Safety and efficacy of the tumor-selective adenovirus enadenotucirev, in combination with nivolumab, in patients with advanced/metastatic epithelial cancer: a phase I clinical trial (SPICE).

BACKGROUND: Novel combination therapies to overcome anti-PD-1 resistance are required. Enadenotucirev, a tumor-selective blood stable adenoviral vector, has demonstrated a manageable safety profile and ability to increase tumor immune-cell infiltration in phase I studies in solid tumors. METHODS: We conducted a phase I multicenter study of intravenous enadenotucirev plus nivolumab in patients with advanced/metastatic epithelial cancer not responding to standard therapy. Co-primary objectives were safety/tolerability and maximum tolerated dose and/or maximum feasible dose (MTD/MFD) of enadenotucirev plus nivolumab. Additional endpoints included response rate, cytokine responses, and anti-tumor immune responses. RESULTS: Overall, 51 heavily pre-treated patients were treated, 45/51 (88%) of whom had colorectal cancer (35/35 patients with information available were microsatellite instability-low/microsatellite stable) and 6/51 (12%) had squamous cell carcinoma of the head and neck. The MTD/MFD of enadenotucirev plus nivolumab was not reached, with the highest dose level tested (1×1012 vp day 1; 6×1012 vp days 3 and 5) shown to be tolerable. Overall, 31/51 (61%) patients experienced a grade 3-4 treatment-emergent adverse event (TEAE), most frequently anemia (12%), infusion-related reaction (8%), hyponatremia (6%), and large intestinal obstruction (6%). Seven (14%) patients experienced serious TEAEs related to enadenotucirev; the only serious TEAE related to enadenotucirev occurring in >1 patient was infusion-related reaction (n=2). Among the 47 patients included in efficacy analyses, median progression-free survival was 1.6 months, objective response rate was 2% (one partial response for 10 months), and 45% of patients achieved stable disease. Median overall survival was 16.0 months; 69% of patients were alive at 12 months. Persistent increases in Th1 and related cytokines (IFNγ, IL-12p70, IL-17A) were seen from ~day 15 in two patients, one of whom had a partial response. Among the 14 patients with matching pre-tumor and post-tumor biopsies, 12 had an increase in intra-tumoral CD8+ T-cell infiltration and 7 had increased markers of CD8 T-cell cytolytic activity. CONCLUSIONS: Intravenously dosed enadenotucirev plus nivolumab demonstrated manageable tolerability, an encouraging overall survival and induced immune cell infiltration and activation in patients with advanced/metastatic epithelial cancer. Studies of next-generation variants of enadenotucirev (T-SIGn vectors) designed to further re-program the tumor microenvironment by expressing immune-enhancer transgenes are ongoing. TRIAL REGISTRATION NUMBER: NCT02636036.

A tumor-selective adenoviral vector platform induces transient antiphospholipid antibodies, without increased risk of thrombosis, in phase 1 clinical studies.

Tumor-selective viruses are a novel therapeutic approach for treating cancer. Tumor-Specific Immuno Gene Therapy (T-SIGn) vectors are tumor-selective adenoviral vectors designed to express immunomodulatory transgenes. Prolonged activated partial thromboplastin time (aPTT), associated with the presence of antiphospholipid antibodies (aPL), has been observed in patients with viral infections, and following administration of adenovirus-based medicines. aPL may be detected as lupus anticoagulant (LA), anti-cardiolipin (aCL) and/or anti-beta 2 glycoprotein antibodies (aß2GPI). No subtype alone is definitive for development of clinical sequalae, however, patients who are 'triple positive' have a greater thrombotic risk. Additionally, isolated aCL and aß2GPI IgM do not appear to add value in thrombotic association to aPL positivity, rather IgG subtypes must also be present to confer an increased risk. Here we report induction of prolonged aPTT and aPL in patients from eight Phase 1 studies who were treated with adenoviral vectors (n = 204). Prolonged aPTT (≥ Grade 2) was observed in 42% of patients, with a peak at 2-3 weeks post-treatment and resolution within ~ 2 months. Among patients with aPTT prolongation, LA, but not aCL IgG nor aß2GPI IgG, was observed. The transience of the prolongation and discordance between positive LA and negative aCL/aß2GPI IgG assays is not typical of a prothrombotic state. Among the patients with prolonged aPTT there was no evidence of an increased rate of thrombosis. These findings elucidate the relationship between viral exposure and aPL in the context of clinical trials. They suggest a framework in which hematologic changes can be monitored in patients receiving similar treatments.Clinical trial registration:NCT02028442, NCT02636036, NCT02028117, NCT03852511, NCT04053283, NCT05165433, NCT04830592, NCT05043714.

Comparison of darbepoetin alfa dosed weekly (QW) vs. extended dosing schedule (EDS) in the treatment of anemia in patients receiving multicycle chemotherapy in a randomized, phase 2, open-label trial.

BACKGROUND: Chemotherapy-induced anemia (CIA) is responsive to treatment with erythropoiesis-stimulating agents (ESAs) such as darbepoetin alfa. Administration of ESAs on a synchronous schedule with chemotherapy administration could benefit patients by reducing clinic visits and potentially enhancing on-time chemotherapy delivery. METHODS: This phase 2, 25-week, open-label study evaluated the noninferiority of darbepoetin alfa administered weekly vs. as an extended dosing schedule (every 2 or 3 weeks) in patients with CIA. Patients were randomized 1:1 to an extended dosing schedule (EDS: darbepoetin alfa 300 µg Q2W if chemotherapy was QW, Q2W, or Q4W or darbepoetin alfa 500 µg Q3W if chemotherapy was Q3W) or weekly (150 µg QW regardless of chemotherapy schedule). Stratification factors included chemotherapy cycle length, screening hemoglobin (<10 g/dL vs. ≥10 g/dL), and tumor type (lung/gynecological vs. other nonmyeloid malignancies). The primary endpoint was change in hemoglobin from baseline to Week 13. RESULTS: Seven hundred fifty-two patients (374 QW patients; 378 EDS patients) received ≥1 dose of darbepoetin alfa and were included in the analysis. Demographics and disease state were similar between groups. Seventy-one percent of patients in the EDS group and 76% in the QW group achieved the target hemoglobin of ≥11.0 g/dL. There was a minimal difference in the primary endpoint of mean change in hemoglobin (baseline to Week 13) between the QW and the EDS groups (-0.04 g/dL; 95% confidence interval: -0.26, 0.17 g/dL). The upper limit of the 95% confidence interval was less than the prespecified limit of <0.75 g/dL, supporting noninferiority of the EDS dosing schedule. Reported adverse events were similar between groups. A slight increase in transfusions was reported in the QW group. CONCLUSION: Darbepoetin alfa, when administered synchronously with chemotherapy, on an EDS appears to be similarly efficacious to darbepoetin alfa weekly dosing with no unexpected adverse events. This study provides prospective data on how multiple dosing regimens available with darbepoetin alfa can be synchronized with chemotherapy administered across a range of dosing schedules. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00144131.

Randomized, double-blind, placebo-controlled trial of every-3-week darbepoetin alfa 300 micrograms for treatment of chemotherapy-induced anemia.

OBJECTIVE: Darbepoetin alfa is effective in treating chemotherapy-induced anemia (CIA). Administration of subcutaneous darbepoetin alfa every 3 weeks (Q3W) could simplify treatment through synchronization with common Q3W chemotherapy regimens. We report results from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy and safety of fixed-dose Q3W darbepoetin alfa in patients with a wide variety of tumor types who experienced CIA. RESEARCH DESIGN AND METHODS: Patients aged > or = 18 years with anemia (hemoglobin <11 g/dL) being treated for nonmyeloid malignancy were randomized 1:1 to receive darbepoetin alfa 300 microg (n = 193) or placebo (n = 193) subcutaneously Q3W from weeks 1 to 13 in this 16-week study. Doses could be adjusted per prespecified rules. MAIN OUTCOME MEASURES: The primary endpoint was the proportion of patients who received > or =1 red blood cell (RBC) transfusion between week 5 and the end of the treatment period (EOTP). The study also analyzed the proportions of patients achieving a hemoglobin concentration > or =11 g/dL and subsequently maintaining hemoglobin levels above 11 g/dL, and the change in hemoglobin concentration over time. RESULTS: The proportion of patients requiring RBC transfusions between week 5 and EOTP was significantly lower in the darbepoetin alfa-treated group than in the placebo-treated group (24 vs. 41% of patients, a 16.3% difference, p < 0.001). There were no differences between the two treatment arms in quality-of-life measures. Cardiovascular/thromboembolic adverse events were uncommon and were not associated with increases in hemoglobin levels. Study limitations suggest caution in the interpretation of these results: transfusions, the primary endpoint, were recommended but not required if hemoglobin concentrations were < or =8.0 g/dL, and protocol deviations (primarily dosing errors) occurred in approximately one-half of the patients in both treatment groups. CONCLUSIONS: In this study, fixed-dose Q3W darbepoetin alfa appeared to be well-tolerated and effective for the treatment of CIA. TRIAL REGISTRATION: Study 20030232; ClinicalTrials.Gov Identifier: NCT00110955.

Treating anemia of cancer with every-4-week darbepoetin alfa: final efficacy and safety results from a phase II, randomized, double-blind, placebo-controlled study.

Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA) approved for treating chemotherapy-induced anemia. This phase II, double-blind, placebo-controlled study examined the efficacy of darbepoetin alfa for treating anemia of cancer (AoC) in patients not receiving chemotherapy or radiotherapy. Patients were randomized 3:1 to receive darbepoetin alfa (6.75 microg/kg) or placebo every 4 weeks; the end of the study was at week 17. The primary endpoint was the percentage of patients with a hematopoietic response. Secondary endpoints included transfusion incidence and safety parameters. Efficacy analyses were performed on 162 patients in the darbepoetin alfa group and 56 patients in the placebo group. The Kaplan-Meier percentages of patients who achieved a hematopoietic response (darbepoetin alfa, 69%; placebo, 24%) or achieved the target hemoglobin (darbepoetin alfa, 85%; placebo, 50%) differed significantly between treatment groups. The transfusion incidence did not differ between treatment groups probably because of the low baseline transfusion rates in AoC patients. The incidence of adverse events (including on-study deaths) was similar in both groups. In conclusion, darbepoetin alfa appeared to be well tolerated and significantly increased hemoglobin levels in these AoC study patients.

Safety and efficacy of darbepoetin alpha in previously untreated extensive-stage small-cell lung cancer treated with platinum plus etoposide.

PURPOSE: A placebo-controlled, double-blind, randomized, phase III study was conducted in patients with extensive-stage small-cell lung cancer receiving first-line platinum-containing chemotherapy to determine if increasing or maintaining hemoglobin concentration with darbepoetin alpha could increase patient survival. PATIENTS AND METHODS: Darbepoetin alpha (300 microg) or placebo was administered once per week for 4 weeks then every 3 weeks for up to six cycles of chemotherapy (carboplatin plus etoposide or cisplatin plus etoposide) plus 3 weeks after the last dose of chemotherapy. Patients with disease progression were observed until death or until all patients completed their end-of-study visit and 496 deaths had occurred. The two coprimary end points were change in hemoglobin concentration from baseline to the end of the chemotherapy period and overall survival; statistical testing of survival was done if change in hemoglobin was significant at P < .05. RESULTS: The study enrolled 600 patients. Patients' hemoglobin levels dropped due to the myelosuppressive chemotherapy; however, treatment with darbepoetin alpha maintained hemoglobin levels significantly higher than placebo (P < .001). There was no statistically significant difference in overall survival between the treatment groups (hazard ratio [HR], 0.93; 95% CI, 0.78 to 1.11; P = .431). As expected, darbepoetin alpha was associated with a higher incidence of thromboembolic events (darbepoetin alpha, 9%; placebo, 5%). The transfusion risk was lower in the darbepoetin versus placebo group (HR, 0.40; 95% CI, 0.29 to 0.55). CONCLUSION: The results of this study did not demonstrate improved survival after treatment with darbepoetin alpha; however, they reinforce the benefit of erythropoiesis-stimulating agents in reducing transfusions and their neutral impact on survival in patients with chemotherapy-induced anemia.

Darbepoetin alpha for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study.

PURPOSE: The efficacy and safety of darbepoetin alpha (DA) for treating patients with active cancer and anemia not receiving or planning to receive cytotoxic chemotherapy or myelosuppressive radiotherapy was evaluated. PATIENTS AND METHODS: Patients with active cancer and anemia not receiving or planning to receive chemotherapy or radiotherapy were enrolled onto a phase III, multicenter, randomized, placebo-controlled study and administered placebo or DA 6.75 microg/kg every 4 weeks (Q4W) for up to 16 weeks with a 2-year follow-up for survival. Patients who completed 16 weeks of treatment could receive the same treatment as randomized Q4W for an additional 16 weeks. The primary end point was all occurrences of transfusions from weeks 5 through 17; safety end points included incidence of adverse events and survival. RESULTS: The incidence of transfusions between weeks 5 and 17 was lower in the DA group but was not statistically significantly different from that of placebo. DA was associated with an increased incidence of cardiovascular and thromboembolic events and more deaths during the initial 16-week treatment period. Long-term survival data demonstrated statistically significantly poorer survival in patients treated with DA versus placebo (P = .022). This effect varied by baseline covariates including, sex, tumor type, and geographic region; statistical significance diminished (P = .12) when the analysis was adjusted for baseline imbalances or known prognostic factors. CONCLUSION: DA was not associated with a statistically significant reduction in transfusions. Shorter survival was observed in the DA arm; thus, this study does not support the use of erythropoiesis-stimulating agents in this subset of patients with anemia of cancer.

The effectiveness of darbepoetin alfa administered every 3 weeks on hematologic outcomes and quality of life in older patients with chemotherapy-induced anemia.

Chemotherapy-induced anemia (CIA) may substantially impact the health-related quality of life (HRQoL) of older cancer patients. This exploratory analysis evaluated the effect of darbepoetin alfa administered as a fixed dose (300 microg) every 3 weeks (Q3W) on hematologic outcomes, HRQoL, and safety in older (> or =65 years old) versus younger (<65 years old) patients with CIA (hemoglobin <11 g/dl). Patients were categorized by age at screening: <65, > or =65 to <70, > or =70 to <75, > or =75 to <80, and > or =80 years old. Patients who received at least one dose of darbepoetin alfa were included in the analysis; of 1,493 patients, 724 were > or =65 years old. Age did not appear to influence hematologic outcomes after treatment with darbepoetin alfa; in all age categories, similar percentages of patients (78%-80%) achieved the target hemoglobin in approximately the same time (4-5 weeks). Also, the percentage of patients in each age category who received RBC transfusions was reduced from 10%-13% in month 1 to 2%-4% in month 4. Although younger patients reported the greatest improvement in HRQoL scores, approximately one half in each older age category reported clinically significant improvement in fatigue, and improvement in the Energy and Overall Health Assessment and Work Productivity and Activity Impairment scales. There were no treatment-related deaths. Treatment-related thromboembolic events were reported by <1% of patients <65 years old and <1% of patients > or =65 to <70 and > or =70 to <75 years old. Darbepoetin alfa Q3W appeared well tolerated and effective for treating older patients with CIA.

Darbepoetin alfa administered every three weeks is effective for the treatment of chemotherapy-induced anemia.

Patients with cancer receiving chemotherapy often have chemotherapy-induced anemia (CIA) and reduced quality of life. Darbepoetin alfa can effectively treat CIA when administered at an extended dosing interval of once every 3 weeks (Q3W). Darbepoetin alfa administered Q3W may allow synchronization of darbepoetin alfa therapy with chemotherapy administered Q3W. This multicenter, open-label, 16-week study evaluated the effectiveness and safety of darbepoetin alfa administered as a fixed dose (300 mug) Q3W in patients with CIA. Eligible patients (> or =18 years) were anemic (hemoglobin <11g/dl), had a nonmyeloid malignancy, and were receiving multicycle chemotherapy. This analysis includes 1,493 patients who received at least one dose of darbepoetin alfa. The effect of baseline hemoglobin (<10 or > or =10 g/dl) on clinical outcomes was evaluated. Patients in the > or =10-g/dl stratum achieved the hemoglobin target range (11-13 g/dl)in less time than patients in the <10-g/dlstratum (3 weeks vs. 9 weeks). More patients in the > or =10-g/dl stratum achieved the hemoglobin target range (87% vs. 66%); however, similar proportions of patients in both strata maintained hemoglobin within the target range (73% vs. 71%). Fewer patients in the > or =10-g/dl stratum received RBC transfusions from week 5 to the end of the study (12% vs. 28%). Over 50% of patients in both strata reported clinically significant improvements (> or =3-point increase) in Functional Assessment of Cancer Therapy-Fatigue score. Twenty-eight percent of patients reported serious adverse events; 3% of all patients had a venous or arterial thrombotic event. This study demonstrates that darbepoetin alfa Q3W is well tolerated and effective for treating CIA.