Key Clinical MessageAlthough tumor lysis syndrome is well described, it is rarely seen or suspected in solid malignancies. Early recognition of this entity is paramount in reducing morbidity and mortality. Treating physicians should be aware of this possibility in solid tumor patients with either bulky disease or extensive liver involvement.

e15052 Background: WEE1 kinase is a cell-cycle regulator that is important in DNA repair, and a validated antitumor target. IMP7068 is a potent and selective WEE1 inhibitor that has demonstrated antitumor activity in preclinical pharmacological models. A first-in-human, multicenter, open-label study was conducted to evaluate the safety, tolerability, pharmacokinetic (PK) characteristics, pharmacodynamic (PD) profiles and preliminary antitumor activity of IMP7068 in patients (pts) with advanced solid tumors. Methods: This phase 1 study included both a dose-escalation and dose-expansion stage. The dose-escalation stage was designed with 6 dose cohorts of IMP7068 at 30, 60, 120, 200, 300, and 400 mg (administered orally, once daily [QD] for 3 days, followed by 4 days off weekly for 21-day cycles). An accelerated titration design was used for the 30- and 60-mg dose levels, and an i3+3 design for all doses > 60 mg. Pts were adults (age ≥18 years) with confirmed advanced solid tumors that were refractory or intolerant to standard treatment, or for which no standard treatment exists. The objectives of the dose-escalation stage were to evaluate the safety and tolerability, PK and PD profiles, and antitumor activity (per RECIST v1.1) of IMP7068. Results: As of Jan 7, 2022, 9 pts were enrolled in the dose-escalation phase (average age, 56 years). An additional cohort of IMP7068 160 mg was recommended by the Safety Monitoring Committee based on PK data from the 120-mg cohort. Pts received escalating doses at 30 mg (n = 1), 60 mg (n = 1), 120 mg (n = 3), and 160 mg (n = 4). No dose-limiting toxicities (DLTs) were observed. Treatment-related adverse events (TRAEs) occurred in 4 pts, most frequently alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, and diarrhea (all in 2 pts each). Most TRAEs were grade 1 or 2 in severity; and only 1 patient had grade 3 TRAEs (AST and ALT increased). Time to reach the maximum plasma concentration of IMP7068 was approximately 2–6 hours following administration of 30–160 mg doses, respectively. Following repeated QD administration for 3 days, the accumulation ratios for IMP7068 exposure parameters Cmax and AUC0-tau were 1.74–2.49 and 3.17–3.46, respectively, across the dose levels. The elimination half-life was approximately 10–28 hours after administration of 60–160 mg IMP7068. PD data showed that levels of phosphorylated cyclin-dependent kinase 1 decreased by ≥50% after treatment in the 160-mg cohort. Five of 8 evaluable pts had a best tumor response of stable disease (SD); 1 patient with colorectal cancer maintained a best response of SD for 22 weeks. Four pts remain on study. Conclusions: IMP7068 was well-tolerated with no DLTs, and conferred a meaningful PD effect and preliminary antitumor activity at doses of up to 160 mg in pts with advanced solid tumors. Dose escalation to establish the recommended phase 2 dose and/or maximum tolerated dose is continuing. Clinical trial information: NCT04768868.

BackgroundTHOR-707 (SAR444245) is a recombinant human IL-2 molecule irreversibly bound to a PEG chain to block alpha-binding while retaining near-native affinity for beta/gamma IL-2 receptor subunits. We report updated results from the ongoing HAMMER phase 1/2 trial.MethodsSAR444245 was given via IV infusion as monotherapy Q2W [A] or Q3W [B], with pembrolizumab 200mg IV Q3W [C], or Q3W with cetuximab 400mg/m2 IV on D1 then 250mg/m2 IV QW [D] after pre-medication and peri-infusion hydration. A 3+3 design was used to identify the MTD/RP2D in pts with advanced solid tumors. Key objectives included assessments of safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD).Results68 pts, median age 61.5 (37–78) yrs with median 3 (1–10) prior therapies enrolled. Most common tumors: melanoma (n=10), colorectal (n=11). Doses tested by cohort: [A]: 8–16 µg/kg (n=9); [B]: 8–40 µg/kg (n=29); [C]: 8–32 µg/kg (n=20); [D]: 16–24 µg/kg (n=10). The most common (>30%) AEs included pyrexia (52.5%), nausea (50.0%), flu-like symptoms (44.1%), vomiting (36.8%), chills (32.4%), fatigue (32.4%), AST elevation (30.9%). AEs generally resolved promptly with supportive care. Grade(G) 3/4 (>5%) related AEs included ALT/AST elevation (5.9%), and decreased lymphocyte count (26.5% within first 24 hrs, recovering by 48–72 hrs, this lymphocyte migration is mechanistically consistent with immune cell margination). G3/4 CRS was observed in 2 pts. Two DLTs occurred: G3 infusion reaction (32 µg/kg [B]) and G3 AST/ALT/G2 bilirubin elevation with G2 CRS (24 µg/kg [C]). No vascular leak syndrome, QTc prolongation, cardiac, or end organ toxicity was observed. Half-life was ~10 h. Sustained increases in CD8 T and NK cells were observed (fold relative to baseline): monotherapy (1–9.4x and 2–43.3x); with pembrolizumab (0.5–5.78x and 1.5–26.9x); with cetuximab (1.3–7.57x and 3.6–45.4x). Max CD4 and eosinophils increased to 136 cell/µL and 1078 cell/µL. No IL-5 elevation or ADAs were observed. Transient IL-6 increases in 4 pts (500, 627, 1000, 1100 pg/mL) were not associated with AEs. Four pts had confirmed PRs (1 PD1-treated SCC, unknown primary [B]; 2 PD1-naïve BCC and 1 PD1-treated HNSCC [C]); 3 pts had minor responses -- prostate (-24%) and PD1-treated melanoma (-17%) [B]; PD1-treated NSCLC (¬-29%) [C] -- after ≥2 scans. 23 pts completed ≥5 cycles.ConclusionsSAR444245 was well tolerated and demonstrated antitumor activity in heavily pretreated patients, including prior checkpoint inhibitor therapy. Clinical safety, efficacy and PD suggest a wide therapeutic window. Combination with pembrolizumab and cetuximab leveraged SAR44245’s effects on CD8 T and NK cells.Trial RegistrationNCT04009681Ethics ApprovalThe clinical trial was approved by each institutions ethics’ and review board prior to beginning study enrollment.

BackgroundBDB001 is an intravenously administered TLR 7/8 dual agonist immune modulator capable of reprogramming dendritic cells to produce antitumor activities. BDB001 monotherapy has demonstrated favorable tolerability and robust systemic immune activation leading to durable clinical responses in a Phase I trial. Here, we report on the safety and efficacy of BDB001 in combination with atezolizumab in a Phase I dose escalation/expansion trial in advanced solid tumors (NCT04196530).MethodsBDB001-102 is a Phase 1, open label, dose escalation/expansion trial of BDB001 (IV, Q1W) in combination with an anti-PD-L1 antibody, atezolizumab (IV, Q3W), in patients with advanced solid tumors. The primary endpoint was safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics and pharmacodynamic profiling of immune activation.ResultsForty-one subjects with 17 different tumor types were enrolled across 4 dose levels. Fifty-nine percent were female, median age was 67 years (range, 32–80), median number of prior therapies was 3 (range, 0–8), and 63% of tumors had progressed on prior anti-PD-(L)1 therapy. Overall, BDB001 in combination with atezolizumab was well tolerated and 13 (31.7%) subjects did not experience any treatment related adverse events (TRAEs). No dose-limiting toxicities were observed. Common TRAEs were transient Grade 1 or 2 fatigue (31.7%), fever (26.8%) and chills/rigor (26.8%). Only 3 (7.3%) subjects experienced Grade 3 TRAEs of fatigue and nausea. There were no Grade 4 or 5 TRAEs and no new safety concerns. Pharmacodynamic evaluation of plasma cytokine levels showed robust increases in interferon gamma and interferon inducible protein-10 (IP-10) at BDB001 Dose Level 4. IP-10 induction was associated with clinical responses. Preliminary efficacy evaluation of the 19 subjects at Dose Level 4 showed durable and deep clinical responses in 3 (16%) subjects, 2 with urothelial carcinoma and 1 with anti-PD-1 mAb refractory NSCLC. All responders remain on treatment, with a duration of response ranging from 7.1+ to 34.1+ weeks. Ten (53%) subjects had stable disease (DCR 68%), 3 of whom had a reduction in tumor burden and were on treatment for over 18 weeks (up to 56 weeks).ConclusionsIntravenous BDB001 in combination with atezolizumab is well tolerated. Deep and durable clinical responses were observed in PD-1 refractory and naive patients, supported by robust systemic immune activation. BDB001 in combination with atezolizumab is a promising therapeutic option for patients with advanced solid tumors. A phase 2 trial (NCT03915678) of BDB001 in combination with atezolizumab and radiotherapy is currently enrolling patients.Ethics ApprovalThis study was approved by the institutional review boards at the five participating institutions. All subjects signed informed consent before enrolling in the clinical trial.

Primary bone marrow lymphoma (PBML) is a rare clinical entity. Because of its rarity, there is no standard therapy defined. Prognosis in this disease is poor, and further studies for effective treatments are needed. In this report, we will discuss a patient with PBML who was treated with a hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine (hyper-CVAD) plus rituximab regimen with a favorable outcome. We believe this is the first reported use of this regimen in this type of lymphoma.