Phase II Study of Lenalidomide and Prednisone for Patients with Myelofibrosis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3545-3545
Author(s):  
Alfonso Quintás-Cardama ◽  
Ayalew Tefferi ◽  
Deborah Thomas ◽  
Jorge Cortes ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factors ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Jak2 V617f ◽  
Prior Therapy ◽  
Grade 3 ◽  
Wbc Count ◽  
Bone Marrow Blasts ◽  
Marrow Fibrosis

Abstract Prompted by the activity of lenalidomide (Revlimid®) in pts with chronic idiopathic myelofibrosis (CIMF), we sought to evaluate the safety and efficacy of the combination of lenalidomide and prednisone in a phase II study for pts with CIMF. The rationale for this combination is that the anti-angiogenic and anti-TNFa effects of lenalidomide may be potentiated by the effects of prednisone to reduce marrow fibrosis and improve hematopoiesis in CIMF. Initial therapy consisted of lenalidomide 10 mg/d (dose level [DL] 0) on days 1–21 of a 28–day cycle for 6 cycles, in combination with prednisone 30 mg/d orally during cycle 1, 15 mg/d orally during cycle 2, and 15 mg/d every other day during cycle 3. The lenalidomide dose could be reduced to 5 mg/d (DL -1) or to 5 mg/d every other day (DL -2), or increased to 15 mg/d (DL +1) or 20 mg/d (DL +2) depending upon toxicity or lack of response, respectively. A total of 40 pts (23 male, 17 female) have been enrolled. The median age was 62 years (range, 41–86), time from CIMF diagnosis to the study treatment 10 months (range, 0–269), WBC count 87x109/L (range, 1.1–89), hemoglobin 9.8 g/dL (range, 7.8–17.3), platelets 137x109/L (range, 8–1183). Pts had received a median of 1 prior therapy (range 0–4): hydroxyurea (HU; n=14), anagrelide (AG; n=4), azacitidine (n=6), steroids (n=5), thalidomide (n=4), and interferon (n=3). Ten (25%) pts had not received any prior therapy. JAK2 V617F mutation was detected in 18 (50%) of 36 tested pts and 20 (50%) of 40 had abnormal cytogenetics. A total of 260 cycles have been administered. All 40 pts are evaluable for response and toxicity. Responses have been observed in 12 (30%) pts, including complete response (CR) in 2 (normal blood counts and <5% bone marrow blasts, off HU, AG, growth factors, and no transfusions); partial response (PR) in 7 (at least 2 of the following: Hb increase by ≥2 g/dL, 50% increase in platelets, decrease of bone marrow blasts or organomegaly by ≥50%, normalization of WBC count without blasts, or reduction in bone marrow fibrosis; off HU, AG, growth factors, and transfusion independence); and hematologic improvement (HI) in 3 (at least 2 of the following: decrease by ≥25% of pretreatment leukocytosis, splenomegaly, or marrow blasts, or increase of Hb by ≥1g/dl without growth factor or transfusion support or platelets by ≥25%; off HU, AG, growth factors). Median time to response was 12 weeks (range, 2–32). Responses have been sustained for a median of 15 wks (range, 5–36) and are ongoing in all 12 responders. Overall, 21 (53%) pts experienced grade 3–4 toxicity, being the most frequent neutropenia, anemia, musculoskeletal pain, and fatigue. Twenty-four (60%) pts have required dose reduction to DL -1, of which 5 (12.5%) further reduced to DL -2. One (2.5%) pt dose-escalated to DL +1, while 15 (25%) remained at DL 0. Twenty-one (53%) pts discontinued lenalidomide due to: lack of response (n=8), pt’s decision (n=7), grade 3–4 toxicity (n=5), and poor compliance (n=1). No deaths or transformation to acute myeloid leukemia occurred. In summary, the combination of lenalidomide and prednisone is an active and generally well-tolerated regimen for pts with CIMF. Longer follow-up is warranted to evaluate the durability of ongoing responses. Updated results will be presented at the meeting.

A Phase II Study of Azacitidine (Vidaza™) for Patients with Myelofibrosis (MF).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2706-2706 ◽  
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Deborah Thomas ◽  
STeven Kornblau ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Retinoic Acid Receptor ◽  
Jak2 V617f ◽  
Complete Response ◽  
Pegylated Interferon ◽  
Prior Therapy ◽  
Grade 3 ◽  
Wbc Count ◽  
Bone Marrow Blasts

Abstract Aberrant DNA methylation of promoter-associated CpG islands is a mechanism of epigenetic silencing frequently encountered in human neoplasia. Hypermethylation of several genes such as p15INK4B, p16INK4A, progesterone receptor, and the retinoic acid receptor β have been detected in patients (pts) with advanced-stage MF. Azacitidine (Vidaza™) is a hypomethylating agent that induces reactivation of methylated genes and has been approved for the treatment of pts with myelodysplastic syndromes. The objective of this phase II trial was to study the efficacy of azacitidine in pts with relapsed or refractory MF (primary, or secondary to essential thrombocythemia or polycythemia vera) or newly-diagnosed with a Lille risk score 1 or 2 (risk factor are white blood cell [WBC] count >30x109/L or <4x109/L, and hemoglobin [Hb] <10 g/dL). Azacitidine was given at 75 mg/m_ daily (dose level [DL] 0) for 7 days every 4 weeks for 6 cycles but this could be reduced to 50 (DL -1), 25 (DL -2), or 12.5 (DL -3) or increased to 100 (DL +1) mg/m_ according to toxicity or lack of response, respectively. Thirty-four pts have been treated, median age 66 years (range 39–82), time from MF diagnosis to azacitidine therapy 21 months (range 1–361), median Hb 10.3 g/dL (range 8.2–14.3), WBC 10.7x109/L (range 1.7–57.7), and platelets 205x109/L (range 11–1216). Pts had received a median of 1 prior therapy (range 0–6), including hydroxyurea (HU; n=16), anagrelide (AG; n=8), lenalidomide (n=6), thalidomide (n=6), etanercept (n=2), and pegylated interferon (n=2). Six pts had not received any prior therapy. The JAK2 V617F mutation was detected in 19 (70%) of 27 tested pts and 12 of 34 (35%) had abnormal cytogenetics. A total of 142 cycles have been administered. All 34 patients are evaluable for response and toxicity. Responses have been observed in 10 (29%) pts so far, including complete response (CR) in 1 (normal blood counts and <5% bone marrow blasts; off HU, AG, growth factors, and no transfusions), partial response (PR) in 7 (defined as at least 2 of the following: Hb increase by ≥2 g/dL, 50% increase in platelets, decrease of bone marrow blasts or organomegaly by ≥50%, normalization of WBC count without blasts, or reduction in bone marrow fibrosis), and hematologic improvement (HI) in 2 (defined as at least 2 of the following: decrease by ≥25% of pretreatment leukocytosis, splenomegaly, or marrow blasts, or increase of Hb by ≥1g/dl or platelets by ≥25%). The median time to best response was 7.5 weeks (range, 3 to 26). Fifteen (44%) pts discontinued azacitidine due to: lack of response in 7, transformation to acute myeloid leukemia in 2, death (unrelated to azacitidine therapy) in 1, pt’s decision in 1, grade 3–4 toxicity in 2, and other medical reasons in 2. Azacitidine has been generally well tolerated; 10 pts (29%) had grade 3 or 4 toxicity; neutropenia was the only grade 4 toxicity (in 4 pts). Eleven pts (32%) have required dose reduction to DL -1, of which 3 reduced to DL -2, and 9 pts (26%) escalated the dose to DL +1. In summary, azacitidine is well tolerated and has activity in a subset of pts with MF, with current overall response rate of 29%. Updated clinical results will be presented.

A Phase II Study of Temsirolimus (CCI-779) in Patients with Advanced Leukemias.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4523-4523 ◽  
Author(s):  
Karen W.L. Yee ◽  
Guillermo Garcia-Manero ◽  
Deborah Thomas ◽  
Farhad Ravandi-Kashani ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Blast Crisis ◽  
Single Agent ◽  
Mammalian Target Of Rapamycin ◽  
Median Number ◽  
Prior Therapy ◽  
Flat Dose ◽  
Grade 3

Abstract Temsirolimus (CCI-779, Wyeth Pharmaceuticals) has been shown to inhibit proliferation of a variety of tumors and induce G1 cell cycle arrest by preventing activation of the serine/threonine kinase, mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/Akt pathway. Several lines of evidence implicate the PI3K/Akt/mTOR pathway in hematological malignancies. Interim results of a phase II study evaluating the efficacy and toxicity of single-agent temsirolimus in patients with advanced malignancies are presented. Temsirolimus was administered weekly, at a flat dose of 25 mg, as a 30-minute intravenous infusion. Treatment was continued until evidence of disease progression or unacceptable toxicity. To date, 8 patients have been enrolled and 7 are evaluable for efficacy and toxicity (one patient did not receive temsirolimus). Of these 7 patients, 5 had AML, 1 CML-myeloid blast crisis, and 1 ALL. Median age was 68 years (range, 21 to 87 years) and 5 were male. All patients had received prior therapy, median 2 regimens (range, 1 to 3 regimens). The median number of temsirolimus doses administered was 3 (range, 1 to 10) with a median time on study of 18 days (range, 3 to 89+ days). The most common temsirolimus-related adverse events were grade ≤ 2 and consisted of anorexia, nausea and/or vomiting and diarrhea, mucositis, dermatitis, hypertriglyceridemia, hyperglycemia, hypomagnesemia, hypocalcemia, hypokalemia, hypophosphatemia, and fatigue/asthenia. No patient developed nonspecific pneumonitis. Grade 3 toxicities included fatigue/asthenia (2), hyperglycemia (1), painful mucositis with dehydration and electrolyte abnormalities (1), diarrhea with hypokalemia (1), and hypophosphatemia (1). No patient experienced grade 4 toxicities or death from temsirolimus. No patient required dose reductions, but 2 did have dose delays due to grade 3 mucositis (1) and out-of-state hospitalization for pneumonia and atrial fibrillation (1). No patient achieved a complete remission. One patient with heavily pre-treated Philadelphia-negative precursor B-cell ALL had a transient 79% to 91% reduction in peripheral blood blasts 4 days after the first dose of temsirolimus that was maintained for 12 days prior to disease progression with involvement of the synovial fluid in bilateral knees. At the time of analysis, 6 of the 7 patients have discontinued treatment due to disease progression (4), patient refusal (1), or physician decision (1). Preliminary findings indicate that temsirolimus is relatively well-tolerated at a dose of 25 mg per week and may have biologic activity in ALL. Accrual onto the study is currently ongoing.

Significant Activity of the JAK2 Inhibitor, INCB018424 in Patients with Secondary, Post-Myeloproliferative Disorder (MPD) Acute Myeloid Leukemia (sAML): Results of An Exploratory Phase II Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 631-631 ◽  
Author(s):  
Farhad Ravandi ◽  
Srdan Verstovsek ◽  
Zeev Estrov ◽  
Jan A. Burger ◽  
Solly George ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stable Disease ◽  
Research Funding ◽  
Phase Ii Study ◽  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
Significant Activity ◽  
Stat Signaling ◽  
V617f Mutation ◽  
Grade 3

Abstract Abstract 631 Background: Mutations of JAK2 gene have been identified in a significant proportion of patients with MPDs with the selective JAK2 inhibitors demonstrating significant activity. Patients with AML following prior MPD (sAML) respond poorly to standard cytotoxic chemotherapy and have a poor outcome. Abnormalities of the Jak-Stat signaling pathway have also been identified in a number of other hematological malignancies; chromosomal translocations resulting in TEL-JAK2 constructs lead to the constitutive activation of STAT5, IL-3-independent cellular proliferation, and leukemogenesis. Similarly, infection with oncogenic viruses such as human T-cell lymphotrophic virus, type I, and Abelson murine leukemia viruses results in enhanced kinase activity of Jaks, possibly accounting for their leukemogenic potential. Furthermore, disrupted Jak-Stat signaling has been reported in a number of leukemias. Aim: To identify potential activity of INCB018424 in patients with advanced hematological cancers. Methods: We are conducting a phase II study of INCB018424 in patients with relapsed/refractory leukemias for which no standard therapies are anticipated to result in a durable remission. Patients with performance status 0,1,and 2 with adequate organ function and no active, uncontrolled intercurrent illness or infection receive INCB018424 orally at 25 mg BID daily for 4 weeks (cycle #1). Response is assessed after 2 cycles of treatment. Responding patients or patients with stable disease are allowed to continue until progression. Predetermined dose modifications to 15 mg or 10 mg BID are allowed for drug related toxicities. Results: Eighteen patients [median age, 68 years; (range, 53-88] with relapsed and refractory leukemias (9 de novo AML, 3 sAML, 2 ALL, 1 MDS, 2 CMML, 1 CML) have been treated. The median number of prior therapies is 2 (range,1 to 6). Five patients (1 with AML, 2 with sAML, and 3 with CMML) had the JAK2 V617F mutation. Cytogenetic abnormalities include diploid in 7, chromosome 5 and 7 in 5, t(2;9) in 1, and the Philadelphia chromosome in 2. Pts have received a median of 1 cycle of therapy (range, 1-5 cycles) with 8 pts having stable disease (3 for 2 cycles, 2 for 3 cycles, 1 for 4 cycles, and 2 for 5 cycles). Three patients (including 2 with sAML and 1 with CMML, all with JAK2 mutation) have had significant declines in their bone marrow blasts (to <5%) associated with significant decrease in the size of the spleen and clinical improvement. The regimen has been very well tolerated with only grade 3 side effects being elevation of liver enzymes in 2 patients (thought not to be related to the study drug) and grade 3 thrombocytopenia in 1 patient. Conclusion: INCB018424 has significant activity in sAML and CMML associated with JAK2 V617F mutation. Clinical studies combining it with chemotherapy in sAML are warranted. Disclosures: Ravandi: Incyte Corporation: Research Funding. Verstovsek:Incyte: Research Funding. Garrett:Incyte Corporation: Employment. Newton:Incyte Corporation: Employment.

Phase II study of AZD2171 for the treatment of patients with myelodysplastic syndromes.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6570-6570
Author(s):  
Shannon Eileen O'Mahar ◽  
Alcee Jumonville ◽  
Patrick J. Flynn ◽  
Alvaro Moreno-Aspitia ◽  
Charles Erlichman ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Prior Therapy ◽  
Starting Dose ◽  
Orally Bioavailable ◽  
Grade 3 ◽  
Endothelial Growth Factor

6570 Background: Inhibition of vascular endothelial growth factor receptors (VEGFR) can block growth and trigger apoptosis in neoplastic cells. AZD2171 (cediranib) is a highly potent, orally bioavailable, VEGFR-1/2 inhibitor. We conducted a phase II study of the efficacy of AZD2171 for the treatment of MDS. Methods: Adults with MDS (IPSS Int-2 or High) were eligible if they exhibited adequate organ function and ECOG 0-2. The primary endpoint was proportion of responses according to the IWG criteria assessed at one and every 3 months. Prior investigation of cediranib at 45 mg daily in patients with acute leukemia demonstrated toxicity concerns and therefore, the starting dose of this study was lowered to 30 mg daily. Results: A total of 16 pts with MDS (median age 73 years) were enrolled at a 30 mg starting dose, and all were evaluable. Median baseline marrow blasts were 12.0 % (range 2-18); 3 pts (18.8 %) had low, 6 (37.5 %) intermediate, and 7 (43.8 %) had high risk cytogenetics. Prior therapy included azacitidine (n=7), decitabine (n=2), cytarabine (n=2), erythropoietin-stimulating agents (ESAs) (n=2), lenalidomide (n=1), or none (n=6). Patients were treated for a median of two 28-day cycles (range 1 to 11). There were no confirmed responses. Patients with baseline blasts > 5% showed no significant reduction in the blast count at 4 and 12 weeks. Median OS was 4.7 mo (95% CI: 2.6 – 11.6). Median TTP was 3.8 mo (95% CI: 1.7 – 10.8). Grade 4 hematological adverse events at least possibly related to cediranib were neutropenia (n=2) and thrombocytopenia (n=4). Grade 3 hematological adverse events at least possibly related to study treatment included: neutropenia (n=3), thrombocytopenia (n=2), and anemia (n=2). Grade 3 non-hematological adverse events included fatigue (n=4), dyspnea (n=3), dehydration (n=2), diarrhea (n=2), nausea (n=2), asthenia (n=1), and hypertension (n=1). Hypertension and proteinuria was uncommon with the 30 mg/day dose. Conclusions: With no confirmed response from 16 patients, cediranib was determined to be ineffective at a dose of 30 mg daily in our patient population. Supported by NCI N01-CM62205, NCI P30-CA014520 and the UW Carbone Comprehensive Cancer Center.

A phase II study of cabozantinib in patients (pts) with relapsed or refractory metastatic urothelial carcinoma (mUC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 307-307 ◽  
Author(s):  
Andrea Borghese Apolo ◽  
Howard L. Parnes ◽  
Ravi Amrit Madan ◽  
James L. Gulley ◽  
John Joseph Wright ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Primary Objective ◽  
Response To Therapy ◽  
Bone Lesions ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Visceral Metastases ◽  
Carcinoma Of The Bladder ◽  
Grade 3

307 Background: Translational studies have shown that shed MET levels in serum and urine of pts with UC correlate with stage and visceral metastases and that cabozantinib reverses HGF-driven UC cell growth and invasion. These data support the evaluation of cabozantinib in pts with mUC. Methods: In this phase II study, pts receive cabozantinib 60 mg daily in 28-day cycles. There are 3 study cohorts (1) mUC, (2) bone only mUC (3) metastatic rare bladder histology. The primary objective is to determine the response rate (RR) by RECIST. Response is assessed every 2 cycles. Tissue, blood, and urine were collected on all pts to test for MET/HGF and immune subsets. Results: 26 out of 55 pts have enrolled (19 M, 7 F): median age 62 (42-82) and median KPS of 80%. Primary sites include bladder (77%) and upper tract UC (23%). Prior therapy includes 30% pts with 1 regimen, 39% with 2, 15% with 3, 8% with 4 and 8% with 6. 81% of pts had visceral metastases (lung, liver and bone) and 19% lymph node only metastases. 23 pts (19 in cohort 1, 3 in cohort 2 and 1 in cohort 3) were evaluable for response after completing at least 4 weeks of therapy. In cohort 1, 2 pts achieved PR (1 remained on study for 10 months and 1 remains on study after >12 months of therapy); 7 pts had SD for at least 16 weeks (1 remained on study for 11 months); 10 had PD; 1 is too early to assess for response; 1 was removed before restaging for toxicity and 1 was removed for not meeting eligibility. The objective RR is 11% and SD 37% for a clinical benefit of 48%. In cohort 2, 1 of 3 pts had a near resolution of bone lesions on NaF PET/CT for 11 months. In cohort 3, only pt enrolled (squamous cell carcinoma of the bladder) achieved SD for 16 weeks. Mixed responses with regression of lung, bone or lymph nodes were observed in 30% of pts with PD. Grade 3/4 toxicities included: fatigue (8%), hyponatremia (8%), hypophosphatemia (8%) diarrhea (4%), thromboembolism (4%), transaminitis (4%), hypothyroidism (4%), thrombocytopenia (4%), dysphonia (4%), hypomagnesemia (4%), creatinine increase (4%) and proteinuria (4%). Conclusions: Cabozantinib has clinical activity in pts with relapsed or refractory mUC with manageable toxicities. Further studies are underway to correlate response to therapy with MET expression. Clinical trial information: NCT01688999.

scholarly journals Updated Phase II Study of Targeted Subcutaneous (SC) Bortezomib for Patients with Low- or Intermediate-1 (Int-1)-Risk Myelodysplastic Syndrome (MDS) with Evidence of NF-κb Activation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3191-3191
Author(s):  
May Daher ◽  
Juliana Elisa Hidalgo Lopez ◽  
Jasleen K. Randhawa ◽  
Kausar Jabeen Jabbar ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Lower Risk ◽  
Research Funding ◽  
Phase Ii Study ◽  
Performance Status ◽  
Eligibility Criteria ◽  
Prior Therapy ◽  
Transfusion Requirements ◽  
Blast Count

Abstract Introduction MDS has been linked to constitutive activation of genes involved in the nuclear factor-kappaB (NF-κB) pathway [Wei et al. Leukemia 2013; Braun et al. Blood 2006]. Hence, NF-kB is an attractive therapeutic target in this disease. Bortezomib is a proteosome inhibitor with inhibitory activity against NF-κB. We designed a phase II trial of SC bortezomib in patients with low- to intermediate (low/int-1)-risk MDS and evidence of NF-κB activation to determine its therapeutic activity in these patients. Methods In this single-arm phase II study in low/int-1-risk MDS patients, bortezomib was administered at 1.3 mg/m2 SC on days 1, 4, 8, and 11 in a 21-day cycle for a maximum of 2 years of therapy. Eligibility criteria included age ≥18 years, adequate performance status and organ function, and having received at least 1 prior therapy. Patients with grade 2 or greater peripheral neuropathy at baseline were excluded. Patients were prescreened prospectively for enrollment by assessing cellular levels of the phosphorylated NF-κB subunit p65 (pp65) in their marrow. This was performed by immunofluorescence with phospho-Ser276 in bone marrow aspirate smears in the Department of Hematopathology (CLIA regulations). Patients were eligible if at least 5% of all nucleated marrow cells were positive for pp65 staining. pp65 levels were assessed again on day 21 of cycles 1 and 2 and then as clinically indicated. Responses were assessed according to IWG [Cheson et al. Blood 2000; Cheson et al, Blood 2006]. The study could accrue a maximum of 40 patients if there were at least a 95% chance of at least a 15% ORR. Results Beginning 9/2013, we enrolled 15 patients with a median age of 71 years (range 56 - 87). Median marrow blast percentage was 1.9% (range 0 - 5%). Eleven patients (73%) had diploid cytogenetics, 2 had del(20q), 1 had Y-, and 1 had del(5q). All had lower-risk MDS by IPSS (low 33.3%, int-1 66.7%). All were transfusion dependent (6 both platelets and red cells (PRBCs), 1 only platelets, 8 only PRBCs). Hypomethylating agents had failed in 12 of the patients. At a median follow-up interval of 22 weeks, the ORR was 20%; 3 patients had hematologic improvement with a mean duration of response of 14.3 weeks (range 4-21). Eight patients had stable disease, and 4 had progression. No correlation between clinical response and molecular or cytogenetic data was observed. Eventually, all patients were taken off study: 7 due to increasing transfusion requirements, 2 worsening cytopenia, 1 lack of response, 1 increased blasts, and 1 grade 2 neuropathy; 2 withdrew by choice, and 1 patient died from causes unrelated to the study. Four patients experienced ≥ 1 grade 3 toxicity. No grade 4 toxicity was observed. Seven patients experienced grade 1 (n=4) or grade 2 (n=3) neuropathy. Morphologic review (n=14) in the responders group (n=3) showed reduction in ring sideroblasts (RS) in 2 patients (60 to 47% and 43% to 30%). Two patients, including 1 of those with reduced RS, had improvement of dysplasia (from severe trilineage dysplasia to moderate bilineage dysplasia). No changes in cytogenetic studies were found in the responder group. Among nonresponders (n=11), 3 had new acquired cytogenetic abnormalities, 3 had worsening dysplasia, and 2 had increase in blast count (1% to 3% and 1% to 4%). Two had no morphologic changes during treatment. One showed improvement in dysplasia and blast count (2% to 0%) and no changes in cytogenetics. Interestingly, 3 nonresponders showed RS reduction during treatment (18% to 1%, 85% to 45%, and 6% to 0%). The median pp65 level at baseline was 30.87% (range 7 - 70%). The pp65 level decreased in 7 of the 15 patients (46.7%), in 6 of them by the end of cycle 1. Interestingly, the 3 responders were among the 7 patients who had a decrease in pp65 level. Eventual loss of response in these patients was accompanied by return to a higher pp65 level. In nonresponders, the pp65 level increased in 7, decreased in 2, and remained unchanged in 1; for 1, the sample was suboptimal. Conclusions In previously treated lower-risk MDS patients, SC Bortezomib was well tolerated and resulted in hematologic improvement and decrease in RS. NF-κB activation, measured by pp65 level, can be a useful biomarker to select patients with lower-risk MDS who could benefit from therapies that target this pathway. The NF-κB pattern of expression suggests an inverse relationship between treatment response and NF-κB level, with associated improvement in bone marrow morphology. Disclosures Konopleva: Calithera: Research Funding; Cellectis: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Phase II Study of Lenalidomide (CC-5013, Revlimid®) for Patients (pts) with Myelofibrosis (MF).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 377-377
Author(s):  
Jorge Cortes ◽  
Deborah Thomas ◽  
Srdan Verstovsek ◽  
Francis Giles ◽  
Miloslav Beran ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Myeloproliferative Disorders ◽  
Clinical Activity ◽  
Toxicity Profile ◽  
Prolonged Administration ◽  
Prior Therapy ◽  
Days Of Therapy ◽  
Grade 3 ◽  
Baseline Hemoglobin

Abstract Introduction: Thalidomide has been shown to induce responses in pts with MF but prolonged administration in these pts may be associated with neurotoxicity and other adverse events. Lenalidomide is the lead clinical compound in a new group of drugs called IMiDs®, which have immunomodulatory properties. It affects cytokine expression 200–5000 times more potently than thalidomide but lacks the teratogenecity, sedation and neurotoxicity. Methods: We thus designed a phase II study for pts with myelofibrosis (primary or associated with myeloproliferative disorders) with a platelet (plt) count of at least 30 x109/L. Pts may have received prior therapies, but were excluded if they had known hypersensitivity to thalidomide. Pts received lenalidomide 10 mg/day orally (5 mg daily for patients with platelet count less than 100,000 at study entry). Results: We have treated 41 pts. Their median age was 65 (range, 42 to 83). Thirty-six pts (88%) had received prior therapy for MF, including thalidomide 13 (32%), hydroxyurea 12 (29%), interferon 11 (27%) (pegylated 7), anagrelide 10 (24%), and erythropoietin 6 (15%). Baseline hemoglobin was &lt;10g/dl in 19 (46%) (13, 32% transfusion dependent); platelets &lt;100 x109/L in 12 (29%); neutrophils &lt;1.5 x109/L in 2 (5%), and 20/34 (59%) had splenomegaly (median 10cm BCM, range 1 to 30) (7 prior splenectomy). Twenty pts are evaluable for response and toxicity (i.e., received at least 30 days of therapy, unless discontinued because of progression or toxicity). One pt discontinued therapy because of toxicity (grade 3 rash). Responses have been observed in 10 (50%) pts. These include CR in 2 pts (normalization of Hgb and WBC, respectively), PR in 2 pts (improvement in plts and hgb, ± spleen), hematologic improvement in 6 pts (improvement in plts 3, spleen 2, WBC 1). Three of 13 transfusion-dependent pts have become transfusion independent. The median time to response was 9 weeks (range, 2 to 22). Responses have been sustained for a median of 14 weeks (range, 2 to 28 weeks). Therapy has been well tolerated. The more common toxicities were rash in 12 (29%), and pruritus in 8 (20%). Grade ≥ 3 toxicities were thrombocytopenia (n=2), rash (n=1), fatigue (n=1), and neutropenia (n=1). Four (10%) pts have required dose reduction and 1 discontinued therapy because of toxicity (rash). Conclusion: We conclude that lenalidomide has clinical activity in a subset of patients with myelofibrosis with an acceptable toxicity profile. Studies using lenalidomide in combination with other agents are justified.

Pegylated Interferon-alfa-2a (PEG-IFN-α-2A; PEGASYS™) for Essential Thrombocythemia (ET) and Polycythemia Vera (PV): An Update of an Ongoing Phase II Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3542-3542 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Hagop Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Jorge Cortes ◽  
Marie Ann Richie ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Philadelphia Chromosome ◽  
Jak2 V617f ◽  
Human Interferon ◽  
Clinical Activity ◽  
Significant Activity ◽  
Starting Dose ◽  
Grade 3 ◽  
Initial Starting

Abstract Therapy for patients with high-risk Philadelphia chromosome-negative myeloproliferative disorders (MPDs) involves the use of cytoreductive agents such as recombinant human interferon-alpha (IFN-α), hydroxyurea (HU), and anagrelide (AG). Despite the significant activity of IFN-α in MPDs, therapy with this agent is frequently hindered by poor tolerance and inconvenient dosing schedules. PEG-IFN-α is formulated by covalently attaching polymers of ethylene glycol to the native IFN-α molecule, which results in decreased renal excretion and increased serum half-life that allows for weekly administration with acceptable toxicity. Based on the superior pharmacokinetic profile of PEG-IFN-α-2a relative to conventional IFN-α, we designed a phase II study of subcutaneous PEG-IFN-α-2a (Pegasys) for patients with ET or PV. A total of 50 patients have been enrolled and treated thus far (22 ET, 28 PV). Median age is 53 years (range, 23–77) and time from diagnosis to PEG-IFN-α-2a 64 months (range, 1–348). Prior therapies (median 2; range 0–6) included HU (n=33), AN (n=22), phlebotomy (n=27), IFN-α (n=8: 5 oral and 3 sc), other (n=10). PEG-IFN-α-2a was the initial therapy in 4 patients. The JAK2 V617F mutation was detected in 11 (50%) of 22 ET and in 26 (93%) of 28 PV patients. Six (12%) patients had abnormal cytogenetics. Initial starting dose of PEG-IFN-α-2a was 450 mcg/week, but that was modified to the current starting dose of 90 mcg/week. Dose modifications are allowed according to response or toxicity. Patients are currently receiving 450 mcg (n=1), 360 mcg (n=1), 270 mcg (n=5), 180 mcg (n=11), 135 mcg (n=8), 90 mcg (n=9), and 45 mcg (n=5). After a median follow-up of 11 months (range, 2–28), 47 (94%) patients have responded. Complete response (CR) was achieved by 46 (92%) patients (for ET: platelets <440x109/L, off HU and AG, in the absence of thromboembolic events; for PV: Hb <15 g/dL, off HU and AG, no phlebotomy, with disappearance of splenomegaly) whereas 1 (2%) patient with PV had a partial response ([PR]; no phlebotomy, off HU and AG, but still palpable spleen). The mutant JAK2 V617F to total JAK2 ratio was determined by PCR (n=37) and by a quantitative pyrosequencing assay (n=30) prior to PEG-IFN-α-2a. JAK2 V617F mutational analysis was subsequently performed after 6 and 12 months into PEG-IFN-α-2a therapy in 20 and 10 patients, respectively. Nine (30%) of the 30 patients assessable for JAK2 V617V quantitation had >10% reduction in JAK2 V617F expression, including 2 (7%) in whom the mutant allele became undetectable. In addition, 4 (13%) patients had a 5%–10% reduction. JAK2 V617F quantitation has not been repeated yet in 9 patients. PEG-IFN-α-2a was well tolerated in most patients. Twenty-two episodes of grade 3–4 toxicity were reported, including neutropenia (n=11), elevated transaminases (n=4), and anemia, thrombocytopenia, depression, fatigue, infection, cardiac, and pain in 1 case each. Ten patients were taken off study, including 6 (12%) due to therapy-related toxicities: grade 3 neutropenia (n=1), fatigue (n=1), depression (n=1), ischemic retinopathy (n=1), dyspnea (n=1),and diarrhea (n=1). In summary, therapy with PEG-IFN-α-2a results in remarkable clinical activity and acceptable toxicity profile in patients with ET or PV. Significant reduction of JAK2 V617F allele burden occurred in a proportion of responders, suggesting selective targeting of the malignant clone.

A Phase II Study of Ofatumumab-High Dose Methylprednisolone Followed By Ofatumumab-Alemtuzumab in 17p Deleted or TP53 Mutated CLL

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4159-4159 ◽  
Author(s):  
Matthew S. Davids ◽  
Haesook T. Kim ◽  
Stacey M. Fernandes ◽  
Jeffrey Hellman ◽  
Karen Francoeur ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Tp53 Mutation ◽  
Phase Ii Study ◽  
Infectious Complications ◽  
High Dose ◽  
Color Flow ◽  
Part C ◽  
High Dose Methylprednisolone ◽  
Grade 3

Abstract BACKGROUND: Even in the age of kinase inhibitors, the prognosis for patients (pts) with CLL with del(17p) or TP53 mutations remains poor, with the median PFS only 28 mo. for pts with relapsed/refractory del(17p) CLL treated with ibrutinib. High dose methylprednisolone (HDMP) and alemtuzumab (alem) both have activity in 17p disease and work independently of TP53. Prior work has demonstrated that giving HDMP/alem simultaneously is efficacious, but toxic. We hypothesized that giving these agents sequentially with ofatumumab (ofa) would maintain efficacy while decreasing toxicity. METHODS: This phase II study of ofa/HDMP followed by ofa/alem in CLL pts with 17p deletion or TP53 mutation employed a parallel 2-arm design (treatment-naive (TN) and relapsed/refractory (R/R)). Therapy was the same in both arms and included ofa/HDMP for 2-4 cycles (part A) followed by ofa/alem for 4-24 weeks, up to maximum response (part B). Responders could proceed to alloHSCT or a maintenance phase with ofa given q2 mo and alem given q2 wks (part C). Antimicrobial prophylaxis for PCP, HSV/VZV, and fungal infections was mandatory, as was G-CSF support. The primary objective was to estimate the ORR at the conclusion of the two-part induction therapy in both cohorts. Secondary objectives were to estimate the rate of CR, objective response by compartment, rate of MRD negativity by 4 color flow cytometry, PFS, and OS, rate at which transplant-eligible pts were able to proceed to alloHSCT, and to assess safety. Toxicity was assessed by IW-CLL and CTCAE v4.0. Response assessments by IW-CLL criteria were performed mid-way and at the end of parts A and B, and q6 mo. on part C. RESULTS: A total of 30 patients were enrolled. Baseline pt characteristics were as follows: TN (n=15): median age 64 (range 45-86), median WBC 58K, Hct 31, Plts 134, B2M 4.3, IGHV unmutated 79%, median %bone marrow (BM) involvement 80%. R/R (n=15): median age 65 (range 58-80), median WBC 31, Hct 33, Plts 114, B2M 4.5, IGHV unmutated 73%, median %BM involvement 60%, median # prior therapies 2 (range 1-4) including 9 pts with prior FCR or FR and 7 pts with prior BR. One patient in each arm had TP53 mutation without 17p deletion, and 4 pts had mut NOTCH1. The median number of copy number changes by SNP array was high, at 12.4 in the TN and 14 in the R/R cohorts. In the TN arm, 14/15 pts moved from part A->B, 5 moved from part B->C, and 5 moved on to alloHSCT in remission. The best ORR for the TN arm was 80% (67% PR, 13% CR), with 12/15 (80%) pts achieving BM MRD negativity. The TN 2-yr PFS and OS are 70% and 85%, respectively. In the R/R arm, 8/15 pts moved from part A->B, 4 moved from part B->C, and 5 moved on to alloHSCT in remission. The best ORR for the R/R arm was 68% (all PRs), with 8/15 (54%) pts achieving BM MRD negativity. The R/R 2-yr PFS and OS are 53% and 67%, respectively. Responses in both arms were independent of TP53 and NOTCH1 mutation status. Studywide, a greater number of somatic mutations was associated with shorter PFS and OS (HR 1.13 per mutation, 95% CI 1.02-1.25, p=0.015 and HR 1.185, 95% CI 1.047-1.341, p=0.0073, respectively). The most common grade 3/4 toxicities were: neutropenia (33%), thrombocytopenia (20%), anemia (10%). Infectious complications included pneumonia (5 cases, 1 Gr2, 3 Gr3, 1 Gr4), febrile neutropenia (2 cases, both Gr3), and cellulitis (1 case, grade 3). Four pts had low-level CMV reactivation, but no CMV infections occurred. Venous thromboembolism occurred in 3 pts. With a median follow-up time among survivors of 25 mo., 21 of the total 30 pts are still alive, and causes of death included: progressive disease n=6, infection n=3. 12/18 (67%) pts who were transplant eligible were able to proceed to HSCT. Discontinuations were due to: progressive/refractory disease (n=10, including 3 Richter's transformations (R/R n=2, TN n=1)), physician decision (n=2), and unacceptable toxicity (n=1). CONCLUSION: Ofa/HDMP followed by Ofa/alem is highly active for both TN and R/R CLL pts with del(17p) and/or TP53 mutation. In addition to a robust ORR, we observed a high rate of MRD-negativity in the bone marrow, which allowed most of the transplant-eligible pts to proceed to alloHSCT. Sequential dosing appears to reduce infectious complications compared to concurrent dosing. This regimen is a feasible option for pts with ultra-high risk CLL to facilitate maximal cytoreduction prior to alloHSCT. <> Disclosures Davids: Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy.

Phase II Study on the Effect of Disease Sites, Age, and Prior Therapy on Response to Iodine-131-Metaiodobenzylguanidine Therapy in Refractory Neuroblastoma

2007 ◽  
Vol 25 (9) ◽  
pp. 1054-1060 ◽  
Author(s):  
Katherine K. Matthay ◽  
Gregory Yanik ◽  
Julia Messina ◽  
Alekist Quach ◽  
John Huberty ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Soft Tissue ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Hematopoietic Stem ◽  
Prior Therapy ◽  
Treatment Regimens ◽  
Iodine 131

Purpose To evaluate the effect of disease sites and prior therapy on response and toxicity after iodine-131-metaiodobenzylguanidine (131I-MIBG) treatment of patients with resistant neuroblastoma. Patients and Methods One hundred sixty-four patients with progressive, refractory or relapsed high-risk neuroblastoma, age 2 to 30 years, were treated in a limited institution phase II study. Patients with cryopreserved hematopoietic stem cells (n = 148) were treated with 18 mCi/kg of 131I-MIBG. Those without hematopoietic stem cells (n = 16) received 12 mCi/kg. Patients were stratified according to prior myeloablative therapy and whether they had measurable soft tissue involvement or only bone and/or bone marrow disease. Results Hematologic toxicity was common, with 33% of patients receiving autologous hematopoietic stem cell support. Nonhematologic grade 3 or 4 toxicity was rare, with 5% of patients experiencing hepatic, 3.6% pulmonary, 10.9% infectious toxicity, and 9.7% with febrile neutropenia. The overall complete plus partial response rate was 36%. The response rate was significantly higher for patients with disease limited either to bone and bone marrow, or to soft tissue (compared with patients with both) for patients with fewer than three prior treatment regimens and for patients older than 12 years. The event-free survival (EFS) and overall survival (OS) times were significantly longer for patients achieving response, for those older than 12 years and with fewer than three prior treatment regimens. The OS was 49% at 1 year and 29% at 2 years; EFS was 18% at 1 year. Conclusion The high response rate and low nonhematologic toxicity with 131I-MIBG suggest incorporation of this agent into initial multimodal therapy of neuroblastoma.

Sign in / Sign up

Export Citation Format

Share Document