A Phase I Dose-Escalation Trial of Oral Clofarabine for Relapsed/Refractory Non-Hodgkin Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1775-1775
Author(s):  
Jeremy S Abramson ◽  
Tak Takvorian ◽  
Eric D Jacobsen ◽  
Jennifer R Brown ◽  
Jeffrey A. Barnes ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Dose Level ◽  
Dose Escalation ◽  
Median Number ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Non Hodgkin Lymphoma ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 1775 Background: Clofarabine is a second-generation purine analogue currently FDA-approved for intravenous use for relapsed/refractory pediatric ALL. Purine analogues demonstrate significant clinical activity in non-Hodgkin lymphomas (NHL), though clofarabine offers potential pharmacologic advantages over existing agents. Clofarabine is a more efficient substrate for deoxycytidine kinase, more completely inhibits ribonucleotide reductase and DNA polymerase α, and demonstrates improved activity in cells that are non-dividing or have a low proliferation rate. This phase I trial is the first evaluation of an oral formulation of clofarabine in relapsed or refractory non-Hodgkin lymphoma. Patients and Methods: The primary objective was to determine the maximum tolerated dose (MTD) and define dose-limiting toxicities (DLT). Efficacy was a secondary objective. Patients (pts) were eligible if they had relapsed or refractory B-cell or T-cell NHL without prior stem cell transplant. All pts were required to have adequate organ function and performance status ≤2 as well as absence of both CNS involvement and HIV infection. No routine infectious prophylaxis was given. Patients were treated at 4 dose levels (1mg, 2mg, 4mg and ultimately 3mg) with oral clofarabine administered once daily on days 1–21 of a 28 day cycle for up to 6 cycles. Three to 6 pts were treated at each dose level in a traditional 3+3 design. Response assessment occurred after cycles 2 and 6. DLT was assessed during cycle 1 and was defined as Grade 4 neutropenia or thrombocytopenia occurring for ≥5 days, any grade 3–4 non-hematologic toxicity, and grade 2 non-hematologic toxicity that did not recover prior to the subsequent cycle of therapy. Results: Twenty-one pts were enrolled on the dose-escalation phase of the study. The median age was 63 years (range 51–85). The median number of prior regimens was 2 (range 1–7). Histologies included follicular lymphomas (FL; 5 pts), small lymphocytic lymphomas (SLL; 5 pts), diffuse large B-cell lymphomas (DLBCL; 4 pts), marginal zone lymphomas (MZL; 4 pts), mantle cell lymphomas (MCL. 2 pts) and lymphoplasmacytic lymphoma (LPL; 1 pt). Median number of cycles administered was 5.5. No DLTs were observed at the 1mg or 2mg dose levels. Three pts were accrued at 4mg with 1 patient experiencing DLT of persistent grade 3 thrombocytopenia and grade 4 neutropenia. No additional DLTs occurred in the cohort, but the majority of pts required late dose reductions due to grade 3–4 hematologic toxicity. The dose was therefore de-escalated to 3mg and 6 additional pts were accrued. No DLTs were observed at the 3mg dose level with a median of 6 cycles administered (range 5–6); 3mg was declared the recommended phase 2 dose. Grade 3–4 hematologic toxicity included neutropenia (7 pts), thrombocytopenia (4 pts), and anemia (2 pts). Grade 1–2 non-hematologic toxicities were uncommon, and included fatigue, diarrhea, cough, and dizziness. There were no grade 3–4 non-hematologic toxicities. Seventeen pts completed one cycle of therapy and were evaluable for response. Radiographic disease reduction was observed in 11 of 17 pts (65%). The overall response rate (ORR) was 35% (6 of 17), all partial responses (PR). Responders included FL (2 pts), MZL (2 pts), SLL and LPL (1 pt ea.). ORR among low grade histologies (FL, MZL, SLL) was 43% in this phase 1 trial. Seven pts had stable disease, including 5 pts with reduction in tumor size that did not reach threshold for PR. Of the 4 pts with progressive disease, 2 had DLBCL, 1 had MCL and 1 had FL with biopsy following relapse identifying ALK-negative anaplastic large T-cell lymphoma. Of the 4 pts not evaluable for response, 1 pt died of progressive DLBCL during cycle 1 on dose level 1 and was replaced, 1 pt was the DLT pt on the 4mg dose level and was removed due to prolonged cytopenias, and 2 pts withdrew consent (1pt at 4mg, 1pt at 3mg), and were replaced. The 3mg dose level has been expanded in a 10-patient dose-expansion cohort limited to low-grade NHL and MCL. Conclusions: Oral clofarabine demonstrates encouraging tolerability and efficacy in relapsed B-cell NHL, particularly in low-grade histologies, warranting further investigation. Disclosures: Abramson: Genzyme: Consultancy. Off Label Use: Clofarabine is not FDA approved for NHL.

scholarly journals Updated Results of a Phase I Study of Ibrutinib and Lenalidomide in Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3983-3983 ◽  
Author(s):  
Beth A Christian ◽  
John G. Kuruvilla ◽  
Sonali M. Smith ◽  
Pierluigi Porcu ◽  
Kami J. Maddocks ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Disease Progression ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase I Study ◽  
Hematologic Toxicity ◽  
Off Label ◽  
Grade 3

Abstract Introduction: Lenalidomide, an immunomodulatory agent, and ibrutinib, a selective and covalent inhibitor of Bruton's tyrosine kinase, are orally bioavailable agents with single-agent activity in several histologic subtypes of relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). We are conducting a phase I study of the combination of ibrutinib and lenalidomide to determine the maximum tolerated dose, dose limiting toxicities (DLT), and preliminary efficacy in pts with relapsed/refractory NHL and updated results are presented. Methods: Patients (pts) with relapsed/refractory B-cell NHL including diffuse large B-cell (DLBCL), transformed, mantle cell (MCL), marginal zone (MZL), lymphoplasmacytic (LPL), and follicular (FL) lymphoma who have received at least one prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant and prior lenalidomide were permitted. Prior ibrutinib, CNS involvement, and pts requiring anticoagulation were not permitted. ANC > 1000/mm3, platelets > 50,000/mm3, and creatinine < 2.0 mg/dL, ALT/AST ≤ 2.5 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required at study entry. Treatment consisted of escalating doses of lenalidomide days 1-21 and ibrutinib days 1-28 of a 28 day cycle. A standard 3+3 dose escalation schema was followed. DLTs included: treatment delays > 14 days for toxicity; grade 5 toxicity; tumor lysis syndrome requiring dialysis; tumor flare reaction nonresponsive to corticosteroids; ANC < 500/mm3 or platelets <25, 000/mm3 persisting > 7 days; grade 3 or 4 febrile neutropenia or infection; and any grade 3 or 4 non-hematologic toxicity with the following exceptions: DVT, diarrhea, nausea or vomiting amenable to medical therapy, correctable electrolyte abnormalities; grade 3 fatigue, or grade 3 maculopapular rash that resolved within 7 days. Pts without significant toxicity could continue treatment until disease progression. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: Twenty-five pts have been treated. Median age is 67 years (range 45-85) with 16 males. Histologies include DLBCL/transformed lymphoma (n=9), MCL (n=7), FL (n=4), MZL (n=2), and LPL (n=3). Four pts were treated at dose level (DL) 1 (lenalidomide 15 mg/ibrutinib 420 mg). One pt was replaced for rapid disease progression and 1 pt experienced DLT consisting of a grade 2 ischemic stroke. As a result of this DLT, DL 1 was expanded to 6 evaluable pts. A second DLT was observed, a grade 3 rash that resolved within 7 days but recurred on day 22. A total of 6 pts were then treated at DL-1 (lenalidomide 10 mg/ibrutinib 280 mg), and no DLTs were encountered. The protocol was amended to include additional dose levels. Pts enrolled on dose level -1A with lenalidomide 10 mg and ibrutinib 420 mg. One DLT occurred at this dose level, a grade 3 rash that failed to resolve within 7 days. The dose level was expanded to 6 pts without further DLT. DL-1B includes an intra-pt dose escalation of the lenalidomide from 10 mg in cycle 1 to 15 mg in cycle 2 with ibrutinib 420 mg. Six pts have been enrolled on this dose level. Three pts have been replaced including 2 with cytopenias not meeting DLT criteria but precluding dose escalation and one with progressive disease. Three pts at DL-1B remain on treatment. Related grade 3-4 toxicities occurred in 16/24 currently evaluated pts (67%), including primarily hematologic toxicity, rash, increased LFTs, pneumonia, hypokalemia, and syncope. Pts have received a median of 3 cycles of therapy to date (range 1-19) and 9 remain on therapy. At DL 1, a pt with DLBCL achieved a complete response (CR) and a pt with transformed follicular achieved a partial response (PR). At DL-1, a pt with DLBCL achieved a CR and 1 pt each with MCL and FL achieved PR. At DL -1A, 1 pt each with MCL and MZL achieved a PR. Overall response rate for 18 assessable pts is 39%. Five pts had best response of stable disease. Sixteen pts have discontinued the study including 3 pts with DLTs, 2 for alternative treatment, 2 for toxicity, and 9 pts with progression. Conclusions: Combined therapy with lenalidomide and ibrutinib in pts with relapsed NHL is well-tolerated, although DLTs of recurrent rash and stroke were encountered. Lenalidomide 10 mg and ibrutinib 420 mg was tolerated and pts are currently enrolling in an intra-pt dose escalation cohort. Preliminary efficacy has been observed in pts with relapsed/refractory DLBCL, MCL, FL, MZL, and transformed NHL. Disclosures Christian: Pharmacyclics: Research Funding; Acerta: Research Funding; Immunomedics: Research Funding; Celgene: Consultancy; Novartis: Other: IDSM; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding. Off Label Use: The use of ibrutnib and lenalidomide in combination in relapsed/refractory non-Hodgkin's lymphoma is off-label. Kuruvilla:Karyopharm: Honoraria, Research Funding; Roche Canada: Honoraria; Seattle Genetics: Honoraria, Research Funding. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy. Porcu:Cell Medica: Research Funding; Infinity: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Shape: Research Funding. Maddocks:Acerta: Research Funding; Pharamcyclics: Research Funding; Novartis: Research Funding. Byrd:Pharmacyclics: Research Funding. Blum:Celgene: Research Funding; cephalon: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding.

scholarly journals A Safety Study of the Addition of Omacetaxine to the Standard-of-Care Induction Regimen of Cytarabine and Idarubicin in Newly-Diagnosed AML Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5218-5218
Author(s):  
Sonia Christian ◽  
Kelley E. Kozma ◽  
Stephanie Barath ◽  
Ardaman Shergill ◽  
Damiano Rondelli ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
De Novo ◽  
Standard Of Care ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Induction Regimen ◽  
Dose Levels

Abstract Background: Omacetaxine mepesuccinate (OM) is a semi-synthetic form of Homoharringtonine (HH), a cephalotaxine alkaloid. OM induces cell apoptosis by inhibiting peptide bond formation during mRNA translation, with rapid loss of short-lived proteins, such as MCL-1, c-MYC, and Cyclin D1 (Lu, J Hematol Oncol. 2014, 7: 2). Notably, cytarabine synergizes with HH in causing apoptosis of leukemia cells in vitro. A phase III RCT in China of 620 patients with de novo AML demonstrated superior CR and 3-yr survival rates upon addition of HH to a standard 2-drug AML induction therapy ('7 + 3'; Jin, Lancet Oncol. 2013, 14:599). Thus, we hypothesized that OM, at an appropriate dose, would similarly enhance the efficacy of a 7 + 3 regimen. OM is FDA-approved for the treatment of TKI-resistant CML. The MTD of 1.25 mg/m2/d SQ for 14 days every 28 days, as determined in a phase I/II CML trial of OM (Quintás-Cardama, Cancer 2007, 109: 248), served as a basis for the dose escalation used in this study. Methods: The primary endpoint of this phase I safety trial was to determine the optimally safe and active dose (OD) of OM when added to a standard 7 + 3 induction regimen, cytarabine and idarubicin. OM was administered SQ q12h d1-7 with cytarabine (100mg/m2 CIV) d1-7 and idarubicin (12mg/m2 IV) d1-3. Four dose levels were tested, starting with OM 0.625 mg/m2 q12h (further dose levels: 1.25, 2.0, 3.0, and 4.2 mg/m2 q12h). All newly diagnosed, untreated de novo or secondary AML patients, aged 18-70y with ECOG PS of 0-3 were eligible for this study. Secondary endpoints included overall response rate (ORR) and overall and event free survival (OS, EFS). Hematologic toxicity (HT) was defined as incomplete hematologic recovery; ANC < 1.0 x 109/L or platelet count < 100 x 109/L present at d49, with the bone marrow documented to be free of leukemic infiltration. Dose escalation was based on the EffTox design (Biometrics 2004, 60:684), a Bayesian adaptive design which considers the trade-off between efficacy and toxicity in determining the OD for Phase II trials. Results: Twenty-two patients, median age 58 (range 25-69) years were enrolled from June 2015 to June 2018. 12 patients (54.5%) had adverse cytogenetics, 6 (27%) intermediate risk, 3 (13.7%) favorable risk and 1 patient's cytogenetic risk was unknown (fibrotic BM). Eight patients demonstrated disease evolution from myelodysplastic syndrome (MDS). Altogether 16 of the 22 patients (73%) were deemed high risk based on cytogenetics or MDS-AML evolution. The EffTox design was implemented until cohort 4 (3 mg/m2 q12h), where 2 of 3 patients experienced a grade 5 non-hematologic toxicity (NHT), resulting in a dose-limiting toxicity (DLT). Since no DLTs were observed in cohort 3, an additional 5 patients were thus enrolled at this dose level to ensure safety. The OD was determined to be the dose level used in cohort 3: OM 2 mg/m2. No HTs were observed in 21 of 22 patients, (one patient not evaluable). The most common non-hematologic treatment emergent adverse events (TEAEs) of any grade were fever (68%), nausea (64%), vomiting (55%), hyperglycemia (41%), diarrhea (41%), mucositis (36%), headache (36%), sinus tachycardia (32%), rash/dermatitis (32%), and abdominal pain (32%). The most prevalent non-hematologic grade 3/4 TEAEs were febrile neutropenia (23%), hypoxia (18%), hyperglycemia (18%), and dyspnea (18%). ORR (CR and CRi) was 45.5%. Median OS was 605 days and EFS was 100 days. Conclusion: In this population with predominantly high-risk AML, the combination of OM with a standard 7 + 3 regimen demonstrates a manageable safety profile with acceptable efficacy. As ~ 25% of patients achieving CR with '7 + 3' do so after a second induction (based on meta-analysis of 6 trials, n = 1980, see Cancer 2010, 116: 5012), the ORR here is comparable to those receiving a single standard of care induction. The results in this high-risk group are therefore promising and warrant further investigation in a phase II trial. At present, we are assessing leukemic blast MCL protein expression in stored pre-treatment samples to determine if this predicts OM efficacy. NCT02440568. Teva has performed a Medical Accuracy Review of this abstract. Figure. Figure. Disclosures Khan: Teva: Speakers Bureau. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

Final Results of a Phase I Study of the Fc Engineered CD19 Antibody XmAb®5574 (MOR00208) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2894-2894 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Farrukh Awan ◽  
Ian W. Flinn ◽  
Rolondo Enoch ◽  
Paul A. Foster ◽  
...  
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Phase I ◽  
B Cell ◽  
Dose Level ◽  
Phase I Trial ◽  
Hematologic Toxicity ◽  
B Cell Malignancies ◽  
Dose Levels

Abstract Abstract 2894 Antibody (Ab) therapies such as the CD20 monoclonal abs rituximab and ofatumumab are commonly used in CLL alone and in combination with chemotherapy, however, CD20 density is low on CLL cells, suggesting this may not be the ideal target. CD19, which is ubiquitously expressed on CLL cells and those of other B cell malignancies is a reasonable candidate for ab targeting. XmAb5574 is a novel humanized IgG1 CD19 monoclonal ab with an engineered Fc region to enhance Fc gamma receptor binding affinity. In vitro, this ab demonstrates direct cytotoxicity and antibody dependent cellular phagocytosis similar to rituximab, however, shows enhanced natural killer antibody dependent cellular cytotoxicity compared to other therapeutic abs used in CLL (Awan, FT Blood 2009). We have performed a first in human trial of this ab as a single agent in relapsed or refractory (R/R) CLL, and present the results in this report. This study is a multi-institutional phase I trial of XmAb5574 in patients (pts) with R/R CLL. Eligible pts were those with CLL who had at least 1 prior therapy and required treatment by International Working Group on CLL (IWCLL) 2008 Guidelines (Hallek, M Blood 2008), had Eastern Cooperative Oncology Group Performance Status <3, had platelets ≥50,000/mm3, and had adequate organ function. Primary endpoints were to determine maximal tolerated dose (MTD), describe toxicity, and characterize pharmacokinetics (PK). A secondary endpoint was to explore efficacy. An accelerated titration design was used in which 1 pt was accrued to the first two dose levels provided there were no dose limiting toxicities (DLT) or ≥ grade 2 adverse events (AE), and then a standard 3×3 design was employed from dose level 3 forward. Dose levels included 0.3, 1, 3, 6, 9, and 12 mg/kg with an expansion to a total of 16 pts at the MTD. XmAb5574 was administered as an intravenous infusion on days 1, 4, 8, 15, and 22 of cycle (C) 1, and on days 1, 8, 15, and 22 of C2. Toxicity was assessed using the National Cancer Institute's Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response assessment by physical exam was performed on C1D28, C2D28, and 4, 8, and 12 weeks after the end of C2. Radiographic assessment was performed C2D28. 27 pts were enrolled to this phase I trial. The median age of all pts was 66 years (range 40–84). The pts were generally high risk: 14 (52%) had high-risk disease by Rai stage, 8 (30%) had del(11q22.3) and 10 (37%) had del(17p13.1) by FISH, and 24 (89%) had IgVH unmutated disease. The median number of prior therapies was 4 (range 1–14). Toxicity with this agent was modest. Dose escalation continued without dose limiting toxicity (DLT) until the highest dose level, in which one patient experienced grade 4 neutropenia associated with febrile neutropenia which required dose discontinuation. 100% of patients experienced any AE, with the majority of AE being grade 1–2. The most common AEs were infusion reactions in 18 patients (67%), all of which were grade 1 or 2. Treatment-related Grade 3 or 4 AEs occurred in 5 pts (19%), and included neutropenia (n=3), thrombocytopenia (n=2), increased aspartate aminotransferase (AST) (n=1), febrile neutropenia (n=1), and tumor lysis syndrome (n=1). All were on the 12 mg/kg dose level except one pt receiving 1mg/kg who experienced neutropenia. Overall response rate by IWCLL 2008 criteria is 11%, all of which have been partial responses (PR). Using IWCLL 1996 response criteria which does not include CT scan assessment of disease resulted in a PR in 13 pts (42%). Only 2 pts had PD at the 8 week evaluation point. Responses occurred at the 6, 9, and 12 mg/kg dose levels. All objective responses were in pts categorized as CLL as opposed to SLL, and no patients with lymph nodes >5cm responded. PK was best modeled by a two-compartment model. Half-life was 14 days, with clearance 5mL/day/kg that was not dose-dependent. Across the dose range, area under the curve increased in a dose-proportional manner, while maximum concentration increased in a less than proportional manner. A steady-state was reached at or before infusion 9. XmAb5574 shows acceptable toxicity and signs of preliminary efficacy in patients with high-risk, heavily pretreated CLL. These results justify movement into phase II study in CLL as well as other B cell malignancies. Modest toxicity, in particular infectious toxicity, will potentially allow combinations with other active agents in CLL. Disclosures: Enoch: Xencor, Inc.: Employment. Foster:Xencor, Inc: Consultancy.

scholarly journals Preliminary Results of a Phase I Study of Obinutuzumab, Venetoclax, and Lenalidomide in Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4185-4185 ◽  
Author(s):  
Kami J. Maddocks ◽  
Farrukh T. Awan ◽  
Ying Huang ◽  
Sabarish Ayyappan ◽  
Robert A Baiocchi ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Phase I Study ◽  
Hematologic Toxicity ◽  
Tumor Lysis ◽  
Genetics Research ◽  
Non Hodgkin Lymphoma ◽  
Grade 3

Abstract Introduction: Combined obinutuzumab (O) and lenalidomide (L) has demonstrated safety and preliminary efficacy in follicular lymphoma1. Venetoclax (V), a BCL2 inhibitor, as a single agent2 and in combination with rituximab3 is under development in several subtypes of B-cell non-Hodgkin lymphoma (NHL). We are conducting a phase I study of the combination of O, V, and L to determine the maximum tolerated dose, dose-limiting toxicities (DLT), and preliminary efficacy. Methods: Pts with relapsed/refractory diffuse large B-cell (DLBCL), transformed, high grade B-cell, Burkitt, marginal zone, and follicular (FL) lymphoma who have received ≥ 1 prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant were permitted. Prior L or BCL2 family inhibitors, CNS involvement, and active hepatitis or HIV infection were not permitted. ANC > 1000/mm3, platelets > 75,000/mm3, creatinine clearance ≥50 ml/min, ALT/AST ≤ 3 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required at study entry. Treatment consisted of escalating doses of L days 1-21 and V days 1-28 of a 28 day cycle (Table 1). O 1000 mg was administered on days 1, 8 and 15 of cycle 1 and then on day 1 of cycles 2-6. A 3+3 dose escalation schema was followed. DLTs included: treatment delays > 28 days; ANC < 500 / mm3 or platelets <25, 000 / mm3 persisting > 28 days; grade 4 febrile neutropenia or infection or grade 3 that fails to resolve within 7 days; and any grade 3 or 4 non-hematologic toxicity with the following exceptions: DVT, tumor flare reaction controllable with steroids, tumor lysis syndrome that does not require dialysis, diarrhea, nausea, or vomiting responsive to medical treatment, transient electrolyte abnormalities or elevations of ALT / AST that resolve ≤ grade 1 within 48 hours, grade 3 infusion reactions responsive to medical therapy. Pts without significant toxicity or progression could continue treatment up to 12 cycles. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: 14 pts have been treated. Median age is 61 years (range 35-78 years) with 10 males. Median prior therapies is 2 (range 1-10). 5 pts had bulky disease (≥ 7.5 cm) and median baseline lactate dehydrogenase was 274 U/L (range 151-894, 12/14 above ULN 190 U/L). 10 pts were refractory to their last therapy. Histologies include DLBCL/transformed lymphoma (n=11) and FL (n=3). 3 pts were treated at dose level (DL) 1 (V 400 mg / L 15 mg). One pt experienced DLT, grade 3 neutropenic fever lasting > 7 days. DL 1 was expanded and no additional DLTs occurred. One pt with DLBCL was replaced for disease progression. 4 pts were then treated at DL 2 (V 600 mg / L 15 mg), and no DLTs were encountered. One pt was replaced due to missed doses of the oral agents. A total of 3 pts have been treated at DL 3 (V 800 mg / L 15 mg) and no DLTs have occurred at the time of data cutoff. Related grade 3-4 toxicities were primarily hematologic including neutropenia (n= 11, 78.6%), anemia (n=1, 7%), and thrombocytopenia (n=2, 14.3%). Grade 3-4 infections included sepsis, febrile neutropenia, pneumonia and a urinary tract infection. No clinically significant tumor lysis has occurred. Pts have received a median of 3 cycles (range 1-12) and 4 remain on therapy. Five pts have achieved a response. At DL 1, a pt with DLBCL, GC type, achieved a complete response (CR) and 2 pts with transformed FL achieved a partial response (PR). At DL 2, 1 pt with FL achieved a CR. At DL 3, 1 pt with transformed FL/double hit achieved a PR. Ten pts have discontinued, 6 with progression and 1 for DLT, alternative treatment, physician preference, and diagnosis of MDS in a patient with 3 prior lines of chemotherapy, respectively. Conclusions: Combined treatment with O, V, and L administered up to 12 cycles has been feasible with hematologic toxicity being the most common adverse event. Enrollment is ongoing and will include expansion cohorts in FL and DLBCL.Fowler et al. Activity of the immunologic doublet of lenalidomide plus obinutuzumab in relapsed follicular lymphoma: Results of a phase I/II study. JCO 2015; 35: 7531.Gerecitano et al. A Phase 1 Study of Venetoclax (ABT-199 / GDC-0199) Monotherapy in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma. Blood 2015; 126: 254.Zinzani et al. Phase 2 Study of Venetoclax Plus Rituximab or Randomized Ven Plus Bendamustine+Rituximab (BR) Versus BR in Patients with Relapsed/Refractory Follicular Lymphoma: Interim Data. Blood 2016; 128:617. Disclosures Maddocks: Merck: Research Funding; Pharmacyclics/Janssen: Honoraria; BMS: Research Funding; Pharmacyclics: Research Funding; Teva: Honoraria; Novartis: Research Funding; AstraZeneca: Honoraria. Jaglowski:Juno: Consultancy; Kite Pharma: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Blum:Celgene: Research Funding; Novartis: Research Funding; Morphosys: Research Funding; Seattle Genetics: Research Funding. Christian:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Immunomedics: Research Funding.

Phase I Study of the Oral Histone Deacetylase Inhibitor SB939 In Patients with Advanced Hematologic Malignancies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3292-3292 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Charles Chuah ◽  
George Wilding ◽  
Julie Chang ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Human Tumor ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Median Number ◽  
Dose Escalation Study ◽  
Neutropenic Sepsis ◽  
Dose Levels

Abstract Abstract 3292 Background: SB939 is a novel orally bioavailable inhibitor of class 1, 2 and 4 histone deacetylases. In human tumor cell lines SB939 inhibits proliferation and promotes apoptosis at an IC50 of 0.1 – 1.3mM. Antitumor activity has been demonstrated in xenograft models of AML (MV4-11) and B-cell lymphoma (Ramos), as well as solid tumors. A phase I, open label, dose escalation study in patients with advanced hematologic malignancies was conducted to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary efficacy of SB939. Methods: SB939 was administered orally every other day 3 times a week for 3 consecutive weeks, in a 4-week cycle. Cohorts of patient were treated with escalating doses of SB939 starting from 10 mg. The MTD was defined as the lowest dose level with less than 2 DLTs. The recommended Phase 2 dose level was defined as one dose level below the MTD. PK and PD (Acetylated Histone 3 in PBMCs) samples were collected in the first cycle. Results: A total of 44 patients were enrolled. 23 patients during dose escalation at dose levels of 10 mg (n=1), 20 mg (n=1), 40 mg (n=6), 60 mg (n=3), 80 mg (n=3), 100 mg (n=3) and 120 mg (n=6). An additional 21 patients were enrolled as part of a cohort expansion at 100 mg. The median age was 70 yr (range 37–84 yr), 57% were male, 61% were caucasian and 27% asian. Median number of prior therapies was 2 (range 0–9), 16 % had a prior transplant. 89% had ECOG performance score of 0–1. The median number of doses received was 17. DLTs included prolonged QTc at 40 mg and neutropenic sepsis at 120 mg. The MTD as defined was not reached; 120 mg was declared as MTD due to the requirement for dose reduction after multiple cycles of treatment. 100 mg was determined to be the recommended Phase II dose. 24 patients, MDS (n=11), AML (n=12), and lymphoma (n=1) were treated at the 100 mg dose level. SB939 was generally well tolerated. Grade 1–2 events included nausea (45%), fatigue (44%), diarrhea (36%), anorexia (34%) and vomiting (30%). Grade 3–4 adverse events included thrombocytopenia (39%), anemia (23%), pneumonia (23%), febrile neutropenia (20%), fatigue (16%), hypokalemia (11%), and neutropenic sepsis (11%). Samples for pharmacokinetics were drawn prior to dosing and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 ± 2 and 30 ± 2 hours after dosing on days 1 and 15 of Cycle 1. Levels of SB939 in plasma were determined using a validated LC-MS/MS method and Non-Compartmental Analysis used WinNonlin, version 5.2 (Pharsight). SB939 was rapidly absorbed with mean Tmax ranging between 0.5–1.3 h; the mean elimination half-life ranged between 6–17 hrs. The Cmax and AUC (0-∞) increased dose-proportionally in the range of doses tested. There was no accumulation of SB939 on day 15 following repeated dosing. Concentrations above IC50 of SB939 for HDAC 1, 2, and 4 were reached at all doses and increased acetylation of H3 was observed in PBMCs across all dose levels. 1 PR (80 mg) and 1 CR (120 mg) were observed in 2 patients with AML with durations of 362 and 206 days respectively. Stable disease for more than 2 cycles was seen in 7 patients, 3 with IPSS intermediate or high risk MDS (duration 72–134 d) and 4 with AML (duration 56–354 d). Conclusions: SB939 demonstrated excellent PK properties and target inhibition and was generally very well tolerated. Toxicities were mild to moderate and similar to some but not all toxicities seen with other HDAC inhibitors. The MTD as defined for this regimen of SB939 in patients with hematologic malignancies was not reached and 100mg is the recommended dose, indicating a favorable therapeutic index. Response data particularly in higher risk MDS and AML encourage further exploration of the therapeutic benefit of SB939 in combination with other anti-cancer therapies. Disclosures: Ethirajulu: S*BIO: Employment. Zhu:S*BIO: Employment.

Oral Formulation of Rigosertib (ON 01910.Na) in Patients with Myelodysplastic Syndrome (MDS) – Phase I Study Results,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3797-3797
Author(s):  
Rami S. Komrokji ◽  
Alan F. List ◽  
Francois Wilhelm ◽  
Jeffrey E. Lancet ◽  
Azra Raza
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Oral Formulation ◽  
Refractory Anemia ◽  
Absolute Bioavailability ◽  
History Of ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 3797 Background: Rigosertib (ON 01910.Na) is a multi-kinase inhibitor that selectively induces mitotic arrest leading to apoptosis in cancer cells and myeloblasts, while non-toxic to normal cells. Biological activity of the intravenous formulation has been demonstrated in myelodysplastic syndromes (MDS), including an ongoing randomized clinical trial in patients with refractory anemia and excess blasts failing azanucleosides. We report the preliminary results of a safety and efficacy study of a novel oral formulation of rigosertib. Methods: The trial is a 3 part phase I dose escalation study. The first part addressed bioavailability and tolerability of single oral dosing administered on a weekly basis for 5 weeks, the second included dose escalation, the third represented a dose expansion of the recommended phase 2 dose (RP2D) with absolute biavailability and food/fasting bioavailability studies. Eligibility included any International prognostic Scoring System (IPSS) MDS risk group with at least one cytopenia, failure to respond to at least one prior standard treatment, good performance status (ECOG≤ 2), adequate kidney and liver functions. Key exclusions included hypoplastic MDS (< 10% cellularity), ascites, history of seizures, uncontrolled hypertension, and history of HIV. Dose limiting toxicity (DLT) was defined as grade 3 or greater non-hematological drug related toxicity or delay in blood count recovery for more than 30 days in the absence of response. Rigosertib dose was escalated based on a defined escalation dose schema (70, 140, 280, 560, and 700 mg). The drug was administered orally twice a day for 14 days of a 21 day cycle. Results: Between January 2010 and July 2011, 33 MDS patients were enrolled in an ongoing phase I dose escalating study. Pharmacokinetic dose proportionality was established in the 70–700 mg single dose range in the first 3 patients, and pharmacodynamically active concentrations were reached. A subsequent escalation phase enrolled 15 patients who were treated with 70 to 700 mg doses of rigosertib capsules bid for 2 weeks of a 3 week cycle (70mg: N=3; 140 mg: N=2; 280mg: N=2; 560: N=2; 700mg: N=6). The formulation was well tolerated. One patient experienced DLT at the 700mg dose level during the first 3-week cycle (dysuria and shortness of breath). Another patient at this dose level had grade 3 dysuria during cycle 2. The RP2D was identified as 560 mg bid and 18 patients were enrolled in the expansion cohort (part 3). Up to 12 patients in this cohort are undergoing full pharmacokinetic evaluation (absolute bioavailability vs. the IV formulation and food effect). Encouraging signs of activity have been observed, including two marrow CR responses at the 140 and 560 mg dose levels; erythroid response (reduction of at least 4 units of RBC transfusions over 56 days) in four Low/Int-1 risk transfusion dependent MDS patients (3 at 560mg and 1 at 700 mg dose levels). Full PK results as well as clinical activity and tolerability at the RP2D dose level will be presented. Conclusion: Oral rigosertib is bioavailable and well tolerated. The RP2D was 560 mg bid for 2 weeks of a 3 week with a DLT of dysuria. Early encouraging responses are being confirmed in the expansion phase of the study. Disclosures: Komrokji: Onconova Therapeutics: Research Funding. List:Onconova Therapeutics: Research Funding. Wilhelm:Onconova Therapeutics: Employment, Equity Ownership. Lancet:Onconova Therapeutics: Research Funding. Raza:Onconova Therapeutics: Research Funding.

scholarly journals A Phase I Study of Ibrutinib and Lenalidomide in Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4476-4476 ◽  
Author(s):  
Beth Christian ◽  
John Kuruvilla ◽  
Sonali Smith ◽  
Pierluigi Porcu ◽  
Amy S. Ruppert ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Disease Progression ◽  
Dose Level ◽  
Dose Escalation ◽  
Stable Disease ◽  
Research Funding ◽  
Phase I Study ◽  
Mantle Cell ◽  
Grade 3

Abstract Introduction: Lenalidomide, an immunomodulatory agent, and ibrutinib, a selective and covalent inhibitor of Bruton’s tyrosine kinase, are orally bioavailable agents with promising single agent activity in relapsed/refractory B-cell NHL. We are conducting a phase I study of the combination of ibrutinib and lenalidomide to determine the maximum tolerated dose, dose limiting toxicities (DLT), and preliminary efficacy in patients with relapsed/refractory NHL. Methods: Patients with relapsed/refractory B-cell NHL including diffuse large B-cell (DLBCL), transformed, mantle cell, marginal zone, lymphoplasmacytic, and follicular lymphoma who have received at least one prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant and prior lenalidomide were permitted. Prior ibrutinib, CNS involvement, and patients requiring anticoagulation were not permitted. ANC > 1000/mm3, platelets > 50,000/mm3, and creatinine < 2.0 mg/dL, ALT/AST ≤ 2.5 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required at study entry. Treatment consisted of escalating doses of lenalidomide days 1-21 and ibrutinib days 1-28 of a 28 day cycle. A standard 3+3 dose escalation schema was followed. DLTs were assessed during cycle 1 and included: treatment delays > 14 days for toxicity; grade 5 toxicity; tumor lysis syndrome requiring dialysis; tumor flare reaction nonresponsive to corticosteroids; ANC < 500 / mm3 or platelets <25, 000 / mm3 persisting > 7 days; grade 3 or 4 febrile neutropenia or infection; and any grade 3 or 4 non-hematologic toxicity with the exception of DVT, diarrhea, nausea, or vomiting amenable to medical therapy, correctable electrolyte abnormalities; grade 3 fatigue, or grade 3 maculopapular rash that resolved within 7 days. Patients without significant toxicity could continue treatment until disease progression. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: From September 2013 until July 2014, 13 patients have been treated. Median age is 68 years (range 45-85) with 9 males. Histologies include DLBCL (4), transformed (4), follicular (2), mantle cell (2), and lymphoplasmacyctic (1) lymphoma. Median number of prior therapies is 3 (range 2-9) with 4 patients having undergone prior autologous transplant. Four patients were treated at dose level (DL) 1 (lenalidomide 15 mg and ibrutinib 420 mg). One patient was replaced for rapid disease progression and 1 patient experienced DLT consisting of a grade 2 ischemic stroke while on aspirin with no history of cardiovascular disease that resulted in discontinuation of study therapy. As a result of this DLT, dose level 1 was expanded to 6 patients. A second DLT was observed, a grade 3 rash that resolved within 7 days with interruption of therapy but recurred with diffuse erythroderma within 4 hours of ibrutinib resumption on day 22 at 280 mg. A total of 6 patients were then treated at DL -1 (lenalidomide 10 mg and ibrutinib 280 mg), and no DLTs were encountered. Related grade 3-4 toxicities occurred in 4/13 patients (31%), including one patient with hypokalemia, neutropenia, thrombocytopenia, and pneumonia, two others with neutropenia and one with maculapapular rash. Patients have received a median of 3 cycles of therapy to date (range 1-5) and 5 remain on therapy. At DL 1, a patient with DLBCL achieved a complete response (CR) and patient with transformed follicular achieved a partial response (PR). At DL -1, a patient with DLBCL achieved a CR and a patient with mantle cell lymphoma achieved a PR. Four patients achieved stable disease. Reasons for study discontinuation include two patients with DLTs who were not evaluated for response, one patient with stable disease who went off study for alternative treatment, and five patients who have progressed. Conclusions: Combined therapy with lenalidomide and ibrutinib in patients with relapsed NHL has been well tolerated at doses of 10 mg and 280 mg respectively, although DLTs of recurrent rash and stroke were encountered with 15 mg lenalidomide and 420 mg ibrutinib. Dose escalation to an intermediate dose level with lenalidomide 10 mg and ibrutinib 420 mg is planned. If this dose level is deemed safe, intra-patient dose escalation of the lenalidomide from 10 mg in cycle 1 to 15 mg in cycle 2 with ibrutinib 420 mg continuously will be tested. Preliminary efficacy has been observed in patients with relapsed/refractory DLCL, MCL, and transformed NHL. Disclosures Christian: Janssen Research & Development, LLC: Research Funding; Celgene: Consultancy. Off Label Use: Use of lenalidomide and ibrutinib in B-cell non-Hodgkin's lymphoma. Smith:Celgene: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy, Speakers Bureau. Porcu:Celgene: Honoraria. Byrd:Phamacyclics: Research Funding. Blum:Janssen, Pharmacyclics: Research Funding.

scholarly journals Phase I Trial of Rituximab, Cladribine and Temsirolimus (RCT) for Initial Therapy of Mantle Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3661-3661 ◽  
Author(s):  
David J. Inwards ◽  
Paul Fishkin ◽  
Betsy R. LaPlant ◽  
Matthew T. Drake ◽  
Paul Kurtin ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Mantle Cell Lymphoma ◽  
Dose Level ◽  
Cell Lymphoma ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Mantle Cell ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 3661 Objective: We conducted this trial to determine the maximum tolerated dose (MTD) and schedule of temsirolimus added to an established regimen comprised of rituximab and cladribine for the initial treatment of mantle cell lymphoma and to generate preliminary information on the toxicity and efficacy of this combination. Methods: A standard phase I cohort of 3 study design was utilized. MTD was defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). DLT was defined as grade 4 ANC (<500) for ≥5 days, grade 4 ANC (<500) associated with fever (>100.5 F) and/or active infection, PLT <25,000, grade 4 infection, or ≥grade 3 non-hematologic toxicity during the first cycle of therapy as per NCI Common Terminology Criteria for Adverse Events v3.0. The fixed doses of rituximab and cladribine were 375 mg/m2 IV day 1 and 5 mg/m2/d IV days 1–5 of a 28 day cycle, respectively, as previously published. There were 5 planned temsirolimus IV dose levels: 15 mg day 1; 25 mg day 1; 25 mg days 1 and 15; 25 mg days 1,8 and 15; and 25 mg days 1,8,15, and 22. The fifth dose level is as previously published in combination with rituximab. Results: A total of 17 patients were treated: 3 each at dose levels 1–4 and 5 at dose level 5 (25 mg temsirolimus days 1,8,15, and 22). The median age was 75 years (52–86). There were 11 males and 6 females. At presentation 88% had stage IV disease, and 94% had extranodal disease. MIPI scores were low in 6% (1 patient), intermediate in 59% (10 patients), and high in 35% (6 patients). There was a single DLT recorded at dose level 3 based on the initial DLT criteria, though this cytokine release syndrome was clearly rituximab related, and occurred prior to the first dose of temsirolimus. Five patients were treated at the highest planned temsirolimus dose level (25 mg days 1,8,15, and 22) with no DLT observed. No further dose escalation was planned, and this level was determined to be tolerated, though higher levels may be tolerable. All patients were evaluable for adverse events. Hematologic toxicity was frequent, with grade 3 anemia in 12% of patients, grade 3 thrombocytopenia in 35%, grade 4 thrombocytopenia in 30%, grade 4 lymphopenia in 47%, grade 3 neutropenia in 24%, and grade 4 neutropenia in 18% of patients. There were 3 thrombotic episodes, 2 of which were attributed to therapy, and 3 episodes of pneumonitis. The overall response rate was 94% with 53% CR and 41% PR. The median progression free survival was 18.7 months. Conclusions: Temsirolimus 25 mg IV weekly may be safely added to rituximab and cladribine at 375 mg/m2 IV day 1 and 5 mg/m2/d IV days 1–5 of a 28 day cycle, respectively. This regimen had promising preliminary activity in an elderly cohort of patients with mantle cell lymphoma. Disclosures: Off Label Use: Temsirolimus for mantle cell lymphoma.

A Phase I Trial of Oblimersen Sodium (G3139) for Relapsed or Refractory Waldenstrom Macroglobulinemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2407-2407
Author(s):  
Morie Abraham Gertz ◽  
Susan M. Geyer ◽  
Brad S. Kahl ◽  
Ashraf Badros ◽  
Craig Reeder ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase I Study ◽  
Protein Translation ◽  
Hematologic Toxicity ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Grade 3 ◽  
Dose Reductions

Abstract Introduction Antisense oligonucleotides are used to inhibit messenger RNA function and inhibit protein translation. Bcl-2 expression proteins have been implicated in mediating resistance to apoptotic cell death in Waldenstrom Macroglobulinemia (WM). Oblimersen sodium is a specific inhibitor of Bcl-2 expression and has shown activity in multiple myeloma and in Waldenstrom cell lines. The in vitro data led to the development of a phase I study for WM patients with relapsed or refractory disease. Materials and Methods Eligible patients had symptomatic WM who had failed prior cytotoxic chemotherapy. All patients had to have one of the following: a hemoglobin &lt;11 g/dL, a platelet count &lt;100,000/uL, bulky lymphadenopathy, or hyperviscosity syndrome. As a phase I study, the primary end point was toxicity assessment, but all patients were assessed for response, using monoclonal protein levels. Patients were enrolled and evaluated in cohorts of three. Drug was administered as a 24-hour continuous infusion for 7 days every 21 days, with intrapatient dose escalation each subsequent cycle beginning at 3 mg/kg/day up to a maximum of 7 mg/kg/day days 1–7 for a maximum of 8 cycles. Results To date 9 patients have been accrued, six at dose level one and three patients at dose level two. Data is available for the first six entered. Five women and 1 man have been accrued with a median age of 74.5 years, ranging from 58 to 81. Four patients had relapsed from prior therapy, 2 were refractory. Three had a history of transfusions. The median number of prior regimens was 4 (range 2–7). One patient had a dose-limiting toxicity on the first cycle of therapy, which was grade 3 fatigue and anorexia, and the dose for this patient was reduced. Two patients had non-hematologic grade 3 toxicity, possibly related to therapy. Five out of six patients on dose level one had grade 3 or greater hematologic toxicity. These toxicities occurred after cycle 1 was completed, during the toxicity observation period and were not considered dose limiting toxicities influencing dose escalation. Three patients required dose reductions in subsequent cycles. To date one patient has had a partial response with her serum M spike falling from 3.6 to 1.1 g/dL. Her quantitative IgM fell from 6,000 mg/dL to 1,000 mg/dL(figure). Conclusion Oblimersen was well tolerated at the first dose level in patients with WM. Hematologic toxicity is frequent in this cohort with heavily involved bone marrows when the dose was escalated during successive cycles. Dose reductions with subsequent cycles were frequently required. Evaluation of the maximum tolerated dose continues. Data on response for this dose level is promising, where efficacy will be fully evaluated in the phase II portion of this trial. Figure Figure

Phase I, Multicenter, Open Label, Dose Escalation of 90yttrium-Ibritumomab Tiuxetan Radioimmunotherapy Using a Modified Regimen for Relapsed or Refractory Follicular or Transformed CD20+ B-Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1648-1648
Author(s):  
Christos Vaklavas ◽  
Ruby F Meredith ◽  
Susan J. Knox ◽  
Gregory Wiseman ◽  
Thomas E. Witzig ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
B Cell ◽  
Dose Escalation ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Ibritumomab Tiuxetan ◽  
Open Label ◽  
Complete Clearance ◽  
Grade 3

Abstract Abstract 1648 Introduction Radioimmunotherapy capitalizes on the radiosensitivity of non-Hodgkin lymphoma (NHL) and the targeted nature of monoclonal antibody therapy. In an attempt to reverse bone marrow infiltration with B-cells and, hence, optimize the biodistribution and tumor dosimetry of 90Y-ibritumomab tiuxetan, we conducted a multicenter, dose escalation, open label study to determine maximum tolerated dose (MTD), safety, and efficacy of a single course of 90Y-ibritumomab tiuxetan after four weekly doses of rituximab in relapsed or refractory low-grade or follicular or transformed CD20+ B-cell NHL. Methods A course of therapy included an initial dose of rituximab 250 mg/m2 plus 5 mCi of 111In- ibritumomab tiuxetan followed by three weekly doses of rituximab at 375 mg/m2 followed two weeks later by rituximab 250 mg/m2 plus 5 mCi of 111In-ibritumomab tiuxetan. Gamma camera imaging for dose estimates was conducted on days 1 and 36 following infusion of 111In- ibritumomab tiuxetan. If dose estimates were in the safe defined limits, and bone marrow on day 29 had less than 25% involvement by NHL, patients received on day 43 250 mg/m2 of rituximab plus a dose of 90Y-ibritumomab tiuxetan. Patients were scheduled to receive 90Y- ibritumomab tiuxetan in one of the dose escalation cohorts (0.4, 0.5, 0.6, 0.7 mCi/kg). Eligible patients were required to have histologically confirmed, relapsed or refractory low-grade or follicular or transformed B-cell NHL with demonstrable monoclonal CD20+ B-cell population in the lymph nodes or bone marrow. Patients with impaired bone marrow reserve, as indicated by prior myeloablative therapies with stem cell rescue, hypocellular marrow, history of failed stem cell collection or external beam radiation therapy to >25% of active bone marrow, and marked reduction in bone marrow precursors of one or more cell lines, were excluded. Results Cohort 1 (0.4 mCi/kg) enrolled 5 patients. Dose escalation was held after significant hematologic toxicity was observed in those patients (1 patient developed grade 4 and 3 grade 3 reversible thrombocytopenia, 4 patients developed grade 4 reversible leukopenia and neutropenia, and 1 patient developed grade 4 febrile neutropenia). One patient in this cohort did not receive the study drug due to the toxicity observed in the previous patients. The protocol was amended and 6 patients were enrolled at a lower dose cohort (0.3 mCi/kg); 1 patient experienced grade 4 neutropenia, whereas grade 3 leukopenia, neutropenia, and thrombocytopenia were seen in 2, 3, and 3 patients respectively. As the 0.3 mCi/kg dose was well tolerated, the 0.4 mCi/kg cohort was expanded to enroll 6 additional patients. In the expansion cohort, Grade 4 leukopenia and neutropenia were seen in 1 and 2 patients respectively; also, grade 3 leukopenia, neutropenia, and thrombocytopenia were seen in 3, 4, and 4 patients, respectively. All hematologic toxicities were reversible and no non-hematologic toxicities were seen with the exception of grade 1 fatigue in 2 patients. Among those who developed hematologic toxicities, the median duration of at least grade 3 leukopenia, neutropenia, and thrombocytopenia were 12 (range, 7–37), 10 (7–30), and 12 (3–44) days, respectively. Six patients had bone marrow involvement by NHL at registration ranging from <5% to 20%. Following 4 weekly doses of rituximab, marrow involvement decreased in all patients with complete clearance in 3 of them. In an intention-to-treat analysis, complete remission, partial remission, stable and progressive disease was achieved in 6 (35%), 8 (47%), 2 (12%), and 1(6%) patients, respectively (fig 1). With a median follow up of 31.7 months (range, 4.3 – 92.6 months), the median progression free survival (fig 2) and time to next treatment (fig 3) were 12.3 and 10.9 months, respectively. The median overall survival has not been reached. Conclusion The MTD of 90Y-ibritumomab tiuxetan administered to patients who have NHL marrow infiltration <25% following 4 weekly doses of rituximab was 0.4 mCi/kg. A 4 weekly course of rituximab decreased NHL marrow infiltration in all patients with marrow involvement and led to complete clearance in 50% of them. Although this regimen was associated with a high response rate, the hematologic toxicity was significant. Disclosures: No relevant conflicts of interest to declare.

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