Search

Background THOR-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. Methods SAR444245 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). Results 68 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.

BACKGROUND: Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials. METHODS: An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001). FINDINGS: Patients were enrolled in ALKA-372

Background CD73 expression is elevated in tumors and contributes to increasing levels of immunosuppressive adenosine in the tumor microenvironment. CD73 knockout mice exhibit reduced tumor growth and resistance to experimental metastasis. Inhibition of CD73 activity with an anti-CD73 antibody blocks adenosine production, shown to inhibit tumor growth in syngeneic models. Dual inhibition of CD73 and A2aR improves anti-tumor immune responses in mouse tumor models[1]. CPI-006 is a humanized IgG1 Fc gamma receptor binding-deficient anti-CD73 antibody that has a dual mechanism of action. It blocks CD73 catalytic activity and adenosine production. In addition, it has immunomodulatory activity on CD73 positive immune cells including B cells, T cells and antigen presenting cells. CPI-006 relieves adenosine-mediated immunosuppression in vitro as a single agent and in combination with ciforadenant[2]. CPI-006 is now being investigated in this Phase 1/1b multicenter, open label trial as single agent (SA), in combination with ciforadenant, an oral, small molecule, selective A2aR antagonist and in combination with pembrolizumab, an anti-PD1 indicated for the treatment of patients across a number of malignancies (NCT03454451). Methods Up to 462 subjects will be enrolled at approximately 35 sites in the US, Canada and Australia. Eligible patients with: non-small cell lung cancer (NSCLC), renal cell carcinoma cancer (RCC), urothelial bladder cancer, cervical cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, head and neck cancer, triple-negative breast cancer, endometrial cancer, select sarcomas and non-Hodgkin lymphoma (NHL) who are relapsed, refractory or intolerant to 1 to 5 standard therapies; aged >= 18 yo; with adequate organ function and measurable disease. Study details is presented in Figure 1. The primary objective of the dose escalation is to assess safety/ tolerability, MTD or MDL of CPI-006 SA, in combination with ciforadenant and with pembr

Background CD73 expression is elevated in tumors and contributes to increasing levels of immunosuppressive adenosine in the tumor microenvironment. CD73 knockout mice exhibit reduced tumor growth and resistance to experimental metastasis. Inhibition of CD73 activity with an anti-CD73 antibody blocks adenosine production, shown to inhibit tumor growth in syngeneic models. Dual inhibition of CD73 and A2aR improves anti-tumor immune responses in mouse tumor models[1]. CPI-006 is a humanized IgG1 Fc gamma receptor binding-deficient anti-CD73 antibody that has a dual mechanism of action. It blocks CD73 catalytic activity and adenosine production. In addition, it has immunomodulatory activity on CD73 positive immune cells including B cells, T cells and antigen presenting cells. CPI-006 relieves adenosine-mediated immunosuppression in vitro as a single agent and in combination with ciforadenant[2]. CPI-006 is now being investigated in this Phase 1/1b multicenter, open label trial as single agent (SA), in combination with ciforadenant, an oral, small molecule, selective A2aR antagonist and in combination with pembrolizumab, an anti-PD1 indicated for the treatment of patients across a number of malignancies (NCT03454451). Methods Up to 462 subjects will be enrolled at approximately 35 sites in the US, Canada and Australia. Eligible patients with: non-small cell lung cancer (NSCLC), renal cell carcinoma cancer (RCC), urothelial bladder cancer, cervical cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, head and neck cancer, triple-negative breast cancer, endometrial cancer, select sarcomas and non-Hodgkin lymphoma (NHL) who are relapsed, refractory or intolerant to 1 to 5 standard therapies; aged >= 18 yo; with adequate organ function and measurable disease. Study details is presented in Figure 1. The primary objective of the dose escalation is to assess safety/ tolerability, MTD or MDL of CPI-006 SA, in combination with ciforadenant and with pembr