A Phase I-II Study of the Efficacy and Safety of Lenalidomide (LEN) Combined to Azacitidine (AZA) in Higher Risk MDS and AML with Del 5q - a Study By the Groupe Francophone Des Myelodysplasies (GFM)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2892-2892 ◽  
Author(s):  
Lionel Ades ◽  
Christian Récher ◽  
Julie Lejeune ◽  
Aspasia Stamatoullas ◽  
Marie Sebert ◽  
...  
Keyword(s):  
Phase I ◽  
Primary Endpoint ◽  
Research Funding ◽  
Response Rate ◽  
Early Death ◽  
Complete Response ◽  
Cytogenetic Response ◽  
Median Number ◽  
Intensive Chemotherapy ◽  
Best Response

Abstract Background: Higher risk MDS and AML with del(5q) carry very poor prognosis, but show some response to AZA and LEN as single agents (Adès Blood 2009, Itzykson, Blood 2010). The combination of LEN and AZA has been tested in non-del 5q MDS patients with encouraging results and limited toxicity (Sekeres, Blood 2012). Sequential combination of AZA and LEN has also shown to be feasible and potentially effective in 20 patients with higher-risk MDS with del(5q) in a phase I study (Platzbecker, Leukemia 2013). In this phase I-II trial, we combined escalating doses of LEN to AZA in higher risk MDS and AML with del(5q). Methods: Patients with IPSS int-2 or high MDS, CMML with WBC < 13,000/mm3 and marrow blasts > 10% and AML (20-30% marrow blasts) with 5q deletion with or without additional cytogenetic abnormalities could be included provided they had not previously received LEN or AZA. Patients should also have contra indication to intensive chemotherapy (IC), precluding inclusion in a GFM competing trial combining IC and LEN in higher risk MDS and AML with del 5q. In the present trial, patients received AZA (75 mg/m2 x5 d, every 28 days) combined with escalating doses of LEN (5 mg/d x14 d in cohort 1, 5 mg/d x21 d in cohort 2 and 10 mg/d x21 d in cohort 3). For patients in hematological CR, PR, HI or marrow CR (MDS) and CR or PR (AML) after cycle 2 or 4, treatment was to be continued at the same schedule unless unacceptable toxicity or overt progression occurred. The primary endpoint was response assessed according to IWG 2006 criteria. Secondary endpoints were best response over the 4 cycles and survival. Medians [IQR] are reported unless specified. Intent-to-treat analyses were made. Results: 49 patients were enrolled, including 15, 10 and 24 patients in cohort 1 (LEN 5 mg/d x14d), 2 (LEN 5 mg/d x21d) and 3 (LEN 10 mg/d x21d). 24 were males and the median age was 69 (63-74). According to WHO classification, 1 patient had CMML, 9 RAEB1, 22 RAEB2 and 17 AML. PS was 0, 1 and 2, in 30.8%, 43.6% and 25.6% patients, respectively. However, as said above, patients included in this trial were considered unfit for IC due to their age and/or comorbidities (cardiovascular in 30 patients, pulmonary e in 10, and neurological in 6 pts). Del(5q) was isolated in only 8.3% pts, while 85.4% had del (5q) and at least 2 additional abnormalities (i.e., complex).. IPSS was int-2 in 33% patients and high in 66% patients. Overall, 143 cycles were administered (median 2/patient, including 9 patients who received 6 or more cycles). In the three cohorts, the median number of cycles received was 2 (1-2), 2 (1-4.75) and 4 (2-5.5) respectively. Fifteen (30.6%) patients discontinued treatment before the second cycle, due to early death (n=9), adverse events (n=3), progression (n=2), or CNS hemorrhage (n=1). They were all considered as non responders (primary endpoint). After 2 cycles, 4 (8.2%) achieved CR, 4 (8.2%) marrow CR and 4 (8.2%) stable disease with hematological improvement (ORR= 24%). The best response rate over the 4 courses was 2/15 (13.3%) in cohort 1, 1/10 (10%) in cohort 2, and 9/24 (37.5%) in cohort 3 (ORR=24%). The response rate was 37.5% in patients receiving 10 mg/d, versus 12% in those receiving 5 mg (p=0.051) while other baseline parameters had no impact on response: IPSS (p=0.073), marrow blasts >10% (p=0.16), sex (p=0.74), cytogenetic complexity (p=0.26) or PS (p=0.419). 2/6 CR patients achieved cytogenetic complete response: 0/2 in cohort 1, 0/0 in cohort 2, and 2/4 in cohort 3. One year OS was estimated at 22.9% [95% IC: 12.3-42.5]. We failed to identified any prognostic factor associated with OS (IPSS (p=0.52), marrow blasts >10% (p=0.28), sex (p=0.99), isolated del(5q) (p=0.68), cohort (p=0.2) and PS (p=0.33)). Regarding toxicity, 58 SAEs (grade 3-4) were reported in 38 patients, including 35 infectious events, 7 bleding events, 3 deep venous thrombosis. Conclusion: In this elderly population of higher risk MDS or AML considered unfit for intensive chemotherapy, and with del 5q that was part of a complex karyotype in almost all cases, the combination of AZA with escalated doses of LEN was associated with early discontinuation (<4 cycles) in 30/49 (61.2%) of the patients, mostly due to progression or toxicity, and only 12/49 (24.5%) response. The fact that some responders also achieved cytogenetic response may however be encouraging. Disclosures Vey: Janssen: Honoraria; Celgene: Honoraria; Roche: Honoraria. Park:Hospira: Research Funding; Celgene: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

Lenalidomide (LEN) Combined to Intensive Chemotherapy (IC) in AML and Higher Risk MDS with Del 5q. Interim Results of a Phase I/II Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1049-1049 ◽  
Author(s):  
Lionel Ades ◽  
Aspasia Stamatoullas ◽  
Emmanuel Raffoux ◽  
Thomas Prebet ◽  
Pascal Lenain ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Reduction ◽  
Multiorgan Failure ◽  
Early Death ◽  
Previous Treatment ◽  
Cytogenetic Response ◽  
Median Number ◽  
Intensive Chemotherapy ◽  
Complex Karyotype ◽  
Cytogenetic Abnormalities

Abstract Abstract 1049 Poster Board I-71 Background: Contrary to the “5q syndrome”, prognosis of MDS with del 5q with increased BM blast % and/or additional cytogenetic abnormalities (abn) and of AML with del 5q (isolated or complex) is poor. Furthermore, del 5q is present in 40-50% of higher risk MDS and AML with complex karyotype. Those patients respond poorly to IC with 20-30% CR, of short duration (Estey et al. Hematologica 2000) and to azacytidine (AZA) (Itzykson, ASH 2008, abstr n° 2682). Lenalidomide (LEN) yields hematological but also frequently cytogenetic CR in lower risk MDS with del 5q. In a recent phase II study of LEN in higher risk MDS or AML with del 5q, 28% responded, some with cytogenetic responses, but with significant myelosuppression (Blood, 2009, vol 113, 3947-52). This prompted us to combine IC and REV in this patient population. Methods: This still ongoing phase I/II study (Clinical trial.gov n° NCT00885508) combines induction Daunorubicin (DNR) (45 mg/m2/d d1-3) + AraC (200mg/m2/d d1-7) to LEN (10 mg/d d1-21) and G-CSF (from day 8 to end of aplasia) in IPSS int 2 or high MDS or AML with del 5q (isolated or not). Responders ie CR, CRi or marrow CR according to AML criteria (Cheson JCO, 2003) receive 6 consolidation courses of DNR (45mg/m2 d1), AraC (120 mg/m2/d d1-5) and LEN 10 mg/d d1-15, followed by maintenance LEN until progression. After the first cohort at this dosing level, escalation to DNR 60 mg/m2/d was planned in the absence of major dose limiting toxicity (DLT), while dose reduction to DNR 30mg/m2/d was planned in case of DLT. We report here results of the first cohort, at the reference date of Aug 1st 2009. Results: Between Feb 2009 and June 2009, 18 patients from 9 centres were included, of whom 17 were evaluable (1 patient did not receive the treatment): 8 F, 9 M, median age 64 (range 30–79), 12 AML and 5 RAEB-2 (WHO classification). 16/17 patients had complex Karyotype (median number of 6 abnormalities (range 2-12) in addition to del 5q) and 1 AML had only one additional abnormality. 4 patients had received previous treatment (1 LD AraC alone, 2 AZA alone and 1 LEN followed by LD AraC and AZA), without response and 5 patients had therapy related disease. At inclusion, ECOG was 0 in 44%, 1 in 44% and 2 in 12%. Median baseline WBC, platelets and Hb level were 2.7 G/l (1.1-13.6), 28 G/l (11-135) and 9 g/dl (7.3-11.5). 2 patients had early discontinuation of LEN (d17 and d13) due to grade 3 increase in bilirubin in 1 patient and multiorgan failure related to sepsis in 1 patient. All 15 other patients received the entire induction course, without dose reduction of LEN or CT. 2 patients had early death (at d24 and d22) from multiorgan failure and fungal infection, respectively. Median duration of hospitalisation was 32 days (24-38). In responders, median time to ANC>1 G/l and platelet >50 G/l was 22 days (15-30) and 23 days (11-28), respectively. Median number of RBC and platelet units transfused in those patients was 8 (4-16) and 7 (2-12), respectively. 7 patients (41%) achieved CR, 1 achieved CRi (6%), 1 PR (6%) and 1 additional MDS patient restored normal PB count without marrow response, leading to an ORR of 10/17 (58%). Of the 8 patients who achieved hematological CR or CRi, 3 (with initially 4, 7 and 10 cytogenetic abnormalities, respectively) achieved cytogenetic CR, 3 cytogenetic PR and 2 had no significant cytogenetic response. All the pts who achieved CR could receive consolidation courses. Conclusion: Intensive chemotherapy and LEN can be combined in higher risk MDS and AML with del 5q without leading to unexpected additive myelosuppression or to extra hematological DLT. 41%, 6% and 6% pts achived CR, CRi and PR respectively, in in population with limited response to other treatments. As DLT was not reached in this cohort, dose escalation is planned in the next pts. Updated results will be presented. Disclosures: Off Label Use: lenalidomide is approved by FDA and EMEA only in the treatment of low risk MDS with 5q deletion. Fenaux:CELGENE: Research Funding.

Lenalidomide (LEN) Combined to Intensive Chemotherapy (IC) In AML and Higher Risk MDS with Del 5q. Results of a Phase I/II Study of the Groupe Francophone Des Myelodysplasies (GFM)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 508-508 ◽  
Author(s):  
Lionel Ades ◽  
Thomas Prebet ◽  
Aspasia Stamatoullas ◽  
Christian Recher ◽  
Romain Guieze ◽  
...  
Keyword(s):  
Phase I ◽  
Multiorgan Failure ◽  
Early Death ◽  
Cytogenetic Response ◽  
Median Number ◽  
Induction Treatment ◽  
Intensive Chemotherapy ◽  
Complex Karyotype ◽  
Recent Phase ◽  
Wbc Count

Abstract Abstract 508 Background: Contrary to the “5q syndrome”, prognosis of MDS with del 5q with increased BM blast % and/or additional cytogenetic abnormalities (abn) and of AML with del 5q (isolated or complex) is poor. Furthermore, del 5q is present in 40–50% of higher risk MDS and AML with complex karyotype. Those patients respond poorly to IC with 20–30% CR, of short duration (Estey, Hematologica 2000) and to azacytidine (AZA) (Mufti, ASH 2009, abstr n° 1755). Lenalidomide (LEN) yields hematological but also frequently cytogenetic CR in lower risk MDS with del 5q. In a recent phase II study of LEN in higher risk MDS or AML with del 5q, 28% responded, some with cytogenetic responses, but with significant myelosuppression (Ades, Blood 2008). This prompted us to combine IC and REV in this patient population. Methods: This still ongoing phase I/II study (Clinical trial.gov n° NCT00885508) combines induction DNR (45 mg/m2/d d1-3, escalated to 60 mg/m2/d d1-3) + AraC (200mg/m2/d d1-7) to LEN (10 mg/d d1-21)and G-CSF (from day 8 to end of aplasia) in IPSS int 2 or high MDS or AML with del 5q (isolated or not). Responders, ie CR, CRi or marrow CR according to AML criteria (Cheson JCO, 2003) receive 6 consolidation courses of DNR (45 mg/m2 d1), AraC (120 mg/m2/d×5) and LEN 10 mg/d d1-15, followed by maintenance LEN (14 days/month) until progression. After the first cohort at DNR 45 mg/m2/d d1-3 (n=31) proved safe, escalation to DNR 60 mg/m2/d during induction and consolidation courses was made (n=17). Results: Between Feb 2009 and April 2010, 48 pts from 11 centres were included: 22 Female, 26 Male, median age was 65 years (range 30–79), 36 (75%) AML and 12 (25%) RAEB-2 (WHO classification). 38/48 (79%) pts had complex Karyotype (median number of 6 abn (range 2–13) in addition to del 5q), 5 pts had isolated del 5q and 5 pts had del 5q+1 abn. 11 (23%) pts had therapy related disease. At inclusion, ECOG was 0 in 14 pts, 1 in 21 pts, 2 in 4 pts and 3 in 1 pt (8 missing data). Median baseline WBC, platelets and Hb level were 2.85 G/l (0.7-100), 45 G/l (11-213) and 8.7 g/dl (7.2-11.5) respectively (resp). 31 pts were included in the fist cohort (DNR 45 mg/m2) and 17 were included in the second cohort (DNR 60 mg). All but 7 pts received the planned schedule of LEN (21 days). Overall, 5 pts had early death related to severe sepsis in 3, multiorgan failure in 1 and myocardial infarction in 1 pt. Median duration of hospitalisation during induction treatment was 30.5 days (range 19–43). In responders, median ti me to ANC>1G/l and platelet >50G/l was 23 days (range 1–36) and 22 days (range 9–38), 19 d and 19 d, 24d and 24d in the whole cohort, in DNR45 cohort and in DNR60 cohort resp (p=0.1). Median number of RBC and platelet units transfused during induction treatment was 9 (4-16) and 7 (3-21), resp. 24 pts (50%) achieved CR, 1 achieved CRi (2%), 1 PR (2%) and 3 pts (6%) normalized PB count without marrow response, leading to an ORR of 29/48 (60%). Of the 17 pts with hematological CR/CRi evaluable for cytogenetic response, 8 (Including 4 complex karyotype, 3 isolated del 5q and 1 del5q+1 abn) achieved cytogenetic CR, 5 cytogenetic PR and 4 had no cytogenetic response. Eight of 12 (66%) MDS achieved CR/CRi compared to 17/36 (47%) AML (p=0.32). Four of 5 (80%), 4/5 (80%) and 17/38 (45%) pts with isolated del5q, del5q+1 abn and complex carytotype, resp, achieved CR/CRi (p=0.134). 17 of 31 (55%) pts in the DNR45 cohort achieved CR, vs 8/17 (47%) pts in the DNR60 cohort (p=0.76). Sex, ECOG status, Age, WBC count, Hb level, Platelet count had no effet on CR achievement. Among the 25 pts in CR, 14 relapsed and 2 died in CR (1 during consolidations and 1 after SCT). 1y DFS was 26.5% and significantly shorter in females (p=0.03) while other factors did not influence DFS. Estimated 2y OS was 30% and WHO diagnosis, Sex, Karyotype, and ECOG had no impact on OS. Conclusion: Intensive chemotherapy (IC) and LEN can be combined in higher risk MDS and AML with del 5q without unexpected additive myelosuppression or extra hematological DLT. In this cohort of elderly pts with very poor cytogenetics, The CR rate was 50%, higher than generally reported with CT alone in similar pts. DFS remained however short, suggesting that induction or consolidation therapy should be improved. Based on the better efficacy of DNR 90 mg/m2/d (Lowenberg et al, and Fernandez H et al, NEJM, 2009) in the chemotherapy of elderly AML, and the adequate tolerance in our DNR 60 cohort, we will increase the DNR dose to 90 mg/m2/d in a next patient cohort. Disclosures: Off Label Use: Lenalidomide in the treatment of AML and High risk MDS. Fenaux:CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

A Phase I-II Study Of The Efficacy and Safety Of Lenalidomide (LEN) Combined To Azacitidine (AZA) In Higher Risk MDS and AML With Del 5q – A Study By The Groupe Francophone Des Myelodysplasies (GFM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2750-2750 ◽  
Author(s):  
Lionel Ades ◽  
Christian Recher ◽  
Aspasia Stamatoullas ◽  
Krimo Bouabdallah ◽  
Jacques Delaunay ◽  
...  
Keyword(s):  
Phase I ◽  
Early Death ◽  
Cytogenetic Response ◽  
Median Number ◽  
Additional Patient ◽  
Intensive Chemotherapy ◽  
Complex Karyotype ◽  
One Year ◽  
Present Trial ◽  
Almost All

Abstract Background Higher risk MDS and AML with del(5q) carry very poor prognosis, but show some response to AZA and LEN as single agents (Adès et al. Blood 2009, Itzykson, Blood, 2010). The combination of LEN and AZA has been tested in non-del 5q MDS patients with encouraging results and limited toxicity (Sekeres, Blood 2012). Sequential combination of AZA and LEN has also shown to be feasible and potentially effective in higher-risk MDS with del(5q) in a phase I study (Platzbecker et al, Leukemia 2013 ). In this phase I-II trial, we combined escalating doses of LEN to AZA in higher risk MDS and AML with del(5q). Methods Patients aged 18 or more, with IPSS int-2 or high MDS, CMML with WBC < 13,000/mm3 and marrow blasts > 10% and AML (20-30% marrow blasts) with 5q deletion with or without additional cytogenetic abnormalities could be included provided they had not previously received LEN or AZA. Patients should also have contra indication to intensive chemotherapy (IC), precluding inclusion in a GFM competing trial combining IC and LEN in higher risk MDS and AML with del 5q (results of that trial are also submitted to ASH 2013). In the present trial, patients received AZA (75 mg/m2 x5days, every 28 days) combined to escalating doses of LEN (5 mg/d x14 days in cohort 1, 5 mg/d x21 days in cohort 2 and 10 mg/d x21 days in cohort 3). For patients in hematological CR, PR , HI or marrow CR (MDS) and CR or PR (AML) after cycle 2 or 4, treatment was to be continued at the same schedule unless unacceptable toxicity or overt progression occurred. The main endpoint was response assessed after 2-4 cycles (IWG 2006 criteria). Median [IQR] are reported unless specified. Results 35 patients were enrolled in the study, including 15, 10 and 10 patients in cohort 1 (LEN 5mg/d x14d), 2 (LEN 5mg/d x21d) and 3 (LEN 10mg/d x21d) respectively. 18 were males and the median age was 68.9 (62.7-73). According to WHO classification, 1 patient had CMML, 7 RAEB1, 15 RAEB2 and 11 AML (with 20 to 30% marrow blasts). PS was 0, 1, 2 in 31%, 40%, 29% patients respectively. However, as said above, patients included in this trial were considered unfit for IC due to their age and/or comorbidities including cardiovascular events in 23 patients (still active in 19 at inclusion), pulmonary events in 7 (still active in 5), and neurological events in 6 pts. Del(5q) was isolated in only 2 pts, and 33 pts (94%) had del (5q) and at least 2 additional abnormalities. Baseline platelet count was 50 G/L (25-74), baseline Hb level was 9.15 (8.60-9.80), and baseline ANC was 1 G/l (0.545-1.66), including 38% patients with less than 0.8 G/L. IPSS was int-2 in 27% patients and high in 73% patients. With a median follow-up of 3.5 months, 98 cycles were administered (median 2 /patient, including 4 patients who received 6 or more cycles). In the three cohorts, the median number of cycles received was 2, 2 and 2 respectively. 15 (43%) patients discontinued treatment before the second cycle, due to early death (n=10), adverse events (n=2), progression (n=2), or CNS hemorrhage (n=1). They were all considered as non responders (primary endpoint). Of the 35 pts, 4 (11%) achieved CR and 2 (5.5 %) marrow CR after 2 cycles. After 4 cycles, The 2 marrow CR converted into CR and one additional patient achieved stable disease with HI leading to an overall response rate (ORR) of 7 (20%). The ORR was 13% in cohort 1, 10% in cohort 2, and 30% in cohort 3 (p=0.53). 4/6 complete responders achieved cytogenetic response, including 1 complete (CCyR) and 3 partial. The 6 CR included one of the 2 patients with isolated del(5q), who also obtained CCyR, and 5 of the 33 (15%) patients with complex karyotype. One year OS was 39%. Regarding toxicity, 31 SAEs (grade 3-4) were reported in 19 patients, including 1 cardiovascular event, 6 pulmonary infection, 5 gut events, 3 neurological events. No difference in grade >2 toxicity was seen in the 3 cohorts (10, 10, and 11 events, respectively). Conclusion In this elderly population of higher risk MDS or AML considered unfit for intensive chemotherapy , and with del 5q that was part of a complex karyotype in almost all cases , the combination of AZA with escalated doses of LEN was associated with early discontinuation (<4 cycles) in 43% of the patients, mostly due to progression or toxicity, and only 20 % response (including 17% CR). The fact that 15% of patients with del 5q and complex karyotype achieved CR, with cytogenetic response in several cases, may however be encouraging. Disclosures: Off Label Use: LEN in higher risk MDS. Fenaux:CELGENE: Research Funding.

scholarly journals A Phase 2 Trial of Ibrutinib and Nivolumab in Patients with Relapsed or Refractory Classical Hodgkin's Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-29
Author(s):  
Walter Hanel ◽  
Beth A. Christian ◽  
Kami J. Maddocks ◽  
Narendranath Epperla ◽  
Basem M. William ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Response Rate ◽  
Immune Escape ◽  
Chronic Gvhd ◽  
Complete Response ◽  
Median Number ◽  
Hodgkin's Lymphoma ◽  
Advisory Committees

Introduction: Classical Hodgkin's Lymphoma (cHL) is characterized by an extensive inflammatory infiltrate with abundant Th2 and Treg cells which facilitate immune escape of Reed Sternberg (RS) cells and provides a growth promoting microenvironment by cytokine secretion and CD40/CD40L engagement. Our group previously show that ibrutinib irreversibly inhibits both Bruton's tyrosine kinase (BTK) and interleukin-2 inducible kinase (ITK), a kinase important in Th2 signaling (Dubovsky et al Blood 2013). We hypothesized that the addition of ibrutinib to nivolumab would lead to deeper and more durable responses in cHL by normalizing the Th1/Th2 balance thus reversing immune escape of RS cells. We present results of a planned interim analysis of the first 10 patients enrolled with a data cutoff of June of 2020. Methods: This is a single arm, phase II, single institutional clinical trial testing the clinical activity of nivolumab in combination with ibrutinib in patients ≥18 years of age with histologically confirmed cHL who have received at least one prior line of therapy and who were either not candidates for or had a prior autologous stem cell transplant (ASCT). Prior treatment with nivolumab was allowed. Ibrutinib was administered at 560 mg daily until progression in combination with nivolumab 3 mg/kg IV every 3 weeks for 16 cycles. The primary objective was complete response rate (CRR) prior to cycle 7 assessed per Lugano criteria. Adverse events (AEs) were reported using CTCAE Version 4.0. Results: Of the first 11 cHL patients enrolled, one patient withdrew consent prior to initiating therapy. Of the remaining 10 patients, the median age was 41 years (range 20-84) and 4 patients (40%) were male. The median number of prior lines of treatment was 4.5 (range 1-11), 5 patients (50%) had prior ASCT, 8 patients (80%) had prior brentuximab, and 5 patients (50%) had prior nivolumab. Four of the five patients with prior nivolumab had progressed while receiving therapy while the remaining patient had stable disease upon completing nivolumab with a median time from the last nivolumab treatment of 15.6 months (range 0.7-23.2). Of the 10 patients who received treatment, one patient came off study after two cycles due to persistent grade 2 transaminitis lasting for several weeks attributed to nivolumab requiring high dose oral steroids. One patient came off study after cycle 9 due to grade 3 hematuria attributed to ibrutinib and another came off study due to a pericardial effusion after 8 cycles of ibrutinib maintenance. In the remaining patients, treatment was generally well tolerated with most AEs being grade 1-2 (Table 1). The median number of total cycles received was 9 (range 2-22). Of the 9 patients evaluable for response, 6 patients responded (ORR = 66%), 4 of whom had a complete response (CRR = 44%) with a median time to response of 2 months (Table 2, Fig.1). In intention-to-treat analysis, the ORR was 60% and CRR was 40% meeting our prespecified interim efficacy endpoint of a 30% CRR for trial continuation. Notably, of the 5 patients with prior nivolumab, 3 responded to nivolumab + ibrutinib (ORR = 60%), with one having a CR (CRR = 20%). Overall, at a median follow up of 9.5 months, both the median PFS and duration of response have not yet been reached, with 3 patients remaining in CR at the time of data cutoff. Three of 4 patients discontinued trial treatment to undergo SCT [2 allogeneic; 1 autologous]. Of the 2 allogeneic SCT patients, the first one underwent SCT 3 weeks after the last nivolumab infusion and developed multi-organ acute graft-versus-host disease (GVHD) followed by severe chronic GVHD requiring extracorporeal photopheresis. The second patient underwent allogeneic SCT 2 months following the last nivolumab infusion and had no acute GVHD and experienced only mild chronic GVHD which was medically managed. Conclusions: Although the numbers are small and further recruitment is ongoing (target n=17), the combination of ibrutinib and nivolumab was generally well tolerated and with high response rate with more than half of responding patients achieving a CR. In addition, responses were seen in patients with prior nivolumab treatment. Our results suggest a possible novel role for BTK inhibition in reversing nivolumab resistance in cHL, at least in some cases. Correlative studies including peripheral blood and tumor immune subset analyses are ongoing and the latest results will be presented at the meeting. Disclosures Christian: Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Merck: Research Funding; Millenium: Research Funding; MorphoSys: Research Funding; F Hoffman-La Roche: Research Funding; Triphase: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AstraZenica: Membership on an entity's Board of Directors or advisory committees. Maddocks:Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Consultancy; ADC Therapeutics, AstraZeneca: Consultancy; BMS: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. William:Incyte: Research Funding; Dova: Research Funding; Celgene: Consultancy, Honoraria; Seattle Genetics: Research Funding; Merck: Research Funding; Kyowa Kirin: Consultancy, Honoraria; Guidepoint Global: Consultancy. Jaglowski:Novartis: Consultancy, Research Funding; CRISPR: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Juno: Consultancy. Bond:Seattle Genetics: Honoraria. Brammer:Celgene Corporation: Research Funding; Seattle Genetics, Inc.: Speakers Bureau. Baiocchi:viracta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Consultancy, Research Funding. OffLabel Disclosure: This trial uses ibrutnib in cHL to augment the responses of concurrent nivolumab administration.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3055-3055
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Saima Dean ◽  
Sharon Fung ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Level ◽  
Research Funding ◽  
Response Rate ◽  
Objective Response ◽  
Median Number ◽  
Prior Therapy ◽  
Best Response ◽  
Level 3 ◽  
Grade 3

Abstract Abstract 3055 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen for relapsed/refractory (rel/ref) multiple myeloma (MM) patients (pts) with an overall response rate of 60% and median time to progression of 13.4 months (Dimopoulos ME, et al. Leukemia 2009; 23: 2147-52). We combined lenalidomide with the alkylating agent combination of cyclophosphamide and prednisone—an older regimen with minimal cumulative myelosuppression and good activity as second or third line therapy (Trieu Y, et al, Mayo Clin Proc 2005; 80: 1582). The CPR regimen consisted of cyclophosphamide (CY) on days 1, 8, and 15, lenalidomide on days 1–21 and prednisone 100 mg q 2 days in a 28-day cycle. ASA 81 mg/day was given as DVT prophylaxis. Three dose levels were evaluated using a 3 × 3 dose escalation design. Thirty-two pts were entered between 11/2007-06/2009; median age was 64 (42-80) yrs, 60% were male, and immunoglobulin isotype was IgG in 19 (62%), IgA in 8 (25%) and light chain in 4 (13%) pts. Median β2-microglobulin level was 257 (92-767) nm/L, albumin 39 (34-48) g/L, creatinine 83 (50-126) μmol/L, platelet count 355 (75-479) × 109/L and ANC 2.5 (1.1-6.1) × 109/L. The median number of prior regimens was 2 (1-5). Prior therapy included: ASCT (single in 91%; double in 19%), thalidomide (28%) and bortezomib (50%). FISH cytogenetics were available in 13 pts; 1 had del 13q but none had t(4;14) or del p53. Table 1 summarizes protocol treatment delivered. Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 12 (12–34+) 2 3 150 25 100 10 (9–23) 3 26 300 25 100 17 (5–28+) 1–3 (All) 32 150–300 15–25 100 19 (5–34+) Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities during the trial included: thrombocytopenia in 7 (22%) and neutropenia in 9 (29%), managed with dose reduction and/or growth factors; five episodes of febrile neutropenia occurred, all at dose level 3. In cohort 3, other grade 3–4 non-hematologic toxicities included 1 episode each of abdominal pain/bacteremia, hypokalemia, fatigue, sick sinus syndrome, cardiac amyloidosis, perforated diverticulum and 2 episodes of DVT. Two heavily pretreated pts developed 2° MDS, including 1 previously treated for lymphoma, 43 and 190 mos after the diagnosis of MM. The best response using modified EBMT criteria was documented at a median of 7 (1-26) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (4 CR, 14 VGPR, 11 PR, 1 MR and 1 stable disease). At a median F/U of 16 (5-34) months, 13 pts remain on study and 18 have progressed at a median of 10 (2-23) mos; 1 was lost to F/U and 9 have died of progressive MM. The 1-year actuarial OS and PFS rates are 93% (95% CI 76–98%) and 78% (95% CI 60–89%), respectively. We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with an acceptable safety profile; 2) the objective response rate (CR + PR + MR) in all 32 pts to date is 94%; 3) the 1-year OS of 93% and PFS of 78% compare favorably with other 3-drug combinations in rel/ref MM pts; 4) further evaluation of this regimen in newly diagnosed pts would be of interest. Disclosures: Reece: Celgene: Honoraria, Research Funding. Off Label Use: Combination of lenalidomide and cyclophosphamide and prednisone in relapsed and refractory myeloma patients. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria.

AAML 1421, a phase I/II study of CPX-351 followed by fludarabine, cytarabine, and G-CSF (FLAG) for children with relapsed acute myeloid leukemia (AML): A Report from the Children’s Oncology Group.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 10003-10003 ◽  
Author(s):  
Todd Michael Cooper ◽  
Michael Absalon ◽  
Todd Allen Alonzo ◽  
Robert B Gerbing ◽  
Kasey Joanne Leger ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Response Rate ◽  
Residual Disease ◽  
Complete Response ◽  
Dose Finding ◽  
Platelet Recovery ◽  
Best Response ◽  
First Relapse ◽  
Grade 3

10003 Background: Effective regimens with favorable toxicity profiles are needed for heavily pre-treated children with relapsed AML. AAML1421 is a Phase I/II study of CPX-351, a liposomal preparation of cytarabine and daunorubicin demonstrating efficacy in adults. AAML1421 sought to determine the recommended Phase 2 Dose (RPD2) of CPX-351 and the response rate (complete response (CR) + complete response without platelet recovery (CRp)) after up to 2 cycles of therapy. Methods: Children > 1 and ≤ 21 years of age with relapsed/refractory AML were eligible for dose finding, and those in first relapse were eligible for efficacy. A modified rolling six design was used for dose-limiting toxicity (DLT) assessment which occurred in Cycle 1. Dose level 1 (DL1) was 135 units/m2 on days 1, 3, and 5 with a single dose de-escalation to 100 units/m2 if DL1 was intolerable. The Efficacy Phase used a Simon-two stage design. The response rate was determined after up to 2 cycles of therapy (Cycle 1: CPX-351; Cycle 2: FLAG). The Overall Response Rate (ORR) was defined as CR+CRp+CRi (CRi = CR with incomplete hematologic recovery). Results: Thirty-eight patients (pts) enrolled: 6 in dose-finding and 32 in the efficacy phase. DLT occurred in 1/6 patients and was a grade 3 decrease in ejection fraction(EF). This was the only Grade 3 cardiac toxicity. Therefore, 135 units/m2 on days 1, 3, 5 was the RP2D. All dose finding pts were eligible for efficacy determination. One pt in the efficacy phase was unevaluable. The most common ≥ Grade 3 toxicities in Cycle 1 included fever/neutropenia (45%), infection (47%), and rash (40%). There was no toxic mortality. Best responses included 20 CR (54%), 5 CRp (14%), and 5 CRi (14%). Seventy percent achieved best response after cycle 1. Twenty-one of 25 patients with CR/CRp had no detectable residual disease (RD) (84%) by flow cytometry. HSCT was used as consolidation in 23/29 responders (79%); 18 of 23 (78%) had no detectable RD prior to HSCT. Conclusions: The RP2D of CPX-351 is 135 units/m2/dose on days 1, 3, 5. CPX-351 was well tolerated and protocol therapy was effective with CR+CRp rates of 68.3% (90% CI 52.9% to 78.0%) and ORR (CR+CRp+CRi) of 81.1% (90% CI 67.4% to 88.8%). AAML1421 response rates are superior to any published North American cooperative group clinical trial for children with AML in first relapse. Clinical trial information: NCT02642965.

AZA In the Treatment of Therapy Related MDS and AML (tMDS/AML): a Report on 60 Patients by the Groupe Francophone Des Syndromes Myelodysplasiques (GFM)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2911-2911
Author(s):  
Jehane Fadlallah ◽  
Cecile Bally ◽  
Bruno Quesnel ◽  
Norbert Vey ◽  
Francois Dreyfus ◽  
...  
Keyword(s):  
Response Rate ◽  
De Novo ◽  
Early Death ◽  
Poor Response ◽  
Female Gender ◽  
Median Number ◽  
Hematological Toxicity ◽  
Similar Response ◽  
Best Response ◽  
Wbc Count

Abstract Abstract 2911 Background: AZA gives 50–60% responses and improves OS in higher-risk MDS but its role in t MDS/AML, characterized by a high frequency of unfavorable karyotypes and poor response to available treatments, remains unknown. Methods: An AZA compassionate program (ATU) was opened in France between Dec 2004 and Jan 2009 for higher risk MDS, and for AML not candidates to or refractory to intensive chemotherapy (IC). We analyzed t MDS/AML included in this program and having received at least 1 cycle of AZA, excluding patients (pts) previously treated with chemotherapy (CT) for their tMDS/AML. Results: 60 tMDS/AML were included: M/F:24/36, median age 69 (range 20–87). Primary disease was Breast Carcinoma (n=17), CLL (n=6), Hodgkin's disease (n=4), NHL (n=7), ALL (n=2), ovarian (n=2), liver(n=2), prostate carcinoma (n=2), other cancers (n=16), immunosuppressive therapy for lupus or Lung transplant in the last 2 pts. Treatment of primary neoplasm consisted in C×T in 86% and R×T in 61%. Diagnosis (WHO) was RCMD+/− RS in 4 pts, RAEB-1 in 10 pts, RAEB-2 in 28 pts MDS with myelofibrosis in 1 pt, and AML in 17 pts (including 12 FAB RAEBt). IPSS cytogenetics were fav in 4 (6.7%), int in 11 (18.3%), and unfav in 45 (75%, including 71% Complex karyotypes). Patients received a median of 4 cycles (range 1–24) of AZA, at FDA/EMEA-approved schedule (75 mg/m2/d ×7d/4 week) in 73% patients and a less intensive schedule (5d/4w, or <75mg/m2/d) in 27% patients. 25 (41.6%) pts received < 4 cycles, mainly due to early death (32%), failure (28%) or hematological toxicity (16%). Best response according to IWG 2006 criteria was CR in 9 pts (15%), marrow CR (mCR) in 8 (13%), PR in 1, stable disease (SD) with HI in 5 (8%) ie an overall response rate (ORR) of 38%. In pts who received >4 cycles, ORR was 21/35 (60%). Age, WBC count, baseline platelet count, % marrow blasts, karyotype (whatever the categorization) and ECOG status had no impact on ORR. 1, 2 and 3 year survival was 35%, 15% and 7%. Female gender (p=0.02), achievement of response (p=0.003) and ECOG status (0-1 vs 2–4) (p=0.04) had significant impact on OS while karyotype and % marrow blasts had no impact. However, there was a trend for lower OS in patients with chrom 5 abn (2y 0S 7.7% vs 23 %, p=0.08). 9 (15%) patients, all females, median age 55 (range 35–66) were allografted after a median number of 6 AZA cycles (range 2–17), including 3 pts, 4 pts and 2 pts who had achieved CR, mCR and no response to AZA, respectively. 4 (44%) of them were alive after 5+,17+,32+ and 42+ months. By comparison to the 232 pts with de novo MDS/AML included in the same program, tMDS/AML had a higher frequency of complex karyotype (71 vs 29.5, p<0.01), received fewer cycles of AZA (4 vs 6, p=0.0014) due to more frequent discontinuation of AZA before 4 cycles (41.6% vs 25%, p=0.025) mainly related to a higher incidence of early deaths. tMDS/AML had a similar response rate (38% vs 45% in de novo MDS/AML, p=0.67), but significantly shorter OS (2yOS 15% vs 33.3, p=0.003, figure 1). Conclusion: In this cohort of tMDS/AML, survival with AZA was shorter than in de novo MDS/AML, probably largely due to their more severe baseline characteristics. Only 15% of tMDS/AML could be allografted, half of them with so far a favorable outcome. Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

Final Report of GFM-VOR2007 Study: a Phase I/II Study of Vorinostat and Low Dose Cytarabine (LDAC) for MDS Patients with Azacitidine (AZA) Failure

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3825-3825 ◽  
Author(s):  
Thomas Prebet ◽  
Thorsten Braun ◽  
Odile Beyne-Rauzy ◽  
Eric Wattel ◽  
Francois Dreyfus ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Research Funding ◽  
Response Rate ◽  
Single Agent ◽  
Therapeutic Index ◽  
Median Number ◽  
Clinical Activity ◽  
Final Report ◽  
Sequential Administration

Abstract Abstract 3825 INTRODUCTION: AZA is the standard of care for patients (pts) treated for high risk MDS. Outcome of patients with AZA failure is poor with no standard treatment currently available (Prebet, JCO, 2012), and alternative strategies are required for this population. Vorinostat is a histone deacetylase inhibitor with clinical activity in MDS and leukemia, although response rate remains low when used as single agent (Garcia-Manero Blood 2008). By contrast, combinations with cytotoxic or targeted therapies seem promising. METHODS: In this study (clinicaltrials.gov NCT00776503), we combined LDAC (10mg/m2/d in the first cycle, then 20 mg/m2/d) for 14 days SC every 28 day cycle and escalating doses of vorinostat. Two schedules of vorinostat, (400mg/day orally) beginning on day 1 (arm A) or on day 14 (arm B), were tested in 3 cohorts receiving escalating treatment duration (7days, 10 days and 14 days per cycle) with a classical 3+3 phase I schedule. 7 additional pts were included at the dose level recommended by the DSMB for each cohort (arm A and B). Inclusion criteria were age >18, MDS or AML with 20–30% blasts, IPSS≥1.5, prior failure of AZA. Toxicity was assessed using CTCAE V3. Patients with clinical benefit could continue on therapy after cycle 3 until progression. RESULTS: A total of 42 pts were included and 40 were treated, 23 pts in arm A and 17 pts in arm B. 2 pts died before the beginning of treatment. Median age was 74 years (range 46– 88), median number of previous treatments was 2 (1–3), and median number of cycles of previous AZA treatment was 11 (range 1–25). All pts were IPSS Int-2 (n=21) or High risk MDS (n=19). A total of 137 cycles of treatment was administered with a median number of 3 cycles/pt and 11 pts received more than 3 cycles (28%). The recommended dose was determined for arm A at 10 days of vorinostat and for arm B at 14 days. During cycle 1, dose limiting toxicities were grade 3 fatigue (n=2), grade 4 bilirubin (n=1), and grade 4 infection (n=2), all in arm A. The most frequent non-limiting toxicities were myelosuppression (37/40), infections (8/40) moderate fatigue (23/40) and mild GI toxicities (25/40). Response was centrally reviewed according to IWG 2006 criteria. Overall response rate was 17% in 35 evaluable pts including 2 CRi, 2 HI and 2 marrow CR. Median duration of response of 3 months (range [2–6+]). There were 2 responders in arm A (1 in the 7 day cohort and 1 in the 14 day cohort) and 4 responders in arm B (1 in the 7 day cohort, 2 in the 10 day cohort, 1 in the 14 day cohort) including the 2 CRi. 18 pts remained stable without HI and 11 progressed during treatment. Median overall survival of the cohort was 9.2 months and 1-year probability of survival was 36%. CONCLUSIONS: Our results show that 400 mg/day vorinostat can be combined to LDAC and given for 10 days (arm A) to 14 days (arm B) with acceptable side effects. It also suggests that the sequential administration might be associated with an increased therapeutic index since longer vorinostat therapy duration could be tolerated. Response rate remains modest but survival compared favorably with conventional care in this group of patients with dismal outcome. Disclosures: Fenaux: Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Final Results of the Phase I/II Study of Chemosensitization Using the CXCR4 Inhibitor Plerixafor in Combination with Bortezomib in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4256-4256 ◽  
Author(s):  
Irene M. Ghobrial ◽  
Kenneth H. Shain ◽  
Jacob Laubach ◽  
Patrick Henrick ◽  
James Vredenburg ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Plasma Cells ◽  
Response Rate ◽  
Phase Ii Study ◽  
Median Number ◽  
Recommended Dose ◽  
Advisory Committees

Abstract PURPOSE: This study aimed to determine activity and safety of the CXCR4 inhibitor plerixafor in combination with bortezomib and dexamethasone in patients with relapsed or refractory Multiple Myeloma (MM). This was based on our preclinical studies showing that plerixafor (Mozobil, Sanofi Corporation) induces de-adhesion of MM cells and sensitization to bortezomib in preclinical animal models. PATIENTS AND METHODS: Theprimary endpoint of the phase I study was the maximum tolerated dose (MTD) and for the phase II study, the safety and response rate of the combination. Eligibility criteria included patients with relapsed or relapsed/refractory MM with 1-5 prior lines of therapy including bortezomib (unless patients were refractory to bortezomib). The phase I included 8 cohorts with different doses and two treatment schedules. In cohorts 1-5, patients received plerixafor at the recommended dose sq on days 1-6 of each cycle and bortezomib at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. In cohort 5b-6, plerixafor was given at the recommended dose sq on days 1, 3, 6, 10, and 13 and bortezomib was given at the recommended dose twice a week on days 3, 6, 10, and 13 every 21 days. For the phase II portion patients received plerixafor at the MTD established in phase I of trial, 320 mcg/kg sq on days 1, 2, 3, 6, 10, and 13. Bortezomib was given 1.3 mg/m2 IV or sq twice a week on days 3, 6, 10, 13, every 21 days. Dexamethasone was given at 40mg on days of Bortezomib. RESULTS: A total of 58 patients were enrolled on this study from June 2009 to March 2015, with 25 on the phase I and 33 on the phase II study. In the phase I study, the median age was 60 years (range, 43-85), the median number of prior therapies was 2 (range, 1-4), with all but 3 patients receiving prior bortezomib. The median number of cycles on therapy was 4 (1-12). Dose limiting toxicities including insomnia, restlessness, and psychosis were observed in two patients at dose level 6 (plerixafor 0.40 mg/kg and bortezomib 1.3 mg/m2). Therefore, 3 additional patients were enrolled at dose level 5b (plerixafor 0.32 mg/kg and bortezomib 1.3 mg/m2). There were no grade 4 toxicities. Grade 3 toxicities included lymphopenia (40%), hypophosphatemia (20%), anemia (10%), hyponatremia (10%), hypercalcemia (10%), and bone fracture due to myeloma bone disease (10%). Twenty-three patients were evaluable for response, including 1 (4%) complete response (CR), 1 (4%) very good partial response (VGPR), 1 partial remission (PR) and 2 (9%) MR, and 15 (65%) having stable disease with only 3 (13%) progressive disease (PD). In the phase II study, the median age was 63 (46-83). The median number of prior therapies was 2 (1-5), with 22 (66%) who have received prior bortezomib. The median number of cycles on therapy is 5 (1-24). The response rate included 5 VGPR (16%), 11 PR (35%) with an overall response rate of 51% and another 11 (35%) stable disease. Grade 3/4 toxicities included thrombocytopenia (68%), lymphopenia (6%), hypophosphatemia (2%), anemia (4%), infections (4%), hyponatremia (2%), hypercalcemia (2%) and neurological toxicity (2%). We also examined in vivo mobilization of plasma cells, CD34+ hematopoietic stem cells and other accessory bone marrow cells. Analysis of these samples showed rapid mobilization of plasma cells at 2 hours post-plerixafor with a rapid return to normal levels at 4 and 24 hours post plerixafor. CONCLUSIONS: The combination of plerixafor and bortezomib is generally well tolerated with minimal neuropathy or other toxicities seen to date. The responses observed are strongly encouraging with 51% ORR in this relapsed and refractory population. This study was supported by R01CA133799-01, and by Sanofi and Takeda Corporations. Disclosures Off Label Use: Plerixafor in myeloma. Azab:Verastem: Research Funding; Selexys: Research Funding; Karyopharm: Research Funding; Cell Works: Research Funding; Targeted Therapeutics LLC: Other: Founder and owner . Schlossman:Millennium: Consultancy. Richardson:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees.

Phase I/II Study of Volasertib (BI 6727), An Intravenous Polo-Like Kinase (Plk) Inhibitor, in Patients with Acute Myeloid Leukemia (AML): Updated Results of the Dose Finding Phase I Part for Volasertib in Combination with Low-Dose Cytarabine (LD-Ara-C) and As Monotherapy in Relapsed/Refractory AML

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1549-1549 ◽  
Author(s):  
Gesine Bug ◽  
Carsten Müller-Tidow ◽  
Richard F Schlenk ◽  
Alwin Krämer ◽  
Michael Lübbert ◽  
...  
Keyword(s):  
Complete Remission ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Research Funding ◽  
Median Number ◽  
Salvage Treatment ◽  
Antileukemic Activity ◽  
Best Response ◽  
Grade 3

Abstract Abstract 1549 Background: The prognosis of patients (pts) with relapsed or refractory (rel/ref) AML who are considered unlikely to benefit from or tolerate intensive salvage treatment is unfavorable and novel treatment strategies are needed. Repeated cycles of LD-Ara-C are a therapeutic option for palliative treatment; however, the outlook for these pts remains unsatisfactory. Plks are critical in cellular division and mitotic progression and Plk1 is overexpressed in many cancers including AML. Volasertib is a first in class, selective and potent cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Plk. In phase I/II trials in pts with solid tumors, volasertib demonstrated a favorable safety profile and encouraging antitumor activity. Here, we present updated results from the phase I part of an ongoing phase I/II study of volasertib in combination with LD-Ara-C or as monotherapy in AML pts considered ineligible for intensive salvage treatment. Material and Methods: This study follows a two-stage design. The phase I part, reported here, investigates the maximum tolerated dose (MTD) of volasertib as a 1-hr intravenous infusion on days 1 and 15 Q4W as monotherapy or in combination with fixed dose LD-Ara-C 20 mg bid subcutaneously on days 1–10 Q4W in pts with rel/ref AML. Dose escalation follows a 3+3 design with de-escalation. Blood samples for pharmacokinetic (PK) analyses were taken in cycles 1 and 2 and concentrations of volasertib and LD-Ara-C were determined. Results: In the monotherapy arm, increasing volasertib doses (150, 200, 350, 400, 450 mg) were evaluated in 29 pts (median age: 71 yrs [range 26–84]). Drug-related adverse events (AEs) were reported in 8 pts (27.6 %). Most frequent drug-related AEs (&gt;5%) were anemia in 3 pts (10.3%), and thrombocytopenia, epistaxis, and nausea in 2 pts each (6.9%). Grade 3/4 drug-related AEs included thrombocytopenia (2 cases), anemia, diarrhea, mucositis, neutropenia, and pneumonia (1 case each); there was 1 fatal (grade 5) drug-related AE (fungal pneumonia). Of the drug-related AEs, the following were dose-limiting toxicities (DLTs) per protocol: grade 4 pneumonia and fatal fungal pneumonia (n=1, at 150 mg), and grade 3 mucositis (n=1, at 400 mg). Monotherapy dose escalation is ongoing; pts have received volasertib doses of 500 mg without having reached the MTD. Preliminary best response data indicated minor antileukemic activity at low doses (150 and 200 mg); with 4/13 pts achieving no change as best response, mostly of short duration (median number of cycles initiated: 1 [range 1–5]). At higher monotherapy doses (≥350 mg), antileukemic activity was observed with 4/16 pts achieving a complete remission with incomplete blood count recovery (CRi) and 5/16 having temporarily stable blood values as best response. In the combination arm, volasertib doses of 150–400 mg were investigated. The MTD for volasertib in combination with LD-Ara-C was 350 mg (Bug et al ASH 2010). Seven out of 32 pts treated with volasertib + LD-Ara-C achieved a complete remission (CR or CRi). In responding patients, a median number of 6 treatment cycles was initiated (range 3–13) and a preliminary analysis revealed a median overall survival of 551 days (range 165–595). PK analysis showed that volasertib is a moderate clearance drug with multi-compartmental PK behavior with a large volume of distribution (&gt;4000 L) and a long terminal half-life (∼111 hrs). No drug interaction after co-administration of LD-Ara-C was observed. Conclusions: The phase I part of the study determined the MTD of volasertib in combination with LD-Ara-C to be 350 mg; the MTD of volasertib monotherapy has not yet been determined. Volasertib was well tolerated in this heavily pretreated AML pt population at doses above the recommended phase II volasertib dose used in pts with solid tumors. Most of the reported higher grade drug-related AEs were due to the myelosuppressive effect of volasertib. Preliminary results from the phase I trial show antileukemic activity of volasertib as monotherapy and in combination with LD-Ara-C. These results indicate Plk to be a potential new target for AML treatment and warrant proceeding with further clinical investigation of volasertib in AML pts. Disclosures: Bug: Novartis Pharma GmbH: Consultancy, Honoraria; Celgene GmbH: Consultancy, Honoraria. Off Label Use: Volasertib is an investigational agent. Müller-Tidow:Boehringer Ingelheim: Research Funding. Krug:Boehringer Ingelheim: Research Funding. Voss:Boehringer Ingelheim: Employment. Taube:Boehringer Ingelheim: Employment. Fritsch:Boehringer Ingelheim: Employment. Garin-Chesa:Boehringer Ingelheim: Employment. Ottmann:Boehringer Ingelheim: Consultancy. Döhner:Celgene, Clavis: Membership on an entity's Board of Directors or advisory committees.

Sign in / Sign up

Export Citation Format

Share Document