Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma.

Background: This two-stage, phase IIa study investigated the antitumor activity and safety of MOR208, an Fc-engineered, humanized, CD19 antibody, in patients with relapsed or refractory (R-R) B-cell non-Hodgkin's lymphoma (NHL). CD19 is broadly expressed across the B-lymphocyte lineage, including in B-cell malignancies, but not by hematological stem cells. Patients and methods: Patients aged ≥18 years, with R-R NHL progressing after ≥1 prior rituximab-containing regimen were enrolled into subtype-specific cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), other indolent (i)NHL and mantle cell lymphoma (MCL). Treatment was MOR208, 12 mg/kg intravenously, weekly, for 8 weeks. Patients with at least stable disease could continue treatment for an additional 4 weeks. Those with a partial or complete response after 12 weeks could receive extended MOR208 treatment (12 mg/kg, either monthly or every second week) until progression. The primary end point was overall response rate. Results: Ninety-two patients were enrolled: DLBCL (n = 35), FL (n = 34), other iNHL (n = 11) and MCL (n = 12). Responses were observed in DLBCL, FL and other iNHL cohorts (26%, 29% and 27%, respectively). They lasted ≥12 months in 5/9 responding patients with DLBCL, 4/9 with FL and 2/3 with other iNHL. Responses in nine patients are ongoing (>26 months in five instances). Patients with rituximab refractory disease showed a similar response rate and progression-free survival time to patients with non-refractory disease. The most common adverse events (any grade) were infusion-related reactions (12%) and neutropenia (12%). One patient experienced a grade 4 infusion-related reaction and eight patients (9%) experienced grade 3/4 neutropenia. No treatment-related deaths were reported. Conclusions: MOR208 monotherapy demonstrated promising clinical activity in patients with R-R DLBCL and R-R FL, including in patients with rituximab refractory tumors. These efficacy data and the favorable safety profile support further investigation of MOR208 in phase II/III combination therapy trials in R-R DLBCL. ClinicalTrials.gov number: NCT01685008.

A phase II trial of lenalidomide plus rituximab in previously untreated follicular non-Hodgkin's lymphoma (NHL): CALGB 50803 (Alliance).

BACKGROUND: This multicenter, phase II trial tested the tolerability and efficacy of lenalidomide plus rituximab in patients with previously untreated follicular lymphoma (FL). PATIENTS AND METHODS: Patients with grade 1-3a FL, stage 3-4 or bulky stage 2, FL international prognostic index (FLIPI) 0-2, and no prior therapy were eligible to receive rituximab 375 mg/m2 weekly during cycle 1 and day 1 of cycles 4, 6, 8, and 10, plus lenalidomide 20-25 mg on days 1-21 for twelve 28-day cycles. The primary objectives were to evaluate response rates [complete (CR) and overall] and time to progression. Secondary objectives included toxicity, response according to polymorphisms in FcgR2A and FcgR3A, and changes in circulating pro-angiogenic cells. RESULTS: From October 2010 to September 2011, 66 patients were enrolled. Median age was 53 years, 34 were female, 15 had bulky disease, 21 were FLIPI 0-1, 43 FLIPI 2, and 2 FLIPI 3. One patient withdrew before receiving treatment. Fifty-one patients completed 12 cycles of lenalidomide. Reasons for discontinuation included withdrawal (n = 6), adverse events (n = 6), progression (n = 2). Grade 3-4 hematologic toxicity included neutropenia (21%), lymphopenia (9%), and thrombocytopenia (2%), infection (11%), and rash (8%). Grade 1-2 toxicity included fatigue (78%), diarrhea (37%), rash (32%), and febrile neutropenia in one patient. The overall response rate was 95%; the CR rate was 72% (95% confidence interval, 60% to 83%). With a median follow-up of 5 years, the 2- and 5-year progression-free survival were 86% and 70%, respectively, and the 5-year overall survival was 100%. There was no association between CR rate or PFS and FLIPI, histological grade, bulky disease, FcgR2A/FcgR3A polymorphism, or change in circulating endothelial cell/hematopoietic progenitor cell. CONCLUSION: Lenalidomide plus rituximab was associated with low rates of grade 3-4 toxicity, yielded a CR rate and PFS similar to chemotherapy-based treatment and may represent a reasonable alternative to immunochemotherapy in previously untreated FL. CLINICALTRIALS.GOV IDENTIFIER: NCT01145495.

Serious pulmonary toxicity in patients with Hodgkin's lymphoma with SGN-30, gemcitabine, vinorelbine, and liposomal doxorubicin is associated with an FcγRIIIa-158 V/F polymorphism.

BACKGROUND: Based on in vitro synergistic cytotoxicity when anti-CD30 antibodies are combined with gemcitabine, the Cancer and Leukemia Group B conducted a double-blind, randomized, phase II trial of SGN-30 with gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD) in patients with relapsed Hodgkin's lymphoma. PATIENTS AND METHODS: In part 1 of the trial, 16 patients received SGN-30 with GVD to assess the safety of the combination. In part 2, patients were randomly allocated to SGN-30 (n = 7) or placebo (n = 7) with GVD to determine overall response rate (ORR). RESULTS: ORR in all 30 patients was 63% (65% with SGN-30 plus GVD, n = 23, and 57% with placebo plus GVD, n = 7). Median event-free survival was 9.0 months, with no difference between the two arms. Grades 3-5 pneumonitis occurred in five patients receiving SGN-30 and GVD, leading to premature closure of the trial. All five patients with pulmonary toxicity had a V/F polymorphism in the FcγRIIIa gene (P = 0.008). CONCLUSIONS: Together with historical data demonstrating a 2% incidence of pulmonary events with GVD, these results indicate that SGN-30 cannot safely be administered concurrently. The risk of pneumonitis with SGN-30 and GVD is greatest in patients with an FcγRIIIa V/F polymorphism.

Clinical use of PI3K inhibitors in B-cell lymphoid malignancies: today and tomorrow.

INTRODUCTION: PI3K inhibitors are an important new therapeutic option for the treatment of relapsed and refractory B-cell lymphoid malignancies. Idelalisib is a PI3Kδ inhibitor that has been approved for the treatment of lymphoma and chronic lymphocytic leukemia in the relapsed/refractory setting, and several other PI3K inhibitors are being developed targeting other isoforms of the PI3K enzyme, which results in distinct toxicities and variable efficacy in the clinical setting. Areas covered: We provide a general overview of PI3K inhibitors, recommended applications, and the mechanism and management of toxicities. We further review trials, ongoing and completed, leading to the approval of idelalisib as well other PI3K inhibitors currently in development. Articles were obtained from PubMed, and abstracts were searched for the past 5 years from the websites for ASCO, ASH, EHA, and ICML/Lugano. Expert commentary: PI3K inhibitors provide an important and powerful pharmacologic tool in the armamentarium against hematologic malignancies, especially for relapsed/refractory B-cell lymphoid malignancies. Unique toxicities are associated with inhibition of different isoforms of the PI3K enzyme, as demonstrated with the infectious and autoimmune toxicities associated with the PI3Kδ inhibitor, idelalisib. Due to these unique toxicities, PI3K inhibitors should only be used in formally approved combinations and settings.

Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is frequently complicated by secondary autoimmune cytopenias (AICs). Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase approved for the treatment of relapsed CLL and CLL with del(17p). The effect of ibrutinib treatment on the incidence of AIC is currently unknown. We reviewed medical records of 301 patients treated with ibrutinib, as participants in therapeutic clinical trials at The Ohio State University Comprehensive Cancer Center between July 2010 and July 2014. Subjects were reviewed with respect to past history of AIC, and treatment-emergent AIC cases were identified. Before starting ibrutinib treatment, 26% of patients had experienced AIC. Information was available for a total of 468 patient-years of ibrutinib exposure, during which there were six cases of treatment-emergent AIC. This corresponds to an estimated incidence rate of 13 episodes for every 1000 patient-years of ibrutinib treatment. We further identified 22 patients receiving therapy for AIC at the time ibrutinib was started. Of these 22 patients, 19 were able to discontinue AIC therapy. We found that ibrutinib treatment is associated with a low rate of treatment-emergent AIC. Patients with an existing AIC have been successfully treated with ibrutinib and subsequently discontinued AIC therapy.

Docetaxel combined with trastuzumab is an active regimen in HER-2 3+ overexpressing and fluorescent in situ hybridization-positive metastatic breast cancer: a multi-institutional phase II trial.

PURPOSE: To determine the efficacy and safety of weekly docetaxel and trastuzumab as first- or second-line therapy in women with HER-2-overexpressing metastatic breast cancer and to correlate the efficacy of trastuzumab with HER-2 status as determined by immunohistochemistry assay and fluorescent in situ hybridization (FISH). PATIENTS AND METHODS: Twenty-six women with HER-2-positive (HercepTest [Dako Corp, Carpenteria, CA]2 to 3+) metastatic breast cancer were enrolled onto this study of trastuzumab (4 mg/kg load; 2 mg/kg/wk administered intravenously) and docetaxel (35 mg/m2/wk for 6 weeks). RESULTS: Using an intent-to-treat analysis, the overall response rate was 50% (13 of 26 patients). Eight patients (31%) had a period of stable disease posttherapy. Among HER-2 3+ patients, the overall response rate was 63% (12 of 19 patients) compared with a 14% response rate (one of seven patients) for HER-2 2+ patients (P=.07). Patients with FISH-positive tumors experienced an overall response rate of 64%. Median time to progression was 12.4 months for the entire cohort (HER-2 3+ tumors, 12.3 months; HER-2 2+ lesions, 9.5 months) and median survival was 22.1 months. All HER-2 3+ patients were FISH-positive; the only HER-2 2+ patient responding to treatment was also FISH-positive. Grade 4 toxicities occurred in four patients; most toxicities were mild. CONCLUSION: Trastuzumab plus docetaxel is an active and well-tolerated regimen in women with HER-2 3+ overexpressing or FISH-positive metastatic breast cancer.

Bruton's tyrosine kinase inhibitors in B-cell non-Hodgkin's lymphomas.

The B-cell receptor pathway (BCR) is aberrantly activated in select B-cell malignancies. This knowledge has allowed for the development of inhibitors of different crucial steps of this pathway. Bruton's tyrosine kinase (BTK) is a key component of BCR signaling and functions as an important regulator of multiple cell functions including differentiation, proliferation, and survival in various B-cell malignancies. Ibrutinib is a potent, selective BTK inhibitor that has shown significant activity in specific subtypes of B-cell non-Hodgkin's lymphomas (NHLs). Given the high response rates, tolerability, and acceptable toxicities, ibrutinib was recently approved by the US Food and Drug Administration (FDA) for the treatment of patients with relapsed mantle cell lymphoma and chronic lymphocytic leukemia. It is also currently being evaluated in combination with chemotherapy and as frontline therapy in B-cell NHL. This review summarizes the preclinical and clinical development of ibrutinib in the treatment of B-cell NHL.

Association of pre-transplantation positron emission tomography/computed tomography and outcome in mantle cell lymphoma.

Positron emission tomography/computed tomography (PET/CT)-positive findings before autologous SCT (auto-SCT) are associated with inferior PFS and OS in patients with relapsed Hodgkin's and diffuse large B-cell lymphoma. We classified pre-transplant PET/CT performed before auto-SCT as positive or negative to evaluate the impact of pre-transplant PET/CT in mantle cell lymphoma (MCL). In 29 patients, 17 were PET/CT(-) and 12 were PET/CT(+). PET/CT(+) patients were younger (P=0.04), had lower MCL International Prognostic Index (MIPI, P=0.04) scores, but increased bulky adenopathy >5 cm (45% vs 13%, P=0.09). With a median follow-up of 27 months (range: 5-55 months), 7 patients relapsed (4 in the PET/CT(-) group and 3 in the PET/CT(+) group) with 2 deaths in the PET/CT(+) group without a documented relapse. The estimated 2-year PFS was 64% (95% confidence interval (CI): 0.30-0.85) vs 87% (95% CI: 0.57-0.97) in PET/CT(+) and PET/CT(-) patients, respectively (P=0.054). OS was significantly decreased in PET/CT(+) patients (P=0.007), with 2-year estimates of 60% (95% CI: 0.23-0.84) vs 100% in PET/CT(-) patients. A positive pre-transplant PET/CT is associated with a poor prognosis in patients with MCL. Additional factors may impact the prognostic value of PET/CT, as several PET/CT(+) patients remain in remission.

Risk factors for tumor lysis syndrome in patients with chronic lymphocytic leukemia treated with the cyclin-dependent kinase inhibitor, flavopiridol.

Tumor lysis syndrome (TLS) has been described in over 40% of patients with chronic lymphocytic leukemia treated with the cyclin-dependent kinase inhibitor, flavopiridol. We conducted a retrospective analysis to determine predictive factors for TLS. In 116 patients, the incidence of TLS was 46% (95% CI: 36-55%). In univariable analysis, female gender, greater number of prior therapies, Rai stages III-IV, adenopathy ≥ 10 cm, splenomegaly, del(11q), decreased albumin and increased absolute lymphocyte count, white blood cell count (WBC), ß2-microglobulin, and lactate dehydrogenase were associated (P < 0.05) with TLS. In multivariable analysis, female gender, adenopathy ≥ 10 cm, elevated WBC, increased ß2-microglobulin, and decreased albumin were associated with TLS (P < 0.05). With respect to patient outcomes, 49 and 44% of patients with and without TLS, respectively, responded to flavopiridol (P = 0.71). In a multivariable analysis, controlling for number of prior therapies, cytogenetics, Rai stage, age and gender, progression-free survival (PFS) was inferior in patients with TLS (P = 0.01). Female patients and patients with elevated ß2-microglobulin, increased WBC, adenopathy ≥ 10 cm and decreased albumin were at highest risk and should be monitored for TLS with flavopiridol. TLS does not appear to be predictive of response or improved PFS in patients receiving flavopiridol.

Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar.

Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction. In animal models, valspodar has minimal interaction with pegylated liposomal doxorubicin (PEG-LD). To determine any pharmacokinetic interaction in humans, we designed a study to determine maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of total doxorubicin, in PEG-LD and valspodar combination therapy in patients with advanced malignancies. Patients received PEG-LD 20-25 mg m(-2) intravenously over 1 h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72 h continuous intravenous infusion with PEG-LD beginning at 8 mg m(-2) and escalated in an accelerated titration design to 25 mg m(-2). Pharmacokinetic data were collected with and without valspodar. A total of 14 patients completed at least two cycles of therapy. No DLTs were observed in six patients treated at the highest level of PEG-LD 25 mg m(-2). The most common toxicities were fatigue, nausea, vomiting, mucositis, palmar plantar erythrodysesthesia, diarrhoea, and ataxia. Partial responses were observed in patients with breast and ovarian carcinoma. The mean (range) total doxorubicin clearance decreased from 27 (10-73) ml h(-1) m(-2) in cycle 1 to 18 (3-37) ml h(-1) m(-2) with the addition of valspodar in cycle 2 (P=0.009). Treatment with PEG-LD 25 mg m(-2) in combination with valspodar results in a moderate prolongation of total doxorubicin clearance and half-life but did not increase the toxicity of this agent.

Antiovulatory antagonists of LHRH related to antide.

We report 104 analogues of the potent antiovulatory antagonist of LHRH, N-Ac-D-Nal-D-Cpa-D-Pal-Ser-Lys(Nic)-D-Lys(Nic)-Leu-Ilys-Pro-D-Ala- NH2, Antide. We replaced the Nic group in Antide with other acyl substituents to modulate size, hydrophilicity or basicity of the molecule, we also replaced the Lys residues with shorter basic amino acids, and made cyclic 5/6 analogues as well as position 5 or 6 dimers. We substituted Ilys8 with other alkyl groups and acyl derivatives. When injected in 0.1% DMSO in water in a typical antiovulatory (AO) assay. Antide gives six rats ovulating out of eight (6/8) at 2 micrograms, 4/8 at 4 micrograms, and in the histamine release assay (HRA). ED50 is > 300 micrograms/ml; [Lys(N-Isobutyl)8]Antide gave 2/8 at 2 micrograms/rat; [Lys (8-Qis)5]Antide gave 1/8 at 1 microgram, and 0/8 at 2 micrograms, and in the HRA ED50. 22 micrograms/ml; [D-Lys(8-Qis)5]Antide gave 4/8 at 1 microgram and 0/8 at 2 micrograms, and in the HRA, ED50 was 27 micrograms/ml; [Lys(8-Qic)8] gave 5/8 at 1 microgram 1/8 at 2 micrograms/ [Lys(2-Pyc)6]Antide gave 3/8 at 1 microgram, and 0/8 at 2 micrograms, and in the HRA ED50 was 116 micrograms/ml; [D-Lys (2-Pyc)5]Antide gave 5/8 at 1 microgram and in the HRA, ED50 was 100- > 300 micrograms/ml; [Lys(2-Pyc)5.D-Lys(2-Pyc)6]Antide gave 2/8 at 1 microgram. The substitutions of the Nic groups of Antide at Lys5 or D-Lys6 with 8-Qis or with 2-Pyc groups seem to give highly potent antiovulatory antagonists of LHRH and constitute significant new leads to generate potent antiovulatory compounds endowed with moderate or low histamine release.