A phase 1b study evaluating the effect of elacestrant treatment on estrogen receptor availability and estradiol binding to the estrogen receptor in metastatic breast cancer lesions using 18F-FES PET/CT imaging.

BACKGROUND: Elacestrant is an oral selective estrogen receptor (ER) degrader. This phase 1b open-label, non-randomized study (RAD1901-106) was initiated to determine the effect of elacestrant on the availability of ER in lesions from postmenopausal women with ER+ advanced breast cancer (ABC) using 16α-18F-fluoro-17ß-estradiol positron emission tomography with low-dose computed tomography (FES-PET/CT). METHODS: Eligible patients were postmenopausal women with ER+, HER2- ABC; tumor progression after ≥ 6 months of 1-3 lines of endocrine treatment for ABC; and measurable or evaluable disease. Two 8-patient cohorts were enrolled: one treated with 400 mg elacestrant once daily (QD) and one treated with 200 mg elacestrant QD with dose escalation to 400 mg QD after 14 days. Elacestrant was dosed continuously until progressive disease, toxicity, or withdrawal. FES-PET/CT was performed pre-dose at baseline and 4 h post-dose on day 14. The primary endpoint was the percentage difference in FES uptake in tumor lesions (maximum 20) after 14 days of treatment compared to baseline. Overall response was investigator-assessed by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1. RESULTS: Patients (n = 16; median age, 53.5 years) had ABC with a median 2.5 prior lines of endocrine therapy. Median reduction in tumor FES uptake from baseline to day 14 was 89.1% (Q1, Q3: 75.1%, 94.1%) and was similar in both cohorts (89.1% [Q1, Q3: 67.4%, 94.2%], 200/400 mg and 88.7% [Q1, Q3: 79.5%, 94.1%], 400 mg). Residual ER availability (> 25% persistence in FES uptake) on day 14 was observed in 3 patients receiving 200/400 mg (3/78, 37.5%) and 1 patient receiving 400 mg (1/8, 12.5%). The overall response rate (ORR) was 11.1% (1 partial response), and clinical benefit rate (CBR) was 30.8%. Median percentage change in FES uptake did not correlate with ORR or CBR. Adverse events occurring in > 20% of the patients were nausea (68.8%), fatigue (50.0%), dyspepsia (43.8%), vomiting (37.5%), and decreased appetite, dysphagia, and hot flush (31.3% each). Most events were grade 2 in severity. CONCLUSION: Elacestrant 200 mg and 400 mg QD greatly reduced ER availability measured by FES-PET/CT. In a heavily pretreated population, elacestrant was associated with antitumor activity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02650817 . Registered on 08 January 2016.

EMERALD: Phase III trial of elacestrant (RAD1901) vs endocrine therapy for previously treated ER+ advanced breast cancer.

Elacestrant is a novel, nonsteroidal, orally bioavailable selective estrogen receptor degrader (SERD) that has demonstrated activity in patients with estrogen receptor (ER)-positive/HER2-negative breast cancer previously treated with endocrine therapies including fulvestrant and/or CDK 4/6 inhibitor therapy, and in those with ESR1 mutations (ESR1-mut) known to confer endocrine resistance. Herein, we describe the design and methodology of EMERALD, an international, multicenter, randomized, open-label, active-controlled, Phase III clinical study comparing the efficacy and safety of elacestrant to standard-of-care endocrine monotherapy treatment (fulvestrant or an aromatase inhibitor, per investigator's choice) in patients with ER-positive/HER2-negative advanced breast cancer. Primary end points are progression-free survival in ESR1-mut patients and in all patients (NCT03778931; EudraCT 2018-002990-24).

Factors influencing long-term efficacy and tolerability of bosutinib in chronic phase chronic myeloid leukaemia resistant or intolerant to imatinib.

The dual SRC/ABL1 tyrosine kinase inhibitor bosutinib is indicated for adults with Ph+ chronic myeloid leukaemia (CML) resistant/intolerant to prior therapy. This analysis of an ongoing phase 1/2 study (NCT00261846) assessed effects of baseline patient characteristics on long-term efficacy and safety of bosutinib 500 mg/day in adults with imatinib (IM)-resistant (IM-R; n = 196)/IM-intolerant (IM-I; n = 90) chronic phase (CP) CML. Median treatment duration was 24·8 months (median follow-up, 43·6 months). Cumulative major cytogenetic response (MCyR) rate [95% confidence interval (CI)], was 59% (53-65%); Kaplan-Meier (KM) probability of maintaining MCyR at 4 years was 75% (66-81%). Cumulative incidence of on-treatment progression/death at 4 years was 19% (95% CI, 15-24%); KM 2-year overall survival was 91% (87-94%). Significant baseline predictors of both MCyR and complete cytogenetic response (newly attained/maintained from baseline) at 3 and 6 months included prior IM cytogenetic response, baseline MCyR, prior interferon therapy and <6 months duration from diagnosis to IM treatment initiation and no interferon treatment before IM. The most common adverse event (AE) was diarrhoea (86%). Baseline bosutinib-sensitive BCR-ABL1 mutation was the only significant predictor of grade 3/4 diarrhoea; no significant predictors were identified for liver-related AEs. Bosutinib demonstrates durable efficacy and manageable toxicity in IM-R/IM-I CP-CML patients.

A Phase II Trial of Rivoceranib, an Oral Vascular Endothelial Growth Factor Receptor 2 Inhibitor, for Recurrent or Metastatic Adenoid Cystic Carcinoma.

PURPOSE: This open-label, single-arm, phase II study evaluated the vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitor (TKI) rivoceranib in patients with recurrent or metastatic (R/M) adenoid cystic carcinoma (ACC). PATIENTS AND METHODS: Eligible patients had confirmed disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) with ≥20% increase in radiologically or clinically measurable lesions or appearance of new lesions within the preceding 6 months. Patients received oral rivoceranib 700 mg once daily. Primary outcomes were objective response rate (ORR) by investigator review and by blinded independent review committee (BIRC). RESULTS: Eighty patients were enrolled and 72 were efficacy evaluable. Seventy-four patients had distant metastases and 49 received prior systemic treatment (14 received VEGFR TKIs). Per investigator and BIRC, respectively, ORR was 15.3% [95% confidence interval (95% CI), 7.9-25.7] and 9.7% (95% CI, 4.0-19.0); median duration of response was 14.9 months (95% CI, 4.9-17.3) and 7.2 months (95% CI, 3.5-8.4); and median progression-free survival was 9.0 months (95% CI, 7.3-11.5) and 9.0 months (95% CI, 7.7-11.5). Grade ≥3 treatment-related adverse events occurred in 56 patients (70.0%); the most common were hypertension (34, 42.5%) and stomatitis (6, 7.5%). Four grade 5 events occurred with one attributed to rivoceranib (epistaxis). Sixty-eight patients (85.0%) had ≥1 dose modifications and 16 patients (20.0%) discontinued rivoceranib for toxicity. CONCLUSIONS: In patients with progressing R/M ACC, rivoceranib demonstrated antitumor activity and a manageable safety profile consistent with other VEGFR TKIs.

Phase I dose-escalation and pharmacokinetic study of ispinesib, a kinesin spindle protein inhibitor, administered on days 1 and 15 of a 28-day schedule in patients with no prior treatment for advanced breast cancer.

The objective of the study was to evaluate the safety, pharmacokinetics, and antitumor activity of ispinesib, a kinesin spindle protein inhibitor. Patients with locally advanced or metastatic breast cancer who had received only prior neoadjuvant or adjuvant chemotherapy were treated with escalating doses of ispinesib administered as a 1-h infusion on days 1 and 15 every 28 days until toxicity or progression of disease. Doses were escalated until dose-limiting toxicity was observed in two out of six patients during cycle 1. A total of 16 patients were treated at three dose levels: 10 mg/m (n=3), 12 mg/m (n=6), and 14 mg/m (n=7). Forty-four percent of the patients had locally advanced disease and 56% had metastatic disease; 50% were estrogen receptor positive, 44% were progesterone receptor positive, 25% human epidermal growth factor 2 were positive, and 31% triple (estrogen receptor, progesterone receptor, human epidermal growth factor 2) negative. Sixty-nine percent of patients were chemo-naive. The maximum tolerated dose was 12 mg/m and dose-limiting toxicity was grade 3 increased aspartate aminotransferase and alanine aminotransferase. The most common toxicities included neutropenia (88%; 38% grade 3 and 44% grade 4), increased alanine aminotransferase (56%), anemia (38%), increased aspartate aminotransferase (31%), and diarrhea (31%). No neuropathy, mucositis, or alopecia was reported. Among the 15 patients evaluable for antitumor activity, there were three partial responses, one confirmed by the response evaluation criteria in solid tumors (7% response rate). Nine patients (60%) had stable disease lasting at least 42 days, with four (27%) lasting for at least 90 days. Disease stabilization (partial responses+stable disease) was observed in 11 (73.3%) patients. In conclusion, ispinesib was well tolerated when administered on days 1 and 15 every 28 days. Limited activity was observed with this schedule in patients with previously untreated advanced breast cancer.

A First-in-Human Phase 1 Study of a Novel Selective Androgen Receptor Modulator (SARM), RAD140, in ER+/HER2- Metastatic Breast Cancer.

INTRODUCTION/BACKGROUND: This first-in-human, phase 1 study aimed to characterize the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetic (PK) profile, and antitumor activity of RAD140, an oral selective androgen receptor (AR) modulator (SARM). PATIENTS AND METHODS: This dose-escalation study with a 3 + 3 design and PK expansion cohort enrolled postmenopausal women with ER+/HER2- metastatic breast cancer (mBC). Serum sex hormone-binding globulin (SHBG) and prostate-specific antigen (PSA) were used as surrogate markers of AR engagement. RESULTS: Twenty-two (21 AR+) heavily pretreated mBC patients were enrolled. Dose levels included 50 mg (n = 6), 100 mg (n = 13), and 150 mg (n = 3) once daily (QD). Most frequent (> 10%) treatment-emergent adverse events (TEAEs) were elevated AST (59.1%), ALT (45.5%), and total blood bilirubin (27.3%), and vomiting, dehydration, and decreased appetite and weight (27.3% each). Grade 3/4 TEAEs occurred in 16 (72.7%) patients and included elevations in AST/ALT and hypophosphatemia (22.7% each). Treatment-related TEAEs occurred in 17 per 22 patients (77.3%); 7 (31.8%) were Grade 3; none were Grade 4. The half-life (t1/2) of 44.7 hours supported QD dosing. At the MTD of 100 mg/day, 1 patient with an ESR1 mutation at baseline had a partial response. Overall, clinical benefit rate at 24 weeks was 18.2%, and median progression-free survival was 2.3 months. SHBG decreased in 18 per 18 patients, and PSA increased in 16 per 20 patients. Paired baseline and on-treatment tumor biopsies demonstrated AR engagement. CONCLUSION: RAD140 is a novel oral AR-targeted agent for the treatment of AR+/ER+/HER2- mBC with an acceptable safety profile and preliminary evidence of target engagement and antitumor activity.

Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial.

PURPOSE: Patients with pretreated estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies. METHODS: This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable ESR1 mutations. RESULTS: Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). ESR1 mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; P = .002) and patients with ESR1 mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; P = .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively). CONCLUSION: Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with ESR1 mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer.

Phase I Study of Elacestrant (RAD1901), a Novel Selective Estrogen Receptor Degrader, in ER-Positive, HER2-Negative Advanced Breast Cancer.

PURPOSE: This phase I study (RAD1901-005; NCT02338349) evaluated elacestrant, an investigational oral selective estrogen receptor degrader (SERD), in heavily pretreated women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer, including those with estrogen receptor gene alpha (ESR1) mutation. The primary objective was to determine the maximum tolerated dose and/or recommended phase II dose (RP2D). METHODS: The study consisted of a 3 + 3 design (elacestrant capsules) followed by expansion at RP2D (400-mg capsules, then 400-mg tablets) for the evaluation of safety and antitumor activity. Elacestrant was taken once daily until progression or intolerability. RESULTS: Of 57 postmenopausal women enrolled, 50 received RP2D (400 mg once daily): median age, 63 years; median three prior anticancer therapies, including cyclin-dependent kinase 4,6 inhibitors (CDK4/6i; 52%), SERD (52%), and ESR1 mutation (circulating tumor DNA; 50%). No dose-limiting toxicities occurred; the most common adverse events at RP2D (400-mg tablet; n = 24) were nausea (33.3%) and increased blood triglycerides and decreased blood phosphorus (25.0% each). Most adverse events were grade 1-2 in severity. The objective response rate was 19.4% (n = 31 evaluable patients receiving RP2D), 15.0% in patients with prior SERD, 16.7% in patients with prior CDK4/6i, and 33.3% in patients with ESR1 mutation (n = 5/15). The clinical benefit rate (24-week) was 42.6% overall (n = 47 patients receiving RP2D), 56.5% (n = 23, ESR1 mutation), and 30.4% (n = 23, prior CDK4/6i). Elacestrant clinical benefit was associated with decline in ESR1 mutant allele fraction. CONCLUSION: Elacestrant 400 mg orally once daily has an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with estrogen receptor-positive metastatic breast cancer. Notably, responses were observed in patients with ESR1 mutation as well as those with prior CDK4/6i and prior SERD. A phase III trial investigating elacestrant versus standard endocrine therapy is ongoing.

A pediatric phase I trial and pharmacokinetic study of ispinesib: a Children's Oncology Group phase I consortium study.

PURPOSE: To determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of the kinesin spindle protein inhibitor ispinesib in pediatric patients with recurrent or refractory solid tumors. SUBJECTS AND METHODS: Ispinesib was administered as 1-hr intravenous infusion weekly × 3, every 28 days. Cohorts of 3-6 patients were enrolled at 5, 7, 9, and 12 mg/m(2) /dose. Serial plasma samples for pharmacokinetic analyses were obtained after the first dose. RESULTS: Twenty-four (13 females) patients with a median (range) age of 10 years (1-19) were enrolled in the study. At the 12 mg/m(2) dose level dose-limiting neutropenia occurred in 2/6 patients and hyperbilirubinemia in 1/6 patients, while at the 9 mg/m(2) dose level 1/6 patients had dose-limiting neutropenia. There were no objective responses, but three patients (diagnoses of anaplastic astrocytoma, alveolar soft part sarcoma, and ependymoblastoma) had stable disease for 4-7 courses. There was substantial interpatient variation in drug disposition. The median (range) terminal elimination half-life was 16 (8-44) hr and the plasma drug clearance was 5 (1-14) L/hr/m(2) . CONCLUSIONS: The maximum tolerated and recommended phase II dose for ispinesib administered weekly × 3 every 28 days for children with solid tumors is 9 mg/m(2) /dose. Plans for a phase II trial in select pediatric solid tumors are in development.

Pharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Healthy Post-Menopausal Women.

BACKGROUND AND OBJECTIVES: Advanced estrogen receptor-positive (ER+) breast cancer is currently treated with endocrine therapy. Elacestrant is a novel, nonsteroidal, selective estrogen receptor degrader with complex dose-related ER agonist/antagonist activity that is being developed as a treatment option for ER+ breast cancer. METHODS: Two first-in-human phase 1 studies of elacestrant in healthy postmenopausal women (Study 001/Study 004) were conducted to determine its pharmacokinetic and pharmacodynamic profile as well as its safety and maximum tolerated dose. RESULTS: In total, 140 postmenopausal subjects received at least one dose of study drug (114 received elacestrant and 26 received placebo). Single-ascending dose and multiple-ascending dose assessments showed that doses up to 1000 mg daily were safe and well tolerated, and the maximum tolerated dose was not reached. Oral administration of elacestrant had an absolute bioavailability of 10% and a mean half-life ranging from 27 to 47 h, reaching steady state after 5-6 days. Mean occupancy of the ER in the uterus after seven daily doses was 83% for 200 mg and 92% for 500 mg daily. The median ratio of elacestrant concentrations in the cerebral spinal fluid vs. plasma was 0.126% (500 mg dose) and 0.205% (200 mg dose). Most adverse events were related to the upper gastrointestinal tract. CONCLUSIONS: These data demonstrate that elacestrant has good bioavailability when administered orally with a half-life that supports once-daily administration. Engagement of the ER and some ability to cross the blood-brain barrier was demonstrated in addition to an acceptable safety profile.

Correction to: Pharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Healthy Post-Menopausal Women.

Authors would like to correct the errors in table 2.

Platelets photochemically treated with amotosalen HCl and ultraviolet A light correct prolonged bleeding times in patients with thrombocytopenia.

BACKGROUND: Photochemical treatment (PCT) with amotosalen HCl with ultraviolet A illumination inactivates pathogens and white blood cells in platelet (PLT) concentrates. STUDY DESIGN AND METHODS: In a Phase II crossover study, 32 patients with thrombocytopenia received one transfusion of PCT and/or one transfusion of untreated (reference) apheresis PLTs. Hemostatic efficacy was assessed with the cutaneous template bleeding time and clinical observations. RESULTS: Paired bleeding time data for PCT and reference transfusions were available for 10 patients. Mean pretransfusion bleeding times were 29.2 +/- 1.6 minutes in the PCT group and 28.7 +/- 2.5 minutes in the reference group. After transfusion of a dose of PLTs of at least 6.0 x 10(11), mean 1-hour posttransfusion template bleeding times corrected to 19.3 +/- 9.5 minutes in the PCT group and 14.3 +/- 6.5 minutes in the reference group (p = 0.25). In 29 patients receiving paired PCT and reference transfusions, mean 1-hour posttransfusion PLT count increments were 41.9 x 10(9) +/- 20.8 x 10(9) and 52.3 x 10(9) +/- 18.3 x 10(9) per L for PCT and reference, respectively (p = 0.007), and mean 1-hour posttransfusion PLT corrected count increments (CCIs) were 10.4 x 10(3) +/- 4.9 x 10(3) and 13.6 x 10(3) +/- 4.3 x 10(3) for PCT and reference, respectively (p < 0.001). The time to next PLT transfusion was 2.9 +/- 1.2 days after PCT transfusions versus 3.4 +/- 1.3 days after reference transfusions (p = 0.18). Clinical hemostasis was not significantly different after PCT and reference transfusions. CONCLUSION: PCT PLTs provided correction of prolonged bleeding times and transfusion intervals not significantly different than reference PLTs despite significantly lower PLT count increments and CCIs.

Platelet dose consistency and its effect on the number of platelet transfusions for support of thrombocytopenia: an analysis of the SPRINT trial of platelets photochemically treated with amotosalen HCl and ultraviolet A light.

BACKGROUND: The SPRINT trial examined efficacy and safety of photochemically treated (PCT) platelets (PLTs). PCT PLTs were equivalent to untreated (control) PLTs for prevention of bleeding. Transfused PLT dose and corrected count increments (CIs), however, were lower and transfusion intervals were shorter for PCT PLTs, resulting in more PCT than control transfusions. PLT dose was analyzed to determine the impact of the number of PLTs transfused on transfusion requirements. STUDY DESIGN AND METHODS: Transfusion response was compared for patients with all doses of >or=3.0 x 10(11) and the complementary subset of patients with any dose of fewer than 3.0 x 10(11). Analyses included comparison of bleeding, number of PLT and red blood cell (RBC) transfusions, transfusion intervals, and CIs between PCT and control groups within each PLT dose subset. RESULTS: Mean PLT dose per transfusion in the PCT group was lower than in the control group (3.7 x 10(11) vs. 4.0 x 10(11); p<0.001). More PCT patients received PLT doses of fewer than 3.0 x 10(11) (n=190) than control patients (n=118; p<0.01). Comparisons of patients receiving comparable PLT doses showed no significant differences between PCT and control groups for bleeding or number of PLT or RBC transfusions; however, transfusion intervals and CIs were significantly better for the control group. CONCLUSIONS: When patients were supported with comparable doses of PCT or conventional PLTs, the mean number of PLT transfusions was similar. Lower CIs and shorter transfusion intervals for PCT PLTs suggest that some PLT injury may occur during PCT. This injury does not result in a detectable increase in bleeding, however.

Pathogen inactivation of platelets with a photochemical treatment with amotosalen HCl and ultraviolet light: process used in the SPRINT trial.

BACKGROUND: A photochemical treatment (PCT) system has been developed to inactivate a broad spectrum of pathogens and white blood cells in platelet (PLT) products. The system comprises PLT additive solution (PAS III), amotosalen HCl, a compound adsorption device (CAD), a microprocessor-controlled ultraviolet A light source, and a commercially assembled system of interconnected plastic containers. STUDY DESIGN AND METHODS: A clinical prototype of the PCT system was used in a large, randomized, controlled, double-blind, Phase III clinical trial (SPRINT) that compared the efficacy and safety of PCT apheresis PLTs to untreated apheresis PLTs. The ability of multiple users was assessed in a blood center setting to perform the PCT and meet target process specifications. RESULTS: Each parameter was evaluated for 2237 to 2855 PCT PLT products. PCT requirements with respect to mean PLT dose, volume, and plasma content were met. Transfused PCT PLT products contained a mean of 3.6 x 10(11) +/- 0.7 x 10(11) PLTs. The clinical process, which included trial-specific samples, resulted in a mean PLT loss of 0.8 x 10(11) +/- 0.6 x 10(11) PLTs per product. CAD treatment effectively reduced the amotosalen concentration from a mean of 31.9 +/- 5.3 micromol per L after illumination to a mean of 0.41 +/- 0.56 micromol per L after CAD. In general, there was little variation between sites for any parameter. CONCLUSIONS: The PCT process was successfully implemented by 12 blood centers in the United States to produce PCT PLTs used in a prospective, randomized trial where therapeutic efficacy of PCT PLTs was demonstrated. Process control was achieved under blood bank operating conditions.

Transfusion of 7-day-old amotosalen photochemically treated buffy-coat platelets to patients with thrombocytopenia: a pilot study.

BACKGROUND: Photochemical treatment (PCT) of platelets (PLTs) with amotosalen and ultraviolet A light to inactivate bacteria may facilitate extension of storage from 5 to 7 days. STUDY DESIGN AND METHODS: A randomized, double-blinded, crossover, noninferiority, single-site pilot study utilizing pooled buffy-coat PLTs was conducted. The primary endpoint was the 1-hour corrected count increment (CCI) after one transfusion each of 7-day-old PCT and reference (R) PLT components. Secondary endpoints included 1-hour count increment, time to next transfusion, hemostasis, transfusion reactions, and serious adverse events. RESULTS: Twenty patients with thrombocytopenia were randomly assigned: 9 to the PCT-R sequence and 11 to the R-PCT sequence. A significant treatment-by-period interaction was observed. Therefore, the first period only was also analyzed for the primary endpoint. Including both treatment periods, mean 1-hour CCI was 6587 +/- 4531 for PCT versus 8935 +/- 5478 for R-PLTs. For the first period only, mean 1-hour CCI was 8739 +/- 3785 for PCT versus 7433 +/- 5408 for R-PLTs. The upper bound of the one-sided 95 percent confidence interval of 2400 for the mean difference was higher than the specified noninferiority margin of 2200 for both analyses. Overall median time to next transfusion was 22 hours for PCT versus 27 hours for R-PLTs. Hemostasis was adequate and no transfusion reactions or serious adverse events were reported. CONCLUSIONS: Although this pilot study of a limited number of patients failed to show noninferiority within the specified noninferiority margin, 7-day-old PCT PLTs showed acceptable efficacy and safety for support of thrombocytopenia. The results, however, warrant evaluation in a larger trial of 7-day-old PCT PLTs.

A randomized, controlled Phase III trial of therapeutic plasma exchange with fresh-frozen plasma (FFP) prepared with amotosalen and ultraviolet A light compared to untreated FFP in thrombotic thrombocytopenic purpura.

BACKGROUND: Photochemical treatment of fresh-frozen plasma (FFP) with amotosalen and ultraviolet (UV) A light (PCT FFP) results in inactivation of a broad spectrum of pathogens while retaining coagulation factor activity, antithrombotic proteins, and von Willebrand factor-cleaving protease (VWF-CP) activity. STUDY DESIGN AND METHODS: A randomized, controlled, double-blind Phase III trial was conducted with PCT FFP or control FFP for therapeutic plasma exchange (TPE) in patients with thrombotic thrombocytopenic purpura (TTP). Owing to the rarity of this diagnosis, the trial was not powered to demonstrate small differences between treatment groups. Patients were treated with study FFP for a maximum of 35 days until remission was achieved (for a maximum of 30 daily study TPEs with no remission) plus an additional 5 days after remission. RESULTS: Among the 35 patients treated, the primary endpoint, remission within 30 days, was achieved by 14 of 17 (82%) PCT patients and 16 of 18 (89%) control patients (p = 0.658) The 90 percent confidence interval for treatment difference in remission rate for test - control was (-0.291 to 0.163). Time to remission, relapse rates, time to relapse, total volume and number of FFP units exchanged, and number of study TPEs were not significantly different between groups. Improvement in VWF-CP and inhibitors was similar for both groups. The overall safety profile of PCT FFP was similar to control FFP. No antibodies to amotosalen neoantigens were detected. CONCLUSION: The comparable results between treatment groups observed from this small trial suggest that TPE with PCT FFP was safe and effective for treatment of TTP.

Amotosalen interactions with platelet and plasma components: absence of neoantigen formation after photochemical treatment.

BACKGROUND: The INTERCEPT Blood System (Baxter Healthcare Corp., and Cerus Corp.) is a photochemical treatment (PCT) process that uses amotosalen (S-59) and ultraviolet A (UVA) illumination to inactivate a broad spectrum of pathogens. STUDY DESIGN AND METHODS: To evaluate the potential of the process to create neoantigens, the amounts of residual amotosalen and photoproducts present in PCT platelets (PLTs) and PCT plasma were quantified. The initial amount of amotosalen was 150 micromol per L. After illumination with 3 J per cm2 UVA and before transfusion, a compound adsorption device was used to substantially reduce the amounts of free amotosalen and unreactive photodegradation products. Patient serum samples from Phase III clinical trials were assayed by enzyme-linked immunosorbent assay (ELISA) for antibodies to potential amotosalen neoantigens. RESULTS: After PCT, 15 percent of the starting amount of amotosalen remains bound to PLTs, and 15 to 22 percent remains bound to plasma components. The majority of bound amotosalen is associated with lipid. Less than 1 percent of PLT-bound amotosalen and approximately 2 percent of plasma-bound amotosalen can be extracted into the water-soluble protein fraction. In seven Phase III clinical trials, 523 patients received more than 8000 units of PCT PLTs or PCT plasma. None of the patients exhibited clinical or laboratory manifestations of neoantigenicity. Furthermore, no other alteration of PLT membrane proteins was identified based on testing for lymphocytotoxic antibodies and PLT-specific alloantibodies. CONCLUSION: These results indicate that no neoantigens were detected by ELISA after PCT, suggesting that transfusion of PCT PLTs or PCT plasma does not induce adverse immunologic responses.

Clinical safety of platelets photochemically treated with amotosalen HCl and ultraviolet A light for pathogen inactivation: the SPRINT trial.

BACKGROUND: A photochemical treatment (PCT) method utilizing a novel psoralen, amotosalen HCl, with ultraviolet A illumination has been developed to inactivate viruses, bacteria, protozoa, and white blood cells in platelet (PLT) concentrates. A randomized, controlled, double-blind, Phase III trial (SPRINT) evaluated hemostatic efficacy and safety of PCT apheresis PLTs compared to untreated conventional (control) apheresis PLTs in 645 thrombocytopenic oncology patients requiring PLT transfusion support. Hemostatic equivalency was demonstrated. The proportion of patients with Grade 2 bleeding was not inferior for PCT PLTs. STUDY DESIGN AND METHODS: To further assess the safety of PCT PLTs, the adverse event (AE) profile of PCT PLTs transfused in the SPRINT trial is reported. Safety assessments included transfusion reactions, AEs, and deaths in patients treated with PCT or control PLTs in the SPRINT trial. RESULTS: A total of 4719 study PLT transfusions were given (2678 PCT and 2041 control). Transfusion reactions were significantly fewer following transfusion of PCT than control PLTs (3.0% vs. 4.1%; p = 0.02). Overall AEs (99.7% PCT vs. 98.2% control), Grade 3 or 4 AEs (79% PCT vs. 79% control), thrombotic AEs (3.8% PCT vs. 3.7% control), and deaths (3.5% PCT vs. 5.2% control) were comparable between treatment groups. Minor hemorrhagic AEs (petechiae [39% PCT vs. 29% control; p < 0.01] and fecal occult blood [33% PCT vs. 25% control; p = 0.03]) and skin rashes (56% PCT vs. 42% control; p < 0.001) were significantly more frequent in the PCT group. CONCLUSION: The overall safety profile of PCT PLTs was comparable to untreated PLTs.

Therapeutic efficacy and safety of red blood cells treated with a chemical process (S-303) for pathogen inactivation: a Phase III clinical trial in cardiac surgery patients.

BACKGROUND: A randomized, double-blind trial is reported of the clinical efficacy of red blood cells (RBCs) treated for pathogen inactivation with S-303, a synthetic labile alkylating agent. STUDY DESIGN AND METHODS: Patients undergoing complex cardiac surgeries were randomly assigned to receive either S-303-treated (test) or conventional (control) RBC transfusion during surgery and for 6 days thereafter. Efficacy was evaluated by comparing the occurrence of a composite primary endpoint of treatment-related morbidity (myocardial infarction and renal failure) and mortality. RESULTS: Two-hundred twenty-three patients were randomly assigned and 148 patients who received transfusions (74 with S-303-treated RBCs and 74 with control RBCs) were evaluable. The incidence of the primary endpoint was equivalent between the two groups (22 and 21% in the S-303-treated and control RBC groups, respectively). Secondary endpoints, including hemoglobin increment (mean, 1.4 vs. 1.5 g/dL), number of RBC transfusions (mean, 4.4 vs. 3.8 units), and other blood product support, were also comparable. The adverse event profile was similar between groups; however, patients who received S-303 RBCs were significantly more likely to develop constipation and less likely to suffer supraventricular extrasystoles. Four patients (2 test and 2 control) demonstrated positive indirect antiglobulin tests with reactivity for S-303 RBCs at one or more time points before or after transfusion, without evidence of hemolysis. CONCLUSION: S-303-treated and conventional RBCs were equivalent with respect to clinical efficacy and safety in supporting the transfusion needs of cardiac surgery patients. Investigations are under way to ascertain the significance of S-303 RBC antibodies and to prevent their occurrence.

Therapeutic efficacy and safety of photochemically treated apheresis platelets processed with an optimized integrated set.

BACKGROUND: This multicenter, randomized, controlled, double-blind Phase III clinical study evaluated the therapeutic efficacy and safety of apheresis platelets (PLTs) photochemically treated (PCT) with amotosalen and ultraviolet A light (INTERCEPT Blood System, Baxter Healthcare Corp.) compared with conventional apheresis PLTs (reference). STUDY DESIGN AND METHODS: Forty-three patients with transfusion-dependent thrombocytopenia were randomly assigned to receive either PCT or reference PLT transfusions for up to 28 days. RESULTS: The mean 1- and 24-hour corrected count increments were lower in response to PCT PLTs (not significant). When analyzed by longitudinal regression analysis, the estimated effect of treatment on 1-hour PLT count was a decrease of 7.2 x 10(9) per L (p = 0.05) and on 24-hour PLT count a decrease of 7.4 x 10(9) per L (p = 0.04). Number, frequency, and dose of PLT transfusions; acute transfusion reactions; and adverse events were similar between the two groups. There was no transfusion-associated bacteremia. Four PCT patients experienced clinical refractoriness; however, only one exhibited lymphocytotoxicity assay seroconversion. Antibodies against potential amotosalen-related neoantigens were not detected. CONCLUSION: PCT PLTs provide effective and safe transfusion support for thrombocytopenic patients.