A Clinical Pharmacology and Exploratory Study of Azacitidine Administered Subcutaneously or Intravenously In Japanese Patients with Myelodysplastic Syndrome

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4964-4964
Author(s):  
Yukio Kobayashi ◽  
Michinori Ogura ◽  
Kiyoshi Ando ◽  
Kensei Tobinai ◽  
Toshiki Uchida ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Median Time ◽  
Research Funding ◽  
Treatment Protocol ◽  
Japanese Patients ◽  
Hematologic Response ◽  
Transfusion Requirements ◽  
Grade 3 ◽  
To Receive

Abstract Abstract 4964 [Background and Purpose]: Azacitidine is a pyrimidine nucleoside analog of cytidine with hypomethylating and cytotoxic activity. Although azacitidine is currently approved for subcutaneous (SC) injection and intravenous(IV) administration for the treatment of myelodysplastic syndromes (MDS) in the US, there are limited data available on the treatment effects of IV versus SC administration. To compare the safety, pharmacokinetics (PK), and efficacy of IV with SC administration, a phase I/II study of azacitidine in Japanese patients with MDS was conducted. [Patients and Method]: Patients with RA, RA with ringed sideroblasts (RARS), RAEB, or RAEB-t defined by the French-American-British (FAB) classification were enrolled. RA and RARS must fulfill the additional criteria of significant marrow dysfunction (defined by cytopenias and/or transfusion requirements). Eligible patients were at least 20 years of age but younger than 80 and had a ECOG PS between 0 and 2. The patients were alternately assigned to receive azacitidine SC or IV (10-minutes) at 75 mg/m2/day for 7 days every 4 weeks for a minimum of 4 cycles. Patients who achieved a complete response (CR) received additional 3 cycles of azacitidine and were followed up without treatment. Subjects with a partial response (PR) or hematologic improvement (HI) received azacitidine until disease progression with a maximum of 18 cycles. Ten patients received azacitidine by both SC and IV administration on the different cycle and PK parameters were compared on day 1 of each cycle. The primary endpoints of this study were the safety, PK and HI according to the International Working Group (IWG 2006) criteria for MDS, respectively. [Results]: A total of 54 patients (10 in phase I portion and 44 in phase II portion) were enrolled between October 2007 and November 2008. Of these, 53 patients received at least one dose of azacitidine; 17 patients (32 %) were female; the median age was 65 years (range 35–77 years). FAB MDS subtypes were: RA (16/53, 30%); RARS (3/53, 6%); RAEB (20/53, 38%); RAEB-t (14/53, 26%). IPSS risk groups were: Low (0%); Int-1(23/53, 43%); Int-2(15/53, 28%); High(15/53, 28%). IPSS cytogenetic groups were: good (24/53, 45%); intermediate (13/53, 25%); poor (16/53, 30%). Fifty-one patients have completed the treatment protocol to date. The median number of treatment cycles was 7(range 1 – 18). Seven patients have completed 18 cycles of treatment. Two patients are continuing to receive treatment in their cycles 16 and 17. HI was observed in 53% (26/49) of patients. Median time to HI was 55 days (range 20–217). Of the 27 patients who were RBC transfusion dependent at baseline, 15 (56%) became transfusion independent. Hematologic response (CR, PR, or marrow CR) was achieved in 29% (15/51) of patients. Median time to hematologic response was 113 days (range 49–247). HI rate in SC and IV administration was 50 % (12/24) and 56 % (14/25), respectively. Hematologic response rate in SC and IV administration was 29% (7/24) and 30% (8/27), respectively. There were no significant differences between SC and IV administration of azacitidine for HI and hematologic response. The Cmax following IV administration was approximately 4-fold of that obtained following SC administration; however, the AUC(0-∞) following SC administration was 92.3 ± 15.8% compared to that of IV, indicating good bioavailability following SC administration. Overall, the PK profile was similar to that of the previously reported study. The most common grade 3 or 4 adverse events included neutropenia 80% (41/51), leukopenia 76% (39/51), hemoglobin decreased 71% (36/51) and thrombocytopenia 65% (33/51). Grade 3 or 4 non-hematologic adverse events which were observed more than 10% included pneumonia 12% (6/51) and hypophosphatemia 16%(8/51). There was no death during the study that occurred within 29 days of last dose of azacitidine. The safety profile did not differ significantly different between SC and IV administration with the exception of injection site reactions observed with SC administration, only. [Conclusions]: Azacitidine is generally well tolerated and demonstrated a beneficial effect in Japanese patients with MDS. The higher Cmax of IV dose was not translated into clinical outcomes; no difference was shown in both efficacy and safety profiles between SC and IV administration. Both IV and SC azacitidine are promising therapeutic options for Japanese patients with MDS. Disclosures: Kobayashi: Nippon Shinyaku Co., Ltd.: Research Funding. Ogura: Nippon Shinyaku Co., Ltd: Research Funding. Ando: Nippon Shinyaku Co., Ltd.: Research Funding. Tobinai: Nippon Shinyaku Co., Ltd.: Research Funding. Uchida: Nippon Shinyaku Co., Ltd.: Research Funding. Ogawa: Nippon Shinyaku Co., Ltd.: Research Funding. Ishikawa: Nippon Shinyaku Co., Ltd.: Research Funding. Ohashi: Nippon Shinyaku Co., Ltd.: Research Funding. Hata: Nippon Shinyaku Co., Ltd.: Research Funding. Usui: Nippon Shinyaku Co., Ltd.: Research Funding. Taniwaki: Nippon Shinyaku Co., Ltd.: Research Funding. Ohnishi: Nippon Shinyaku Co., Ltd.: Research Funding. Akiyama: Nippon Shinyaku Co., Ltd.: Research Funding. Ozawa: Nippon Shinyaku Co., Ltd.: Research Funding. Ohyashiki: Nippon Shinyaku Co., Ltd.: Research Funding. Okamoto: Nippon Shinyaku Co., Ltd.: Research Funding. Tomita: Nippon Shinyaku Co., Ltd.: Research Funding. Nakao: Nippon Shinyaku Co., Ltd.: Research Funding. Hotta: Nippon Shinyaku Co., Ltd.: Research Funding.

Phase I Study of Rituximab, Lenalidomide, and Ibrutinib in Previously Untreated Follicular Lymphoma (Alliance 051103)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 471-471 ◽  
Author(s):  
Chaitra S. Ujjani ◽  
Sin-Ho Jung ◽  
Brandelyn Pitcher ◽  
Peter Martin ◽  
Steven I. Park ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Phase I ◽  
Follicular Lymphoma ◽  
Atrial Flutter ◽  
Median Time ◽  
Dose Level ◽  
Research Funding ◽  
Phase I Study ◽  
Grade 3

Abstract Background Chemoimmunotherapy for advanced stage follicular lymphoma (FL) is associated with acute and long-term toxicity; targeted therapy may improve efficacy and tolerability in this incurable, multiply-relapsing disease. The Alliance for Clinical Trials in Oncology previously demonstrated the efficacy of lenalidomide (20 mg D1-21/28) and rituximab (R2) in untreated FL patients (pts): ORR 93%, CR 72%, 2-yr PFS 89% (Martin P, et al. ASCO 2014), which supported the ongoing phase III RELEVANCE study of R2 vs. R-chemo. Attempts at improving R2 include incorporation of other agents. The BTK inhibitor, ibrutinib (I), demonstrated an ORR of 30-55% (Bartlett N et al. ASH 2014, Fowler N et al. ASH 2012) in relapsed/refractory FL. Based on these data, the Alliance designed a multicenter phase I study of this triplet as a front-line regimen for FL. Methods Pts with previously untreated, grade 1-3a FL, Stage III, IV, or bulky stage II disease, performance status < 2, and adequate organ function were eligible. Pts received R 375 mg/m2 on Cycle 1 D 1, 8, 15, 22 and at week 13, 21, 29, and 37 for 8 doses, lenalidomide (L) as per cohort dose on D1-21/28 for 18 months, and I as per cohort dose on D1-28/28 until progression or unacceptable toxicity. Dose escalation used a 3+3 design from a starting level of L 15 mg and I 420 mg (DL0) to DL2 (L 20 mg, I 560 mg). Pts received allopurinol 300 mg daily for tumor lysis prophylaxis. The primary endpoint was the recommended phase II doses (RP2D) of L and I for combination with R in previously untreated FL. The secondary endpoints were toxicity, pharmacokinetics, and preliminary efficacy. Once the MTD was determined, there was a 10-patient expansion cohort. Due to the known incidence of rash with L, grade 3 rash that resolved to < grade 2 in 10 days with supportive care including systemic corticosteroids was prospectively not included as a DLT. The incidence of grade 3/4 rash with R2 and ibrutinib are 8% and 3%, respectively. Results Twenty-two pts were enrolled between June 2013 - May 2015: DL0 (n=3), DL1 (n=3), DL2 (n=16). Median age was 53.5 years (range 36-81); 68% were male, 73% had grade 1/2 disease, 77% had Stage IV disease. By FLIPI, 18% were low risk, 55% were intermediate risk, and 27% were high risk. There were no dose limiting toxicities reported at any dose level. Dose level 2 (L 20 mg, I 560 mg) was found to be the RP2D. Grade 3/4 hematologic toxicities included neutropenia 18.2%, thrombocytopenia 4.5%, and anemia 4.5%. There were no grade 4 non-hematologic toxicities. Rash occurred in 73% of pts (grade 1/2: 41%, grade 3: 32%), typically during C1-4. Grade 3 rash was noted at every dose level: DL 0 (n=1), DL1 (n=1), DL2 (n=6); 4 pts were on allopurinol at time of grade 3 rash. Several pts successfully continued therapy with discontinuation of allopurinol and/or reduction in treatment dose. Other notable grade 3 non-hematologic adverse events included atrial flutter/chest pain (n=1), diarrhea (n=1), and febrile neutropenia (n=1). Other grade 1/2 non-hematologic adverse events included diarrhea 41%, fatigue 36%, nausea 27%, and AST/ALT elevation 18%. Elevenpts required dose reduction, 8 due to rash. The ORR for all pts was 91% (CR/CRu 63%). Seven pts with bone marrow involvement did not undergo a confirmatory bone marrow biopsy to rule out residual disease after achieving a negative PET/CT. The ORR at DL2 was 94% (CR/CRu 63%). Median time to response was 5.6 months (range 1.9-18.4), and median time on treatment was 12.6 months (range 3.4-23.4). At the time of this report, 3 pts have progressed (DL1 (n=1), DL 2 (n=2)). At median follow-up time of 12 months, the 12-month PFS for all pts was 84% (95% CI: 57-94%). The 12-month PFS for the DL2 cohort was 86% (95% CI: 54% - 96%). Twelve pts discontinued therapy: progression (n=2), adverse events [grade 3 rash (n=2), grade 3 atrial flutter (n=1), grade 3 diarrhea (n=1)], patient decision (n=3), new diagnosis of carcinoma (n=2), depression (n=1). Conclusion Although protocol-defined DLT was not observed, the combination of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma was associated with a significant incidence of rash, which may have been related to allopurinol, the individual study drugs, or drug interactions. Preliminary ORR data of the regimen were comparable to prior reports of the R2 regimen in this population. Efficacy of the combination, including CR rate, may be affected by the reduction in dose intensity. Disclosures Ujjani: Genentech: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide and ibrutinib have activity in follicular lymphoma but are not approved.. Martin:Janssen: Consultancy, Honoraria; Acerta: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bayer: Consultancy. Park:Teva: Research Funding; Seattle Genetics: Research Funding; Janssen: Other: travel. Blum:cephalon: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy. Czuczman:Celgene: Employment; Morphosys: Consultancy; Boehringer-Ingelheim: Other: ad board; Immunogen: Other: ad board. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy. Leonard:Weill Cornell Medical College: Employment; Genentech: Consultancy; Medimmune: Consultancy; AstraZeneca: Consultancy; Spectrum: Consultancy; Boehringer Ingelheim: Consultancy; Vertex: Consultancy; ProNAI: Consultancy; Biotest: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy; Mirati Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy. Cheson:Roche/Genentech: Consultancy, Research Funding; Teva: Research Funding; AstraZeneca: Consultancy; Ascenta: Research Funding; Spectrum: Consultancy; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Astellas: Consultancy; MedImmune: Research Funding; Pharmacyclics: Consultancy, Research Funding.

Romiplostim in Patients Undergoing Allogeneic Stem Cell Transplantation: Results of a Phase I/II Multicenter Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 65-65 ◽  
Author(s):  
Régis Peffault de Latour ◽  
Sylvie Chevret ◽  
Annalisa Ruggeri ◽  
Felipe Suarez ◽  
Laetitia Souchet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Septic Shock ◽  
Stem Cell ◽  
Adverse Events ◽  
Stem Cell Transplantation ◽  
Phase I ◽  
Median Time ◽  
Research Funding ◽  
Allogeneic Hsct ◽  
Grade 3

Abstract Background: Delayed platelet (plt) recovery and secondary thrombocytopenia occur in 5-25% of patients (pts) after hematopoietic stem cell transplantation (HSCT) and is of adverse prognostic significance. Plt transfusion to prevent bleeding remains a mainstay of therapy and role of thrombopoietic agents is not known. In this phase I/II multicenter open trial, we investigated the safety and efficacy of romiplostim (Nplate; Amgen, thousand Oaks, CA) for (pts) with transfusion-dependent thrombocytopenia after allogeneic HSCT (NCT01980030). Patients and methods: Adult pts undergoing standard of care allogeneic HSCT for any disease except myelodysplastic syndrome were eligible for this study 45 days or more after transplantation if they had plt count ² 20 x 109/L sustained for 7 days (² 50 x 109/L with a history of bleeding) or if they were plt transfusion dependent. Pts were excluded if they had abnormal liver function tests, serum creatinine ³ 176.8 μmol/L or had prior venous thrombosis. Pts were given weekly romiplostim for 12 weeks with intra-pt weekly dose escalation from 1µg/Kg to a maximum dose of 10 µg/Kg (with a dose reduction schema in case of plt overshoot). The study was composed of a 12-week treatment period. The primarysafety endpoint was the incidence of any grade 3 or 4 adverse events after HSCT, excluding those expected from the HSCT, as well as clinically significant bleeding events. The primary efficacy endpoint was time to reach a plt count above 50 x 109/L free of plt transfusion. Secondary endpoints were the durable plt response defined as a plt count above 50 x 109/L during 8 consecutive weeks independent of plts transfusions, the 1-year cumulative incidence (CumI) after HSCT of Graft versus host disease (GvHD), relapse and non-relapse mortality rates. All pts had a bone marrow biopsy before treatment and at one year. This study was approved by the research review board of the Hospital Saint-Louis (Paris, France). Statistical analysis was based on a modified intent-to-treat basis, excluding pts who did not fulfill the inclusion criteria. CumI were estimated using nonparametric methods, where deaths prior to the event of interest defined competing risks. Results: 25 pts were included in 4 different HSCT French units between April 2013 and November 2015. The analysis was restricted to 24 pts (one pt with plt count > 20x109/L after inclusion). All but one pt have malignant disease (13/24 acute leukemia). Donor type was related for 12 pts. Stem cell source was peripheral blood in 15 pts and bone marrow in 9 pts, myeloablative conditioning regimen was used in 17 pts. Median time between HSCT and romiplostim initiation was 85 days (interquartile range, IQR 63 - 117). Nineteen pts completed the 12 investigational injections of romiplostim, while five did not due to 3 deaths (1 post transplantation EBV-related lymphoproliferative disorder, 1 relapse and 1 septic shock), 1 boost of donor stem cells and one pt with plt count above 50 Giga/L after 8 injections. A total of 21 adverse events (grade 3, n=10; grade 4 n=11) considered possibly related to romiplostim were reported in 6 pts. Hematological complications appeared in 4 pts (2 neutropenia, 1 anemia and 1 pancytopenia) and liver dysfunction was present in 2 pts (mild cytolysis). Overall, romiplostim was well tolerated with a 6 months adverse events CI of 25.2% (95%IC 7.3 - 43.2). No bleeding event as well as no thrombotic complications appeared. None of the pts developed fibrosis 1 year post treatment (2 pts not yet at 1 year). After romiplostim initiation, 20 pts received a plt transfusion. The median time to reach a plt count above 50 x 109/L free of plt transfusion was 36 days (Figure 1), with required doses of 4 mg/Kg (IQR, 3-6). Fifteen pts obtained a durable plt response. A total of 17 and 12 pts experienced aGVHD and cGVHD, respectively, with 100 days CumI of aGVHD of 67% (95%CI, 47-87) and 1-year CumI of cGvHD of 55% (95%CI, 32-78), respectively. Six pts died during the study (1 PTLD, 1 relapse, 1 septic shock, 1 lung aspergillosis and 2 acute distress respiratory syndrome of unknown origin). CumI of non-relapse mortality was thus of 21% (95%CI, 7-42%). Conclusion: Romiplostim can be safely administered and improves plt count in pts with thrombocytopenia after allogeneic HSCT. The required dose to reach plt count above 50 x 109/L is 4 mg/Kg with a median time of 36 days. Research support was provided in part by Amgen. Disclosures Peffault de Latour: Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

Oral HDAC Inhibitor HBI8000 in Japanese Patients with Non-Hodgkin Lymphoma (NHL): Phase I Safety and Efficacy Results

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1827-1827 ◽  
Author(s):  
Makoto Onizuka ◽  
Kiyoshi Ando ◽  
Makoto Yoshimitsu ◽  
Takashi Ishida ◽  
S Yoshida ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Phase I Trial ◽  
Cell Lymphoma ◽  
Japanese Patients ◽  
Dose Cohort ◽  
Grade 3 ◽  
Anti Tumor Activity

Abstract Background: HBI-8000 is an orally bioavailable member of the benzamide class of histone deacetylase inhibitors (HDACi), that inhibits cancer-associated HDAC enzymes (Class I and IIb). HBI-8000 has anti-tumor activity through various mechanisms of action, including epigenetic reprogramming and immunomodulation. It was recently approved by the Chinese FDA under the name chidamide (Epidaza) for relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) with a recommended dose of 30 mg twice weekly (BIW). HBI-8000 is also being manufactured in the USA for clinical development outside of China. The preliminary results of a phase I trial of HBI-8000 to confirm the safety and maximum tolerated dose (MTD) in Japanese patients (pts) with advanced NHL are presented (NCT02697552). Methods: This is a multicenter, prospective phase I trial in Japan. Inclusion criteria: patients are eligible if they have histologically or cytologically proven NHL and no other standard therapy is available. The primary endpoint is the MTD based on the frequency of dose-limiting toxicities (DLTs) observed within 28 days of the first dose. Secondary endpoints include pharmacokinetic (PK) profile and anti-tumor activity. At the time of this abstract submission, the trial is still ongoing. Results: Thirteen out of 14 pts were eligible for the 1st cycle DLT assessment (6 pts in the 30 mg, 7 pts in the 40 mg cohort). Median age was 68 years, gender well balanced, and the majority of pts had ≥ 2 prior treatment regimens. Five pts had the diagnosis of adult T-cell leukemia-lymphoma (ATL), 2 pts presented with PTCL, 3 with diffuse large B-cell lymphoma (DLBLC), 2 with follicular lymphoma (FL), 1 with cutaneous T-cell lymphoma (CTCL), and 1 with marginal zone lymphoma. Overall, the treatment was well tolerated, and adverse drug reactions (ADRs) were predominantly hematologic, consistent with the previous experiences. There were 7 pts in the 40 mg dose cohort because one of the first 3 pts had to be replaced for incomplete dosing due to grade 3 hypertriglyceridemia which was not regarded as DLT by the Data Monitoring Safety Committee (DMC/SMC). In the 40 mg cohort, 2 pts were considered as DLTs by definition in the protocol: grade 4 neutropenia and grade 3 alanine transaminase (ALT) increase. Both pts were asymptomatic. The grade 4 neutropenia promptly resolved with the administration of G-CSF and the grade 3 ALT elevation resolved with dose interruption. The 30 mg dose cohort completed with no DLT after the 1st cycle in 6 pts. The following hematologic grade 3/4 toxicities were noted in the 40 mg dose cohort (N=7): leukopenia (2 pts, 29%), neutropenia (3 pts, 43%), and thrombocytopenia (3 pts, 43%). Non-hematologic ADRs included fatigue, nausea, diarrhea, decreased appetite, erythema and pyrexia. The preliminary pharmacokinetic (PK) results from the 3 patients in the 30 mg cohort, and 7 patients in the 40 mg dose cohort show inter-patient variability as expected of an oral agent. Mean half-life (t ½ ) was between16.5 and 20 hours (h) with a Tmax between 2.5 and 3.5h and consistent with previous findings. Mean Cmax and AUC increased with dose (30 mg: 210 ng/mL; 3660 h*ng/mL and 40 mg: 590 ng/mL; 7200 h*ng/mL). The patient with neutropenia as DLT presented with the highest exposure. Cardiovascular assessments including serial ECGs and troponin assessments did not reveal clinically relevant findings. Best overall response was noted in 40 mg BIW cohort (N=7): 1 CR (10%), 5 PR (30%), 1 SD (20%). Four of the partial responders were ATL patients. In the 30 mg BIW dose cohort, 4/6 patients had stable disease after the 1st cycle. Summary: In this phase l trial evaluating the safety of twice weekly 30 mg and 40 mg doses, HBI-8000 was well tolerated with expected toxicities that could be managed with dose interruptions/reductions. Tumor response results in pts who completed at least one cycle of treatment indicate some clinical benefit especially in pts who started with the 40 mg dose level. The DMC/SMC has provided an opinion that the 2 observed DLTs with HBI-8000 in the phase I trial were clinically manageable and that 40 mg BIW would be recommended as the dosage for subsequent phase II studies. Registration enabling phase II trials to evaluate efficacy and safety in R/R ATL pts (Japan) and R/R PTCL pts (Japan and Korea) are being initiated. Disclosures Ando: SymBio Pharmaceuticals: Research Funding. Yoshimitsu:HUYA Bioscience International: Research Funding. Ishida:Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Celgene KK: Research Funding; Bayer Pharma AG: Research Funding. Hidaka:Chugai-pharm: Research Funding. Nagashima:HUYA Bioscience International: Employment. Miyazato:HUYA Bioscience International: Employment. Schupp:HUYA Bioscience International: Employment. Rolland:HUYA Bioscience International: Employment. Gillings:HUYA Bioscience International: Employment. Lee:HUYA Bioscience International: Employment. Tobinai:Eisai: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; HUYA Bioscience: Honoraria; Janssen Pharmaceuticals: Honoraria, Research Funding; Kyowa Hakko Kirin: Research Funding; Mundipharma: Honoraria, Research Funding; Ono Pharmaceuticals: Research Funding; Servier: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Chugai Pharma: Research Funding; Celgene: Research Funding; Abbvie: Research Funding.

A Phase I Study of Ruxolitinib Plus Nilotinib in Chronic Phase CML Patients with Molecular Evidence of Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1892-1892 ◽  
Author(s):  
Kendra L. Sweet ◽  
Lori Hazlehurst ◽  
Eva Sahakian ◽  
John J. Powers ◽  
Lisa Nodzon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Phase I ◽  
Research Funding ◽  
Rt Pcr ◽  
Transcript Levels ◽  
Future Studies ◽  
Fatigue Severity ◽  
Grade 3 ◽  
The Impact

Abstract Background: BCR-ABL tyrosine kinase inhibitors (TKI) are the standard treatment for CP-CML. A subset of patients have profound molecular responses with BCR-ABL transcripts no longer detectable using RT-PCR (MR4.5). The ENESTnd trial compared nilotinib versus imatinib as frontline therapy in CML, and reported an increase in the cumulative incidence of MR4.5 of approximately 11% per year for the first five years in nilotinib treated patients. Discontinuation of TKIs is successful in 40-50% of patients who have a durable MR4.5. The phosphorylation of STAT3-Y705 via the JAK-STAT signaling pathway provides a protective microenvironment for the leukemic stem cells (LSC) and is a well described mechanism of resistance to TKIs. The residual LSCs likely contribute to relapse after TKI discontinuation. Data suggests that by simultaneously blocking JAK2 and TYK2, pSTAT3 is inhibited, thereby eliminating the protective environment in the bone marrow, and sensitizing the LSCs to TKIs. Ruxolitinib is a JAK2 and TYK2 inhibitor. Here we used ruxolitinib in combination with nilotinib in CP-CML patients to establish the maximal tolerated dose (MTD) of ruxolitinib, and obtain preliminary data about the impact of this combination on BCR-ABL transcript levels. Methods: This phase I, dose-escalation study used ruxolitinib plus nilotinib in CP-CML. All subjects were taking nilotinib prior to enrollment. Eligible subjects had a complete cytogenetic response (CCyR), yet had detectable BCR-ABL transcripts by RT-PCR at enrollment. We used a 3+3 design with 3 cohorts. The nilotinib dose remained unchanged, and the three doses of ruxolitinib were 5mg BID, 10mg BID and 15mg BID. Two additional subjects were treated at the MTD. Subjects remained on combination therapy for six months, at which point ruxolitinib was discontinued. RT-PCR was used to measure BCR-ABL transcript levels in the peripheral blood and/or bone marrow at baseline and every 3 months. The primary endpoint was the MTD of ruxolitinib. Secondary endpoints included toxicity assessment, incidence of MR4.5 at six months, change in fatigue severity scores and impact of ruxolitinib on pSTAT3/5 inhibition assessed with a plasma inhibitory assay (PIA) Descriptive statistics were used for baseline demographics, toxicity, MR4.5 and pSTAT3 levels. Subjects completed the fatigue severity index (FSI) questionnaire at baseline and every 3 months. A paired samples t-test was used to measure the difference in fatigue severity over time. Results: A total of 11 patients were enrolled between April 2013 and March 2016. Median age was 41 (25-63). 73% (n=8) were male. 36% (n=4) had received one TKI prior to nilotinib. The nilotinib dose was 300mg (n=8) or 400mg BID (n=3). Median time from diagnosis to enrollment was 11 months (6-135). Each cohort enrolled 3 subjects, and two additional subjects were treated at the MTD. There were no dose limiting toxicities; therefore the MTD/RP2D of ruxolitinib was 15mg PO BID. There were no grade 3/4 adverse events in any cohort, and no clinically significant cytopenias. Grade 1/2 transaminitis occurred in 1 subject in cohorts 1 and 2. No dose reductions were needed. At data cutoff, 9 subjects have completed six months on trial, and 2 remain active. Of those nine, 3 (33%) had ≥1-log reduction in BCR-ABL transcripts from baseline and 4 (44%) achieved MR4.5. One subject in cohort 1 progressed after three months and a kinase domain mutation analysis found a T315I mutation. FSI data available on seven subjects showed a non-significant decline in average fatigue severity from baseline (mean 2.78, SD 1.79) to follow-up (mean 1.86, SD 1.21), p=0.29. Results from the plasma inhibitory assay and updated results of all 11 subjects will be presented at the meeting after all subjects will have completed the trial. Conclusion: Our data suggest that ruxolitinib is safe and tolerable at 15mg PO BID when combined with nilotinib in CP-CML, and with no grade 3/4 adverse events reported, this should be considered the RP2D for future studies. The incidence of MR4.5 after six months was 44% which surpasses that of historical controls, although the sample size is small and a larger study is needed to confirm these results. The combination leads to an improvement in fatigue severity that did not reach statistical significance. This data serves as justification for future studies using ruxolitinib in combination with TKIs to determine the true impact on eradication of MRD in CP-CML. Disclosures Sweet: Karyopharm: Honoraria, Research Funding; Pfizer: Speakers Bureau; Incyte Corporation: Research Funding; Ariad: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Nodzon:Novartis: Speakers Bureau. Pinilla-Ibarz:Janssen: Consultancy, Honoraria; Pharmacyclics: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Novartis: Consultancy; Abbvie: Consultancy, Speakers Bureau.

A phase I/II study of biweekly XELIRI plus bevacizumab for patients with metastatic colorectal cancer as second-line chemotherapy (BIXER study): Reports of phase I part and interim analysis of phase II part.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 643-643
Author(s):  
Mitsukuni Suenaga ◽  
Satoshi Matsusaka ◽  
Eiji Shinozaki ◽  
Nobuyuki Mizunuma ◽  
Kiyohiko Hatake ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Interim Analysis ◽  
Japanese Patients ◽  
Recommended Dose ◽  
Grade 3 ◽  
Dose Limiting Toxicity

643 Background: Capecitabine is an oral fluoropyrimidine prodrug, which is converted to fluorouracil (5-FU) predominantly in the tumor cells. In Japan, capecitabine is mainly used in combination with oxaliplatin (XELOX) in treatment for metastatic colorectal cancer (mCRC) since its approval in 2009. The results of capecitabine plus Irinotecan (CPT) (XELIRI) with or without bevacizumab (BV) in EU or US patients were previously reported, but not in Japanese. Thus, we conducted this study to assess the safety and efficacy of XELIRI plus BV in Japanese patients with mCRC. Methods: Patients with prior chemotherapy including oxaliplatin and BV for mCRC, wild or hetero type of UGT1A1 *6*28 were eligible for this study. This was a phase I study composed of two steps, and dose limiting toxicity (DLT) was assessed during the first treatment cycle. Treatment comprised capecitabine 1,000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous CPT 180 mg/m2 on day 1, and BV 5mg/kg on day 1 every two weeks. To evaluate the initial safety, 3-6 patients received XELIRI+BV (CPT 150mg/m2) in step 1, and 6 patients received XELIRI+BV (CPT 180mg/m2) in step 2. If DLT occurred in 1 patient in step1, 3 patients would be newly added to step 1, and if in none of 3 or 1-2 of 6 patients, the step 2 would be started. If DLT occurred in less than or equal to 2 of 6 patients in step 2, phase II study would be proceeded, and if In more than 2 of 6 patients, phase II would be conducted at the recommended dose of step 1. Results: In step 1 and 2 of phase I, initial safety of 9 patients was confirmed without occurrence of DLT. Adverse events observed in step 1 and 2 were: neutropenia in 2 and 1; anorexia in 1 and 1; diarrhea in 1 and 1; stomatitis in 1 and 1; alanine or aspartate aminotransferase increased in 1 and 3, respectively. There was no grade 3 or greater adverse events. Conclusions: In mCRC patients with wild or hetero of UGT1A1*6*28 genotype, safety of biweekly XELIRI+BV was confirmed and recommended dose of CPT-11 was determined as 180mg/m2. Interim analysis of safety of phase II part will be reported at the meeting.

scholarly journals A Phase I/II Study of Lenalidomide Plus Obinutuzumab in Relapsed Indolent Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 348-348 ◽  
Author(s):  
Nathan H Fowler ◽  
Loretta J. Nastoupil ◽  
Collin Chin ◽  
Paolo Strati ◽  
Fredrick B. Hagemeister ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Marginal Zone ◽  
Advisory Board ◽  
Indolent Lymphoma ◽  
Advisory Committees ◽  
Grade 3

Background: Patients with advanced indolent non-Hodgkin lymphoma (iNHL) can develop chemoresistance and most relapse following standard therapy. Although multiple treatment options exist, most are associated with short remission or intolerable side effects. Lenalidomide activates NK cells ± T cells and leads to in vivo expansion of immune effector cells in NHL models. The combination of rituximab and lenalidomide (R2) in relapsed iNHL is highly active and was recently approved. Obinutuzumab is a glycosylated type II anti-CD20 molecule with enhanced affinity for the FcγRIIIa receptors leading to improved ADCC. The primary objective of this phase I/II study was to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide and obinutuzumab in relapsed indolent lymphoma. Methods: Patients with relapsed small lymphocytic lymphoma (SLL), marginal zone, and follicular lymphoma (gr 1-3a) were eligible. Patients enrolled in three predefined dose cohorts of lenalidomide (10mg,15mg, 20mg) given on days 2-22 of a 28 day cycle. Obinutuzumab was given at a fixed dose (1000mg) IV on days 1,8,15 and 22 of cycle 1 and day 1 of subsequent cycles for 6 cycles. The combination was given for up to 12 cycles in responding pts. Antihistamines were given in pts who developed rash. Prophylactic growth factor was not allowed. In the absence of progression or toxicity, single agent obinutuzumab was continued every 2 months for maximum of 30 months on study. Traditional 3+3 dose escalation was used with dose limiting toxicities (DLT) assessed during cycle 1. Once the MTD was established, 60 additional patients were enrolled in the phase II portion of the study. Adverse events were graded using CTCAE version 4.03. Results: 66 pts were enrolled between May 2014 until March 2019, and all are eligible for safety and response assessment. No DLTs were observed in dose escalation, and 60 pts were enrolled in the phase II portion of the study at 20mg of lenalidomide daily. Histologies included follicular lymphoma (FL) n=57, marginal zone n=4, SLL n=5. The median age was 64 (36-81), with 2 (1-5) median prior lines of treatment. For 53% of pts, the combination represented the third or greater line of treatment. The overall response (OR) rate for all pts was 98% with 72% attaining a complete response (CR). Eighteen pts (27%) had a partial response, and stable disease was noted in 1 (2%). At a median follow up of 17 months, 14 pts have progressed, with an estimated 24mo progression-free survival (PFS) of 73% (57-83% 95% CI). The estimated 24 mo PFS for ≥ third line pts was 63%. Twenty five pts (38%) remain on treatment and 95% remain alive at last follow up. The most common grade ≥ 3 non-hematologic toxicities included fatigue (5 pts), rash (4 pts), and cough (3 pts). Grade ≥3 neutropenia and thrombocytopenia occurred in 11 (17%) and 7 (11%) pts respectively. Two pts stopped treatment due to adverse events, including 1 transient bradycardia and 1 grade 3 fatigue. Conclusion: The combination of 20 mg of lenalidomide and 1000mg obinutuzumab is safe and effective in patients with relapsed indolent lymphoma. Adverse events appeared similar to our prior experience with lenalidomide and rituximab and were generally well tolerated. Overall response rates were high, with many pts achieving prolonged remission, including pts who had relapsed after 2 or more lines of prior therapy. Validation studies in the frontline and salvage setting are ongoing. Disclosures Fowler: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; MorphoSys: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; 47 Inc: Research Funding. Neelapu:Precision Biosciences: Consultancy; Merck: Consultancy, Research Funding; Cellectis: Research Funding; Novartis: Consultancy; BMS: Research Funding; Karus: Research Funding; Acerta: Research Funding; Poseida: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Celgene: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Allogene: Consultancy; Pfizer: Consultancy; Cell Medica: Consultancy.

scholarly journals Safety and Efficacy of Combined Ruxolitinib and Decitabine in Patients with Blast-Phase MPN and Post-MPN AML: Results of a Phase I Study (Myeloproliferative Disorders Research Consortium 109 trial)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1124-1124 ◽  
Author(s):  
Raajit K. Rampal ◽  
John O. Mascarenhas ◽  
Heidi E. Kosiorek ◽  
Dmitriy Berenzon ◽  
Elizabeth Hexner ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Phase I ◽  
Peripheral Blood ◽  
Research Funding ◽  
Phase I Trial ◽  
Fixed Dose ◽  
Hematologic Toxicity ◽  
Blast Phase ◽  
Grade 3

Abstract Background: The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) includePolycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). These stem cell disorders carry a propensity to evolve into acute myeloid leukemia (MPN-blast phase [BP] or post-MPN AML) with a dismal prognosis not meaningfully improved by conventional anti-leukemia therapy. Thus, MPN-BP is an urgent unmet clinical need. Responses in patients with MPN-BP to hypomethylating agents and single agent ruxolitinib have been reported. More recently, combination of ruxolitnib and decitabine has demonstrated synergistic activity in vitro in cells derived from patients with MPN-BP and from a murine model of MPN-BP (Rampal et al PNAS 2014). These observations led us to explore the safety of combined decitabine and dose escalation of ruxolitinib in MPN-BP. Objective: To establish the maximum tolerated dose (MTD) of ruxolitinib in combination with a fixed dose of decitabine (DEC-RUX). Methods: We conducted an open label Phase I trial in patients with MPN acceleration phase (AP) as defined by 10%-19% blasts in the peripheral blood or bone marrow or a diagnosis of MPN-BP as defined by ≥ 20% blasts in the blood or bone marrow, following a previous diagnosis of ET, PV or PMF. Patients were enrolled in a standard 3+3 phase I design with an MTD defined as a dose <33% DLT. Ruxolitinib was administered at doses of 10mg, 15mg, 25mg, or 50mg every 12 hours in combination with concurrent decitabine at a dose of 20mg/m2 daily intravenously over 5 days and repeated every 28 days. Adverse events were assessed using the NCI CTCAE v. 4.0. DLTs were defined as Grade 3 or higher non-hematologic toxicity events not clearly related to disease and grade 4 hematologic events with a bone marrow cellularity of ≤5% and no evidence of leukemia. Response assessment was carried out every cycle using modified Cheson criteria: CR required 0% peripheral blood blasts, WBC ≥4x109/L, hemoglobin ≥10g/L, and platelets ≥100x109/L; CRi required 0% peripheral blood blasts with incomplete count recovery; and PR required ≥50% decrease in peripheral blood blasts regardless of blood counts. Results: A total of 21 patients were accrued to study (Table 1). The median age was 63 years (range 48-88). 52% carried a diagnosis of MPN-AP, and 48% carried a diagnosis of MPN-BP. 29% of patients and 24% of patients had prior exposure to ruxolitinb and decitabine, respectively. The median number of cycles received varied from 10.5 cycles in the 10mg BID cohort to 2 and 2.5 cycles in the 25mg BID and 50mg BID cohorts, respectively (Table 2). The most common Grade 3/4 non-hematologic AEs observed were due to infection in all dosing cohorts. In terms of hematologic toxicity, treatment emergent Grade 3/4 anemia was observed in 1 patient in each of the 10mg BID, 15mg BID, and 50mg BID cohorts. Grade 3/4 leukopenia was observed in only 1 patient at the 50mg BID cohort, and Grade 3/4 thrombocytopenia was observed in 2 patients in the 10mg BID cohort and 1 patient in the 15mg BID cohort. DLT rate was below 33% for all dose levels so the MTD was not reached. The most common reason for ending study treatment was toxicity/adverse events (33%) followed by disease progression (22%). 9 patients died during study or follow-up. Of those, 5 (56%, 2 in 10mg BID cohort, 1 in 15mg BID cohort, 2 in 50mg BID cohort) died of infection, 3 (33%, 1 in each of 10mg, 25mg, and 50mg BID cohorts) of progressive disease, and 1 (11%, 25mg BID cohort) of hemorrhage. The median overall survival for patients on study was 10.4 months (95% CI 3.3 mo - not reached). CR/CRi as best response was observed in 7/21 patients (33%, 95% CI 15-57%; 2 CR, 5 CRi; Table 2). Conclusions: DEC-RUX combination therapy was safely administered to patients with MPN-AP/BP and an MTD was not reached. Based on pre-clinical data, observed safety profile, duration of treatment, and clinical responses in this phase I trial, the Recommended Phase II Dose of RUX was selected as 25mg BID for an induction cycle followed by 10mg BID in all ensuing cycles. Molecular and bone marrow pathology responses will be presented at the meeting. Disclosures Mascarenhas: Promedior: Research Funding; CTI Biopharma: Research Funding; Novartis: Other: DSMB , Research Funding; Janssen: Research Funding; Roche: Research Funding; Incyte: Other: Clinical Trial Steereing Committee, Research Funding. Hexner:Blueprint medicines: Consultancy; Novartis: Research Funding. Abboud:Alexion: Honoraria; Takeda: Honoraria; Novartis: Research Funding; Teva: Research Funding, Speakers Bureau; Pfizer: Research Funding; Merck: Research Funding; Pharmacyclics: Honoraria; Baxalta: Honoraria; Seattle Genetics: Research Funding; Gerson and Lehman Group: Consultancy; Cardinal: Honoraria. Levine:Novartis: Consultancy; Qiagen: Membership on an entity's Board of Directors or advisory committees. Mesa:Promedior: Research Funding; Novartis: Consultancy; Incyte: Research Funding; Celgene: Research Funding; Galena: Consultancy; Ariad: Consultancy; Gilead: Research Funding; CTI: Research Funding.

Phase I study of sunitinib (SU) in combination with pemetrexed (Pem) in patients (pts) with advanced solid tumors (ST)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14630-e14630
Author(s):  
K. Nakagawa ◽  
I. Okamoto ◽  
T. Shimizu ◽  
M. Miyazaki ◽  
J. Tsurutani ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Japanese Patients ◽  
Fixed Dose ◽  
Solid Malignancies ◽  
Grade 3 ◽  
Multitargeted Tyrosine Kinase Inhibitor ◽  
To Receive

e14630 Background: SU is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, FLT3, and CSR-1, and shows antitumor activities in several types of solid malignancies. Non-small-cell lung cancer (NSCLC) xenograft data indicate SU enhanced the antitumor activity of Pem. This phase I study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of combination therapy with the oral SU and Pem for Japanese patients with advanced ST. Methods: Pts with ST refractory to standard therapy were randomly assigned to receive either oral SU 50 mg/day for 2 weeks followed by 1 week rest (Schedule 2/1, S-2/1) or SU 37.5 mg continuous daily dose (CDD). Fixed-dose Pem (500mg/m2 IV) was administered on day1 every 21 days. A standard “3+3” design was employed in both treatment schedules and treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed. Results: A total of 12 pts (med. age 63 years, range 49–69; 10 Male/ 2 Female) have been enrolled (6 pts in the S-2/1 arm and 6 pts in the CDD arm). The most common cancer is NSCLC (9 pts, 75%). All patients completed their first cycle for DLT evaluation, and no DLTs were observed in either treatment arm. The most common toxicities were fatigue (n=8), anorexia (n=6), and thrombocytopenia (n=12). Treatment-related ≥ grade 3 adverse events (AEs) included fatigue (n=1), hypertension (n=1), neutropenia (n=4), leucopenia (n=3), thrombocytopenia (n=2), lymphopenia (n=2), and increased ALT (n=1). Three pts (S-2/1: 2, CDD: 1) required dose reduction of SU due to G3 toxicities. All toxicities were clinically manageable and reversible. One pt with NSCLC had a documented PR with cavity formation inside the tumor. Conclusions: SU 37.5 mg/day (CDD schedule) plus Pem 500mg/m2 every 21 days, and SU 50 mg/day (S-2/1 schedule) plus Pem 500mg/m2 every 21 days were well tolerated and associated with encouraging antitumor activity. [Table: see text]

scholarly journals Ibrutinib Plus Obinutuzumab and Venetoclax in Relapsed/Refractory Mantle Cells Lymphoma Patients, Results of the OASIS Phase I Clinical Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4158-4158 ◽  
Author(s):  
Steven Le Gouill ◽  
Franck Morschhauser ◽  
Krimo Bouabdallah ◽  
Guillaume Cartron ◽  
Rene-Olivier Casasnovas ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Phase I ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Primary Objective ◽  
Clinical Relapse ◽  
Advisory Committees ◽  
Grade 3

Abstract Background. Mantle Cell Lymphoma (MCL) drug resistance are highly dependent on B-cell-receptor signaling, Bcl-2 and the microenvironment. Ibrutinib inhibits both tumor cell proliferation and binding to the microenvironment. Venetoclax is a Bcl-2 inhibitor and Bcl-2 family members like Mcl-1 and Bcl-xL confers resistance to Venetoclax and are upregulated by the tumor microenvironment but downregulated by Ibrutinib (Touzeau, 2011, Chiron, 2015). Ibrutinib plus venetoclax has recently demonstrated high efficacy in relapsed/refractory (R/R) MCL (Tam et al NEJM 2018). Preclinical investigations show that microenvironment-dependent long-term expansion and drug resistance to venetoclax are counteracted by obinutuzumab (type II glycoengineered humanized anti-CD20 antibody) and obinutuzumab/venetoclax/ibrutinib is highly active against primary MCL cells. (Chiron Blood 2016). All together these findings gave the rational to investigate Obinutuzumab/Ibrutinib (step A) and Obinutuzumab/Venetoclax/Ibrutinib (step B) combinations. The OAsIs trial (NCT02558816) has been designed to assess the safety, tolerability and efficacy of these two combos in R/R MCL. DLTs were assessed during the first 2 months (step A) and 3 months (step B) of treatment. Methods: Oasis is a multicenter, non-randomized, phase I study. Step A evaluates the safety of obinutuzumab (1000mg IV C1D1, 8,15, C2-6 D1 and every 2 months until C24) plus Ibrutinib (560mg/d until progression) (n=9). Step B primary objective is to determine the MTD of obinutuzumab/venetoclax/ibrutinib. Venetoclax is administered from C2 (C2W1 100mg/d, C2W2 200mg/d, C2W3 400mg/d and C2W4-C6: 400, 600 or 800mg/d). A continual reassessment method is used to allocate venetoclax doses (3 patients-pts- per dose-level). Enrolment in step A and B for R/R MCL started in November 2015 and October 2016, respectively. Results. Step A (Obinutuzumab/Ibrutinib) (n=9). Median age at inclusion was 64y (range 58-82) and median lines of treatment prior to inclusion is 1 (1-4), including ASCT in 7 patients and allo-SCT in one case. Median time from diagnosis to C1D1 is 46.5m (18.4-103). Two pts presented with blastoid variant. One of nine step A patients presented TP53 mutation. Median time from diagnosis to C1D1 is 46.5m (18.5-103). During the first 3 months of treatment, there was no clinically relevant non-hematological grade 3-4 AEs. Eight grade 3-4 hematological AEs were reported in 4 pts (lymphopenia 4 ; neutropenia 4 ; thrombocytopenia 1). One patient progressed at end of C2 and died few weeks later while 7 (87%) were in CR according to Lugano criteria at end of C6. MRD status was assessed by ASO qPCR targeted to clonal immunoglobulin rearrangements in 6 /9 step A pts (one progressed before C6, data missing = 2). Of these, 4 were MRD negative in both blood and bone marrow after C6 (one remained MRD pos with no clinical relapse and underwent allo-SCT, one was not evaluated in BM). At the 12 months time point, the 3 evaluated pts remained MRD negative. With a median follow-up of 23,5m (8,9-31.6), 8 pts are alive (6 completed the 2y treatment program and are in CR). Step B (Obinutuzumab/ Ibrutinib/Venetoclax; Ven 400mg (n=3); at Ven=600mg (n=3) and Ven=800mg (n=6)). Median age at inclusion is 64.5y (range 45-74). Median lines of treatment prior inclusion is 2 (1-3), including ASCT in 8 patients. Five pts presented with blastoid MCL. TP53 status was assessed in 3/10 pts (2 ongoing). Of these 10, 3 presented TP53 mutations. Median time from diagnosis to C1D1 is 50.2m (12.8-123). The median follow-up for living pts (n=8) is 6.5m (2.5-15). During the first three months of treatment, there was no clinically relevant non-hematological grade 3-4 AEs. Twenty-nine grade 3-4 hematological AEs were reported in 7 pts (febrile neutropenia 1, neutropenia 4 ; thombopenia 4, anemia 2 and lymphopenia 3). At end of C2 , 3 achieved CR, 5 PR and 4 pts had PD. Among 9 pts assessed after C6, 5 patients were in CR (MRD analysis ongoing) Conclusion. No DLT has been reported in both step A and B. Both combinations are well tolerated and provide high disease control including CR at the molecular level. Oasis step C (obinutuzumab/venetoclax/ibrutinib) for untreated MCL pts is now open for inclusion since July 2018. Disclosures Le Gouill: Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria. Morschhauser:BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cartron:Sanofi: Honoraria; Janssen: Honoraria; Gilead Sciences: Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Gastinne:Millennium/Takeda: Honoraria. Davies:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; ADC-Therapeutics: Research Funding; Janssen: Honoraria; Karyopharma: Membership on an entity's Board of Directors or advisory committees. Herbaux:Gilead Sciences, Inc.: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Rule:Kite: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

A Pilot Study of Pomalidomide and Dexamethasone in Previously Treated Light Chain Amyloidosis Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3854-3854 ◽  
Author(s):  
Angela Dispenzieri ◽  
Morie A Gertz ◽  
Suzanne R. Hayman ◽  
Francis Buadi ◽  
Shaji Kumar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Median Time ◽  
Light Chain ◽  
Research Funding ◽  
M Protein ◽  
Autonomic Nerve ◽  
Nerve Involvement ◽  
Previously Treated ◽  
Grade 3

Abstract Abstract 3854 Poster Board III-790 Background Primary systemic amyloidosis (AL) is an incurable plasma cell disorder. Lenalidomide, especially in conjunction with dexamethasone, has been shown to be active in patients with multiple myeloma. Pomalidomide is a derivative of thalidomide that acts as an immunomodulator. Preliminary data in multiple myeloma demonstrate that this agent is highly active and well tolerated. Methods Eligible patients were accrued into an IRB approved treatment trial with pomalidomide and dexamethasone after signing informed consent. Pomalidomide (2 mg) and dexamethasone (40 mg) were scheduled to be taken orally, the former on a continuous schedule and the latter once weekly. All patients were instructed to take an aspirin daily. Patients were eligible if they had previously treated, biopsy proven, symptomatic AL. Patients were required to have measurable hematologic disease, defined as either a serum M-protein greater than 1 g/dL, a urinary M-protein greater than 200 mg/24-hours, or a serum immunoglobulin free light chain greater than 10 mg/dL. Other eligibility criteria included an ECOG PS>=2, adequate hematologic reserve (ANC>=1000/uL, platelets>=75/uL) and adequate renal function (creatinine <=2.5 mg/dL). They also were required to comply with contraceptive requirements. Patients were excluded if they had uncontrolled infection, another active malignancy, NYHA classification III or IV, a serum troponin T >0.1 ng/mL, >=grade 3 peripheral neuropathy, untreated active thrombosis, or other chemotherapy within 2 weeks of study enrollment. Thirty-four patients are to be enrolled to allow for 2 possible cancels and to provide 90% power to detect a true hematologic response rate of at least 20%. Between 11/24/08-7/28/09, 20 patients have been enrolled. Baseline characteristics and adverse events are available for 17 of the 20 enrolled patients. Results Median age was 63 years (range 52 78), with 60% male. The median time from diagnosis to study entry was 45 months (range 4.5-103). Eighty-two percent had cardiac involvement; 41% renal involvement; 18% peripheral nerve involvement; and 12% autonomic nerve involvement. The cardiac biomarker staging breakdown was: I, 13%; II, 56%; and III, 31%. Patients were heavily treated, with 100% having received prior alkylator (including prior transplant in 9), 44% prior lenalidomide, 31% prior thalidomide, and 37% prior bortezomib. Thirty-three percent of patients had non-hematological adverse events (AEs) >=grade 3 (severe) that were deemed to be at least possibly related to therapy. Thirty-three percent had >=grade 3 hematologic AEs. Neutropenia was most the most common severe hematologic AE; severe thrombocytopenia was observed in only 1 patient, and there was no severe anemia. The most common severe non-hematologic AE was fatigue, which was observed in 3 patients. The only other severe AEs, each of which was observed in one subject each, were pneumonia, weakness, dyspnea, and ascites. As of 8/14/09, 17 patients remain on active therapy. Median time on study is only 3.7 months (range 0.2-8.1). Three patients have discontinued therapy: two progressions; and one death 5 days into treatment, presumably due to cardiac amyloidosis. At the time of this writing response rates could not be calculated given the short follow-up, but hematologic responses have been observed, and details on efficacy will be presented at the meeting. Conclusions Pomalidomide is well tolerated in previously treated AL patients. More information about its activity will be provided at the meeting. Disclosures: Dispenzieri: Celgene: Research Funding. Gertz:Celgene: Honoraria. Kumar:Celgene: Research Funding. Rajkumar:Celgene: Research Funding. Witzig:Novartis: Research Funding. Greipp:Celgene: Research Funding. Fonseca:Celgene: Consultancy. Bergsagel:Celgene: Consultancy. Mikhael:Celgene: Research Funding. Roy:Celgene: Research Funding. Lacy:Celgene: Research Funding.

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