Treatment-related Treatment-emergent Adverse Events Research Articles

P1138: COPANLISIB + RITUXIMAB VS RITUXIMAB + PLACEBO IN PATIENTS WITH RELAPSED INDOLENT NON-HODGKIN LYMPHOMA (NHL): UPDATED SAFETY AND EFFICACY FROM THE PHASE III CHRONOS-3 TRIAL

Background: The Phase III CHRONOS-3 trial of copanlisib plus rituximab (C+R) vs placebo plus rituximab (P+R) in patients (pts) with indolent NHL (iNHL) showed a significant improvement in progression-free survival (PFS; hazard ratio [HR] 0.52; Matasar et al. Lancet Oncol 2021). At the time of data cut-off (August 31, 2020), 23% of pts were ongoing on treatment in the C+R arm and 43% of pts had discontinued treatment and entered active follow-up; corresponding numbers in the P+R arm were 19% and 17%. Aims: Here we report an updated 1-year follow-up analysis of efficacy and safety for all pts from CHRONOS-3 based on a data cut-off of August 6, 2021. Methods: Eligible pts with iNHL who relapsed after the last R-containing regimen and were progression-free and treatment-free for ≥12 months (mo) after the last R-containing regimen, or for >6 mo if unwilling/unfit to receive chemotherapy, were randomized 2:1 to receive C+R or P+R. All pts provided informed consent. Treatment continued until progression or unacceptable toxicity and was administered i.v. on a 28-day cycle, with C 60 mg/P given on days 1, 8, and 15 and R 375 mg/m2 given on days 1, 8, 15, and 22 of cycle 1 and on day 1 of cycles 3, 5, 7, and 9. Primary endpoint was centrally assessed PFS and secondary efficacy endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR), complete response rate (CRR), and treatment-emergent adverse events (TEAEs). Results: 307 pts were randomized to C+R and 151 to P+R. As of the August 2021 cut-off, 46 pts (15.0%) receiving C+R and 16 (10.6%) receiving P+R were ongoing on treatment. The most common reason for discontinuation was adverse events (AEs) unrelated to clinical progression (35.8%) for C+R and radiologic progression (49.7%) for P+R. Similar to the initial disclosure, C+R reduced the risk of progression or death vs P+R by 47%, with median PFS of 22.3 mo (95% confidence interval [CI] 19.4, 30.7) for C+R and 13.8 mo (10.8, 17.5) for P+R (HR 0.53 [95% CI 0.41, 0.70]; p=0.000001). PFS benefit was preserved across all cancer subtypes (HR [95% CI]): follicular lymphoma (n=275; 0.57 [0.41, 0.80]); marginal zone lymphoma (n=95; 0.53 [0.28, 0.99]); small lymphocytic lymphoma (n=50; 0.22 [0.10, 0.49]); lymphoplasmacytic/Waldenström macroglobulinemia (n=38; 0.42 [0.15, 1.16]). Updated ORRs were 80.8% vs 49.7% and CRRs were 34.9% vs 14.6% for C+R vs P+R, respectively. Median OS was not estimable and no significant benefit was seen for C+R over P+R, although the risk of death was reduced (HR 0.86 [95% CI 0.55, 1.32]) vs the August 2020 disclosure (HR 1.07 [0.63, 1.82]). Median DoR was 25.7 mo (17.6, 31.5) for C+R vs 17.3 mo (12.6, 25.3) for P+R; for pts with complete responses, median DoR was 42.3 mo (29.2, not estimable) vs 24.7 mo (10.2, 29.7) (HR 0.46 [0.24, 0.87]). Safety profiles for C+R and P+R were mostly unchanged from the initial disclosure, and the most common treatment-related AEs for pts receiving C+R were hyperglycemia (69.4%), hypertension (49.5%), and diarrhea (33.9%). For C+R, 6 additional pts (2.0%) discontinued C due to an AE, bringing the total to 33.2%. The incidence of grade 3/4 treatment-related TEAEs was generally unchanged with the longer follow-up (2 new grade 4 for C+R; 1 new grade 4 for P+R), with no new grade 5 events. Summary/Conclusion: 1 year after the primary disclosure of CHRONOS-3, C+R continued to demonstrate acceptable safety and superior efficacy with durable complete responses vs P+R in pts with relapsed iNHL. These data support the long-term use of C+R in pts with relapsed iNHL.

Efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma

BackgroundRipretinib, a broad-spectrum KIT and platelet-derived growth factor receptor A switch-control tyrosine kinase inhibitor, is approved for the treatment of adult patients with advanced gastrointestinal stromal tumor as ≥ fourth-line therapy. We present the efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma enrolled in the expansion phase of the ripretinib phase I study.Patients and methodsPatients with KIT-altered metastatic melanoma were enrolled and treated with ripretinib at the recommended phase II dose of 150 mg once daily in 28-day cycles. Investigator-assessed responses according to Response Evaluation Criteria In Solid Tumors version 1.1 were carried out on day 1 of cycles 3, 5, 7, every three cycles thereafter, and at a final study visit.ResultsA total of 26 patients with KIT-altered metastatic melanoma (25 with KIT mutations, 1 with KIT-amplification) were enrolled. Patients had received prior immunotherapy (n = 23, 88%) and KIT inhibitor therapy (n = 9, 35%). Confirmed objective response rate (ORR) was 23% [95% confidence interval (CI) 9%-44%; one complete and five partial responses] with a median duration of response of 9.1 months (range, 6.9-31.3 months). Median progression-free survival (mPFS) was 7.3 months (95% CI 1.9-13.6 months). Patients without prior KIT inhibitor therapy had a higher ORR and longer mPFS (n = 17, ORR 29%, mPFS 10.2 months) than those who had received prior KIT inhibitor treatment (n = 9, ORR 11%, mPFS 2.9 months). The most common treatment-related treatment-emergent adverse events (TEAEs) of any grade in ≥15% of patients were increased lipase, alopecia, actinic keratosis, myalgia, arthralgia, decreased appetite, fatigue, hyperkeratosis, nausea, and palmar-plantar erythrodysesthesia syndrome. There were no grade ≥4 treatment-related TEAEs.ConclusionsIn this phase I study, ripretinib demonstrated encouraging efficacy and a well-tolerated safety profile in patients with KIT-altered metastatic melanoma, suggesting ripretinib may have a clinically meaningful role in treating these patients.

Phase 1 trial of TIM-3 inhibitor cobolimab monotherapy and in combination with PD-1 inhibitors nivolumab or dostarlimab (AMBER).

2504 Background: TIM-3 expressed on tumor-infiltrating T cells is associated with T-cell suppression. AMBER (NCT02817633) is evaluating cobolimab (TSR-022/GSK4069889) monotherapy and with PD-1 inhibitors in advanced solid tumors. Methods: Multi-center, open-label study conducted with the following escalation arm (Parts 1A–C primary analysis reported here): (1A) cobolimab (IV Q2W) monotherapy at 7 doses (6 weight-based [0.03–10 mg/kg] and 1 flat [1200 mg] dose); (1B) cobolimab (1 mg/kg) + nivolumab (3 mg/kg IV Q2W); and (1C) cobolimab (100, 300, or 900 mg) + dostarlimab (500 mg IV Q3W). Primary endpoints were safety, tolerability, and recommended phase 2 dose (RP2D, monotherapy and combination). Results: 104 patients (pts) were included: 1A (n=46), 1B (n=7), or 1C (n=55); 4 pts from 1A crossed over to 1C (included in 1A and 1C safety and efficacy analyses). Most common cancers were non-small cell lung cancer (NSCLC) and melanoma (1A), NSCLC (1B), and NSCLC, skin, and peritoneal mesothelioma (1C). In 1A, 30.4% had ≥5 lines (L) of prior therapy; 42.9% had 3L in 1B; 33.3% had 2L in 1C. Treatment-related treatment-emergent adverse events (TR-TEAE) occurred in 67.4% (1A), 85.7% (1B), and 67.3% (1C); most commonly in 1A (n≥4) fatigue (13.0%) and nausea (8.7%); 1B (n≥3) diarrhea (57.1%) and nausea and vomiting (42.9% each); and 1C (n≥8) fatigue (20.0%) and rash (14.5%). Grade (Gr)≥3 TR-TEAEs occurred in 4.3% (1A), 28.6% (1B), and 14.5% (1C). There were no Gr5 TR-TEAEs or TR-TEAEs leading to dose delay. Serious TR-TEAEs occurred in 2.2% (1A), 0% (1B), and 12.7% (1C). TR-TEAEs led to discontinuation in 2.2% (1A), 28.6% (1B), and 9.0% (1C). Dose limiting toxicities (DLTs) occurred in 3.0% (1/33) in 1A (Gr3 lipase increased [10 mg/kg]); 40.0% (2/5) in 1B (Gr3 diarrhea and ALT and AST elevation); and 0% in 1C. Cobolimab serum exposure increased in a dose proportional manner at the therapeutic dose range. Preliminary mean terminal phase t1/2 ranged from 2.5–5.8 days for 0.03–0.3 mg/kg and 6.9–10.2 days for 1–10 mg/kg doses (1A), 6.9 days for 1B, and 9.5–12.3 days for 1C. Conclusions: Cobolimab + dostarlimab was well tolerated and showed preliminary anti-tumor activity, warranting further investigation of the RP2D + docetaxel in a randomized, phase 2 study. Funding: GSK (213348). Clinical trial information: NCT02817633. [Table: see text]

AMBER parts 1c and 1e: A phase 1 study of cobolimab plus dostarlimab in patients (pts) with advanced/metastatic melanoma.

9513 Background: TIM-3 and PD-1 are markers of T-cell suppression that are upregulated in melanoma. AMBER (NCT02817633) is evaluating cobolimab (TSR-022/GSK4069889), an anti-TIM-3 therapy, monotherapy or with PD-1 inhibitors, including dostarlimab, in pts with solid tumors. Methods: This multicenter, open-label study was conducted in 2 parts: dose escalation (Parts 1 A–D and F–H) and cohort expansion (Parts 2 A–D). Part 1C and exploratory cohort 1E (reported here) included pts with advanced/metastatic melanoma; prior therapies, except for immunotherapies, were permitted. Pts received cobolimab (100 [1C only], 300, or 900 mg IV) with dostarlimab (500 mg IV) Q3W. Part 1C primary endpoints were safety, tolerability, and recommended Phase 2 dose. Objective response rate (ORR; complete [CR] or partial [PR] response per RECIST v1.1) was a secondary endpoint in 1C and the primary endpoint in 1E (ad hoc efficacy analysis reported). An integrated safety analysis for all pts (Parts 1 and 2) receiving cobolimab with dostarlimab, regardless of tumor type or cobolimab dose, is reported here. Results: 28 pts were enrolled in 1C (n=10) and 1E (n=18). Most pts (n=23; 82.1%) had cutaneous disease of the skin. One pt had anorectal mucosal disease and 3 pts in the 900-mg cohort had uveal melanoma. Most pts (67.9%) had an ECOG PS=0. At data cut-off (May 19, 2021), treatment was ongoing in 5 pts. In the integrated safety analysis of pts who received cobolimab 100 mg (n=41), 300 mg (n=167), or 900 mg (n=69) with dostarlimab, treatment-related treatment-emergent AEs (TR-TEAEs) occurred in 53.7%, 57.5%, and 59.4%, respectively. The most common TR-TEAEs (any grade, ≥10% in 100 mg, 300 mg, or 900 mg groups, respectively) were fatigue (22.0%, 13.2%, 24.6%), rash (9.8%, 5.4%, 11.6%), diarrhea (4.9%, 6.0%, 10.1%), and dyspnea (2.4%, 0%, 10.1%). Grade ≥3 TR-TEAEs occurred in 12.2% (100 mg), 10.8% (300 mg), and 20.3% (900 mg); serious TR-TEAEs occurred in 7.3%, 7.8%, and 11.6%, respectively. No pts died due to TR-TEAEs; 2.4% (100 mg), 4.2% (300 mg), and 7.2% (900 mg) discontinued due to TR-TEAEs. ORR and disease control rate (DCR: stable disease [SD] ≥16 weeks, PR, or CR) are shown in the Table. Twelve pts achieved a PR and an immune-related (ir)PR (1 in 100 mg; 8 in 300 mg; 3 in 900 mg groups). Three pts achieved SD (2 in 300 mg; 1 in 900 mg groups); 8 pts had irSD (1 in 100 mg; 4 in 300 mg; 3 in 900 mg groups). Conclusions: Cobolimab with dostarlimab showed preliminary clinical responses in pts with advanced/metastatic melanoma and an acceptable safety profile across advanced cancers. Funding: GSK (213348). Clinical trial information: NCT02817633. [Table: see text]

P.021 Evaluation of PREEMPT fixed-dose, fixed-site and follow the pain treatment paradigms in the PREDICT Study

Background: Phase 3 PREEMPT established safety and efficacy of 155-195U onabotulinumtoxinA in adults with chronic migraine (CM). This analysis of the PREDICT study (NCT02502123) evaluates real-world effectiveness and safety of 155U, 156-195U and 195U-onabotulinumtoxinA in CM. Methods: Patients received onabotulinumtoxinA approximately every 12-weeks (≤7 treatment cycles [Tx]) per Canadian product monograph). Primary endpoint was mean change from baseline in Migraine-Specific Quality of Life (MSQ) at Tx4. Headache days, physician and patient satisfaction were evaluated. Analysis stratified safety population (≥1 onabotulinumtoxin A dose) into 3 groups (155U,156-195U,195U) by dose received on ≥3 of the first 4 Tx. Results: 184 patients received ≥1 onabotulinumtoxin A dose (155U, n=68; 156-195U, n=156; 195U, n=13 on ≥3 Tx). Headache days decreased over time compared to baseline (Tx4: -7.1[6.7] 155U; -6.5[6.7] 156-195U; -11.2[6.4] 195U). Physicians rated most patients as improved, and majority of patients were satisfied at final visit (80.8% 155U; 83.6% 156-195U; 90% 195U). Treatment-emergent adverse events (TEAEs) were reported in 18/68(26.5%) patients in 155U-group, 41/65(63.1%) in 156-195U-group and 10/13(76.9%) in 195U-group; treatment-related TEAEs were 9(13.2%), 10(15.4%) and 3(23.1%) respectively; serious TEAEs were 0, 3(4.6%) and 1(7.7%), none treatment-related. Conclusions: Long-term treatment with 155U, 156-195U, and 195U-onabotulinumtoxinA in PREDICT was safe and effective CM treatment. No new safety signals were identified.

A phase 1, multicenter, open-label, first-in-human study of DS-6157a in patients (pts) with advanced gastrointestinal stromal tumor (GIST).

11512 Background: GPR20 is selectively and abundantly expressed in GISTs, the most common sarcoma of digestive tract. DS-6157a is an anti-GPR20 antibody-drug conjugate with a novel tetrapeptide-based linker and DNA topoisomerase I inhibitor exatecan derivative (DXd). The target drug-to-antibody ratio is ̃8. The DXd payload, when released, inhibits topoisomerase I and induces cell apoptosis. Methods: This study conducted in the US and Japan was designed to include a dose-escalation (Part 1) and a dose-expansion (Part 2) in adult pts with advanced GIST (NCT04276415). Part 1 evaluated safety, tolerability, efficacy, and pharmacokinetics (PK) to determine the maximum-tolerated dose (MTD) and/or recommended dose for expansion. Key eligibility criteria included ECOG PS of 0 or 1, measurable disease per RECIST v1.1, and adequate bone marrow, hepatic, and renal function. DS-6157a was administered every 3 weeks as monotherapy. Pts had tumor assessments per RECIST 1.1 every 6 weeks (wks) for 36 wks, then every 9 wks thereafter. Results: At data cutoff, 34 pts were available for full analysis: median treatment duration was 9.9 wks (range, 3-56 wks) and 5 pts (14.7%) were ongoing; median age 60.5 years (y) (range, 29-81 y); 19 pts (56%) were male; 47% of pts were Asian and 47% were white. Baseline GPR20 expression was highly prevalent, and dose-dependent PK exposure was confirmed within the range of dose levels. The MTD was 6.4 mg/kg. One pt with SDH-deficient GIST with both SDH B and NF1 mutations, had a confirmed PR with shrinkage of -75%; 18 pts (53%) experienced stable disease and 10 pts (29%) experienced progressive disease as best response. Median progression-free survival across all dose levels was 3.6 months (95% CI, 1.6, 6.9). Treatment-emergent AEs (TEAEs) occurred in all pts and treatment-related TEAEs (TRAEs) in 32 pts (94%). The most common (≥25%) all-grade (Gr) TEAEs were nausea (82%), decreased appetite (59%), fatigue (47%), anemia (44%), constipation (38%), decreased platelets (35%), and vomiting (32%). Gr ≥3 TRAEs occurred in 14 pts (41%); the most common were decreased platelets (21%) and anemia (18%). Serious TEAEs (SAEs) occurred in 9 pts (27%) and related SAEs in 4 pts (12%). Related Gr 4 SAEs in 2 pts included abnormal hepatic function, neutropenia, thrombocytopenia and leukopenia. There was 1 treatment related death (hepatic failure). Further investigations are on-going to understand the modest clinical efficacy observed. The study did not proceed to Part 2, because the data from Part 1 did not meet efficacy targets. Conclusions: DS-6157a was generally well tolerated with early signs of moderate clinical activity. While there were no objective responses in pts with KIT-mutant GIST, tumor shrinkage was observed in all 4 pts with KIT wild-type GIST treated at different doses, including a confirmed PR at the MTD in a pt with SDH-deficient GIST with both SDH B and NF1 mutations. Clinical trial information: NCT04276415.

Efficacy and safety of lucitanib + nivolumab in patients with advanced gynecologic malignancies: Phase 2 results from the LIO-1 study (NCT04042116; ENGOT-GYN3/AGO/LIO).

5517 Background: LIO-1 is assessing the oral antiangiogenic, multikinase inhibitor lucitanib in combination with the programmed cell death receptor 1 (PD-1) inhibitor nivolumab. Individualized lucitanib dose titration is being explored to maximize lucitanib exposure and potential clinical benefit of the combination. Here, we present data from stage 1 of a Simon 2-stage design across 4 different types of advanced gynecologic cancers from the phase 2 part of LIO-1. Methods: Patients (pts) with advanced, recurrent, or metastatic endometrial cancer (EC, who received ≥1 prior platinum-based chemotherapy); cervical cancer (CC, who received ≥1 prior platinum-based chemotherapy ± bevacizumab); high-grade ovarian cancer (OC, who received ≥2 prior chemotherapies); or EC/OC with clear-cell histology (EOCC, who received ≥1 prior platinum-based chemotherapy + taxane) were enrolled. Prior PD-1 or programmed cell death ligand 1 (PD-L1) inhibitor treatment was excluded, except for up to 10 pts in the EC cohort. Pts received lucitanib at a starting dose of 6 mg once daily (QD), escalating to 8 mg QD and then 10 mg QD if safety-based titration criteria were met, plus intravenous nivolumab 480 mg every 28 days. The data cutoff was Jan 10, 2022. Results: Across cohorts, 100 pts were enrolled to stage 1; 27 (27%) remain on treatment. To date, 28 (28%) have escalated to lucitanib 8 mg, and 17 (17%) have escalated to the maximum dose of 10 mg. Confirmed responses per RECIST v1.1 have been reported in 5/22 (22.7%; 5 partial responses [PRs]) EC pts, 7/22 (31.8%; 2 complete responses [CRs], 5 PRs) CC pts, 4/33 (12.1%; 4 PRs) OC pts, and 5/23 (21.7%; 1 CR, 4 PRs) EOCC pts. Response duration ranges from 1.9+ to 13.1+ months. Of 5 pts with EC who received prior PD-1 inhibitor, there were 2 PRs, and 1 pt with ongoing stable disease of 7+ months. Grade ≥3 treatment-emergent adverse events (TEAEs) considered related to study treatment were reported in 43 (43%) pts, with hypertension the most frequent (n = 25 [25%]). Forty-six (46%) pts had a lucitanib-related TEAE that led to lucitanib interruption and 12 (12%) had one that led to lucitanib dose reduction. Eleven (11%) and 8 (8%) pts discontinued lucitanib and nivolumab, respectively, due to a treatment-related TEAE. Safety results were generally consistent across tumor cohorts. Conclusions: The combination of lucitanib + nivolumab is active in the treatment of advanced gynecological malignancies and has a manageable safety profile through effective dose titration. Stage 2 enrollment has continued in the CC cohort. Biomarker analysis is ongoing, and more mature efficacy and safety data will be presented at the meeting. Clinical trial information: NCT04042116.

Update on phase 1 study of tazemetostat, an enhancer of zeste homolog 2 inhibitor, in pediatric patients with relapsed or refractory integrase interactor 1–negative tumors.

10040 Background: A defining feature of malignant rhabdoid tumors (MRTs), epithelioid sarcoma (ES), and poorly differentiated chordomas (PDC) is loss of integrase interactor 1 (INI1) expression, which induces dependence on enhancer of zeste homolog 2 (EZH2). Tazemetostat (TAZ) is a selective EZH2 inhibitor approved by the US Food and Drug Administration for patients (pts) aged ≥16 y with metastatic or locally advanced ES ineligible for complete resection. Pediatric dose escalation and interim efficacy and safety data for the dose expansion were previously reported. Updated efficacy, safety, subgroup analyses, and translational results are reported here. Methods: NCT02601937 is a phase 1 multicenter study evaluating TAZ monotherapy ≤2400 mg/m2 daily in pediatric pts with relapsed or refractory INI1− tumors (MRT, atypical teratoid rhabdoid tumor [ATRT], select tumors with rhabdoid features, other INI1− tumors, and SS18-SSX synovial sarcoma). Primary endpoint for dose expansion was objective response rate (ORR). Secondary endpoints included safety/tolerability, duration of response (DOR), progression-free survival (PFS), and overall survival. Selected exploratory flow data using 250,000 cells from peripheral blood were available for up to 25 pts. Results: Phase 1 enrolled 109 pts (escalation, n=46; expansion, n=63; Table) with mean ages of 5.4 y in the dose escalation and 7.4 y in the dose expansion. ORRs were 7% (3/46) in the dose escalation and 14% (9/63) in the dose expansion. Per tumor category in the dose expansion, ORRs were 24% (5/21) ATRT, 33% (2/6) PDC, 22% (2/9) ES, and 0% in non–CNS RTs (n=21) and other tumors (n=6). ORR for pts with prior radiotherapy was 14% (11/80) vs 3% (1/29) with prior radiotherapy ( P>0.05). In the dose expansion, median PFS was 8 wk (95% CI: 8–13), OS was 21 wk (95% CI: 13–38), and DOR was 35 wk (95% CI: 24–121). Grade 3–4 treatment-related treatment-emergent adverse event rates were 15% (7/46) in the dose escalation and 22% (14/63) in dose expansion. Differences between responders (R) and nonresponders (NR) at C1D1 for neutrophil counts were significant ( P<0.05). All R (6/6) had <125,000 total neutrophils at C1D1 vs 42% (8/19) of NR; 50% (3/6) of R had >50,000 total CD3 T cells vs 0% (0/19) of NR. Conclusions: TAZ showed promising antitumor activity in ATRT, ES, and PDC. Potential synergism between prior radiotherapy and TAZ requires further investigation. TAZ was generally well tolerated. The biological/clinical significance of differences in peripheral blood cell counts between R and NR at C1D1 needs further investigation. Clinical trial information: NCT02601937. [Table: see text]

POS0755 SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF A SINGLE ORALLY ADMINISTERED DOSE OF ENPATORAN IN A PHASE I STUDY OF HEALTHY JAPANESE AND CAUCASIAN PARTICIPANTS

BackgroundEnpatoran, a novel, highly selective and potent dual toll-like receptor (TLR) 7 and TLR8 inhibitor, is in development for the treatment of autoimmune disorders including systemic and cutaneous lupus erythematosus. A first-in-human study in healthy participants has shown that enpatoran is well-tolerated and has a linear pharmacokinetic (PK) profile.ObjectivesTo compare the PK parameters, safety, and tolerability of single ascending oral doses of enpatoran in a Phase I study in Japanese and Caucasian participants, and to explore a potential PK/pharmacodynamic (PD) relationship.MethodsA single-centre, open-label, sequential dose group study enrolled healthy Japanese and Caucasian participants into three dose cohorts. Each Caucasian participant was matched by body weight (± 20%), height (± 15%) and sex to a Japanese participant. Participants received a single orally administered enpatoran dose of 100 mg, 200 mg, or 300 mg as a film-coated tablet under fasting conditions. PK parameters, (maximum plasma concentration [Cmax]; area under the plasma concentration–time curve (AUC) from time 0 to infinity [AUC0-inf]; AUC from time 0 to the last sampling time [AUC0-tlast]) determined using noncompartmental analysis, were estimated post-dose from Day 1–3. Safety was assessed from Day -1 to 8. PK (exposure) between the two ethnic groups was compared using an analysis of covariance (ANCOVA) model including ethnic group, natural log-transformed dose, and ethnic group by natural log dose interaction. Ex vivo secretion of cytokines (PD) under stimulated (using the TLR7/8 agonist, R848) and unstimulated conditions, was assessed pre- and post-dose. A panel of cytokines was analysed by multiplex immunoassay; IL-6 was considered the primary PD biomarker.ResultsThe study included 36 male participants (18 Japanese and 18 Caucasian) with a mean (± SD) age of 35.1 (± 10.8) years and mean (± SD) body mass index of 23.1 (± 2.1) kg/m2. Each dose group included six Japanese and six Caucasian participants. The geometric mean enpatoran plasma exposure parameters (Cmax, AUC0-inf, and AUC0-tlast) were consistent between the two ethnic groups for each dose level (Table 1) and indicated dose proportionality. ANCOVA modeling demonstrated comparable exposure between the two groups (geometric least square mean ratio [Japanese/Caucasian;90% CI] of Cmax: 0.9409 [0.7855–1.1270]; AUC0-inf: 0.8959 [0.7497–1.0704] and AUC0-tlast: 0.8963 [0.7511–1.0695]). Treatment-emergent adverse events (TEAEs) were observed in six Japanese (n = 0, 100 mg; n = 3, 200 mg; n = 3, 300 mg) and four Caucasian (n = 1, 100 mg; n = 0, 200 mg; n = 3, 300 mg) participants. There we no serious TEAEs; most were mild and not dose dependent. Treatment-related TEAEs were mild diarrhoea, mild flatulence, and moderate headache. There were no deaths, withdrawals, or early terminations due to TEAEs. Administering enpatoran effectively reduced ex vivo stimulated cytokine release, with maximal inhibition observed at 2 hours post-dose (IL-6: mean ≥99%). High inhibition levels were sustained through 24 hours in a dose-dependent manner (IL-6: mean ~76–97%). The pattern of cytokine release inhibition was consistent across doses and ethnic groups.Table 1.PK parameters in Japanese and Caucasian participants at the three enpatoran dose levelsParameter100 mg200 mg300 mgJapaneseCaucasianJapaneseCaucasianJapaneseCaucasianN = 6N = 6N = 6N = 6N = 6N = 6Cmax139175260245486490(ng/mL)AUC0-inf7749481910185028403330(h*ng/mL)AUC0-tlast7589311880183028103270(h*ng/mL)All values are Geometric mean.Cmax, maximum plasma concentration AUC0-inf, area under the plasma concentration–time curve (AUC) from time 0 to infinity; AUC0-tlast, AUC from time 0 to the last sampling time.ConclusionThere were no relevant ethnic differences in PK, PD, and safety between healthy Japanese and Caucasian participants across a range of single oral enpatoran doses, thus supporting the inclusion of Asian participants in future global Phase II studies.AcknowledgementsWe would like to thank those who took part in the study. This study was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945), who funded medical writing support by Bioscript Stirling Ltd.Disclosure of InterestsSathej Gopalakrishnan Shareholder of: Merck Healthcare KGaA, Employee of: Merck Healthcare KGaA, Axel Krebs-Brown Employee of: Merck Healthcare KGaA, Marco Nogueira Filho Employee of: Merck Healthcare KGaA, Yoshihiro Kuroki Employee of: Merck Biopharma Co., Ltd., Angelika Bachmann Employee of: Merck Healthcare KGaA, Andreas Becker Shareholder of: Merck Healthcare KGaA, Employee of: Merck Healthcare KGaA, Frank Schippers Employee of: Merck Healthcare KGaA, Markus Fluck Shareholder of: Merck Healthcare KGaA, Employee of: Merck Healthcare KGaA, Özkan Yalkinoglu Employee of: Merck Healthcare KGaA, Lena Klopp-Schulze Employee of: Merck Healthcare KGaA

Safety and Efficacy of Dostarlimab in Patients With Recurrent/Advanced Non–small Cell Lung Cancer: Results from Cohort E of the Phase I GARNET Trial

BackgroundDostarlimab is an anti-programmed cell death protein-1 antibody being evaluated in recurrent/advanced solid tumors, including non–small cell lung cancer (NSCLC), in the ongoing Phase I, multi-center, open-label, 2-part (dose escalation and cohort expansion) GARNET study (NCT02715284). Materials and MethodsHere, we report an interim analysis of patients with recurrent/advanced NSCLC who progressed following platinum-based chemotherapy. Patients received dostarlimab (500 mg IV every 3 weeks [Q3W] for Cycles 1-4, then 1000 mg Q6W) until disease progression or unacceptable toxicity for > 2 years. The primary endpoints were immune-related objective response rate (irORR) per investigator-assessed irRECIST and safety. ResultsAs of 8, July 2019, 67 patients with recurrent/advanced NSCLC were enrolled and treated with dostarlimab; the majority had programmed death ligand 1 (PD-L1) tumor proportion score (TPS) < 1% (35.8% of patients) or PD-L1 TPS 1%-49% (29.9% of patients); 7.5% had PD-L1 TPS ≥ 50%, and 26.9% had unknown PD-L1 TPS status. Median follow-up was 13.8 months (range: 0.0-22.6). irORR was 26.9%, including 2 complete and 16 partial responses. The median duration of response of 11.6 months (range: 2.8-19.4). Responses were observed in 2 of 24 (16.7%) patients with PD-L1 TPS < 1%, 4 of 20 (20.0%) patients with PD-L1 TPS 1%-49% and 2 of 5 (40.0%) patients with PD-L1 TPS ≥ 50%. Fatigue (4.5%) was the most common Grade ≥ 3 treatment-related treatment-emergent adverse event (TRAE). Immune-related TRAEs (any grade) were observed in 28.4% of patients. ConclusionDostarlimab demonstrated promising antitumor activity in advanced/recurrent NSCLC that progressed following platinum-based chemotherapy, including across all PD-L1 subgroups, and has an acceptable safety profile.

Phase 1 study of the liposomal formulation of eribulin (E7389-LF): Results from the breast cancer expansion cohort

BackgroundA liposomal formulation of eribulin, E7389-LF, may provide improved pharmacokinetics and allow increased access to tumour tissues. This expansion of a phase 1 study assessed the safety and efficacy of E7389-LF in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. MethodsPatients received E7389-LF 2.0 mg/m2 every three weeks. Tumour assessments were conducted every six weeks by the investigator by Response Evaluation Criteria in Solid Tumours v1.1. All adverse events were monitored and recorded. Serum biomarker assessments were conducted. ResultsOf 28 patients included, 75.0% had hormone receptor-positive breast cancer (HR+ BC) and 25.0% had triple-negative breast cancer (TNBC). The most common grade ≥3 treatment-related treatment-emergent adverse events included neutropenia (67.9%), leukopenia (42.9%), thrombocytopenia (32.1%), and febrile neutropenia (25.0%). Rates of neutropenia and febrile neutropenia were lower among patients who received prophylactic pegfilgrastim. Objective response rate was 35.7% (95% confidence interval [CI]: 18.6–55.9) for all patients and 42.9% (95% CI: 21.8–66.0) for patients with HR+ BC. Median progression-free survival was 5.7 months (95% CI: 3.9–8.3). The median overall survival was 18.3 months (95% CI: 13.2–not estimable). Among the 54 biomarkers assessed, 27, including 5 of 7 vascular markers, were significantly altered by E7389-LF treatment from baseline to any time point. ConclusionE7389-LF was tolerable and favourable antitumour activity was observed, particularly in patients with HR+ BC. Prophylactic pegfilgrastim can be considered in patients at high risk for neutropenia and febrile neutropenia. Clinicaltrials.gov numberNCT03207672.

Safety of Diazepam Nasal Spray in Children and Adolescents With Epilepsy: Results From a Long-Term Phase 3 Safety Study

BackgroundTo evaluate safety and tolerability of long-term treatment with diazepam nasal spray (Valtoco) for seizure clusters in patients aged six to 17 years. MethodsThe study enrolled patients aged six to 65 years with frequent seizure clusters. Age- and weight-based doses of diazepam nasal spray were administered; second doses were permitted if needed. Safety assessments included treatment-emergent adverse events (TEAEs). ResultsOf 163 treated patients, 45 (27.6%) were aged six to 11 years and 33 (20.2%) were aged 12 to 17 years. Mean doses per month were 2.1 in the 6 to 11 subgroup and 2.4 in the 12 to 17 subgroup. Of 1634 seizure clusters in pediatric patients, 186 (11.4%) required a second dose of diazepam nasal spray within 24 hours of the first dose. Similar proportions of TEAEs and serious TEAEs were reported in 6 to 11 (91.1%, 40.0%) and 12 to 17 subgroups (81.8%, 30.3%), respectively. No serious TEAEs were considered treatment related, and no patients discontinued because of TEAEs. Treatment-related TEAEs were more frequent in the 12 to 17 subgroup; only epistaxis and somnolence occurred in two or more patients overall. TEAE rates were similar across subgroups that received concomitant clobazam (90.0%), received prior diazepam rectal gel (90.9%), and were administered less than two versus greater than or equal to two doses per month (87.2% for both) of diazepam nasal spray. Most survey respondents (88%) were satisfied or very satisfied with treatment. ConclusionsIn this long-term safety analysis in pediatric patients with seizure clusters, repeated doses of diazepam nasal spray demonstrated a safety profile consistent across subgroups. These data support the dosing guidelines for diazepam nasal spray according to age and weight for pediatric patients.

Lack of clinically relevant differences in safety and pharmacokinetics after second‐dose administration of intranasal diazepam within 4 h for acute treatment of seizure clusters: A population analysis

ObjectiveCurrent diazepam nasal spray labeling requires waiting 4 h before administering a second dose. The objective of the current analyses was to examine safety and pharmacokinetic profiles of second doses of diazepam nasal spray given 0−4 h after the first dose.MethodsTwo datasets were analyzed. The first, a long‐term, repeat‐dose safety study of diazepam nasal spray, compared rates of treatment‐emergent adverse events (TEAEs), serious TEAEs, and treatment‐related TEAEs for patients receiving ≥1 second dose ≤4 h versus all second doses >4 h after the first. The second was a population pharmacokinetic analysis using data from three phase 1 studies to model drug exposure when a second dose of diazepam nasal spray was administered across multiple time points (1 min−4 h) following the first dose.ResultsIn the repeat‐dose safety study, a second dose of diazepam nasal spray was administered ≤24 h after the first to treat 485 seizure clusters in 79 patients. Rates of TEAEs were similar between patients receiving ≥1 second dose in ≤4 h (89.5%, n = 38) compared with >4–24 h only (80.5%, n = 41). The most common treatment‐related TEAEs were associated with nasal discomfort, which was mild or moderate and transient. There were no reports of respiratory or cardiac depression. The pharmacokinetic simulations of second doses predicted comparable elevations of plasma diazepam concentrations with administrations across a range of intervals after the first dose (1 min−4 h).SignificanceThese data indicate that the safety and pharmacokinetic profiles of a second dose of diazepam nasal spray administered within 4 h of the first dose are consistent with those associated with current labeling. This is potentially important for patients with seizure clusters who have a recurrent seizure within 4 h of first treatment and might benefit from immediate retreatment to reduce the risk of progression to status epilepticus.

Updated analysis with longer follow up of a phase 2a study evaluating erdafitinib in Asian patients (pts) with advanced cholangiocarcinoma (CCA) and fibroblast growth factor receptor (FGFR) alterations.

430 Background: Pts with CCA progressing after first-line therapy have limited treatment options. We report an updated analysis of the ongoing LUC2001 open-label, multicenter, phase 2a study (NCT02699606) investigating the efficacy and safety of erdafitinib in Asian pts with advanced CCA and FGFR alterations who progressed after ≥1 prior systemic treatment. Methods: Eligible adults (aged ≥18 years) received erdafitinib 8 mg once daily (QD) with pharmacodynamically guided up-titration to 9 mg QD. The primary endpoint was objective response rate (ORR; RECIST 1.1); secondary endpoints included best overall response (BOR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Survival estimates were determined by the Kaplan–Meier method. Results: Of 232 patients with CCA who underwent molecular screening, 39 (16.8%) had FGFR alterations (21 [9.1%] fusions and 19 [8.2%] mutations). Overall, 22 (9.5%) eligible pts (median age, 52 [range, 29–69] years) were enrolled and received treatment. Median follow-up was 22.4 (range, 2.3–47.0) months; median treatment duration was 6.2 (range, 1.5–35.6) months. All 22 pts received ≥1 line of prior systemic therapy and 12 (55.0%) pts had ≥2 prior lines of therapy. The ORR was 40.9% (95% CI, 20.7%–63.6%) and median time to response was 1.8 (range, 1.5–5.6) months. Median DOR was 7.3 (95% CI, 3.7–17.5) months, median PFS was 5.6 (95% CI, 3.6–12.7) months, and median OS was 40.2 (95% CI: 9.9–not estimable) months (Table). Responses were observed in 8/14 pts with FGFR fusions and 1/8 pts with FGFR mutations and in pts who received 1 or ≥2 prior lines of therapy. All 22 pts had ≥1 treatment-emergent adverse event (TEAE), the most common being dry mouth (15/22 [68.2%]) and stomatitis (14/22 [63.6%]). Grade ≥3 TEAEs occurred in 15/22 (68.2%) pts (11/22 [50.0%] were treatment related), of which the most common were stomatitis (3/22 [13.6%]) and alanine aminotransferase (ALT) increased (3/22 [13.6%]); 11/22 (50.0%) pts had ≥1 serious TEAE (1/22 [4.5%] pts had a serious treatment-related TEAE). A TEAE leading to death occurred in 1 patient (sepsis; not treatment-related). Conclusions: Asian pts with advanced CCA and FGFR alterations treated with erdafitinib had durable efficacy and a manageable safety profile, supporting the earlier findings of erdafitinib benefit in this population. Clinical trial information: NCT02699606. [Table: see text]

Safety and Efficacy of Subcutaneous Rituximab in Previously Untreated Patients with CD20+ Diffuse Large B-Cell Lymphoma or Follicular Lymphoma: Results from an Italian Phase IIIb Study.

Subcutaneous (SC) rituximab may be beneficial in terms of convenience and tolerability, with potentially fewer and less severe administration-related reactions (ARRs) compared to the intravenous (IV) form. This report presents the results of a phase IIIb study conducted in Italy. The study included adult patients with CD20+ DLBCL or FL having received at least one full dose of IV RTX 375 mg/m2 during induction or maintenance. Patients on induction received ≥4 cycles of RTX SC 1400 mg plus standard chemotherapy and FL patients on maintenance received ≥6 cycles of RTX SC. Overall, 159 patients (73 DLBCL, 86 FL) were enrolled: 103 (54 DLBCL, 49 FL) completed induction and 42 patients with FL completed 12 maintenance cycles. ARRs were reported in 10 patients (6.3%), 3 (4.2%) with DLBCL and 7 (8.1%) with FL, all of mild severity, and resolved without dose delay/discontinuation. Treatment-emergent adverse events (TEAEs) and serious adverse events occurred in 41 (25.9%) and 14 patients (8.9%), respectively. Two patients with DLBCL had fatal events: Klebsiella infection (related to rituximab) and septic shock (related to chemotherapy). Neutropenia (14 patients, 8.9%) was the most common treatment-related TEAE. Two patients with DLBCL (2.8%) and 6 with FL (7.0%) discontinued rituximab due to TEAEs. 65.2% and 69.7% of patients with DLBCL and 67.9% and 73.6% of patients with FL had complete response (CR) and CR unconfirmed, respectively. The median time to events (EFS, PFS, and OS) was not estimable due to the low rate of events. At a median follow-up of 29.5 and 47.8 months in patients with DLBCL and FL, respectively, EFS, PFS, and OS were 70.8%, 70.8%, and 80.6% in patients with DLBCL and 77.9%, 77.9%, and 95.3% in patients with FL, respectively. The switch from IV to SC rituximab in patients with DLBCL and FL was associated with low risk of ARRs and satisfactory response in both groups. This trial was registered with NCT01987505.

Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody–drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study

Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate composed of a humanized monoclonal antibody that binds carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and a cytotoxic maytansinoid that selectively targets CEACAM5-expressing tumor cells. In this phase I dose-escalation study, we evaluated the safety, pharmacokinetics, and preliminary antitumor activity of tusamitamab ravtansine in patients with solid tumors. Eligible patients were aged ≥18 years, had locally advanced/metastatic solid tumors that expressed or were likely to express CEACAM5, and had an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were treated with ascending doses of tusamitamab ravtansine intravenously every 2 weeks (Q2W). The first three dose levels (5, 10, and 20 mg/m2) were evaluated using an accelerated escalation protocol, after which an adaptive Bayesian procedure was used. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the first two cycles, graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. Thirty-one patients received tusamitamab ravtansine (range 5-150 mg/m2). The DLT population comprised 28 patients; DLTs (reversible grade 3 microcystic keratopathy) occurred in three of eight patients treated with tusamitamab ravtansine 120 mg/m2 and in two of three patients treated with 150 mg/m2. The maximum tolerated dose was identified as 100 mg/m2. Twenty-two patients (71%) experienced ≥1 treatment-related treatment-emergent adverse event (TEAE), seven patients (22.6%) experienced ≥1 treatment-related grade ≥3 TEAE, and three patients (9.7%) discontinued treatment due to TEAEs. The most common TEAEs were asthenia, decreased appetite, keratopathy, and nausea. Three patients had confirmed partial responses. The mean plasma exposure of tusamitamab ravtansine increased in a dose-proportional manner from 10 to 150 mg/m2. Tusamitamab ravtansine had a favorable safety profile with reversible, dose-related keratopathy as the DLT. Based on the overall safety profile, pharmacokinetic data, and Bayesian model recommendations, the maximum tolerated dose of tusamitamab ravtansine was defined as 100 mg/m2 Q2W.

Safety and tolerability of asunercept plus standard radiotherapy/temozolomide in Asian patients with newly-diagnosed glioblastoma: a phase I study

Asunercept (company code APG101 [Apogenix AG]; company code CAN008 [CANbridge Pharmaceuticals]) is a novel glycosylated fusion protein that has shown promising effectiveness in glioblastoma. This Phase I study was initiated to evaluate the tolerability and safety of asunercept in combination with standard radiotherapy and temozolomide (RT/TMZ) in Asian patients with newly diagnosed glioblastoma. This was the Phase I portion of a Phase I/II open label, multicenter trial of asunercept plus standard RT/TMZ. Adults with newly-diagnosed glioblastoma received surgical resection followed by standard RT/TMZ plus asunercept 200 mg/week (Cohort 1) or 400 mg/week (Cohort 2) by 30-min IV infusion. The primary endpoint was the safety and tolerability of asunercept during concurrent asunercept and RT/TMZ; dose-limiting toxicities were observed for each dose. Secondary endpoints included pharmacokinetics (PK) and 6-month progression-free survival (PFS6). All patients (Cohort 1, n = 3; Cohort 2, n = 7) completed ≥ 7 weeks of asunercept treatment. No DLTs were experienced. Only one possibly treatment-related treatment emergent adverse event (TEAE), Grade 1 gingival swelling, was observed. No Grade > 3 TEAEs were reported and no TEAE led to treatment discontinuation. Systemic asunercept exposure increased proportionally with dose and showed low inter-patient variability. The PFS6 rate was 33.3% and 57.1% for patients in Cohort 1 and 2, respectively. Patients in Cohort 2 maintained a PFS rate of 57.1% at Month 12. Adding asunercept to standard RT/TMZ was safe and well tolerated in patients with newly-diagnosed glioblastoma and 400 mg/week resulted in encouraging efficacy.Trial registration NCT02853565, August 3, 2016.

Long-term efficacy and safety of once-monthly Risperidone ISM® in the treatment of schizophrenia: Results from a 12-month open-label extension study

ObjectiveTo evaluate long-term efficacy, safety and tolerability of Risperidone ISM® in patients with schizophrenia, a multicenter, open-label extension of the PRISMA-3 study was conducted. MethodsEligible placebo (unstable) and Risperidone ISM® (stabilized) rollover patients from a previous 12-week double-blind phase and de novo stable patients received once-monthly intramuscular injections of Risperidone ISM® 75 or 100 mg for 12 months. The long term-efficacy assessment included the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales. Safety evaluation included treatment-emergent adverse events (TEAEs), injection site reactions (ISR), laboratory tests and several safety scales. ResultsAltogether, 215 patients entered the study (55 unstable, 119 stabilized and 41 stable patients). Most patients (74.9%) completed, and discontinuation rates were broadly similar across the study subgroups, mainly due to withdrawal of consent (12.1%). PANSS total and subscales scores decreased from baseline to endpoint in all groups, with the largest decrease for unstable patients. Improvement from baseline to 12 months was also shown for CGI-S and CGI-I scores for both unstable and stabilized patients; the CGI-S and CGI-I scores remained almost unchanged for the stable group. At least one treatment-related TEAE was reported in 39.1% of patients; the most common were headache (12.1%), hyperprolactinemia (9.8%) and asthenia (5.1%). ISR were reported in 8 (0.3%) patients; injection site pain score was low across the 2355 doses assessed. ConclusionRisperidone ISM® is an effective, safe, and well-tolerated long-term treatment of schizophrenia in adults, regardless of the initial disease severity or whether patients were previously treated with Risperidone ISM® during an acute exacerbation or switched from stable doses of oral risperidone.

Final Results from a Phase 2 Study of Tipifarnib in Subjects with Relapsed or Refractory Peripheral T-Cell Lymphoma

Final Results from a Phase 2 Study of Tipifarnib in Subjects with Relapsed or Refractory Peripheral T-Cell Lymphoma

Interim Analysis of the Randomized Phase 1b/3 Study Evaluating the Safety and Efficacy of Tazemetostat Plus Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma

Interim Analysis of the Randomized Phase 1b/3 Study Evaluating the Safety and Efficacy of Tazemetostat Plus Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma