ASTEROID:A Phase I Trial of ASTX660 in Combination With Pembrolizumab in Patients With Solid Tumours: Utilizing Triple IAP Blockade as a Strategy to Maximize Immunogenic Cell Death and the Generation of an Efficient Adaptive Immune Response
This is a multi-centre Phase I dose finding and proof-of-concept study of the combination of ASTX660 together with Pembrolizumab with expansion cohorts testing preliminary efficacy in immune-refractory cancers, triple negative breast cancer (TNBC), cervical cancer, and glioblastoma. In contrast to the existing studies combining first-generation cIAP1/2 selective Smac mimetics with immune check point inhibitors, the ASTEROID Phase I clinical trial will be the first trial utilising triple cIAP1/2 and XIAP blockade by ASTX660 as a strategy to maximise immunogenic cell death and the generation of an efficient adaptive immune response. ASTX660 is not simply being used to repeat the data already being acquired with other first generation Smac mimetics. In contrast, we will investigate more in depth the mechanisms by which ASTX660 elicits its therapeutic effects both on tumour and on the host immune system. This will be critical to determine the best strategy to pursue in future later stage tumour specific trials of IAP antagonists in combination with immunotherapy, and to ensure appropriate molecular stratification biomarkers for the greatest benefit to patients.
∙ \- 1. PART A: Patients with histologically or cytologically confirmed malignant advanced solid tumours, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient.
∙ PART B1: Patients with histologically or cytologically confirmed malignant advanced solid tumours, refractory to immune checkpoint inhibitors and for which no conventional therapy exists or is declined by the patient.
∙ PART B2: Patients with histologically or cytologically confirmed cervical cancer, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient.
∙ PART B3: Patients with histologically or cytologically confirmed triple negative breast cancer, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient.
∙ For Immune Checkpoint inhibitor refractory tumours, participants must have progressed on treatment with an anti-PD-1/L1 mAb administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria:
⁃ Has received at least 2 doses of an approved anti-PD-1/PD-L1 mAb.
⁃ Has demonstrated disease progression after anti-PD-1/PD-L1 as defined by RECIST v1.1. The initial evidence of PD is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented disease progression, in the absence of rapid clinical progression (as defined in c below).
⁃ Progressive disease has been documented within 12 weeks from the last dose of anti-PD-1/PD-L1 mAb.
∙ i) Progressive disease is determined according to iRECIST. ii) This determination is made by the investigator. Once disease progression is confirmed, the initial date of disease progression documentation will be considered the date of disease progression.
∙ 2\. Parts A, B1, B2 and B3: Measurable disease as assessed by imRECIST. 3. All patients with advanced solid tumours must be willing and able to have fresh paired tissue biopsies for biomarker analysis.
∙ 4\. Life expectancy of at least 12 weeks. 5. World Health Organisation (WHO) performance status of 0 or 1. 6. Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day 1) prior to the patient's first dose of IMP.
∙ Laboratory Test Value required Haemoglobin (Hb)
∙ ≥ 9.0 g/dL Absolute neutrophil count
• 1.5 x 109/L Lymphocyte count \>0.5 x 109/L Platelet count
• 100 x 109/L Total Serum bilirubin
‣ 1.5 x upper limit of normal (ULN) Alanine aminotransferase (ALT)
⁃ 2.5 x (ULN) unless raised due to known metastatic liver disease in which case ≤ 5 x ULN is permissible Aspartate aminotransferase (AST)
⁃ 2.5 x (ULN) unless raised due to to known metastatic liver disease in which case ≤ 5 x ULN is permissible
∙ Either:
∙ Calculated creatinine clearance
∙ Or:
∙ Creatinine ≥ 50 mL/min (uncorrected value) Or \< 1.5 x upper limit of normal (ULN) Albumin \>28 g/L LDH \<3 x ULN Amylase
∙ ≤ ULN Lipase
∙ ≤ ULN
∙ 7\. 18 years or over 8. Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up 9. Female patients with reproductive potential must have a negative urine or serum pregnancy test performed within 72 hours of first dose