Otlertuzumab is a novel humanized anti-CD37 protein therapeutic. This study evaluated the safety of otlertuzumab administered intravenously to patients with chronic lymphocytic leukemia (CLL). ...Otlertuzumab was administered weekly for up to 8 weeks followed by 1 dose per month for 4 months ranging from 0.03 to 20 mg/kg in the dose-escalation phase and 10 to 30 mg/kg in the dose-expansion phase. Responses were determined by using the 1996 National Cancer Institute (NCI-96) and 2008 International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) criteria. Fifty-seven patients were treated in the dose-escalation phase and 26 in the dose-expansion phase. A maximum-tolerated dose was not identified. Response occurred in 19 (23%) of 83 treated patients by NCI-96 criteria. All responses were partial and occurred more commonly in patients with symptomatic untreated CLL (6/7) or 1 to 2 prior therapies (12/28) vs 3 or more therapies (1/48). Twenty percent (12/61) with serial computed tomography scan assessment had a response per IWCLL criteria. The most frequent adverse events were infusion reactions, fatigue, nausea, and diarrhea and were not dose related. Otlertuzumab was well tolerated, and modest clinical activity was observed. Otlertuzumab warrants further evaluation in combination with other agents for the treatment of CLL. This trial was registered at www.clinicaltrials.gov as #NCT00614042.
•Otlertuzumab (formerly TRU-016) has modest single-agent activity in symptomatic treated and untreated CLL.•Otlertuzumab demonstrates an acceptable safety profile, providing rationale for combination with other effective CLL therapies.
Summary
Otlertuzumab (TRU‐016) is a humanized anti‐CD37 protein therapeutic that triggers direct caspase‐independent apoptosis of malignant B cells and induces antibody‐dependent cell‐mediated ...cytotoxicity. Patients with relapsed chronic lymphocytic leukaemia (CLL) received either otlertuzumab (20 mg/kg) weekly by IV infusion for two 28‐day cycles then every 14 days for four 28‐day cycles and IV bendamustine (70 mg/m2) on Days 1 and 2 of each cycle for up to six 28‐day cycles or bendamustine alone. Thirty‐two patients were treated with otlertuzumab and bendamustine and 33 with bendamustine alone. Overall response rate according to the International Workshop on Chronic Lymphocytic Leukaemia criteria was 69% in the otlertuzumab and bendamustine arm and 39% in the bendamustine alone arm (P = 0·025). Median progression‐free survival (PFS) was 15·9 months in the otlertuzumab and bendamustine arm and 10·2 months in the bendamustine alone arm (P = 0·0192). There was a higher incidence of pyrexia (34% vs. 12%) and neutropenia (59% vs. 39%) with the combination but this did not result in a higher incidence of severe (grade 3/4) infections (13% vs. 27%). This combination significantly increased the response rate and prolonged the PFS over single agent bendamustine in patients with relapsed or refractory CLL.
Summary
CD37 is cell surface tetraspanin present on normal and malignant B cells. Otlertuzumab (TRU‐016) is a novel humanized anti‐CD37 protein therapeutic. Patients with relapsed or refractory ...follicular non‐Hodgkin lymphoma (FL), mantle cell lymphoma (MCL), or Waldenström's macroglobulinaemia (WM) received otlertuzumab at 20 mg/kg administered intravenously once a week for up to 8 weeks followed by 4 monthly doses. Sixteen patients were treated; median age was 62·5 years (range, 41–81), and median number of prior regimens was 4 (range, 1–7). Twelve patients were refractory to prior treatment, 5 were refractory to rituximab. The mean terminal half‐life was 9·5 days. Lymph node reduction of ≥50% by computerized tomography scan measurements was seen in 3 of 12 patients, including one FL patient who had a partial response. One WM patient had a minor response. The most frequent adverse events were neutropenia, fatigue, nausea, thrombocytopenia, diarrhoea, and peripheral oedema; most were grade 1/2. Otlertuzumab treatment appears to have been well tolerated by the patients in this study. Clinical activity was observed in this small heterogeneous cohort of highly refractory, heavily pretreated B‐cell non‐Hodgkin lymphoma patients. These data suggest that further clinical investigation in non‐Hodgkin lymphoma is warranted.
CT-2106 is a 20(S)-camptothecin poly-L-glutamate conjugate. This linkage stabilizes the active lactone form of camptothecin and enhances aqueous solubility. In addition, poly-L-glutamate is ...postulated to increase tumor delivery of the active compound through enhanced permeability and retention effect in tumor. We studied a weekly schedule of CT-2106 in patients with refractory solid tumor malignancies.
CT-2106 was infused (10 min i.v. infusion) on days 1, 8, and 15 of each 28-day cycle. Plasma and urine were analyzed for total and unconjugated camptothecin by high-performance liquid chromatography equipped with a fluorescence detector. Toxicity and response assessments were done with Common Toxicity Criteria for Adverse Events version 3 and Response Evaluation Criteria in Solid Tumors, respectively.
Twenty-six patients were enrolled. Median age was 58 years (range, 36-83) and median number of doses was 6 (range, 1-9). The most frequent tumor type (50%) was melanoma. Dose limiting toxicities were thrombocytopenia and fatigue. A weekly dose of 25 mg/m2 given every 3 of 4 weeks was the maximum tolerated dose. The majority of grade 3 and 4 toxicities were hematologic. The pharmacokinetic profile of conjugated and unconjugated camptothecin showed a polyexponential decline with similar terminal half life (t1/2 range was 44-63 and 31-48 h for conjugated and unconjugated, respectively). Pharmacokinetics of conjugated and unconjugated camptothecin were dose and time independent in the tested dose range. Urinary excretion of conjugated and unconjugated camptothecin accounted for about 30% and 4% of the administered dose, respectively.
CT-2106 has a more manageable toxicity profile compared with unconjugated camptothecin. The maximum tolerated dose is 25 mg/m2 weekly given 3 of 4 weeks. This compound results in prolonged release of unconjugated camptothecin.
Summary
Purpose
CD37 is cell surface tetraspanin present on normal and malignant B cells. Otlertuzumab (TRU-016) is a novel humanized anti-CD37 protein therapeutic that triggers direct caspase ...independent apoptosis of malignant B cells and induces antibody-dependent cell-mediated cytotoxicity. This study evaluated the safety, pharmacokinetics, and efficacy of otlertuzumab administered in combination with rituximab and bendamustine to patients with relapsed, indolent B-cell non-Hodgkin Lymphoma (NHL).
Methods
Patients with relapsed or refractory NHL received otlertuzumab (10 or 20 mg/kg) intravenously (IV) on days 1 and 15, bendamustine (90 mg/m
2
) on days 1 and 2, and rituximab (375 mg/m
2
) on day 1 for up to six 28 day cycles. Responses were determined using standard criteria.
Results
Twelve patients were treated with 6 patients at each dose level; median age was 57 years (range, 51–79), and median number of prior regimens was 3 (range, 1–4). All patients had relapsed after prior rituximab including 7 refractory to their most recent previous treatment. In the 10 and 20 mg/kg dose cohorts, the mean half-life was 8 and 10 days following the first dose, and 12 or 14 days following 12 doses of otlertuzumab, respectively. Overall response rate was 83 % (10/12) with 4 CRs (32 %). The most frequent adverse events were neutropenia, nausea, fatigue, leukopenia, and insomnia; most were grade 1 or 2.
Conclusions
Otlertuzumab in combination with rituximab and bendamustine was well tolerated and induced responses in the majority of patients with relapsed indolent B-NHL. NCI Clinical Trials Network registration: NCT01317901.
Preclinical investigations indicated that recombinant human ciliary neurotrophic factor (rhCNTF) may have potential as therapy for amyotrophic lateral sclerosis (ALS). We evaluated the safety and ...efficacy of rhCNTF in a prospective, double‐blind, placebo‐controlled trial in 570 patients with US. Patients were randomized to receive 0.5, 2, or 5 μg/kg/day rhCNTF, or placebo, for 6 months. The primary efficacy end point was the change from baseline to the last on‐ treatment value of a combination megascore for limb strength (maximum voluntary isometric contraction) and pulmonary function. Secondary end points included individual arm and leg megascores, pulmonary function tests, an activities‐of‐daily‐living outcome measure, and survival. The four treatment groups were similar at baseline with respect to age, sex, disease duration, and muscle strength values. At all doses tested, rhCNTF had no beneficial effect on the primary or secondary end points. Certain adverse events, as follows, appeared to be dose related: injection site reactions, cough, asthenia, nausea, anorexia, weight loss, and increased salivation. There was an increased number of deaths at the highest dose level. rhCNTF had no benefical effect on any measure of ALS progression. There were increased adverse events in the 5 μg/kg group and increased deaths.
INTRODUCTION. Hemophilia B is a rare bleeding disorder caused by missing or defective factor IX, a clotting protein in the coagulation cascade. Patients with hemophilia B are treated with infusion of ...concentrated factor IX to replace the deficiency. As a chronic disease, patient quality of life and treatment satisfaction is a fundamental component of overall patient care in hemophilia B. Anecdotal evidence has suggested that some patients experience improved clinical outcomes and increased satisfaction when treated with IB1001, approved in the US as IXINITY®, coagulation factor IX (recombinant) (current factor treatment) as compared to their previous treatment. The objective of this study was to undertake a systematic assessment of IB1001 patient responses to measures of clinical care and quality of life that are relevant in hemophilia B in order to provide a more comprehensive description. METHODS. This was a cross-sectional study of hemophilia B patients in the United States currently being treated with IB1001. The study protocol was reviewed and approved by a central IRB. A survey was developed to capture patient-reported responses to clinical and quality of life questions of interest, including demographic characteristics, disease status, bleeding events, treatment, quality of life, and patient satisfaction. Where possible, patients were asked to compare responses on current factor treatment to those while on previous treatment with other available products. Patients were invited to complete the survey online. This was a pilot study to generate a descriptive analysis of patient experience. RESULTS. A total of 17 patients completed the survey. Most patients were male (76.5%) with a mean age of 43.8 years (range 16-73), and had been taking IB1001 for a mean 18 months at the time of this study. The elements most important for patient treatment choice were a high recovery rate, 24-hour half-life, no inhibitor development, and few side effects. Fewer annualized bleeding events were reported with the current factor treatment (mean 3.3 vs 6.7). Joint bleeds were most commonly reported, and most patients stated their bleed frequency was less (41%) or about the same (35%) on their current factor treatment compared to their previous treatment. Most patients reported their activity level as either ‘very active’ (23%), or ‘somewhat active’ (53%), and 47% of patients indicated they are more active now than on prior treatment. Overall, patients were either ‘very satisfied’ (76%) or ‘somewhat satisfied’ (12%) with their current factor treatment, compared with 12% and 23%, respectively, on prior treatment. Patients reported more mobility (29%), less pain (41%), and less anxiety or depression (18%) now than on prior treatment. CONCLUSIONS. In this study, we showed the utility of an online, survey-based instrument in characterizing patient experience with factor replacement products in hemophilia B. This study quantified the details of the patient experience that may have been driving the anecdotes of improved patient satisfaction and quality of life with IB1001. Overall, patients reported increased satisfaction, and improved clinical outcomes on their current factor treatment compared to products they had used in the past. While the data from this pilot study are encouraging, further study is warranted such as linking patient-reported outcomes to medical chart data to validate the clinical response and to better understand the variables that most influence patient satisfaction and quality of life.
Schaaf:Aptevo Therapeutics: Employment, Equity Ownership. Lockhart:Aptevo Therapeutics: Consultancy. Fritz:Aptevo Therapeutics: Employment, Equity Ownership. Stromatt:Aptevo Therapeutics: Employment, Equity Ownership.
Tetraspanins are commonly believed to act only as “molecular facilitators,” with no direct role in signal transduction. We herein demonstrate that upon ligation, CD37, a tetraspanin molecule ...expressed on mature normal and transformed B cells, becomes tyrosine phosphorylated, associates with proximal signaling molecules, and initiates a cascade of events leading to apoptosis. Moreover, we have identified two tyrosine residues with opposing regulatory functions: one lies in the N-terminal domain of CD37 in a predicted “ITIM-like” motif and mediates SHP1-dependent death, whereas the second lies in a predicted “ITAM motif” in the C-terminal domain of CD37 and counteracts death signals by mediating phosphatidylinositol 3-kinase-dependent survival.
► CD37 is a tetraspanin directly involved in signal transduction ► CD37 possesses dual noncanonical ITIM and ITAM motifs that regulate cell death ► CD37 ligation mediates BIM-dependent mitochondrial apoptosis of CLL B cells
Background: CD37 is a tetraspanin protein expressed on the surface of normal and transformed B cells across a wide range of maturational stages that mediates death signaling via SHP1. Otlertuzumab is ...a CD37-specific therapeutic protein built on the ADAPTIRTM(modular protein technology) platform that has shown significantly greater direct killing of CLL cells than rituximab and higher levels of Fc-mediated cellular cytotoxicity of CLL cells than either alemtuzumab or rituximab in pre-clinical models. This phase 1b trial was conducted to evaluate the safety and efficacy of otlertuzumab in combination with rituximab in patients with CLL.
Methods: Eligibility included CLL patients with adequate organ function, ECOG ≤2, and absolute neutrophil count ≥800/μL. Three cohorts have been enrolled. In the 1st cohort, 24 patients previously untreated patients who were considered ineligible for standard chemotherapy based on age, comorbidity or patient preference (naive) were enrolled and received IV infusion of otlertuzumab weekly for two 28-day cycles then once a month for 4 months. The first dose was 10 mg/kg and all subsequent doses were 20 mg/kg. In the 2nd cohort, 16 relapsed patients who had received 1-3 prior therapies were treated on the same dose and schedule as the 1st cohort except the first dose was 6 mg/kg. In the 3rd cohort, 16 naive patients received 6 mg/kg on Day 1 and 10 mg/kg on Days 8 and 15 and then monthly for 5 months. In all cohorts, rituximab (375 mg/m2 the first dose then 500 mg/m2) was administered after otlertuzumab by on the same schedule. Safety was evaluated using CTCAE and IWCLL 2008 Grading scale for Hematologic Toxicity in CLL Studies. Response was determined using the 1996 NCI and the 2008 IWCLL Criteria.
Results: Patient characteristics and adverse events are shown in the table. All but 9 patients completed all cycles of therapy: 3 discontinued early due to progressive disease; 3 due to lack of response, and 3 due to AEs (reaction to allopurinol, systemic inflammatory response, and rash). Grade 3/4 neutropenia was reported in 9% of patients; the incidence of severe infections was low (9%). Serious adverse events occurred in 61% of pts and included infusion related reaction (28 pts, 2 grade 3, 26 ≤grade 2), febrile neutropenia (4 patients), infection (2 pneumonia and 1 each sinusitis and diverticulitis), pyrexia (2 patients), and deep vein thrombosis, lymph node pain, grade 1 acute coronary syndrome, atrial fibrillation, small intestinal obstruction, systemic inflammatory response syndrome, and hyperkalemia in 1 pt each. For the 20 mg/kg previously untreated patients (n=24) IWCLL response rate is 54% (8% CR); 1 patient is not yet evaluable. NCI response rate is 96% (38% CR). Median progression-free survival is 16 months. In the other 2 cohorts, patients have been followed from 1 to 5 months after end of treatment and response results will be presented at the meeting.
Conclusions: The preliminary response rate with otlertuzumab in combination with rituximab is promising. This study is ongoing. The results for cohort 2 and 3 will be updated. The fourth cohort is currently being treated with otlertuzumab in combination with obinutuzumab instead of rituximab. Tablel 1Basic characteristics, therapeutic efficacy and CTCAE grade III/IV toxicity.Baseline CharacteristicsNaiveRelapsed20 mg/kg (n=24)10 mg/kg (n=16)20 mg/kg (n=16)Age, median (range)65 (27-85)62 (48-88)63(47-74)Male, n (%)13 (54)10 (63)9 (56)Β2 Microglobulin, mg/dL, median (range)3.5 (2-6)2.9 (1-6)4..0 (2-10)CIRS ≤6, n (%)14 (58)10 (63)11 (69)Rai III/IV, n (%)5 (21)5 (31)11 (69)del17p, n (%)2 (8)1 (6)5 (31)del11q, n (%)7 (29)2 (13)2 (13)del13q, n (%)13 (54)5 (31)7 (44)Trisomy 12, n (%)9 (38)4 (25)0Adverse Events, %Any Event10094100Any Grade 3/4 Event462563Any Serious Event756338Nonhematologic Events in ≥10% of patients*Infusion-related reaction67*5619Any infection583125Nausea331325Diarrhea331331Headache17625Hypertension171913*Cough13196Pyrexia131913MyelosuppressionNeutropenia*13019Thrombocytopenia000Anemia4019 *All grade 1/2 except 2 patients with Grade 3/4 infusion related reaction, 1 with Grade 3/4 hypertension, and 5 with Grade 4 neutropenia
Off Label Use: Ibrutinib is approved for previously treated MCL but was used as first-line therapy in 2 patients in this report.. Byrd:Emergent Product Development: Research Funding. Stromatt:Emergent Product Development: Employment. Awan:Lymphoma Research Foundation: Research Funding; Boehringer Ingelheim: Consultancy.
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