Baseline Liver Function and Subsequent Outcomes in the Phase 3 REFLECT Study of Patients with Unresectable Hepatocellular Carcinoma

<b><i>Introduction:</i></b> Baseline liver function among patients starting treatment for unresectable hepatocellular carcinoma (uHCC) impacts survival and could impact efficacy outcomes and safety profiles of treatments. This post hoc analysis of the phase 3 REFLECT study examined the efficacy and safety outcomes for lenvatinib and for sorafenib in patients with uHCC, assessed by Child-Pugh score (CPS) and albumin-bilirubin (ALBI) grade. <b><i>Methods:</i></b> Efficacy and safety were assessed in patient cohorts from REFLECT according to study entry baseline ALBI grade and CPS. <b><i>Results:</i></b> Lenvatinib treatment generally provided survival benefits in all groups. Median overall survival (OS) among patients with an ALBI grade of 1 was consistently higher than among patients with an ALBI grade of 2 for both the lenvatinib and sorafenib arms (lenvatinib: 17.4 vs. 8.6 months; sorafenib: 14.6 vs. 7.7 months, respectively). Median OS among patients with a CPS of 5 was consistently higher than among patients with a CPS of 6 (lenvatinib: 15.3 vs. 9.4 months; sorafenib: 14.2 vs. 7.9 months, respectively). Progression-free survival and objective response rates for these ALBI grades and CPS demonstrated similar patterns. Among patients who received lenvatinib and experienced a treatment-related treatment-emergent adverse event leading to withdrawal, 6.6% had an ALBI grade of 1, while 13.3% had an ALBI grade of 2, and 7.9% had a CPS of 5, while 12.1% had a CPS of 6. <b><i>Conclusions:</i></b> Better liver function at baseline, as measured by ALBI grade or CPS, may be prognostic for better survival outcomes in patients with uHCC undergoing treatment with lenvatinib or sorafenib.

Phase 1 Study of Axatilimab (SNDX-6352), a CSF-1R Humanized Antibody, for Chronic Graft-Versus-Host Disease after 2 or More Lines of Systemic Treatment

Background: Chronic graft versus host disease (cGVHD) is a major cause of morbidity and late non-relapse mortality after allogeneic hematopoietic cell transplantation and is commonly associated with prolonged immune suppression. Patients (pts) with inadequate response to steroids have few effective therapeutic options and represent an unmet medical need. Available therapies are associated with significant toxicity, immunosuppression, and increased risk of infections. Preclinical studies demonstrate that CSF-1/CSF-1R is a key regulatory pathway involved in the expansion and infiltration of donor-derived macrophages that mediate cGVHD. Axatilimab (SNDX-6352, axa) is a humanized, full-length IgG4 antibody with high affinity to CSF-1R. Axa affects the migration, proliferation, differentiation, and survival of monocytes and macrophages by binding to CSF-1R and blocking its activation by its two known ligands, CSF-1 and IL-34. It offers a novel therapeutic option for treatment of these pts Methods: SNDX-6352-0503 is a Phase 1/2 dose-escalation and dose-expansion study evaluating safety, tolerability, pharmacokinetics (PK)/pharmacodynamics (PD), and efficacy of axa in pts &gt;6 years of age with active symptomatic cGVHD despite ≥2 prior lines of therapy. The Phase 1 endpoints were safety, tolerability, PK and PD with the primary objective of defining optimal biologic dose; the primary endpoint of the Phase 2 study is overall response rate (CR+PR) by 6 months. Pts were dosed in 28-day cycles. The data cutoff was 22 July 2020. Results: Twelve pts have been enrolled in the Phase 1 study. Median age at enrollment was 58y (range, 29-73y), 8 pts were male. Pts had failed a median of 5 prior lines of treatment (range 4-9). Doses included 0.15 mg/kg (n=1), 0.5mg/kg (n=1), 1mg/kg (n=3), 3 mg/kg (n=6) every 2 weeks (q2w), and 3mg/kg q4w (n=1). Of these, 5 pts (42%) are still receiving axa. The median number of cycles for all pts is 5 (range 1-12). Of the 3 pts whose starting dose was 3 mg/kg q2w and remain on study, 2 dose reduced; one to 2 mg/kg q4w and one to 1 mg/kg q2w. Seven pts (58%) discontinued due to: adverse events (3 mg/kg q2w, n=2); death due to traumatic fall (1 mg/kg q2w, n=1); investigator decision (0.5 mg/kg q2w, n=1); progressive cGVHD (1 and 0.15 mg/kg q2w, n=1 each); and non-compliance (3 mg/kg q2w, n=1). Two of 6 pts (17%) at a dose of 3 mg/kg q2w reported a treatment emergent adverse event that was considered a dose limiting toxicity (DLT): 1 with CTCAE Grade 4 creatine kinase increase with symptoms of myositis after dose 1, and the 2nd with an elevation in amylase/lipase that delayed the 3rd dose for &gt;2 weeks. The latter pt restarted therapy at 1 mg/kg q2w and remains on treatment after 5 cycles. Four pts (1 at 0.15 mg/kg and 3 at 3 mg/kg q2w, 33%) had a related treatment emergent adverse event that was ≥Grade 3: increase in aspartate aminotransferase (n=2); increase in creatine phosphokinase (n=2); and increase in gamma-glutamyl transferase (n=2). Such biochemical elevations may be a consequence of CSF-1R blockade on Kupffer cells leading to an inhibition in the clearance of these enzymes, consistent with the mechanism of action of axa and when asymptomatic have not been associated with clinical manifestations of hepatitis, pancreatitis, or rhabdomyolysis. Periorbital edema was observed in 2 pts (≤Grade 2); no additional CSF-1Ri class-effect associated TEAEs were observed Clinical responses as defined by the 2014 NIH cGVHD Consensus Criteria have been observed in 7 pts (58%) across all dose levels; median time to response was 12 weeks. Organ-specific responses have been observed in esophagus (n=1/1), eyes (n=3/10), joints/fascia (n=5/9), mouth (n=1/7), and skin (n=3/8). Prior therapies received by the responders included ibrutinib (6 pts), ruxolitinib (5 pts), and KD025 (3 pts); 3 of the responding pts had received all of these. Six pts (50%) reported at least a 7-point improvement in the Lee Symptom Score. Preliminary PK profiles and pharmacodynamic endpoints, including circulating CD14+CD16+ nonclassical and CD14++CD16+ intermediate monocyte kinetics, are consistent with those observed in healthy volunteers and pts with solid tumors see figure below. Conclusions: These data demonstrate that axatilimab is clinically active with acceptable safety profile and responses observed in heavily pretreated pts with active cGVHD. Enrollment continues in the Phase 1 study at 3 mg/kg q4w and Phase 2 study at a dose of 1 mg/kg q2w. Figure Disclosures Arora: Syndax: Research Funding; Fate Therapeutics: Consultancy; Pharmacyclics: Research Funding; Kadmon: Research Funding. Jagasia:Janssen: Research Funding; Mallinckrodt: Research Funding; Ocugen: Other. Meyers:Syndax Pharmaceuticals, Inc: Current Employment. Quaranto:Syndax Pharmaceuticals, Inc: Current Employment. Schmitt:Syndax Pharmaceuticals, Inc: Current Employment. Sankoh:Syndax Pharmaceuticals, Inc: Current Employment. Abu Zaid:Syndax: Research Funding. Hill:Roche: Research Funding; Generon: Consultancy; CSL: Research Funding; Implicit Bioscience: Research Funding; Pharmacyclics: Research Funding; Compass Pharmaceuticals: Research Funding. Weisdorf:Incyte: Research Funding; FATE Therapeutics: Consultancy. Blazar:BlueRock Therapeuetic: Consultancy; Magenta Therapeutics: Consultancy; BlueRock Therapeutics: Research Funding; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-founder; Fate Therapeutics Inc.: Research Funding. Ordentlich:Syndax Pharmaceuticals, Inc: Current Employment. Lee:Takeda: Research Funding; AstraZeneca: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Research Funding; Novartis: Research Funding; Kadmon: Research Funding; Incyte: Consultancy, Research Funding; Syndax: Research Funding. OffLabel Disclosure: The drug (Axatilimab) is a humanized antibody against CSF-1R. The study is a phase I trial testing this drug in patients with chronic graft versus host disease

Pomalidomide, dexamethasone, and daratumumab in relapsed refractory multiple myeloma after lenalidomide treatment

Patients with multiple myeloma who have relapsed after or become refractory to lenalidomide in early treatment lines represent a clinically important population in need of effective therapies. The safety and efficacy of pomalidomide, low-dose dexamethasone, and daratumumab was evaluated in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM) after one to two prior treatment lines in the phase 2 MM-014 study. Patients received pomalidomide 4 mg daily from days 1–21 and dexamethasone 40 mg weekly (28-day cycles). Daratumumab 16 mg/kg was administered per label. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS) and safety. Per protocol, all patients (N = 112) had received lenalidomide in their most recent prior regimen (75.0% lenalidomide refractory). ORR was 77.7% (76.2% in lenalidomide-refractory patients); median follow-up was 17.2 months. Median PFS was not reached (1-year PFS rate 75.1%). The most common hematologic grade 3/4 treatment-emergent adverse event was neutropenia (62.5%). Grade 3/4 infections were reported in 31.3% of patients, including 13.4% with grade 3/4 pneumonia. These results demonstrate the safety and efficacy of pomalidomide-based therapy as early as second line in patients with RRMM, even immediately after lenalidomide failure, indicating that switching from the immunomodulatory agent class is not necessary.

Sorafenib - induced thyroiditis in patient with a relapse of acute myelomonocytic leukemia with FLT3-ITD mutation

Sorafenib has been used in acute myeloid leukemias with FLT3-ITD mutation improving the outcomes. However the high incidence of treatment - emergent adverse event may be associated with treatment using sorafenib with cytotoxic chemotherapy. We have reported a case of severe thyroiditis in patient with a relapse of acute myelomonocytic leukemia.

Lesinurad in combination with allopurinol: results of a phase 2, randomised, double-blind study in patients with gout with an inadequate response to allopurinol

ObjectivesTo assess the efficacy and tolerability of lesinurad, an oral selective uric acid reabsorption inhibitor, in combination with allopurinol versus allopurinol alone in patients with gout and an inadequate response to allopurinol.MethodsPatients (N=227) with an inadequate response to allopurinol, defined as serum urate (sUA) ≥6 mg/dL on ≥2 occasions ≥2 weeks apart despite ≥6 weeks of allopurinol, were randomised 2:1 to 4 weeks of double-blind treatment with lesinurad (200, 400 or 600 mg/day) or matching placebo in combination with their prestudy allopurinol dose (200–600 mg/day). Colchicine prophylaxis for gout flares was required. The primary end point was percent reduction from baseline sUA levels at 4 weeks. A pharmacokinetic substudy was also conducted. Safety was assessed throughout.ResultsPatients (n=208) received ≥1 dose of blinded medication. Lesinurad 200, 400 and 600 mg in combination with allopurinol produced significant mean percent reductions from baseline sUA of 16%, 22% and 30%, respectively, versus a mean 3% increase with placebo (p<0.0001, all doses vs placebo). Similar results were observed in patients with mild or moderate renal insufficiency (estimated creatinine clearance 30 to <90 mL/min). The incidence of ≥1 treatment-emergent adverse event was 46%, 48% and 54% with lesinurad 200, 400 and 600 mg, respectively, and 46% with placebo (most frequent, gout flares, arthralgia, headache and nasopharyngitis), with no deaths or serious adverse events.ConclusionsLesinurad achieves clinically relevant and statistically significant reductions in sUA in combination with allopurinol in patients who warrant additional therapy on allopurinol alone.Trial registration numberNCT01001338.

Randomized, Double-Blind, Multicenter Safety and Efficacy Study of Rifalazil Compared with Azithromycin for Treatment of Uncomplicated Genital Chlamydia trachomatis Infection in Women

ABSTRACTA randomized, double-blind study comparing single-dose chlamydia therapies of oral rifalazil (25 mg) and azithromycin (1 g) was conducted in 82 women with uncomplicated genitalChlamydia trachomatisinfection. The microbiologic cure rate ofC. trachomatiswith rifalazil (n= 33) was 84.8% at the visit on day 22 to 26 (test-of-cure visit), versus 92.1% with azithromycin (n= 38), and the number of treatment failures in each group was 5 and 3, respectively. The difference in cure rate was −7.3%, with a lower limit of the 95% confidence interval (95% CI) of −22.5, and thus, noninferiority was not established at the prespecified margin (lower limit of CI of −15%). The overall treatment-emergent adverse event (TEAE) and treatment-related TEAE rates were lower in the rifalazil group (68% and 55%) than in the azithromycin group (71% and 62%), respectively. Subjects classified as treatment failures at day 22 to 26 had a lower mean plasma concentration of rifalazil at the visit on day 8 to 12 than those classified as treatment cures, but this difference was not significant; however, the levels were similar for both groups at the visit on day 22 to 26. A single 25-mg dose of rifalazil was well tolerated and eradicatedC. trachomatisin most of these women with uncomplicated genitalC. trachomatisinfection. (The study was registered at clinicaltrials.gov under registration no. NCT01631201).