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

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.

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

Blood ◽

10.1182/blood.v126.23.471.471 ◽

2015 ◽

Vol 126 (23) ◽

pp. 471-471 ◽

Cited By ~ 3

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.

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Clofarabine (CLO) Has Single Agent Activity in Relapsed and Refractory Non-Hodgkin Lymphoma (NHL) Including Rituximab (R)-Refractory Patients (pts).

Blood ◽

10.1182/blood.v114.22.921.921 ◽

2009 ◽

Vol 114 (22) ◽

pp. 921-921

Author(s):

Chadi Nabhan ◽

Jacob David Bitran ◽

Walter Fried ◽

Angel G. Galvez ◽

Laura Magid ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Stem Cell Transplantation ◽

Phase I ◽

Phase Ii ◽

Research Funding ◽

Large Cell ◽

Median Number ◽

Low Grade ◽

Grade 3

Abstract Abstract 921 Background: CLO is a second generation nucleoside analogue with known activity in acute leukemia and myelodysplasia. As there is no standard therapy for refractory and transplant-ineligible relapsed NHL, and given the activity that purine analogues have in lymphoid malignancies, we sought to investigate the activity of CLO in this pt population regardless of histology. Methods: Eligible pts had measurable disease by CT and/or PET, ECOG performance status ≤ 2, and adequate renal, cardiac, liver, and bone marrow function (unless cytopenias were disease-related). CLO was given in the outpatient setting intravenously over 1-hour days 1-5 every 28 days for 6 cycles maximum. All pts received anti-viral and anti-pneumocystis jiroveci prophylaxis. First, we initiated a phase I portion using a standard 3×3 study design. CLO was given at 4 mg/m2 in cohort 1 with subsequent cohorts to be escalated by 2 mg/m2 each. Once the maximum tolerated dose (MTD) was determined, the phase II portion of this study was initiated at the MTD. All pts were followed until disease progression. Results: Thirty-three pts (18 females, 15 males) have been enrolled (7 in the phase I portion and 26 in the phase II), of which 29 are evaluable for response and/or toxicity (2 just started therapy, 1 taken off due to persistent cytopenias, and 1 withdrew consent). Median age was 69 years (range 27-88), median number of prior therapies was 3 (range 1-8), with 21% failing prior stem cell transplantation and 74% being R-refractory. Median time from original diagnosis to first CLO treatment was 36 months (range 6-216). Histologies included 12 diffuse large cell, 5 follicular, 5 small lymphocytic, 4 anaplastic large T-cell, and 1 each for Richter, mantle cell, marginal zone, peripheral T-cell, transformed, non-specific T-cell, and mixed histology. Median number of CLO cycles was 4 (range 1-6). Thrombocytopenia was the dose-limiting toxicity at 6 mg/m2 in 2/6 pts. The MTD recommended for phase II was 4 mg/m2. With a median follow up of 8 months (range 1-33), 7 pts (24%) showed complete response (CR) and 8 (27%) had partial response (PR) for an overall response rate of 51%. Four pts (13%) demonstrated stable disease and 10 (34%) showed progression. Median duration of response was 7 months (range 2-33+) with 6 pts continuing in remission including a patient who is undergoing stem cell transplantation. Median time to progression (TTP) was 3.5 months with median overall survival of 8 months. sEVEN pts (24%) remain progression-free. Of patients who were followed for more than 12 months, 60% were alive at 1-year. Five of the CR pts were of low-grade histology while only 2 had large cell lymphoma. All pts required growth factor support. Toxicity was mainly hematologic with 63% experiencing grade 3/4 thrombocytopenia, 60% grade 3/4 neutropenia, and 39% grade3/4 anemia, and 63%. Grade 3 and/or 4 non-hematologic toxicity included 2 (6%) with tumor lysis syndrome, 2 (6%) infectious episodes (pneumonia and bilateral cellulitis), 2 (6%) renal insufficiency, 2 (6%) fatigue, 1 (3%) seizure activity, 1 (3%) pleural effusion, and 1 hypokalemia (3%). No treatment-related mortality. Conclusions: CLO is active in heavily pre-treated B-cell NHL including R-refractory pts. Activity appears more pronounced in low-grade histology. The drug is well-tolerated and can be administered as an outpatient. Reversible myelosuppression is the major toxicity. Future studies in front-line in combination with R are warranted. Disclosures: Nabhan: Bayer: Honoraria, Research Funding, Speakers Bureau; Genzyme: Research Funding; Genentech: Honoraria, Speakers Bureau. Venugopal:Genzyme: Honoraria, Research Funding; Genentech: Honoraria, Research Funding, Speakers Bureau.

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

Blood ◽

10.1182/blood.v116.21.4964.4964 ◽

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.

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

Blood ◽

10.1182/blood.v128.22.1892.1892 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1892-1892 ◽

Cited By ~ 2

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.

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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 ◽

10.1182/blood.v128.22.1124.1124 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1124-1124 ◽

Cited By ~ 10

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.

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First Interim Analysis of HOVON 76: Lenalidomide Maintenance Following Non Myeloablative Allogeneic Stem Cell Transplantation in Patients with Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.2285.2285 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2285-2285 ◽

Cited By ~ 1

Author(s):

Monique C. Minnema ◽

Bronno van der Holt ◽

Marie Jose Kersten ◽

Sonja Zweegman ◽

Ellen Meijer ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Stem Cell ◽

Adverse Events ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Maintenance Treatment ◽

Acute Gvhd ◽

Bone Marrow Toxicity ◽

Grade 3

Abstract Abstract 2285 Poster Board II-262 The phase II HOVON 76 study examines the efficacy and safety of maintenance treatment with lenalidomide 10 mgr daily for 21 days in a 28 day cycle for a maximum of 24 months following non myeloablative allogeneic stem cell transplantation (NMA allo-SCT). Patients with newly diagnosed Multiple Myeloma who had received intensive treatment including autologous stem cell transplantation (auto-SCT) and have a HLA identical sibling can be included. The NMA allo-SCT is performed within 2-6 months after the auto-SCT after a conditioning regimen of 2Gy total body irradiation. Immunosuppression consists of mycophenolate mofetil 15 mg/kg twice daily until day +84 and ciclosporin 4.5 mg/kg twice daily until day +120. Lenalidomide is started between 1 and 6 months after allo-SCT but preferably within 3 months. Before start the absolute neutrophil count must be ≥ 1.0 × 109/L and platelets ≥ 75 × 109/L. Acute graft versus host disease (GvHD) is an exclusion criterion to start with Lenalidomide except when affecting the skin for less than 50%. If during treatment acute GvHD grade II or higher develops Lenalidomide is stopped and only re-initiated at a lower dose level of 5 mgr once GvHD resolves within 2 months. Dose reduction is also applied in case of other CTCAE grade 3 or higher toxicities, including bone marrow suppression. As of January 2008, 31 patients have been included from 5 academic hospitals. Patients are predominantly male (68%) and median age is 53 years (range 32-65). Partial or complete treatment data are currently available from 24 patients. The total of maximal CTCAE grade 3 and 4 toxicities reported were 50% and 17%, respectively and consists of blood/bone marrow toxicity grade 3 in 29% and grade 4 in 13%, metabolic/laboratory 25% and 4% and dermatology grade 3 in 8%. Seven serious adverse events have been reported, consisting of acute GvHD of the liver in 3 patients, 1 acute GvHD of the intestines, 1 pleural effusion after start of prednisone treatment for skin GvHD, 1 EBV reactivation with fever and malaise, 1 fever of unknown origin. All patients are alive at this moment. After 1 cycle of Lenalidomide 6/24 patients (25%) went off protocol treatment mainly due to the development of acute GvHD (n=4), 1 because of progression and 1 refusal to continue. After cycle 2 another 4 patients (17%) went off protocol treatment due to adverse events and/or dose reductions below 5 mgr. Consequently only 58% of patients could continue with Lenalidomide maintenance after cycle 2. Of those patients, 2 went off protocol due to disease progression, 2 because of GvHD and 2 because of adverse events/dose reductions below 5 mgr after cycles 3-11. In conclusion, the most encountered toxicity with Lenalidomide maintenance treatment after NMA allo-SCT is bone marrow toxicity and acute GvHD. The incidence of GvHD is not higher than expected from our previous NMA allo-SCT study HOVON 54 without Lenalidomide treatment. Because of this toxicity only 58% of patients could continue with treatment after cycle 2. An update of the results with longer follow up will be presented. Disclosures: Off Label Use: lenalidomide is indicated for treatment of relapse multiple myeloma, in this study it is used as maintenance treatment after first line therapy.

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Phase I/II Clinical Trial of Temsirolimus and Lenalidomide in Patients with Relapsed and Refractory Lymphomas

Blood ◽

10.1182/blood-2020-134750 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 43-44

Author(s):

Ajay Major ◽

Justin Kline ◽

Theodore G. Karrison ◽

Paul A S Fishkin ◽

Amy S Kimball ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Phase I ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

The Other ◽

Advisory Committees ◽

Grade 3

Background Targeting the PI3K/Akt/mTOR axis in relapsed lymphomas is of interest based on constitutive activation in many lymphoma subtypes, and has had varying degrees of success. We previously showed that the first generation mTOR inhibitor, temsirolimus (TEM), has activity across histologies with an acceptable toxicity profile (Smith, et al., JCO 2010). Lenalidomide (LEN) is currently approved for use in indolent non-Hodgkin lymphomas, and has several potential synergistic and overlapping targets with PI3K/mTOR/Akt inhibition. We designed this phase I/II clinical trial to evaluate the efficacy and tolerability of the combination of TEM and LEN in relapsed/refractory lymphomas. Methods The phase I dose-finding study utilized a standard "3+3" design and was open to all patients with mature B-cell malignancies. TEM was 25 mg IV weekly for all dose levels. LEN was dosed orally on D1-D21 every 28 days at three dose levels: 15 mg, 20 mg, and 25 mg. The phase II study accrued patients in a two-stage "minimax" design with stratification into three histologically-defined cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and other lymphomas. Primary endpoints of the phase II study were rates of complete (CR) and overall response (ORR), and secondary endpoints were duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results In the phase I study, 18 patients were enrolled and available for toxicity assessment. Patients were treated to intolerance, progression, or discontinuation at physician discretion. Of these, 15 patients were evaluable for dose-limiting toxicity (DLT) assessment. At dose level 3, there were 2 DLTs: grade 3 diarrhea and grade 3 HSV mucositis. Dose level 2 was thus established as the recommended phase II dose: TEM 25 mg weekly and LEN 20 mg on D1-D21 every 28 days. Of the 18 patients, there were 5 partial responses, 4 stable disease, 3 progressive disease, 4 on active treatment, and 2 not adequately assessed. The phase II study enrolled an additional 93 patients (Table 1): 39 DLBCL, 15 FL, and 39 other lymphomas which included 20 relapsed/refractory Hodgkin lymphoma (HL) patients. The median number of prior treatments was 4 (range, 1-14), and 31 patients (33%) had relapsed following prior autologous stem cell transplantation (ASCT). The median number of cycles delivered was 4 (range, 1-21). The FL cohort closed prematurely due to slow accrual. The ORR were 25.6% (12.8% CR) and 64.1% (17.9% CR) for DLBCL and other lymphoma cohorts, respectively (Table 2). The ORR for HL patients in the other lymphoma cohort, the majority of whom had relapsed after brentuximab vedotin (BV) and autologous stem cell transplantation (ASCT), was 80% (35% CR). Eight HL patients (40%) proceeded to allogeneic transplantation after TEM and LEN therapy. The high response rate in the other lymphoma cohort was sufficient to reject the null hypothesis of a 30% response rate under the minimax design. Median PFS was 7.0 mo (90% CI 3.5-8.0) and 7.0 mo (90% CI 4.6-9.9) for DLBCL and other lymphoma cohorts, respectively (Table 2). Median OS was 9.1 mo (90% CI 6.0-16.0) and 25.5 mo (90% CI 10.8-60.6) for DLBCL and other lymphoma cohorts, respectively (Table 2). Median DOR was 13.8 mo (90% CI 4.1-19.0) and 5.5 mo (90% CI 2.6-23.7) for DLBCL and other lymphoma cohorts, respectively (Table 2). Median PFS, OS and DOR for HL patients in the other lymphoma cohort were 9.2 mo (90% CI 4.6-25.5), 39.6 mo (90% CI 17.4-NR), and 8.1 mo (90% CI 5.1-38.3), respectively. Kaplan-Meier curves are displayed in Figure 1. Grade ≥3 non-hematologic adverse events (AE) related to treatment were uncommon, with no cases of pneumonitis and one grade 3 thromboembolism. Grade ≥3 hematologic AEs were common and reversible. Three Grade 5 AEs occurred (colonic perforation, myocardial infarction and sepsis). Conclusions Combination therapy with TEM and LEN demonstrated encouraging activity in heavily-pretreated and relapsed/refractory lymphomas. Survival in the other lymphoma cohort was primarily driven by favorable activity in relapsed/refractory HL. TEM and LEN may be a suitable option for treatment of HL after BV and ASCT, including as a bridge to allogeneic stem cell transplantation. Further study of PI3K/Akt/mTOR inhibition in combination with lenalidomide is warranted, particularly in relapsed HL. Disclosures Kline: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Kite/Gilead: Speakers Bureau. Kimball:Amgen: Current Employment; Amgen: Current equity holder in publicly-traded company. Petrich:Daiichi-Sankyo: Current Employment; AbbVie: Current equity holder in publicly-traded company. Smith:Celgene: Consultancy, Research Funding; Janssen: Consultancy; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; TG Therapeutics: Consultancy, Research Funding; FortySeven: Research Funding; Pharmacyclics: Research Funding; Karyopharm: Consultancy, Research Funding; BMS: Consultancy; Acerta: Research Funding. OffLabel Disclosure: Temsirolimus is FDA-approved for renal cell carcinoma.

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Phase I Study of Ipilimumab (Neutralizing Monoclonal Anti-CTLA4 Antibody) To Treat Relapse of Malignancy after Allogeneic Hematopoietic Stem Cell Transplantation: Evidence of Tumor Regression without Induction of GVHD.

Blood ◽

10.1182/blood.v108.11.410.410 ◽

2006 ◽

Vol 108 (11) ◽

pp. 410-410

Author(s):

Asad Bashey ◽

Bridget Medina ◽

Sue Corringham ◽

Mildred Pasek ◽

Ewa Carrier ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Phase I ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Negative Regulator ◽

Hematopoietic Stem ◽

Anti Cancer ◽

Grade 3

Abstract Failure of adoptive cellular immunotherapy is an important cause of relapse of malignancy (RM) and death following allogeneic hematopoietic stem cell transplantation (allo-HCT). CTLA-4 is a negative regulator of activated T-cells. Therapeutic blockade of CTLA-4 has demonstrated potent anti-cancer effects in animal models, and in patients with some solid tumors. Although CTLA-4 blockade may augment graft-versus-malignancy following allo-HCT, GVHD and other immune complications may also be increased. We report the results of a completed phase I dose-escalation trial of a neutralizing human monoclonal anti-CTLA-4 antibody (ipilimumab) in patients with RM following allo-HCT. Eligibility criteria included allo-HCT ≥90 days previously, > 50% donor T-cell chimerism, no prior grade 3/4 GVHD, no prophylaxis/therapy for GVHD for ≥ 6 weeks. Patients received a single dose of ipilimumab over 90 min. (Donor lymphocyte infusion (DLI) at a dose of 5 x 10e6 CD3 cells/kg was allowed 8 weeks following ipilimumab if no GVHD occurred and malignancy was present. Seventeen patients (13M, 4F; median age 42 (21–64); Hodgkin’s disease [HD] =7 Myeloma [MM]=3, CML=2, CLL=1, AML=1, NHL=1, Renal Ca =1, Breast Ca=1; 14 related donors, 3 unrelated; 5 myeloablative, 12 RICT) were treated at three centers (4 at dose-level 1 [DL1] 0.1 mg/kg, 3 at 0.33 mg/kg [DL2], 4 at 0.66 mg/kg [DL3], 3 at 1.0 mg/kg [DL4] and 3 at 3.0 mg/kg [DL5]). Six patients had failed prior DLI. Median time between BMT and ipilimumab was 374 d (125–2368). Seven patients received additional DLI. Ipilimumab was well tolerated in this setting. No DLT was seen at levels up to DL5. No infusional toxicity was seen. No patient developed clinically significant GVHD within 90 days following ipilimumab. One patient developed grade II acute GVHD of the skin 12 weeks following DLI. Two possible immune breakthrough events were documented: grade 3 polyarthropathy 14 weeks following ipilimumab, but also 6 weeks post DLI, which resolved with corticosteroid therapy, (AML, DL1, RhF+ pre- ipilimumab); grade 1 chemical hyperthyroidism with thyroid-stimulating antibody 6 weeks post ipilimumab (CLL, DL3). Two patients developed objective evidence of disease response after ipilimumab alone: regression of refractory lymphadenopathy in a patient with mantle cell NHL lasting 3m [DL4]; CR in a patient with HD ongoing at 2m [DL5].Both patients had failed prior DLI. Two additional patients demonstrated possible anti-cancer effects (reduction of PB and BM blasts in AML, DL1; maintenance of molecular remission in a CML patient given ipilimumab alone for 2.5 yrs despite stopping imatinib, DL1). PK data will be presented. This study shows that clinically active doses of ipilimumab (up to 3.0 mg/kg) can safely be administered to patients with RM following allo-HCT without inducing/exacerbating GVHD. Organ specific immune breakthrough events can be seen as in non-allo-HCT patients.

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Phase I/II Dose-Escalation Study of Tositumomab and Iodine I 131 Tositumomab for Relapsed/Refractory Classical or Lymphocyte-Predominant Hodgkin’s Lymphoma: Feasibility and Initial Safety

Blood ◽

10.1182/blood.v112.11.3059.3059 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3059-3059 ◽

Cited By ~ 5

Author(s):

Heather A. Jacene ◽

Yvette L. Kasamon ◽

Richard F. Ambinder ◽

Wayne Kasecamp ◽

Donna Serena ◽

...

Keyword(s):

Stem Cell ◽

Adverse Events ◽

Phase I ◽

Dose Escalation ◽

Hodgkin’S Lymphoma ◽

Hodgkin's Lymphoma ◽

Cd20 Expression ◽

Grade 3 ◽

Experienced Grade ◽

131I Tositumomab

Abstract Objective : CD20 has been recently recognized as a potential immunotherapeutic target in Hodgkin’s lymphoma (HL), being expressed in all malignant cells in lymphocyte-predominant HL (LPHL), a subset of classical HL (cHL), and in normal surrounding B-cells. Recent data also suggest that the cancer stem cell in cHL is phenotypically distinct from Reed-Sternberg cells and expresses B-cell antigens including CD20 (Jones RJ et al, Blood2006; 108: abstract 470). Given the single agent activity of the unlabeled antiCD20 monoclonal antibody, rituximab, in HL, we are conducting a phase I/II study of tositumomab and Iodine I 131 (131I-) tositumomab (BEXXAR ®, GlaxoSmithKline) for HL in the relapsed/refractory setting, regardless of tumor CD20 expression. We report on feasibility and initial safety. Methods : Separate dose-escalation studies were performed for patients with and without prior stem cell transplantation, starting at 55 and 75 cGy total body radiation doses (TBD), respectively. Dosimetry imaging studies were performed after administration of 450 mg tositumomab and 5 mCi 131I-tositumomab. Patients then received a single patient-specific therapeutic dosage of 450 mg tositumomab and 131I-tositumomab. The TBD was escalated or de-escalated based on a continual reassessment method (CRM). Results : Seven patients with relapsed/refractory disease (6 cHL, 1 LPHL; mean age 36 ± 9) have been enrolled. Four patients with cHL were negative for CD20 on malignant Reed-Sternberg cells and two had mixed expression. Three patients who had failed transplant received a 55 cGy TBD of 131I-tositumomab and three ineligible for transplant received 75 cGy. No dose-limiting toxicities were observed and based on the CRM, the TBD was escalated to 79 cGy for the post-transplant group and to 87 cGy for the no transplant group. To date, one in the next post-transplant cohort received 79 cGy and experienced grade 1 thrombocytopenia and grade 3 lymphopenia with count recovery. No adverse reactions occurred during infusion of unlabeled or radiolabeled tositumomab, and the agent was generally well-tolerated in all dosing cohorts. The expected hematologic adverse events were common and are summarized in the Table. No patients experienced grade 3 or 4 non-hematologic toxicity. One patient had grade 1 or 2 fever, chills, joint and muscle pain suggesting possible human anti-mouse antibody formation and immune complex mediated inflammation. One patient with LPHL had a complete response, two with cHL had stable disease (1 mixed CD20 expression, 1 CD20 negative) and 4 with cHL had progressive disease (1 mixed CD20 expression, 3 CD20 negative) at 12 weeks post-131I-tositumomab. Conclusions : Tositumomab and 131I-tositumomab can be safely administered to patients with relapsed/refractory HL. Major toxicities are hematologic, similar to its effect in patients with non-Hodgkin’s lymphoma. The CRM was used successfully for determining TBD for subsequent cohorts, and the transplant recipients have tolerated higher doses than those previously reported in non-Hodgkin’s lymphoma. These encouraging preliminary data support further dose escalation and suggests some therapeutic effect of tositumomab and 131I-tositumomab against HL. Hematologic Adverse Events All (n=7) Grade Range of Duration of Grade 3/4 Toxicity (days) 1/2 3 4 Thrombocytopenia 6 0 1 1 7–34 Neutropenia 2 1 0 1 7 Lymphopenia 7 2 3 2 1–35 Anemia 2 1 1 0 4

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Phase I Study of Bortezomib(Bz), Pegylated Doxorubicin(DOX) and Dexamethasone(dex); ( VDD) with Escalating Doses of Cyclophosphamide(Cy) in Patients with Newly Diagnosed Myeloma.

Blood ◽

10.1182/blood.v114.22.617.617 ◽

2009 ◽

Vol 114 (22) ◽

pp. 617-617

Author(s):

Melissa Alsina ◽

Rachid Baz ◽

Jose L Ochoa ◽

Jyotishankar Raychaudhuri ◽

Kara Kosakowski ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Phase I ◽

Research Funding ◽

Stem Cell Mobilization ◽

Cell Transplant ◽

Newly Diagnosed ◽

Long Term Outcome ◽

Cell Mobilization ◽

Grade 3

Abstract Abstract 617 Background: The VDD treatment regimen has been shown to be highly effective as initial therapy for multiple myeloma. Given the established synergy between bortezomib and alkylating agents, incorporating an alkylator to VDD may increase the depth of response and may improve long term outcome. We report the results from a Phase I trial combining VDD with escalating doses of cyclophosphamide ( CVDD) in patients (Pts) with newly diagnosed myeloma. Methods: Pts received Bz 1.0–1.3 mg/m2 on days 1, 4, 8, 11, DOX 30mg/m2 on day 4, Dex 20 mg on days 1, 2, 4, 5, 8, 9, 11, 12 and Cy 250-750 mg/m2 on day 1, for up to eight 21-day cycles, at four planned dose levels (Cy/Bz: 250/1.0, 500/1.0, 750/1.0, 750/1.3). Dose-escalation proceeded (three-pt cohorts) depending on dose-limiting toxicities (DLTs) grade 3 non-hematologic toxicity; thrombocytopenia with platelets <10,000/mm3 on >1 occasion despite transfusion support; Grade 4 neutropenia for >5 days and/or resulting in neutropenic fever; inability to receive cycle 2/day 1 dose due to drug-related toxicity). Pts with Grade 2 peripheral neuropathy (PNY) were excluded. Responses were assessed by International Working Group criteria. Pts with at least partial response ( PR) and standard risk cytogenetics could proceed to autologous stem cell transplant (ASCT) after 6 cycles. Responsive pts with high risk cytogenetics defined as the presence of one of the following at diagnosis; deletion of chromosome 13 by cytogenetics, hypodiploidy, or t (4;14), t(14;16) or deletion of 17 p by FISH, completed 8 cycles of therapy. Results: 26 pts have been enrolled to date: 12 in phase l, and 14 additional pts at the maximum planned dose (MPD). Median age 60 yrs, 62% men, 50% IgG MM, 81% with ISS stage II/III. Pts have received a median of 6 cycles; 17 have completed all 6-8 cycles, 1 has discontinued therapy. No DLTs were observed in the phase I portion of study. Dose reductions in cycle 2 and beyond have occurred in 31% of patients. Toxicities to date have been manageable, including all Grade 3/4 hematological toxicities (4-35%), Grade 3 hand foot syndrome( 15%), Grade 3 pneumonia (8%), Grade 3 UTI (8%), and Grade 3/4 metabolic (19%). There were no grade 3/4 PNY. There was 1 treatment-related mortality secondary to infection. The overall response rate in patients that have completed at least 4 cycles of therapy (ORR; ≥PR) is 90%, including 57% ≥VGPR, and 24% CR. ORR and VGPR rates were similar in patients with standard or high risk cytogenetics. Nine patients have proceeded to transplant and all have had successful stem cell mobilization with G-CSF alone. Conclusions: CVDD produces high quality responses and is well tolerated in newly diagnosed MM pts, regardless of their cytogenetic status or ISS stage. MPD has been reached at CY 750 mg/m2, Bz 1.3 mg/m2, DOX 30 mg/m2, and Dex 20 mg, with phase II enrollment ongoing. Stem cell mobilization has been successful in all pts, with transplant course in pts otherwise unremarkable. Updated efficacy will be presented at the meeting. Disclosures: Alsina: Millenium: Research Funding, Speakers Bureau; Ortho Biotech: Research Funding, Speakers Bureau.

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