Research Spotlight

Hussain, M., C. M. Tangen, I. M. Thompson, Jr., G. P. Swanson, D. P. Wood, W. Sakr, N. A. Dawson, N. B. Haas, T. W. Flaig, T. B. Dorff, D. W. Lin, E. D. Crawford, D. I. Quinn, N. J. Vogelzang and L. M. Glode (2018). “Phase III Intergroup Trial of Adjuvant Androgen Deprivation With or Without Mitoxantrone Plus Prednisone in Patients With High-Risk Prostate Cancer After Radical Prostatectomy: SWOG S9921.” J Clin Oncol 36(15): 1498-1504.

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Purpose Patients with high-risk prostate cancer after radical prostatectomy are at risk for death. Adjuvant androgen-deprivation therapy (ADT) may reduce this risk. We hypothesized that the addition of mitoxantrone and prednisone (MP) to adjuvant ADT could reduce mortality compared with adjuvant ADT alone. Methods Eligible patients had cT1-3N0 prostate cancer with one or more high-risk factors after radical prostatectomy (Gleason score [GS] >/= 8; pT3b, pT4, or pN+ disease; GS 7 and positive margins; or preoperative prostate-specific antigen [PSA] > 15 ng/mL, biopsy GS score > 7, or PSA > 10 ng/mL plus biopsy GS > 6. Patients with PSA less-than-or-equal-to 0.2 ng/mL after radical prostatectomy were stratified by pT/N stage, GS, and adjuvant radiation plan and randomly assigned to ADT (bicalutamide and goserelin for 2 years) or ADT plus six cycles of MP. The primary end point was overall survival (OS). Median OS was projected to be 10 years in the ADT arm, requiring 680 patients per arm to detect a hazard ratio of 1.30 with 92% power and one-sided alpha = .05. Results Nine hundred sixty-one eligible intent-to-treat patients were randomly assigned to ADT or ADT + MP from October 1999 to January 2007, when the Data Safety Monitoring Committee recommended stopping accrual as a result of higher leukemia incidence with ADT + MP. Median follow-up was 11.2 years. The 10-year OS estimates were 87% with ADT (expected 50%) and 86% with ADT + MP (hazard ratio, 1.06; 95% CI, 0.79 to 1.43). The 10-year estimate for disease-free survival was 72% for both arms. Prostate cancer was the cause of death in 18% of patients in the ADT arm and 22% in the ADT + MP arm. More patients in the MP arm died of other cancers (36% v 18% in ADT alone arm). Conclusion MP did not improve OS and increased deaths from other malignancies. The DFS and 10-year OS in these patients treated with 2 years of ADT were encouraging compared with historical estimates, although a definitive conclusion regarding value of ADT may not be made without a nontreatment control arm.

Home, P. D., R. L. H. Lam, W. L. Carofano, G. T. Golm, R. Eldor, M. F. Crutchlow, M. C. Marcos, J. Rosenstock, P. A. Hollander and B. Gallwitz (2018). “Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 1 diabetes: a randomized, open-label clinical trial.” Diabetes Obes Metab. May 15. [Epub ahead of print].

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AIMS: Comparison of the efficacy and safety of MK-1293 insulin glargine (Mk-Gla; 100 U/ml) with originator insulin glargine, Lantus (Sa-Gla) in people with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: This phase 3, randomized, active-controlled, open-label, 52-week study enrolled 508 people with T1DM (HbA1c less-than-or-equal-to 11.0%; 97 mmol/mol) taking basal and prandial insulin. Participants were randomized 1:1 to once-daily Mk-Gla (n=245) or Sa-Gla (n=263). Dose titration of basal insulin was by a pre-breakfast plasma glucose dosing algorithm. The primary efficacy objective was assessment of the non-inferiority of HbA1c change from baseline (margin of 0.40% [4.4 mmol/mol]) for Mk-Gla compared with Sa-Gla over 24 weeks. The primary safety objective was assessment of anti-insulin antibody development over 24 weeks. RESULTS: The LS mean HbA1c change from baseline at week 24 was -0.62 (95% CI -0.79, -0.45) % [-6.8 (-8.7, -4.9) mmol/mol] and -0.66 (-0.82, -0.50) % [-7.2 (-9.0, -5.4) mmol/mol] for Mk-Gla and Sa-Gla. The LS mean HbA1c difference was 0.04 (-0.11, 0.19) % [0.4 (-1.2, 2.0) mmol/mol] for Mk-Gla minus Sa-Gla, meeting the primary and secondary objective criteria for non-inferiority and equivalence. Week 24 mean insulin glargine dose for Mk-Gla and Sa-Gla was 0.46 and 0.48 U/kg. Similarity of HbA1c response and basal insulin dose trajectory persisted over the 52 weeks. Safety and tolerability, including anti-insulin antibody responses, hypoglycemia, adverse events and body weight, were similar between insulins over the 52-week study duration. CONCLUSIONS: Mk-Gla and Sa-Gla exhibited similar efficacy and safety over 52 weeks in people with T1DM. ClinicalTrials.gov number: NCT02059161.

Hollander, P. A., W. L. Carofano, R. L. H. Lam, G. T. Golm, R. Eldor, M. F. Crutchlow, M. C. Marcos, M. S. Rendell, P. D. Home, B. Gallwitz and J. Rosenstock (2018). “Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 2 diabetes: a randomized, open-label clinical trial.” Diabetes Obes Metab. May 14. [Epub ahead of print].

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AIMS: To compare the efficacy and safety of MK-1293 insulin glargine (Mk-Gla) and Lantus (Sa-Gla) in people with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This Phase 3, randomized, active-controlled, open-label, 24-week clinical trial enrolled 531 participants with T2DM (HbA1c /=10 U/day). Participants were randomized 1:1 to once-daily Mk-Gla (n=263) or Sa-Gla (n=263). Titration of insulin was guided by a fasting plasma glucose (FPG)-based dosing algorithm. The primary efficacy objective was to demonstrate the non-inferiority of change from baseline in HbA1c (margin of 0.40% [4.4 mmol/mol]) with Mk-Gla versus Sa-Gla after 24 weeks. The primary safety objective was anti-insulin antibody development after 24 weeks. RESULTS: For Mk-Gla and Sa-Gla, the least squares (LS) mean HbA1c change from baseline (95% CI) was -1.28 (-1.41, -1.15) % [-14.0 (-15.4, -12.6) mmol/mol] and -1.30 (-1.43, -1.18) % [-14.2 (-15.6, -12.8) mmol/mol]. The LS mean HbA1c difference (Mk-Gla minus Sa-Gla) was 0.03 (-0.12, 0.18) % [0.3 (-1.4, 1.9) mmol/mol], meeting non-inferiority and equivalence (secondary objective) criteria. Insulin doses, FPG, and seven-point plasma glucose profiles were similar between groups. Safety and tolerability, including anti-insulin antibody responses, hypoglycemia, adverse events and body weight, were similar between insulins. The efficacy and safety of Mk-Gla and Sa-Gla were similar both in participants who were insulin treated or insulin naive at baseline. CONCLUSIONS: Mk-Gla and Sa-Gla demonstrated similar efficacy and safety over 24 weeks of treatment in participants with T2DM.

Hansen, V. L., M. Coleman, S. Elkins, J. P. Letzer, M. Y. Levy, L. Seneviratne, J. Rine, M. White and E. T. Kuriakose (2018). “An Expanded Treatment Protocol of Panobinostat Plus Bortezomib and Dexamethasone in Patients With Previously Treated Myeloma.” Clin Lymphoma Myeloma Leuk 18(6): 400-407.e401.

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BACKGROUND: Panobinostat was recently approved by the US Food and Drug Administration and European Commission in combination with bortezomib and dexamethasone for patients with multiple myeloma who have received >/= 2 regimens, including bortezomib and an immunomodulatory drug. The PANEX (panobinostat expansion) treatment protocol provided access to panobinostat and gathered additional safety data before commercial availability. PATIENTS AND METHODS: In treatment phase 1, patients received panobinostat 20 mg 3 times per week plus bortezomib 1.3 mg/m(2) twice weekly with dexamethasone 20 mg on the days of and after bortezomib treatment. Patients with no change or better in treatment phase 1 proceeded to treatment phase 2, when bortezomib was reduced to once weekly. Unlike in the phase III trial, PANORAMA-1 (panobinostat or placebo with bortezomib and dexamethasone in patients with relapsed multiple myeloma), bortezomib could be administered either subcutaneously or intravenously. RESULTS: Thirty-nine patients with a median number of previous treatments of 4 (range, 1-12) were enrolled; most received subcutaneous bortezomib (87%). The overall response rate (partial response or better) was 56%. Grade 3/4 adverse events included thrombocytopenia (47%), fatigue (31%), dehydration (26%), and diarrhea (18%). Among the patients who received subcutaneous bortezomib, relatively low rates of peripheral neuropathy (all grade, 15%) and notable grade 3/4 adverse events (thrombocytopenia, 47%; diarrhea, 12%) were observed. CONCLUSION: Overall, data from the PANEX trial support regulatory approval of panobinostat plus bortezomib and dexamethasone and suggest the potential tolerability benefits of subcutaneous bortezomib in this regimen.

Goraya, N. and D. E. Wesson (2018). “Kidney Response to the Spectrum of Diet-Induced Acid Stress.” Nutrients 10(5). May 11.

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Chronic ingestion of the acid (H(+))-producing diets that are typical of developed societies appears to pose a long-term threat to kidney health. Mechanisms employed by kidneys to excrete this high dietary H(+) load appear to cause long-term kidney injury when deployed over many years. In addition, cumulative urine H(+) excretion is less than the cumulative increment in dietary H(+), consistent with H(+) retention. This H(+) retention associated with the described high dietary H(+) worsens as the glomerular filtration rate (GFR) declines which further exacerbates kidney injury. Modest H(+) retention does not measurably change plasma acid(-)base parameters but, nevertheless, causes kidney injury and might contribute to progressive nephropathy. Current clinical methods do not detect H(+) retention in its early stages but the condition manifests as metabolic acidosis as it worsens, with progressive decline of the glomerular filtration rate. We discuss this spectrum of H(+) injury, which we characterize as “H(+) stress”, and the emerging evidence that high dietary H(+) constitutes a threat to long-term kidney health.