Evaluable Patients In Group Research Articles

P.103 Onasemnogene abeparvovec (OA) treatment outcomes by patient weight at infusion: Initial findings from the RESTORE registry

Interventional trials of OA demonstrated safety and efficacy for infants typically weighing <8.5 kg at infusion. We aimed to describe real-world outcomes for patients with SMA according to weight at the time of OA infusion. We compared baseline characteristics, effectiveness (measured by CHOP INTEND), and safety of OA for patients weighing <8.5 kg (Group 1) or ≥8.5 kg (Group 2) at the time of infusion in the RESTORE SMA patient registry. As of Nov. 23, 2021, RESTORE included 221 patients with available data on weight at OA infusion. 165 patients weighed <8.5 kg (Group 1), and 56 weighed ≥8.5 kg (Group 2). More patients in group 1 had 2 SMN2 gene copies (72.7% vs. 42.9% in Group 2), while more patients in group 2 had 3 SMN2 gene copies (48.2% vs. 20.6% in Group 1). A majority in group 1 were diagnosed with SMA type 1 (66.1%) or were presymptomatic (25.5%), and most in group 2 were diagnosed with SMA type 1 (44.6%) or type 2 (39.3%). Most patients in group 1 (105/165; 63.6%) were aged <6 months at infusion, and most in group 2 (53/56; 94.6%) were aged ≥6 months at infusion. Monotherapy with OA was greater in group 1 (60.6%) vs. group 2 (37.5%). Different polytherapy regimens were observed in both groups. Of 75 patients in group 1 who were evaluable for CHOP INTEND, 70 (93.3%) improved/maintained score, and 63 (84.0%) achieved increases of ≥4 points. All 14 evaluable patients in Group 2 improved/maintained score. Eight (57.1%) achieved ≥4-point increases. In group 1, 79/165 (47.9%) patients experienced ≥1 treatment-emergent AEs (TEAEs) of any grade, and 41 (24.8%) reported ≥1 serious AEs. In group 2, TEAEs of any grade were reported in 34/56 (60.7%) patients, and 12 (21.4%) reported ≥1 serious AE. No deaths or unexpected OA-related serious AEs were reported. These results suggest that patients weighing ≥8.5 kg at OA infusion may benefit from treatment. We did not observe a difference in the incidence of TEAEs or serious AEs based on patient weight at OA infusion.

Phase I study of lurbinectedin in combination with weekly paclitaxel with or without bevacizumab in patients with advanced solid tumors

SummaryLurbinectedin and paclitaxel showed synergism in preclinical studies and have non-completely overlapping toxicity profiles. This phase I trial evaluated a combination of paclitaxel and lurbinectedin with/without bevacizumab in advanced tumors. This trial was divided into Group A, which evaluated weekly paclitaxel (60 or 80 mg) plus lurbinectedin (3.0–5.0 mg flat dose [FD] or 2.2 mg/m2) every 3 weeks in advanced solid tumors; and Group B, which evaluated bevacizumab (BEV, 15 mg/kg) added to the recommended dose (RD) defined in Group A in advanced epithelial ovarian or non-small cell lung cancer (NSCLC). 67 patients (A, n = 55; B, n = 12) were treated. The RD was paclitaxel 80 mg/m2 on Day (D)1,D8 plus lurbinectedin 2.2 mg/m2 on D1. At this RD, myelotoxicity was reversible and manageable, and most non-hematological toxicities were mild/moderate. Adding BEV did not notably change tolerability. Twenty-five confirmed responses were observed: 20/51 evaluable patients in Group A (overall response rate [ORR] = 39% at all dose levels and at the RD), and 5/10 evaluable patients in Group B (ORR = 50%). Most responders had breast (n = 7/12 patients), small cell lung (SCLC) (n = 5/7), epithelial ovarian (n = 3/9) and endometrial cancer (n = 3/11) in Group A, and epithelial ovarian (n = 3/4) and NSCLC (n = 2/6) in Group B. Clinical benefit rate was 61% in Group A (58% at the RD), and 90% in Group B. No major pharmacokinetic drug-drug interactions were observed. Paclitaxel/lurbinectedin and paclitaxel/lurbinectedin/BEV are feasible combinations. Further development is warranted of paclitaxel/lurbinectedin in SCLC, breast, and endometrial cancer, and of paclitaxel/lurbinectedin/BEV in epithelial ovarian cancer.

Tubularised incised-plate versus tubularisation of an intact and laterally augmented plate for hypospadias repair: A prospective randomised study

ObjectivesTo compare the outcome of hypospadias repair using tubularised incised-plate (TIP) urethroplasty and tubularisation of an intact and laterally augmented urethral plate. Patients and methodsThis prospective randomised study included 370 patients with primary distal hypospadias. All had urethral plate widths of 8–10mm and a glans of ⩾15mm. Exclusion criteria were previous repair, circumcision, a wide urethral plate of >10mm or a narrow plate of <8mm in diameter, a small glans of <15mm in diameter, chordee of >30°, and hormonal stimulation. Patients were randomised into two groups: Group 1 (185 patients) underwent TIP urethroplasty and Group 2 (185 patients) underwent tubularisation of the intact plate with lateral augmentation of the urethral plate using penile skin. The follow-up period was 12–28months. ResultsThere were 172 evaluable patients in Group 1 and 177 in Group 2. The urethroplasty was successful in 83.2% and 94.4% in Groups 1 and 2, respectively. Complications occurred in 16.8% in Group 1 and 5.6% in Group 2 (P=0.001). Meatal stenosis occurred in 7% and 3.4% in Groups 1 and 2, respectively (P=0.130). There were statistically significant differences in the wound dehiscence, fistula, and re-operation rates of Group 1 versus Group 2, at 6% versus 0%, 9.8% versus 2.8%, and 13.4% versus 5.6%, respectively. The presence of mild chordee did not affect the complication rate (P=0.242). The mean (SD) operative time was 56.7 (8.9) min in Group 1 and 93.7 (8.3) min in Group 2 (P<0.001). ConclusionThe outcome of tubularised intact and laterally augmented plate is better than classical TIP urethroplasty of hypospadias. Further trials are mandatory to extend the indications of the technique.

Long-term results after transplantation of CD34+ selected (CellPro) versus unselected peripheral blood progenitor cells (PBPC) from related allogeneic donors

To determine the long-term outcome of patients after allogeneic transplantation of T-cell depleted versus unmanipulated hematopoietic stem cell grafts with respect to incidence of GvHD and overall survival in 50 consecutive patients. In this prospective phase II study utilizing biological randomization, 50 sibling donors were mobilized with G-CSF. Positive selection of CD34+ cells (Ceprate SC; CellPro, USA) was performed in good mobilizers (n = 25; group A), but not in poor mobilizers (n = 25; group B). Patients had hematological malignancies. Median patient age was 44 years (range, 19-57). Numbers of CD3+ cells were 0.5 ± 0.4 × 10(6)/kg in group A and 216 ± 127 × 10(6)/kg in group B. Hematological recovery was rapid in both groups. Patients in group A had no grade III-IV acute GvHD, whereas 6 out of 22 evaluable patients in group B had grade III-IV acute GvHD with fatal outcome in four cases (P < 0.01). Similarly, the incidence of chronic GvHD was lower in patients in group A (35 vs. 65%). However, there was a higher relapse rate in group A (11/25) versus group B (4/25, P < 0.05). At a follow-up of 10 years after transplantation, eight (32%) and 10 patients (40%) were relapse-free and alive in groups A and B, respectively. Risk factors for survival in a multivariate analysis were remission status prior to transplantation (CR vs. no CR), occurrence of acute and chronic GvHD, and relapse. The use of the CellPro device for CD34 positive selection per se did not have an influence on overall survival.

Successful Prevention of Acute Graft-versus-Host Disease Using Low-Dose Antithymocyte Globulin after Mismatched, Unrelated, Hematopoietic Stem Cell Transplantation for Acute Myelogenous Leukemia

In this study, we investigated the effects of low-dose antithymocyte globulin (ATG, thymoglobulin) in the prevention of acute graft-versus-host disease (aGVHD) in mismatched, unrelated hematopoietic stem cell transplantations (uHSCTs) in patients with the single disease entity of acute myelogenous leukemia (AML). Patients (n = 103) with a variable risk for AML who received uHSCTs from available Asian and Caucasian donors were enrolled. First, we compared HLA-matched (group 1, n = 54) and HLA-mismatched (group 2, n = 49) transplantation patients. Then, we divided the patients in group 2, who had received transplants from allele(s)/antigen-mismatched donors, into 2 subgroups: patients who used ATG (group 3, n = 24) and those who did not (group 4, n = 25). To prevent the development of aGVHD, the patients in group 3 received ATG at a dose of 1.25 mg/kg body weight per day for 2 consecutive days, together with our standard regimen of methotrexate (MTX) and tacrolimus. The median CD34(+) cell infusion was 4.2 x 10(6)/kg (range: 1.2-34.4). The median patient age was 41 years (range: 16-57), and the median follow-up duration of patients who were event-free survivors was 23 months (range: 2-72). The overall incidences of aGVHD and chronic GVHD (cGVHD) were 38% and 56%, respectively. Of 48 evaluable patients in group 2, 10 (21%) developed moderate to severe aGVHD (grades II-IV). In contrast, 2 (8%) of the 24 patients in group 3 and 7 (29%) of the 24 evaluated patients in group 4 required therapy for aGVHD (grades II-IV; P = .038). The incidence of cGVHD was not different between groups 3 and 4. The estimated probabilities of overall survival (OS) and event-free survival (EFS) at 2 years for group 2 were 55% and 44%, respectively. In comparison, the estimated probabilities of OS and EFS at 2 years for groups 3 and 4 were 68% versus 38% (P = .043) and 58% versus 38% (P = .103), respectively. The overall cumulative incidence of nonrelapse mortality (NRM) was 29% in group 2. The cumulative incidence of NRM differed markedly between group 3 (16%; 95% confidence interval [CI], 4%-28%) and group 4 (44%, 95% CI, 34%-54%) (P = .013). We found no difference in cytomegalovirus (CMV) reactivation between groups 3 and 4. These results suggest that in mismatched uHSCT, a low dose of ATG (total 2.5 mg/kg) may prevent moderate to severe aGVHD, with comparable rates of relapse and CMV reactivation and a greatly decreased rate of NRM.

E7389, a novel anti-tubulin, in patients with refractory breast cancer

653 Background: E7389 is a synthetic analog of halichondrin B, with a broad anti- proliferative activity against tumor cells. Methods: E7389 was evaluated in an open-label, single-arm Phase II trial as monotherapy for patients with refractory breast cancer (≥2 prior chemotherapy regimens, which must have included an anthracycline and a taxane). E7389 was administered as an IV bolus of 1.4 mg/m2 on Days 1, 8, and 15 of a 28-day cycle (group 1), or on Days 1 and 8 of a 21-day cycle (group 2). The primary efficacy endpoint was ORR. Results: As of 9 December 2005, 88 patients had received treatment, 68 in group 1 and 20 in group 2. Median age was 55 yrs (range 36–84) and ECOG performance status 0–1. Sixty-six percent of the tumors were ductal carcinomas, 6% lobular, and 27% were unclassified. Sixty percent of the tumors were ER+, 47% PR+, and 17% Her2/neu 3+. The patients had received at least two previous regimens, with a median number of 5 (range 2–14). Forty-eight percent of the patients had also used hormonal therapy. Forty-nine patients in group 1 and 12 patients in group 2 had completed their 2nd cycle of treatment, and twenty-one in group1 and 1 in group 2 their 4th cycle. Safety: The major toxicity related to study drug was neutropenia. Among 73 patients with preliminary safety data available, two patients had Grade 3 febrile neutropenia, and 31 had Grade 3 or 4 neutropenia or leukopenia. The other Grade 3 toxicities encountered in more than two patients were dehydration (4 patients) and dyspnea (4 patients). Grade 3 peripheral neuropathy was reported in 2 patients. Efficacy: At the end of cycle four there were 10 (15.2%) confirmed partial responses (PRs) out of 66 evaluable patients in group 1, and 1 confirmed PR (5.6%) out of 18 evaluable patients in group 2. The median duration of confirmed responses was 113 days. Conclusions: Based on the safety and efficacy in this refractory breast cancer population, E7389 appears to be a therapy worthy of continued investigation in patients with heavily pretreated breast cancer. In order to comply with the current demand for individualized cancer care, bio-markers which would predict the sensitivity to E7389 are being searched in the tumor samples of the patients in the current and forthcoming studies. [Table: see text]

Inosiplex for Treatment of Alopecia Areata: a Randomized Placebo-controlled Study

Treatment of alopecia areata remains unsatisfactory. We decided to test if systemic therapy with inosiplex (Isoprinosine(R)), an immunomodulator could influence the disease. Thirty-two subjects with recalcitrant alopecia areata, aged 16-48 years (mean 30.3+/-5.1 years), were randomized into two treatment groups of 16 subjects each. They were assigned to receive either oral inosiplex (group 1), or placebo (group 2) on a double-blind basis. Inosiplex dosage was 50 mg/kg/day in five divided doses for 12 weeks. Of the 15 evaluable patients in group 1, 5 (33.3%) had full remission, 8 (53.3%) responded partially and 2 (13.3%) did not respond. Of the 14 evaluable patients in the placebo group, none had full remission, 4 (28.5%) responded partially and 10 (71.4%) did not respond. The therapeutic difference between patients receiving active and placebo therapy was statistically significant (?2=7.82, p<0.01). Compared with placebo, oral inosiplex showed considerable efficacy in alopecia areata with insignificant side-effects. Larger studies are required, however, before inosiplex may be recommended as an efficacious and safe alternative systemic form of therapy for recalcitrant alopecia areata.

First-line ifosfamide, methotrexate, etoposide and prednisolone chemotherapy ± radiotherapy is active in stage I/II extranodal NK/T-cell lymphoma

Although most patients diagnosed with extranodal NK/T-cell lymphoma (NTCL) have localized disease, radiotherapy alone is unsatisfactory because of frequent systemic failure and conventional doxorubicin-based chemotherapy has low efficacy. Twenty-six patients with NTCL received ifosfamide, methotrexate, etoposide and prednisolone (IMEP) chemotherapy as first-line treatment [ifosfamide 1.5 g/m2 (days 1 – 3), methotrexate 30 mg/m2 (days 3 and 10), etoposide 100 mg/m2 (days 1 – 3) and prednisolone 120 mg (days 1 – 5)]. Radiotherapy was administered only to patients with Ann Arbor stage I/II that had not achieved complete remission (CR) or to those that developed local failure after completing chemotherapy. Sixteen patients (group A) had nasal or upper aerodigestive tract localization (stage I/II) and 10 (group B) had extranasal or disseminated disease. Of the 14 evaluable patients in group A, 11 (79%) achieved CR after IMEP alone and 13 (93%) after chemotherapy ± additional radiotherapy. Although, out of the 11 patients who achieved CR with chemotherapy alone, seven developed recurrence, all recurrences were local failure and successfully treated by additional curative radiotherapy. However, patients in group B responded poorly (CR 13%). IMEP regimen was active in NTCL patients with nasal or upper aerodigestive tract localization. Considering local failure rate after IMEP alone, initial IMEP chemotherapy followed by radiotherapy may be a promising treatment strategy in this subset of NTCL.

High response rates in patients with pancreatic cancer using the novel oral fluoropyrimidine S-1

S-1 is a newly developed oral fluoropyrimidine derivative with demonstrated activity against several tumor types. The aim of this study was to evaluate the feasibility and efficacy of S-1 administered as a single-agent and in combination with cisplatin, for the treatment of patients with pancreatic cancer. A total of 33 patients with locally advanced or recurrent pancreatic cancer were entered into this study. Seventeen patients were treated with S-1 alone (group A), and 16 patients were treated with S-1 plus weekly cisplatin (group B). Objective tumor responses among the 15 evaluable patients in group A were 1 CR, 2 PR, 9 SD and 3 PD, and among the 14 evaluable patients in group B were 8 PR, 5 SD, and 1 PD. The overall response rates were 20.0% and 57.1% in groups A and B respectively. Seven of the 17 patients in group A with elevated CA19-9 serum concentration and 12 of the 13 patients in group B with elevated CA19-9 level, reduced their CA19-9 by more than 50%. The median follow-up periods/median durations of response were 152/102 days in group A and 105/66 days in group B. Median survivals have not been reached in either group. In group A, no patient developed severe toxicities over grade 3, but in group B, 3 patients developed hematotoxicity over grade 3, and 2 patients experienced grade 3 anorexia. S-1, especially in combination with CDDP, shows promising activity with acceptable toxicities against pancreatic cancer. Further evaluation of this combination in patients with this disease is warranted.

Infection after colorectal surgery: A randomized trial of prophylaxis with piperacillin versus sulbactam/piperacillin

Antibiotics used for prophylaxis in elective colorectal surgery should be effective against the organisms contaminating the soft tissues and isolated from postoperative infections. These are usually the enterobacteriaceae commensal to the colon. However, staphylococcal and anaerobic infections are not uncommon. Piperacillin has been used as antibiotic prophylaxis and been shown to be as efficacious as an aminoglycoside with metronidazole. Piperacillin is susceptible to many β-lactamases and we have therefore conducted a study to assess the efficacy of adding sulbactam, a β-lactamase inhibitor, to piperacillin for prophylaxis in elective colorectal surgery. Three hundred and seventy-nine patients were randomized to receive a single dose of piperacillin 4 g intravenously (iv) (group P, n = 192) or piperacillin 4 g with sulbactam 2 g iv (group SP n = 187). Fifty-three patients were withdrawn from analysis leaving 168 evaluable patients in group P and 158 patients in group SP. Postoperative infective complications occurred in 91 (28%) patients, 55 (33%) in group P and 36 (23%) in group SP ( X 2 = 4·0 P < 0·05). Surprisingly Staphylococcus aureus was isolated from wound infections in 22 patients (12 in group P and 10 in group SP) which represents 24% of those patients who developed infective morbidity. We conclude that sulbactam improves the efficacy of piperacillin as prophylaxis in elective colorectal surgery but does little to protect against staphylococcal wound infection.