene prior to standard therapy can improve the overall response rate and remission status in relapsed/refractory AML. This may provide an opportunity to responding patients to proceed to curative therapy with stem cell transplant. Disclosures No relevant conflicts of interest to declare.

Clinical Activity of Azacitidine In Combination with the Oral mTOR Inhibitor Everolimus (RAD001) In Relapsed and Refractory AML: Interim Analysis of a Phase Ib/II Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3301-3301
Author(s):  
Andrew H Wei ◽  
Sonali Sadawarte ◽  
John Catalano ◽  
Anthony P. Schwarer ◽  
Sharon Avery ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Overall Response Rate ◽  
Mtor Inhibitor ◽  
Response Rate ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Phase Ib ◽  
Overall Response ◽  
Refractory Aml

Abstract Abstract 3301 Background Although the demethylating agent azacitidine has an established role in myelodysplastic syndromes and encouraging activity in oligoblastic acute myeloid leukemia (AML), information regarding its role in relapsed and refractory AML is still emerging. The French ATU reported an overall response rate (ORR; CR/CRi+PR) in relapsed and refractory AML of 11% (Itzykson et al. ASH 2009 #1054). In a similar population, azacitidine salvage therapy produced a CR/CRi rate of 19% (Ayari S, et al. ASH 2009 #2044). Rapamycin, an inhibitor of the AKT downstream target mammalian Target Of Rapamycin (mTOR), is reported to specifically target leukemic stem cells and orally bioavailable rapamycin derivatives, such as everolimus (RAD001), are in active clinical development. Clinical responses with single agent everolimus in relapsed, refractory AML, however, have been modest (Yee et al, Clin Cancer Research 2006 and Boehm et al, European Journal of Internal Medicine 2009). Aim Building on our experience combining everolimus with low dose cytarabine (submitted to ASH, 2010), we have sought to investigate the feasibility and preliminary efficacy of combining everolimus with azacitidine in relapsed and refractory AML. Methods Phase Ib/II open label dose escalation study. Patients were treated with azacitidine 75 mg/m2 s.c. daily on days 1–5 and 8–9 of each 28-day cycle with either 2.5, 5 or 10 mg everolimus orally on days 5–21 for a maximum of 12 cycles. Results This preliminary analysis includes 20 patients (M 14, F 6), median age 64 years (range 17–76) receiving 2.5 mg (n=6), 5 mg (n=12) or 10 mg (n=2) everolimus. 9 (45%) had chemotherapy refractory and 11 (55%) relapsed AML after 1 (n=8), 2 (n=10) or 3 (n=2) previous lines of therapy. 7/17 (41%) had poor risk and 10/17 (59%) intermediate risk cytogenetics. 6/19 (32%) had secondary AML. The overall response rate (ORR) in 14 evaluable patients was 36% (2 CR, 3 PR). Stable disease (SD) was observed in 7 (50%) patients and 2 (14%) had progressive disease. Absolute bone marrow blast reductions from baseline in the 5 responders ranged from 9 to 88% (Figure 1). Grade 3/4 non-hematologic toxicities are summarized as follows: 2.5 mg everolimus cohort- septicemia (n=1) and mucositis (n=1, dose limiting toxicity; DLT), 5 mg everolimus cohort- septic arthritis (n=1, DLT). Febrile neutropenia during the first cycle of therapy was reported in 5/20 (25%). Safety analysis in the 10 mg everolimus cohort is ongoing. With a median follow up of 82 days, 30 day mortality was 0%. Enrolment continues to a planned 40 patients. Of interest, 2 out of 3 patients with FLT3-ITD+ AML refractory to high-dose cytarabine and antracyclines, had a striking reduction in bone marrow blasts after commencing azacitidine + everolimus (2.5 mg) therapy, with the absolute blast count falling from 95% to 16% and 92% to 5%, respectively, and lasting for at least 5 months in both. One of these patients has so far proceeded to allogeneic stem cell transplant (allo-SCT). Another patient with 3rd relapse of AML after failing allo-SCT, achieved CR after 3 cycles of treatment with azacitidine + everolimus (2.5 mg) and remains in CR after 157 days. Conclusion In relapsed and refractory AML, azacitidine in combination with the mTOR inhibitor everolimus was well tolerated and demonstrates substantial clinical activity in this advanced AML population. Further evaluation of this promising combination is ongoing. Disclosures: Wei: Novartis: Advisory board, Research Funding; Celgene: Research Funding. Off Label Use: AML therapy. Catalano:Celgene: Research Funding; Roche: Honoraria, Research Funding, Travel Grants.

Bendamustine Combined With Rituximab in Patients With Relapsed and/or Refractory Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group

2011 ◽  
Vol 29 (26) ◽  
pp. 3559-3566 ◽  
Author(s):  
Kirsten Fischer ◽  
Paula Cramer ◽  
Raymonde Busch ◽  
Stephan Stilgenbauer ◽  
Jasmin Bahlo ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Partial Response ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Refractory Disease ◽  
Overall Response

Purpose The objective of this trial was to evaluate safety and efficacy of bendamustine combined with rituximab (BR) in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL). Patients and Methods Seventy-eight patients, including 22 patients with fludarabine-refractory disease (28.2%) and 14 patients (17.9%) with deletion of 17p, received BR chemoimmunotherapy. Bendamustine was administered at a dose of 70 mg/m2 on days 1 and 2 combined with rituximab 375 mg/m2 on day 0 of the first course and 500 mg/m2 on day 1 during subsequent courses for up to six courses. Results On the basis of intent-to-treat analysis, the overall response rate was 59.0% (95% CI, 47.3% to 70.0%). Complete response, partial response, and nodular partial response were achieved in 9.0%, 47.4%, and 2.6% of patients, respectively. Overall response rate was 45.5% in fludarabine-refractory patients and 60.5% in fludarabine-sensitive patients. Among genetic subgroups, 92.3% of patients with del(11q), 100% with trisomy 12, 7.1% with del(17p), and 58.7% with unmutated IGHV status responded to treatment. After a median follow-up time of 24 months, the median event-free survival was 14.7 months. Severe infections occurred in 12.8% of patients. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia were documented in 23.1%, 28.2%, and 16.6% of patients, respectively. Conclusion Chemoimmunotherapy with BR is effective and safe in patients with relapsed CLL and has notable activity in fludarabine-refractory disease. Major but tolerable toxicities were myelosuppression and infections. These promising results encouraged us to initiate a further phase II trial evaluating the BR regimen in patients with previously untreated CLL.

scholarly journals Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma

2020 ◽  
Vol 4 (17) ◽  
pp. 4091-4101
Author(s):  
Arne Kolstad ◽  
Tim Illidge ◽  
Nils Bolstad ◽  
Signe Spetalen ◽  
Ulf Madsbu ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Hematologic Toxicity ◽  
Overall Response ◽  
Non Hodgkin Lymphoma ◽  
Anti Cd20

Abstract For patients with indolent non-Hodgkin lymphoma who fail initial anti-CD20–based immunochemotherapy or develop relapsed or refractory disease, there remains a significant unmet clinical need for new therapeutic approaches to improve outcomes and quality of life. 177Lu-lilotomab satetraxetan is a next-generation single-dose CD37-directed radioimmunotherapy (RIT) which was investigated in a phase 1/2a study in 74 patients with relapsed/refractory indolent non-Hodgkin B-cell lymphoma, including 57 patients with follicular lymphoma (FL). To improve targeting of 177Lu-lilotomab satetraxetan to tumor tissue and decrease hematologic toxicity, its administration was preceded by the anti-CD20 monoclonal antibody rituximab and the “cold” anti-CD37 antibody lilotomab. The most common adverse events (AEs) were reversible grade 3/4 neutropenia (31.6%) and thrombocytopenia (26.3%) with neutrophil and platelet count nadirs 5 to 7 weeks after RIT. The most frequent nonhematologic AE was grade 1/2 nausea (15.8%). With a single administration, the overall response rate was 61% (65% in patients with FL), including 30% complete responses. For FL with ≥2 prior therapies (n = 37), the overall response rate was 70%, including 32% complete responses. For patients with rituximab-refractory FL ≥2 prior therapies (n = 21), the overall response rate was 67%, and the complete response rate was 24%. The overall median duration of response was 13.6 months (32.0 months for patients with a complete response). 177Lu-lilotomab satetraxetan may provide a valuable alternative treatment approach in relapsed/refractory non-Hodgkin lymphoma, particularly in patients with comorbidities unsuitable for more intensive approaches. This trial was registered at www.clinicaltrials.gov as #NCT01796171.

SDX-105 Demonstrates a High Response Rate as a Single-Agent with Acceptable Safety in Rituximab-Refractory, Relpased Indolent or Transformed Non-Hodgkin’s Lymphoma (NHL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2480-2480 ◽  
Author(s):  
Jonathan Friedberg ◽  
Philip Cohen ◽  
Robert O. Kerr ◽  
K. Sue Robinson ◽  
Andres Forero-Torres ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dose Reduction ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Mitotic Catastrophe ◽  
Hematologic Toxicity ◽  
Overall Response ◽  
Cell Death Pathway ◽  
Grade 3

Abstract SDX-105 (Treanda™, Bendamustine HCl) is an alkylating agent that may exert its anti-tumor activity via mitotic catastrophe, an apoptosis-independent cell-death pathway, as well as, through apoptosis. Its cytotoxic potency is unattenuated in chemotherapy-resistant lymphoma cell lines. We initiated a multi-center Phase II trial to investigate the safety and efficacy of SDX-105 in patients with rituximab-refractory, relapsed indolent or transformed B cell NHL. Patients must have pathologically-confirmed disease that has been demonstrated to be rituximab-refractory (no response or progression within 6 months) or must be intolerant of rituximab. Other requirements include measurable disease, adequate renal, hepatic and bone marrow function (ANC ≥1K/mm3, platelet ≥ 100K/mm3, except in cases of >50% NHL in bone marrow), up to 3 prior chemotherapies, and no prior allogeneic transplant. Patients receive SDX-105, 120 mg/m2 IV over 30–60 min, days 1 and 2, every 21 days. Grade 4 hematologic toxicity during a cycle results in dose reduction for subsequent cycles (to 90 mg/m2 and then to 60 mg/m2). Patients achieving stable disease or better after 6 cycles may receive up to 6 more cycles. 49 patients have been accrued to date with data available on the first 15 patients. The median age is 69 yrs (range 47–84), 47% male, median 6 yrs since diagnosis with NHL. Histologies: 10 follicular (6 Grade 1, 3 Grade 2, 1 Grade 3), 2 SLL, 1 marginal zone and 2 transformed NHL. Other features include: 93% Stage III/IV, 20% with B symptoms, 87% with extranodal disease, median 2 prior chemotherapies with 40% not responding to last chemotherapy. 4 patients have required dose reduction to 90 mg/m2 and 2 patients have withdrawn prior to completing 6 cycles due to treatment-associated toxicity. The current overall response rate (ORR) based upon best response in the intent-to-treat population is 80% (CR/CRu 20%, PR 60%). Overall 73% of patients experienced a related non-hematologic adverse event (AE), of which 20% were Grade 3 and 0% Grade 4. The most frequent AEs were nausea (40%), vomiting (27%), fatigue (33%), anorexia (20%), and constipation (20%). Alopecia was not observed. Grade 3 or 4 hematologic toxicity was seen in 53% (neutropenia), 20% (thrombocytopenia), and 13% (anemia) of patients. 4 patients experienced serious AEs, including 1 patient with baseline renal insufficiency who died on study from renal failure and pulmonary edema; other events include admissions for fever and anemia, urinary tract infection, and dehydration. Based upon these preliminary findings, SDX-105 demonstrates a high overall response rate with acceptable hematologic toxicity and modest non-hematologic toxicity in a relapsed lymphoma patient population, many of whom are refractory to rituximab-chemotherapy combinations. An additional study evaluating the combination of SDX-105 and rituximab in patients with relapsed indolent NHL who are rituximab-sensitive is also ongoing.

High Overall Response Rate in Calcineurin Inhibitor-Free Treatment with the mTOR Inhibitor Everolimus in Advanced Extensive Chronic GvHD after Allogeneic Stem Cell Transplantation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2210-2210 ◽  
Author(s):  
Anne Klink ◽  
Kristina Schilling ◽  
Katrin Rapp ◽  
Klaus Höffken ◽  
Herbert G. Sayer
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Overall Response Rate ◽  
Mtor Inhibitor ◽  
Response Rate ◽  
Complete Response ◽  
Overall Response ◽  
Free Treatment ◽  
Unrelated Donors ◽  
Grade Ii

Abstract Background: The mammalian target of rapamycin (mTOR) inhibitor Everolimus (RAD001, Certican®) is a new immunosuppressive drug and beside of sirolimus used and approved in solid organ transplantation. Recently, it was reported that mTOR-inhibitors in combination with calcineurin inhibitors (CNI) showed clinical responses in chronic graft-versus-host disease (cGvHD). In this single centre retrospective analysis, we report on 29 patients (pts) with severe cGvHD treated with Everolimus without CNI. Patients and Methods: Twenty-nine pts (17 AML, 3 CML, 4 ALL, 3 CLL, 2 NHL) with a median age of 44 years [range: 25–61] underwent allogeneic stem cell transplantation between September 1999 and August 2007. Myeloablative conditioning was used in 21 pts, reduced-intensity conditioning in 8 pts. Except for one patient receiving bone marrow, all pts received peripheral blood stem cells for transplantation. Family donors (2 non-fully HLA matched) were used in 7 pts (24%) and unrelated donors (7 non-fully HLA-matched) in 22 pts (76%). GvHD-prophylaxis consisted of CNI (cyclosporine or tacrolimus) in 4 pts, CNI+Methotrexate (MTX) in 8 pts, CNI+Mycophenolate (MPA) in 8 pts and CNI+MPA+MTX in 9 pts. Antithymocyte globulin (ATG) as in vivo T-cell depletion was used in 9 pts. Cytomegalovirus (CMV)-serostatus was positive in 14 pts, with seronegative donors in 5 pts. Acute GvHD occurred in 27/29 (93.3%), grade II-IV in 25 (86.2%). At the same time, CMV reactivation/infection was observed in 11 pts and thrombotic microangiopathy (TMA) in 3 pts. All pts developed severe cGVHD with extensive disease. Organ involvement included skin with scleroderma in 21 pts, mucous membranes in 22 pts, eyes in 22 pts, lungs in 8 pts, liver in 11 pts, gut in 9 pts and arthralgia in 6 pts. At the time of treatment start with everolimus (0.75 mg Certican ® twice a day orally), CNI medication was stopped. The intended plasma therapeutic levels of everolimus were 3–8 mg/l. In addition all pts received prednisone and in 18 pts (62%) MPA as third immunosuppressive agent was continued. Results: Median treatment duration was 8.4 months [range: 2.5–21.7]. None of the pts developed CMV disease or TMA. Adverse events were: arterial hypertension in 1 patient, atrial fibrillation in 1 patient, pneumonia in 1 patient, sinusitis in 1 patient, herpes labials infection in 1 patient, renal insufficiency grade II in 2 pts and myalgia in 2 pts. 96.6% are still alive, 1 patient (3.4%) died due to relapse of ALL. Two pts (6.9%) achieved a complete response of their cGvHD and 18 pts (62.1%) a partial response resulting in an overall response rate of 69.0% (n=20) according to the recent consensus NIH report (Biol. Blood Marrow Transplant. 2006 May; 12(5): 491–505). No change was observed in 3 pts (10.3%) and progression occurred in 6 pts (20.7%). Complete response in HLA-identical related donors was 20% (1/5) and with HLA-matched unrelated donors was 6.7% (1/15). 100% (n=2) of pts with a HLA-mismatched related donor achieved a partial remission and 85.7% (n=6) of pts with a HLA-mismatched unrelated donor. The gender of recipient or donor did not impair the observed responses with everolimus. Prednisone could be tapered in 62.1% of all pts (18/29). In the triple combination with MPA, MPA could be tapered in 22.2% (4/18) and could be stopped in 38.9% (7/18). Conclusions: A CNI-free treatment of advanced extensive cGvHD with everolimus seems to be feasible and effective with a high overall response rate of nearly 70 %. It should be emphasized that a low toxicity profile without TMA was observed. Our data supports further clinical and immunological investigations with m-TOR inhibitor everolimus in treating GvHD.

Gemcitabine in Combination with Oxaliplatin (GEMOX) As a Salvage Regimen in Patients with Relapsed/Refractory Hodgkin's Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1517-1517 ◽  
Author(s):  
Evren Ozdemir ◽  
Alma Aslan ◽  
Alev Turker ◽  
Ibrahim Barista ◽  
Ayse Kars
Keyword(s):  
Hodgkin’S Lymphoma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Median Number ◽  
Hodgkin's Lymphoma ◽  
Hematological Toxicity ◽  
Hematologic Toxicity ◽  
Refractory Disease ◽  
Salvage Regimen ◽  
Overall Response

Abstract This study's objective was to evaluate the efficacy and safety of gemcitabine in combination with oxaliplatin (GEMOX) as a salvage regimen in patients with relapsed or refractory Hodgkin's lymphoma. Twenty-five patients were enrolled. All patients had received ≥ 2 prior chemotherapy regimens, had an ECOG performance status ≤ 2 and had adequate organ function. Patients received intravenous gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) on days 1 and 15, every 4 weeks. The median age was 29 years (range, 18-64) and 16 (68%) were male. Twenty-one (84%) had primary refractory disease (n=13) or relapsed within 12 months after initial therapy (n=8). All had previous platinum-based salvage chemotherapy (ICE, 23; DHAP, 2). Ten patients (40%) had relapsed/refractory disease following autologous stem cell transplantation (SCT). None had previous brentuximab vedotin treatment. Twenty-one (84%) patients were refractory or progressive on the last treatment. Median number of previous lines of chemotherapy was 2 (range, 2-4). Median number of GEMOX cycles administered to the patients was 3 (range, 2-6). Treatment response was evaluated with PET-CT before and 2-3 cycles after treatment, and those patients who demonstrated a response continued to receive a maximum of 6 courses of GEMOX or bridged to SCT. Of 25 patients, 2 (8%) had complete response, 9 (36%) had partial response and the remaining patients had refractory/progressive disease with an overall response rate of 44%. Seven of the 10 patients who had relapsed/refractory disease after autologous SCT achieved a response (CR, 2; PR, 5). The median time to progression for responding patients was 3 months (range, 1-40 months). One patient is disease free for 40 months. Three patients were successfully bridged to SCT (autologous, 2; allogeneic, 1). Main toxicity was hematological. Grade ≥ 3 hematologic toxicity occurred in 10 patients: thrombocytopenia (36%), neutropenia (16%) and anemia (8%). Among these, 7 had previous autologous SCT. One patient had grade 4 neutropenia and thrombocytopenia. Treatment cycle postponed in 6 patients without dose reduction because of hematological toxicity. Seven patients (28%) needed G-CSF support. One patient developed febrile neutropenia. No treatment-related deaths occurred. GEMOX was shown to be an effective salvage regimen in patients with relapsed/refractory Hodgkin's lymphoma, producing an overall response rate of 44%. It is an active regimen in patients who had relapsed/refractory disease after autologous SCT. Although, the median PFS time was short, some patients can be bridged to SCT and some can get long-term PFS. Hematological toxicity was common, especially in patients with previous autologous SCT. Disclosures Off Label Use: Gemcitabine in Hodgkin's Lymphoma Oxaliplatin in Hodgkin's Lymphoma.

Phase Ib dose escalation study of oral quisinostat, a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone for patients with relapsed multiple myeloma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8530-8530
Author(s):  
Xavier Leleu ◽  
Cyrille Touzeau ◽  
Lotfi Benboubker ◽  
Thierry Facon ◽  
Martine Delain ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Mononuclear Cells ◽  
Response Rate ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Peripheral Blood Mononuclear ◽  
Overall Response ◽  
Aggresome Formation

8530 Background: Aggresome formation is a mechanism of resistance to agents (e.g., bortezomib) which block proteasome activity. HDACi (e.g., quisinostat) prevents aggresome formation by deacetylation of tubulin that allows the transport of unfolded proteins to lysosomes for degradation. Methods: Patients received quisinostat (Q) at escalated doses (6, 8, 10 and 12 mg) on days 1, 3, and 5 weekly, subcutaneous VELCADE (V) at 1.3 mg/m2on days 1, 4, 8, and 11 of a 3-week cycle, and oral dexamethasone (D) at 20 mg on the day of and the day after VELCADE dosing. The primary endpoint was the maximum tolerated dose (MTD) of Q in the combination (Q+V+D). The secondary endpoints included safety, overall response rate, and pharmacodynamic biomarkers. Results: Eighteen patients (3, 3, 6, and 6 in increasing Q doses) were enrolled: 56% male; median age = 69 (range 50-82) years; multiple myeloma stage: IA = 11% and IIIA = 89%; prior lines of therapy: 1 = 100%, 2 = 55.6%, and 3 = 11.1%; prior VELCADE treatment = 50%. At the highest dose (12 mg) 2 patients had dose-limiting toxicity, 1 with QTc prolongation and 1 with atrial fibrillation. The MTD was established at the 10 mg Q for the Q+V+D regimen. The most common adverse events (≥ 10% of patients) were diarrhea (39%), asthenia (33%), peripheral oedema (22%), nausea (17%), thrombocytopenia (17%), alopecia (11%), constipation (11%), and vomiting (11%); most were grade 2 or lower in toxicity. To date, 13 patients have discontinued treatment, of which 5 completed 11 cycles of treatment. The overall response rate was 87.5% (14/16, 95% CI: 61.7% to 98.5%), including 1 complete response, 2 very good partial response, and 11 partial responses. Most patients (9/11) showed a decrease in number of circulating multiple myeloma cells after 1 cycle. Two of 5 patients showed an increase in acetylated histone 3 from baseline as measured in peripheral blood mononuclear cells. Conclusions: The MTD is 10 mg quisinostat in combination with VELCADE and dexamethasone. The combination is active in the treatment of relapsed multiple myeloma and has an acceptable safety profile. Clinical trial information: NCT01464112.

scholarly journals Ανάλυση και συσχέτιση των απεικονιστικών ευρημάτων με την ανταπόκριση στη (α) Λιποπλατίνη και Γεμσιταβίνη και (β) Σισπλατίνη και Γεμσιταβίνη σε ασθενείς με μη μικροκυτταρικό καρκίνο του πνεύμονα σταδίου ΙΙΙΒ / ΙV

2017 ◽  
Author(s):  
Φωτεινή Λαζαριώτη
Keyword(s):  
Partial Response ◽  
Stable Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Complete Response ◽  
Overall Response ◽  
Recist 1.1

Εισαγωγή: O καρκίνος του πνεύμονα αποτελεί το 28% όλων των θανάτων που σχετίζονται με καρκίνο και περίπου στο 80% των περιπτώσεων αφορά στο Μη Μικροκυτταρικό καρκίνωμα. H σισπλατίνη είναι από τα δραστικότερα και πιο αποτελεσματικά κυτταροτοξικά φάρμακα στη θεραπεία των επιθηλιακών κακοηθειών, που όμως οι σοβαρές ανεπιθύμητες ενέργειες και η αντίσταση στην χορήγηση της, εγείρουν την ανάγκη βελτιωμένων μορφών αυτού του φαρμάκου. Mία λιποσωμιακή μορφή της σισπλατίνης, είναι η Λιποπλατίνη (Lipoplatin™), η οποία αναπτύχθηκε με σκοπό να μειώσει τη συστηματική τοξικότητα της σισπλατίνης και να αυξήσει τη δραστικότητά της έναντι των όγκων. Σκοπός: Η ανάλυση και εκτίμηση των απεικονιστικών ευρημάτων, στα οποία κατά κύριο λόγο βασίζεται η αξιολόγηση της ανταπόκρισης στη χημειοθεραπεία (σύμφωνα με τα κριτήρια RECIST 1.1) η συσχέτιση τους με τον ιστολογικό τύπο του καρκίνου σε ασθενείς που λαμβάνουν μέρος σε τυχαιοποιημένη, συγκριτική, ανοιχτής αγωγής, προοδευτική μελέτη φάσης II και η εκτίμηση του ποσοστού αντικειμενικής ανταπόκρισης (Overall Response Rate-ORR) στους ασθενείς των δύο ομάδων. Οι συνδυασμοί χημειοθεραπείας είναι για την πρώτη ομάδα της μελέτης, Λιποπλατίνη και γεμσιταβίνη, ενώ για την δεύτερη ομάδα σισπλατίνη και γεμσιταβίνη, ως θεραπείες πρώτης γραμμής σε Μη Μικροκυτταρικού τύπου, καρκίνο του πνεύμονα (Στάδιο IIIβ/ IV).Δευτερεύοντες στόχοι είναι να συγκριθούν στις δύο ομάδες : το ποσοστό ελέγχου της ασθένειας (DCR), η επιβίωση χωρίς εξέλιξη της νόσου (PFS), η διάρκεια της ανταπόκρισης, η συνολική επιβίωση, η ασφάλεια και η ανεκτικότητα του συνδυασμού θεραπείας.Ασθενείς και Μέθοδος: Η Μελέτη πραγματοποιήθηκε στο νοσοκομείο Μεταξά (2η παθολογική κλινική, υπεύθυνος ερευνητής: Μυλωνάκης Νικόλαος). Τα βασικά κριτήρια συμπερίληψης ασθενών στη μελέτη είναι η ιστολογικά ή κυτταρολογικά επιβεβαιωμένη διάγνωση Μη μικροκυτταρικού καρκίνου του πνεύμονα (NSCLC) σε ασθενείς άνω των 18 ετών με τοπικά προχωρημένο ή μεταστατικό NSCLC.Τα κυριότερα κριτήρια αποκλεισμού είναι η προηγηθείσα χορήγηση άλλου είδους χημειοθεραπεία, βεβαρημένο ιατρικό ιστορικό και η είσοδος στη μελέτη σε χρονικό διάστημα λιγότερο των 3 εβδομάδων από μεγάλη χειρουργική επέμβαση.Οι ασθενείς τυχαιοποιούνται κεντρικά κατά την εισαγωγή τους στην ομάδα Α (Λιποπλατίνη και γεμσιταβίνη) ή στην ομάδα Β (σισπλατίνη και γεμσιταβίνη). Τo θεραπευτικό σχήμα της ομάδας A αποτελείται από: Λιποπλατίνη 120 mg/m2 (ημέρες 1, 8, 15 σε έναν κύκλο 21 ημερών, για 3 διαδοχικούς κύκλους) και γεμσιταβίνη 1000 mg/m2 (ημέρες 1, 8 σε έναν κύκλο 21 ημερών, για 3 διαδοχικούς κύκλους). Στην ομάδα Α δεν θα γίνεται προ- ή μετά- ενυδάτωση και δεν θα χρησιμοποιείται φυσιολογικός ορός, ενώ ο ρυθμός έγχυσης θα πρέπει να είναι αργός ιδίως στην αρχή αυτής. Το σχήμα της ομάδας B (χημειοθεραπευτική αγωγή αναφοράς) αποτελείται από σισπλατίνη 100 mg/m2 (ημέρα 1, σε έναν κύκλο 21 ημερών, για 3 διαδοχικούς κύκλους) και γεμσιταβίνη 1000 mg/m2 (Hμέρες 1, 8 σε έναν κύκλο 21 ημερών, για 3 διαδοχικούς κύκλους). Η σισπλατίνη θα χορηγείται ως δίωρη ενδοφλέβια έγχυση με ένα λίτρο φυσιολογικού ορού προενυδάτωση και βεβιασμένη διούρηση. Σε αμφότερες τις ομάδες θα συνεχιστεί η ίδια θεραπευτική αγωγή για 3 κύκλους επιπλέον, κατόπιν ανταπόκρισης ή σταθεροποίησης της νόσου. Η αξιολόγηση των ασθενών θα γίνεται σε 4 χρονικές περιόδους: πριν από την έναρξη της θεραπείας, εβδομαδιαία αξιολόγηση (την έβδομη ημέρα μετά από κάθε έγχυση), μετά από 3 και 6 κύκλους θεραπείας και κάθε 3 μήνες δια βίου. Ο έλεγχος των ασθενών θα περιλαμβάνει ιατρικό ιστορικό, φυσική εξέταση, γενική αίματος και πλήρη βιοχημικό έλεγχο με καταγραφή των ανεπιθύμητων ενεργειών. Η αξιολόγηση των ασθενών απεικονιστικά πριν την έναρξη και μετά από 3 και 6 κύκλους θεραπείας. Οι απεικονιστικές μέθοδοι περιλαμβάνουν ακτινογραφία και αξονική τομογραφία θώρακος, αξονικές τομογραφίες κοιλίας, εγκεφάλου και σπινθηρογράφημα οστών αν είναι απαραίτητο. Όλες οι απεικονιστικές εξετάσεις θα διενεργούνται σύμφωνα με τα συνήθη διεθνή πρωτόκολλα, όχι απαραίτητα σε προεπιλεγμένα κέντρα αφού η εισαγωγή και παρακολούθηση των ασθενών στη μελέτη θα πραγματοποιείται κατόπιν διάγνωσης NSCLC σε οποιοδήποτε κέντρο.Αποτελέσματα: Τα απεικονιστικά ευρήματα ανά ιστολογικό τύπο, των ασθενών που έλαβαν μέρος στη μελέτη δεν ήταν διαφορετικά από αυτά που αναφέρονται στην βιβλιογραφία. Η εντόπιση του αδενοκαρκινώματος είναι στις περισσότερες περιπτώσεις περιφερική. Το καρκίνωμα εκ πλακωδών κυττάρων έχει κεντρική εντόπιση στο μεγαλύτερο ποσοστό των ασθενών. Στο σύνολο των ασθενών η εντόπιση υπερέχει στον δεξιό πνεύμονα και στον άνω λοβό. Η κοιλοποίηση, οι αποτιτανώσεις και η προσβολή των πλευρών είναι πιο συχνή στο εκ πλακωδών κυττάρων καρκίνωμα. Η ανάλυση της αποτελεσματικότητας της μελέτης πραγματοποιήθηκε με βάση τα απεικονιστικά ευρήματα χρησιμοποιώντας τα κριτήρια RECIST 1.1. Μερική ανταπόκριση (Partial Response-PR) μετά από την ολοκλήρωση 3 κύκλων παρουσίασε το 31,7% των ασθενών στο Α σκέλος και το 25,6% στο Β αντίστοιχα. Σταθερή νόσος (Stable Disease-SD) παρατηρήθηκε στο 39% των ασθενών στο Α σκέλος, ενώ στο Β ήταν 30,8%. Σε κανένα σκέλος δεν υπήρξε πλήρης ανταπόκριση (Complete Response-CR). Αν και η διαφορά στην ανταπόκριση μεταξύ των δύο ομάδων δεν είναι στατιστικά σημαντική ωστόσο τα αποτελέσματα είναι ενθαρρυντικά αφού η Λιποπλατίνη όχι μόνο δεν υπήρξε υποδεέστερη της σισπλατίνης αλλά επιπλέον είχε μικρότερη τοξικότητα συγκριτικά με την σισπλατίνη. Μια διαφορά που ήταν στατιστικά σημαντική μεταξύ των δύο ομάδων ήταν στη νεφροτοξικότητα. Επιπροσθέτως στην περίπτωση του αδενοκαρκινώματος φαίνεται ότι η Λιποπλατίνη έχει πολύ καλύτερη ανταπόκριση συγκριτικά με την σισπλατίνη (16,7% πρόοδο νόσου έναντι 45,8%) ενώ στην περίπτωση του καρκινώματος εκ πλακωδών κυττάρων τα αντίστοιχα ποσοστά ήταν 46,1% και 37,5%. Συμπέρασμα: Η λιποσωμιακή μορφή της σισπλατίνης παρουσιάζει λιγότερες παρενέργειες συγκριτικά με την σισπλατίνη όταν συνδυάζεται με την γεμσιταβίνη και ειδικότερα στατιστικά σημαντική μικρότερη νεφροτοξικότητα. Ιδιαίτερα σημαντικό επίσης είναι το γεγονός ότι στους ασθενείς της ομάδας που έλαβαν Λιποπλατίνη δεν έγινε προ ενυδάτωση ούτε βεβιασμένη διούρηση. Επιπροσθέτως η Λιποπλατίνη παρουσιάζει μία μεγαλύτερη αποτελεσματικότητα η οποία δεν είναι στατιστικά σημαντική λόγω του μικρού δείγματος ασθενών ωστόσο στην περίπτωση του αδενοκαρκινώματος παρουσιάζει μία στατιστικά σημαντική διαφορά στην ανταπόκριση έναντι της σισπλατίνης.

Carboplatin plus ifosfamide as salvage treatment of epithelial ovarian cancer: a pilot study.

1993 ◽  
Vol 11 (10) ◽  
pp. 1952-1956 ◽  
Author(s):  
V Lorusso ◽  
A Catino ◽  
B Leone ◽  
M Rabinovich ◽  
G Gargano ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Overall Response Rate ◽  
Response Rate ◽  
Advanced Ovarian Cancer ◽  
Complete Response ◽  
Salvage Treatment ◽  
Previous Response ◽  
Overall Response ◽  
Platinum Resistant

PURPOSE This study aimed to evaluate the activity and toxicity of carboplatin (PPL) and ifosfamide (IFO) in patients with epithelial ovarian cancer previously treated with cisplatin (CDDP)-containing regimens. PATIENTS AND METHODS From July 1989 to December 1991, 35 patients with epithelial ovarian cancer relapsed or refractory to CDDP as first-line chemotherapy were treated. PPL was administered at a dose of 300 mg/m2 intravenously (IV) on day 1 and IFO at a dose of 1,500 mg/m2 IV on days 1 to 3 every 3 to 4 weeks. Criteria for evaluating previous response to CDDP were strictly defined. RESULTS The overall response rate was 43% (complete response [CR], 6%; partial response [PR], 37%) and the median duration of response was 7 months (range, 3 to 16). In potentially platinum-sensitive (PPS; relapsed) patients, the overall response rate was 56%. None of the primary platinum-resistant (PPR) patients obtained a clinical response to PPL plus IFO, whereas one of five secondary platinum-resistant (SPR) patients obtained a PR. The regimen was easily manageable. CONCLUSION PPL plus IFO is useful and well-tolerated combination in salvage treatment of patients with advanced ovarian cancer. However, clear synergism between PPL and IFO that could overcome intrinsic or acquired CDDP resistance was not observed. The advantage of PPL plus IFO as compared with CDDP-containing regimens is represented by the increased tolerability and the reduced neurotoxicity, nephrotoxicity, and ototoxicity as compared with CDDP-containing regimens. It is essential that the patient population be defined according to their previous response to platinum therapy in trials involving second-line therapy of ovarian cancer.

Dasatinib therapy for patients with Philadelphia-negative (ph-) myeloproliferative disorders (MPDs), including systemic mastocytosis

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7086-7086
Author(s):  
S. Verstovsek ◽  
E. Atallah ◽  
D. Thomas ◽  
J. Cortes ◽  
F. Ravanid-Kashami ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Complete Remission ◽  
Tyrosine Kinases ◽  
Overall Response Rate ◽  
Response Rate ◽  
Kinase Inhibitor ◽  
Systemic Mastocytosis ◽  
Fusion Transcript ◽  
Kit Mutation ◽  
Overall Response

7086 There are no curative medical therapies for Ph- MPDs. Over last several years several of the MPDs have been associated with the abnormal expression of selected tyrosine kinases (e.g. c-kit in SM) and others are suspected to be involved too. Therefore, we engaged in conducting a Phase II study with dasatinib, an orally available multi targeted kinase inhibitor, for patient with Ph- MPDs. Dasatinib is administered at 70 mg PO BID continuously (one month equals one cycle). Response is assessed every 3 cycles, and the therapy is discontinued in those without response after 6 cycles of therapy. Patients are observed for any toxicity; in such cases the dose of dasatinib is adjusted to 50 mg PO BID, then to 40 mg PO BID, or discontinued. The study is ongoing and has enrolled 55 patients; 44 are evaluable for response and toxicity, including 24 with SM (6 with aggressive SM, 4 with SM and associated hematologic non-mast cell disease and 14 with indolent SM with uncontrolled symptoms despite optimal supportive care measures), 10 CIMF, 6 HES, 3 unclassifiable MPD and one PV. Median age is 65 years (range, 27–75); 25 males and 19 females. The overall response rate in SM was 42% (10 pts). Of those, two patients (8%) achieved complete remission, one with SM-CIMF, and one with SM-HES. Both were c-KIT mutation negative and had low, not significant tryptase levels. Both were anemic (Hb 9.4g/dL) and failed erythropoietin therapy, and had abnormal WBC differential; one had low platelets (90×109/L). Symptoms related to SM improved significantly in additional 8 patients, however, no significant response in percentage of bone marrow mast cells or blood tryptase levels have been observed so far. The 6 patients with HES had previously failed imatinib therapy and had no evidence of the FIP1L1-PDGFRA fusion transcript; one achieved complete remission (normalization of blood and bone marrow eosinophil percentage) while others did not respond. No responses have been recorded in patients with CIMF, PV and unclassifiable MPD. No grade 4 toxicity has been observed. Dasatinib is active in SM (overall response rate 42%) mainly by improving symptoms. Updated clinical results on all enrolled patients will be presented. No significant financial relationships to disclose.

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