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

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

Blood ◽

10.1182/blood.v128.22.65.65 ◽

2016 ◽

Vol 128 (22) ◽

pp. 65-65 ◽

Cited By ~ 2

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.

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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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Effect Of Treatment With The JAK2-Selective Inhibitor Fedratinib (SAR302503) On Bone Marrow Histology In Patients With Myeloproliferative Neoplasms With Myelofibrosis

Blood ◽

10.1182/blood.v122.21.2823.2823 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2823-2823 ◽

Cited By ~ 3

Author(s):

Catriona HM Jamieson ◽

Robert P Hasserjian ◽

Jason Gotlib ◽

Jorge E. Cortes ◽

Richard M. Stone ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Phase I ◽

Board Of Directors ◽

Clinical Benefit ◽

Research Funding ◽

Selective Inhibitor ◽

Advisory Committees ◽

Grade 3

Abstract Introduction Fedratinib, a JAK2-selective inhibitor, demonstrated clinical benefit through a reduction in splenomegaly and symptoms in patients with myelofibrosis (MF), including post-polycythemia vera MF (post-PV MF), post-essential thrombocythemia MF (post-ET MF) and primary MF (PMF), in Phase I and II studies (J Clin Oncol 2011;29:789; Haematologica 2013;98:S1113). Bone marrow fibrosis (BMF) has been associated with splenomegaly and cytopenias (Ann Hematol 2006;85:226). Hence, stabilization and/or reversal of BMF remain important therapeutic goals. This report represents an exploratory analysis of sequential BMF data from patients with MF in an open-label Phase I/II study to evaluate the long-term effects of orally administered fedratinib (TED12015; NCT00724334). Methods Patients with intermediate or high-risk MF (Mayo Prognostic Scoring System) received fedratinib therapy in consecutive cycles (1 cycle = 28 days) as long as they derived clinical benefit. Bone marrow trephine biopsies were performed at baseline and after every 6 cycles. Hematoxylin and eosin, reticulin, and Masson's trichrome staining of core biopsy slides were used to grade BMF on a scale from 0 to 3 using the 2008 WHO MF grading criteria. BMF was graded independently in a blinded fashion by 3 hematopathologists. BMF grades were established as long as at least 2 of the 3 pathologists agreed independently. Changes in BMF grade from baseline were categorized as improvement (≥1 grade reduction), stabilization (no change), or worsening (≥1 grade increase). Results Of the 43 patients enrolled in the TED12015 study, the median fedratinib dose received was 473 (range 144–683) mg/day and median treatment duration was 32.3 (range 7–61) cycles. Bone marrow biopsies at baseline and at least one other time point were available for 21/43 (49%) patients, whose baseline characteristics were: median age 61 years (range 43–85); 57% male; 38% high-risk MF by WHO 2008 criteria (Leukemia 2008; 22:14); and 90% JAK2V617F positive. A consensus grade was achieved for 96% of the samples. At baseline, 2, 10, and 9 patients had grade 1, 2, and 3 BMF, respectively. Changes in BMF grade from baseline are shown in the figure. BMF improvement with 1 grade reduction was observed in 8/18 (44%) patients at Cycle 6. By Cycle 30, 4/9 (44%) evaluable patients had BMF improvement, including 2 patients with improvement by 2 grades and 2 patients with improvement by 1 grade. Of patients with Grade 3 BMF at baseline, 6/9 (67%) exhibited 1 grade improvement at Cycle 6. Two patients had 2 grades of BMF reduction from baseline during treatment (grade 3 to 1, and grade 2 to 0, both at Cycle 12), and the latter achieved a complete clinical remission at Cycle 30 assessed by IWG-MRT response criteria. The two patients who experienced complete reversal of BMF to grade 0 (one from grade 2 and one from grade 1) had normalization of not only hemoglobin level but also white blood cell and platelet counts at Cycle 18. Conclusions These exploratory analyses suggest that a proportion of patients treated long-term with fedratinib demonstrate stable or improved BMF. The disease modifying impact of fedratinib on BMF changes will be further assessed in a randomized, placebo-controlled Phase III clinical trial (JAKARTA; NCT01437787). This study was sponsored by Sanofi. Disclosures: Jamieson: J&J, Roche: Research Funding; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Hasserjian:Sanofi, Inc: Consultancy. Gotlib:Sanofi: Travel to EHA 2012, Travel to EHA 2012 Other; Sanofi: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau. Thiele:AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Consultancy; Novartis, Shire: Research Funding; AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Honoraria. Rodig:Ventana/Roche Inc.: Research Funding; Daiichi-Sankyo/Arqule Inc., Ventana/Roche Inc., Shape Pharmaceuticals Inc.: Consultancy. Patki:Sanofi: Employment. Wu:Sanofi: Employment. Wu:Sanofi: Employment. Pozdnyakova:Sanofi: Honoraria; Sanofi: Consultancy.

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

Blood ◽

10.1182/blood-2019-131045 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 348-348 ◽

Cited By ~ 6

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.

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Phase I Study Results of Gimatecan In the Treatment of Myelodysplastic Syndrome (MDS)

Blood ◽

10.1182/blood.v116.21.1883.1883 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1883-1883

Author(s):

Naveen Pemmaraju ◽

Hagop Kantarjian ◽

Guillermo Garcia-Manero ◽

Stefan Faderl ◽

Alessandra Ferrajoli ◽

...

Keyword(s):

Bone Marrow ◽

Phase I ◽

Standard Therapy ◽

Research Funding ◽

Topoisomerase I ◽

Clinical Activity ◽

Hypomethylating Agents ◽

Monosomy 7 ◽

Study Results ◽

Grade 3

Abstract Abstract 1883 Background: Hypomethylating agents (decitabine and 5-azacytadine) are standard therapy for patients (pts) with MDS. Responses are frequently characterized by hematologic improvement with CR rates usually <10%, and responses generally have a median duration of less than 12 months. No standard therapy is available for patients who fail therapy with hypomethylating agents. Topotecan, a topoisomerase I (topo I) inhibitor has previously shown some clinical activity in MDS, although with significant toxicity. We hypothesized that Gimatecan, an oral topo I inhibitor, would be better tolerated, more convenient for patients, and have less toxicity than intravenous topo I inhibitors in treatment of MDS. Objectives: To define the maximum tolerated dose (MTD), dose limiting toxicity (DLT), and efficacy of treatment with gimatecan in pts with MDS. Methods: This was a Phase I trial conducted in relapsed/refractory pts failing at least one prior treatment. Inclusion criteria: MDS pts with greater than or equal to 5% blasts or IPSS risk group intermediate (1 or 2) or high (i.e., IPSS 0.5 and higher), age 18 years and older, ECOG PS 0–2, and adequate liver and renal function. Exclusion criteria: Pts who have received only supportive care or transfusions for MDS, pts with prior chemotherapy within 4 weeks of starting study, uncontrolled ongoing systemic illness including congestive heart failure, and women who or pregnant or breast-feeding. Hydroxyurea usage was allowed up to 48 hours prior to start of therapy. Gimatecan was administered orally once daily for 5 days every 28 days. Dose levels explored were 0.6mg, 1.0mg, 1.5mg, and 1.75mg based on a modified Fibonacci schedule. DLTs were monitored as events occurring within first 4 weeks of treatment (1st cycle) and were defined as any non-hematologic grade 3 or 4 toxicity or as grade 33 neutropenia and/or thrombocytopenia with a hypocellular bone marrow and no marrow blasts lasting for 6 weeks or more after the start of a course. All toxicities graded by NCI Common Terminology Criteria 3.0. Results: A total of 16 pts were included. Median age was 62.5 years (range, 37–83). Patients had received a median of 1.5 prior therapies (range,1-5). Cytogenetic analysis revealed: 4 diploid, 4 complex abnormalities, 3 monosomy 7, and 5 with other abnormalities. Median baseline bone marrow blasts prior to enrollment was 5%, with 4 pts having >10%. Baseline neutrophil count was <1×109/L in 8 pts (50%) and platelets <100×109/L in14 pts (88%). IPSS was INT-1 in 7, INT-2 in 6, and High in 3. Six pts had prior malignancies. Only one patient had grade 3 toxicity (mucositis) at a dose of 1.5 mg daily dosing that was considered related to the study drug. No other DLT were observed and an MTD was not defined. The study was ended prematurely because of drug availability. Other toxicities possibly related to gimatecan (all grade 1–2) were: nausea (4), vomiting (2), alopecia, (2) and one each diarrhea, dyspnea, mucositis, peripheral neuropathy, joint pain, and skin rash. Three patients had transient responses, all of them hematologic improvement only: one patient had improvement in hemoglobin and platelets, one in neutrophils and platelets, and one in neutrophils only. There were no pts with CR, CRp/CRn, or PR. Three patients died on study or within one week of discontinuation from study. Conclusions: Gimatecan is well tolerated in patients with MDS but shows minimal clinical benefit for patients with MDS at the doses used. Disclosures: Off Label Use: gimatecan in MDS. Faderl:Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes:Pfizer: Consultancy, Research Funding; BMS: Research Funding; Novartis: Research Funding.

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Phase I Trial of Combination Therapy with 90y Ibritumomab Tiuxetan and Gemcitabine in Patients with Non-Hodgkin's Lymphoma, Final Report.

Blood ◽

10.1182/blood.v120.21.2753.2753 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2753-2753

Author(s):

Hossein Borghaei ◽

Russell J. Schilder ◽

Samuel Litwin ◽

Michael Millenson ◽

Adam D Cohen ◽

...

Keyword(s):

Bone Marrow ◽

Phase I ◽

B Cell ◽

Research Funding ◽

Phase I Trial ◽

Hodgkin's Lymphoma ◽

Low Grade ◽

Ibritumomab Tiuxetan ◽

Non Hodgkin's Lymphoma ◽

Grade 3

Abstract Abstract 2753 Y90-ibritumomab tiuxetan radioimmuotherapy (Y90-RIT) is an effective therapy against CD20+ lymphomas approved for use in patients (pts) with relapsed/refractory low grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL), as well as consolidation of first remission low grade NHL. Gemcitabine (Gem) also is active against NHL and is a potent radiation sensitizer. We conducted a phase I trial to assess the safety of concomitant administration of Y90-RIT and G in patients with NHL. Eligible pts had any histologic subtype of recurrent CD20+ NHL (not candidates for potentially curative options) and met standard Y90-RIT criteria: platelets 150,000/ul; < 25% bone marrow involvement by lymphoma; prior radiation to <25% of bone marrow and no prior bone marrow or stem cell transplant. Initially, nine pts in three cohorts were treated with 250 mg/m2 of Gem IV on days 1 and 8 of the Y90-RIT treatment program (rituximab + 111In-ibritumomab day 1 and rituximab + Y90 ibritumomab day 8), with Y90-RIT at 0.2, 0.3 or 0.4 mCi/kg respectively. We confirmed that a standard Y90-RIT dose of 0.4 mg/kg can be safely administered with Gem at 250 mg/m2. In subsequent cohorts, escalating doses of Gem were used according to a Bayesian based system. Response evaluation was by CT scan criteria (IWG JCO 1999). Between 2004–2012, twenty pts were treated (10 follicular (FL), 3 marginal zone (MZL), 7 diffuse large B-cell (DLBCL) lymphomas). Median age is 71.5 (range 55–82). The median number of prior treatments is 3 (range 1–6). Gem doses ranged from 250 mg/m2 to the maximum planned dose of 800 mg/m2 on days 1 and 8. One DLT occurred (thrombocytopenia) and MTD was not reached. Treatment-related toxicities consisted of grades 3 (N=11) and 4 (N = 2) neutropenia, grade 3 (N=11) leukopenia, grades 3 (N=14) and 4 (N=8) thrombocytopenia. One grade 3 infection occurred, unrelated to study drugs. All pts recovered counts to ≤ grade 1 by week 12. The only grade 3 non-hematologic toxicity was elevated bilirubin in 1 and increased GGT in 2 pts. Best responses seen include: 3 CR/CRu, 7 PR, 4 SD, 4 PD and 2 patients still in follow up. Median PFS for all patients is 192 days. Median PFS for all non-DLBCL histologies (10 FL and 3 MALT) is 202 days and for DLBCL is 77 days. Conclusion: Standard dose Y90-RIT combined with gemcitabine days 1 and 8 is safe and well-tolerated at doses up to 800 mg/m2 in pts with relapsed/refractory NHL. Further investigation with the established doses in non-DLBCL histologies is warranted. Disclosures: Borghaei: Biogen-IDEC: Research Funding. Off Label Use: 90Y Ibritumomab Tiuxetan in relapsed DLBCL. Schilder:Biogen-IDEC: Research Funding. Smith:Biogen-IDEC: Research Funding.

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Plerixafor, G-CSF and Azacitidine For The Treatment Of MDS: Results Of a Phase I Trial

Blood ◽

10.1182/blood.v122.21.2816.2816 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2816-2816

Author(s):

Mark A. Schroeder ◽

Marcus Grillot ◽

Teresa Reineck ◽

Meagan A Jacoby ◽

Rizwan Romee ◽

...

Keyword(s):

Cell Cycle ◽

Bone Marrow ◽

Phase I ◽

Research Funding ◽

Phase I Trial ◽

Response Rates ◽

Response To Treatment ◽

Hematologic Toxicity ◽

Oncology Research ◽

Grade 3

Abstract Azacitidine has been shown to prolong survival and delay progression to leukemia in intermediate-2 and high risk myelodysplastic syndrome (MDS) in a randomized study compared to best supportive care. The combination of G-CSF and plerixafor is synergistic in increasing the release of stem and progenitor cells from the bone marrow through disruption of critical bone marrow stromal interactions including the CXCR4 / CXCL12 axis. The interaction of bone marrow stromal cells with the MDS tumor clone may play a roll in pathogenesis and response to treatment. We hypothesized that resistance of MDS to azacitidine may be related to MDS tumor and BM-stromal cell interactions, and disruption of these interactions by treatment with plerixafor + G-CSF could enhance sensitivity to azacitidine, thus improving complete and partial response rates. We conducted a phase I trial to investigate the safety and tolerability of plerixafor + G-CSF in combination with azacitidine in adult (18 years or older) MDS patients. Secondary objectives included response rates and biologic correlates evaluating: kinetics, phenotype, cell cycle status and kinetics of mobilization of MDS blasts compared to normal stem cells in select patients with informative cytogenetics. Major inclusion criteria included MDS defined by WHO criteria, 5 – 20% blasts on bone marrow aspirate, and at least one cytopenia in one cell lineage. Subjects receiving prior hypomethylating therapy were allowed. A standard 3+3 trial with 3 cohorts (320, 440, and 560 mcg/kg/day SC) was conducted. Dose limiting toxicity was defined as grade 3 or higher non-hematologic toxicity and hematologic toxicity of leukostasis or tumor lysis. Myelosuppression, infection, grade III nausea, fatigue, weight loss and electrolyte abnormalities were not considered dose limiting. Subjects initially received G-CSF 10 mcg/kg subcutaneous (SC) daily D1 – D8, plerixafor SC daily D3 – D8 and azacitidine 75mg/m2 SC D3 – D8, 4 hours after plerixafor administration. The trial was amended after the first 3 subjects to reduce G-CSF dose and administration to 5 days. Results Two of the first three subjects enrolled in cohort 1 (320 mcg/kg/d plerixafor) had leukocytosis. The trial was amended to reduce the G-CSF dose (10 mcg/kg to 5 mcg/kg) and duration (8 days to 5 days) because of this. One subject had symptoms of leukostasis with a WBC reaching nearly 100K/uL and a subsequent subject developed hyperleukocytosis (WBC = 80K/uL) without leukostasis. The trial was amended to reduce the G-CSF to 5 days concurrent with plerixafor and azacitidine along with defining dose holding parameters for G-CSF and plerixafor if the peripheral blood WBC exceeded 40K/uL or if absolute blast count exceeded 10K/uL. Since amendment of the trial, 64 subjects have been screened and 20 subjects have been enrolled and are evaluable. Subjects included 65% males, median age 67, and MDS diagnosis at study entry including 6/18 (33%) RAEB-1 and 12/18 (67%) RAEB-2. 5/18 subjects (28%) had plerixafor and G-CSF held during treatment because of leukocytosis. 9/18 subjects (50%) had received no prior treatment for their MDS. DLTs were experienced in Cohort 1 related to thrombocytosis (n =1) and in Cohort 2 related to atrial fibrillation (n = 1) with near syncope. Major non-hematologic grade 3 or 4 adverse events included epistaxis, hypocalcemia, GI bleed, headache, dyspnea, infection with neutropenia, and bone pain. The MTD was determined to be 560mcg/kg plerixafor SC with no subjects (n = 6) in this cohort experiencing a DLT. The median number of cycles completed was 3. Reasons for stopping treatment included progression to leukemia (n = 6), physician choice (n = 2), withdrawal of consent (n = 1), adverse event (n = 2). Best response in those evaluable after completing 2 cycles of treatment (n = 14) showed marrow CR in 5/14 (36%, 3 in those not previously treated for MDS), stable disease in 5/14 (36%) and progressive disease 4/14 (29%). Conclusion Plerixafor plus G-CSF in combination with azacitidine was well tolerated in the studied MDS patients when given over 5 days and may be associated with encouraging response rates. Correlative studies are ongoing to evaluate changes in cell cycle, apoptosis and preferential mobilization of blasts using this regimen. We are currently enrolling an expanded cohort of 7 subjects at the MTD dose to evaluate preferential mobilization of blasts with plerixafor alone in cases using informative cytogenetics. Disclosures: Schroeder: Celgene: Research Funding; Sanofi Oncology: Research Funding. Off Label Use: Plerixafor and G-CSF for the treatment of MDS. Welch:Eisai: Research Funding. Stockerl-Goldstein:Millennium: Speakers Bureau; Celgene : Speakers Bureau.

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PRM-151 in Myelofibrosis: Durable Efficacy and Safety at 72 Weeks

Blood ◽

10.1182/blood.v126.23.56.56 ◽

2015 ◽

Vol 126 (23) ◽

pp. 56-56 ◽

Cited By ~ 25

Author(s):

Srdan Verstovsek ◽

Ruben A. Mesa ◽

Lynda M Foltz ◽

Vikas Gupta ◽

John O. Mascarenhas ◽

...

Keyword(s):

Bone Marrow ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Negative Slope ◽

Computer Assisted ◽

Jak Inhibitor ◽

Efficacy And Safety ◽

Advisory Committees ◽

Grade 3

Abstract Background: PRM-151 (PRM) is a recombinant form of pentraxin-2, an endogenous human protein that acts at sites of tissue damage, inducing macrophage differentiation to prevent and reverse fibrosis. 27 patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, or post-polycythemia vera MF and Grade 2 or 3 bone marrow (BM) fibrosis enrolled in the first stage of a 2-stage adaptive trial in which PRM-151 10 mg/kg IV was administered for 24 weeks in four different arms: PRM-151 QW (n=8), PRM-151 Q4W (n=7), PRM-151 QW + ruxolitinib (RUX) (n=6), or PRM-151 Q4W + RUX (n=6). At 24 weeks, reductions in BM fibrosis, improvements in hemoglobin (Hgb) and platelets (PLT), decreases in symptoms (MPN-SAF Total Symptom Score [TSS]), and modest reductions in spleen size by palpation were observed in all arms, with a favorable safety profile (Verstovsek, ASH 2014, Abstract 713). Patients experiencing clinical benefit were allowed to continue beyond 24 weeks. We now report efficacy and safety in 13 patients who have completed at least 72 weeks of treatment. Bone marrow fibrosis status by morphologic WHO grading and computer-assisted image analysis (CIA) are available up to 48 weeks in some patients, as assessed by central hematopathologist reviewers blinded to patient, treatment, and timepoint. BM data through 72 weeks is pending. WHO response was defined as ≥1 grade reduction in MF grade at any time and CIA response was defined as a decrease in the % fibrosis compared to baseline with a negative slope > 1. (Pozdnyakova, EHA 2015, Abstract P677). Baseline Demographics (N=13): Median age 60 (51-76); 46% DIPSS Int-1, 54% DIPSS Int-2; 62% PMF, 15% post-ET MF, 23% post-PV MF; 46% grade 3 BM fibrosis, Hgb < 100 g/L in 38%, PLT < 100 x 109/L in 69% and <50 x 109/L in 38%; 31% JAK inhibitor-naive and 69% received a prior or current JAK inhibitor. Study treatment (N=13): In the first 24 weeks, treatment was PRM-151 QW (n=5), PRM-151 Q4W (n=3), PRM-151 QW + RUX (n=2), PRM-151 Q4W + RUX (n=3). At 28 weeks, treatment changed to PRM-151 QW (n=2), PRM-151 Q4W (n=7), and PRM-151 Q4W + RUX (n=4), with 1 patient stopping RUX for thrombocytopenia. Both PRM-151 QW patients switched to PRM-151 Q4W after 40 and 52 weeks. Two patients missed weeks 64 and 68 due to complications of a motor vehicle accident and abdominal surgery, respectively, but are continuing treatment as of week 72. BM (n=13): 54% had a morphologic response, and 85% had a CIA response. Hgb (g/L): In 5 pts with baseline Hgb < 100, median Hgb increased by 24% from 86 (range 77-97) at baseline to 107 (range 71-113) at Week 72. 3 of 5 patients who were receiving transfusions at baseline became transfusion independent, with durations of 32-60 weeks. (Figure 1) PLT (x 109/L): In 9 pts with baseline < 100, median PLT count increased by 37% from 38 (range 10-89) at baseline to 52 (range 26-159) at Week 72. All 4 patients who were receiving PLT transfusions at baseline became transfusion independent, with durations of 24-44 weeks. (Figure 2) Symptoms (N=13): 69% and 38% of patients had ≥ 50% and 100% reductions from baseline in TSS between 24 and 72 weeks, with durations of up to 48 and 12 weeks, respectively. (Figure 3) Spleen (N= 9 with palpable spleens at baseline): 50% of pts had ≥25% reduction, 2 of whom had ≥50% reduction lasting > 12 weeks. (Figure 4) Safety (N=13): Most common adverse events (AEs) regardless of relatedness were fatigue (4), nausea (3), fever (3), cough (2), diarrhea (2), tooth infection (2), headache (2), upper respiratory infection (2), hyperglycemia (2), and hyperuricemia (2). There were 13 possibly or probably related adverse events in 3 patients from beginning of study through 71 weeks, 11 Grade 1, 1 Grade 2 and 1 Grade 3, with no event occurring in > 1 patient. There were no related serious AEs in these patients. Conclusion: In 13 patients completing at least 72 weeks, PRM-151 treatment was well tolerated, and improvements in Hgb, PLT, symptoms and spleen appeared to increase with longer treatment duration. Disclosures Mesa: Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Genentech: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Pfizer: Research Funding. Foltz:Promedior: Research Funding. Gupta:Incyte Corporation: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Promedior: Research Funding. Mascarenhas:Kalobios: Research Funding; Roche: Research Funding; Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding. Ritchie:Incyte: Speakers Bureau; Celgene: Speakers Bureau. Hoffman:All Cells, LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding. Silver:Promedior: Research Funding. Pozdnyakova:Promedior: Consultancy. Hasserjian:Promedior: Consultancy. Trehu:Promedior: Employment, Equity Ownership. Salama:Promedior: Consultancy. Gotlib:Allakos, Inc.: Consultancy.

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