Metastatic colorectal cancer Cancer
Conditions
Interventions
This study is a single-arm phase I study for participants with metastatic colorectal cancer in whom second-line palliative FOLFOX chemotherapy is an appropriate treatment option. Participants will be
Dose level ASTX660 Fluorouracil Folinic acid (mg) Oxaliplatin (mg/m²)
(tolinapant) (mg) (mg/m²)
1 (starting) 60 320mg/m² IV bolus 350 68
1920mg/m² IV infusion
2 60 400mg/
Sponsors
NHS Greater Glasgow and Clyde
University of Glasgow
Eligibility
Sex/Gender
All
Age
16 Years to 100 Years
Inclusion criteria
Inclusion criteria: 1. Willing and able to provide written informed consent and be capable of co-operating with treatment and follow-up 2. Histologically confirmed unresectable metastatic colorectal adenocarcinoma 3. Clinically and/or radiographically documented measurable disease (as per RECIST v1.1) 4. Have had 1 previous line of systemic therapy for treatment of metastatic disease, and for whom FOLFOX alone would otherwise be a reasonable second-line treatment option. This includes patients with progressive disease on or within 6 months of completion of neoadjuvant or adjuvant therapy 5. Disease which is amenable to biopsy and provides consent to pre- and on-treatment tumour biopsies (applies to participants who are to be treated at dose levels 3-5 only) 6. Provides consent for use of archival tumour tissue 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2 and stable over preceding 4 weeks. 8. Life expectancy > 6 months 9. Age 16 years or older 10. Haematological and biochemical indices within the ranges shown - Haemoglobin (Hb) =9.0 g/dL / 90g/L (no prior transfusion within last 4 weeks) or =10.0 g/dL / 100g/L (transfusion within last 4 weeks) - Absolute neutrophil count (ANC) =1.5 x 109/L - Platelet count =100 x 109/L - Serum bilirubin =1.5 x upper limit of normal (ULN) - Alanine amino-transferase (ALT) and aspartate amino-transferase (AST) = 2.5 x (ULN) (or =5 x ULN in the presence of liver metastases) - Calculated creatinine clearance (using the Cockcroft & Gault formula or other mathemtaical calculation e.g. Wright formula if used as standard of care at site) = 50 mL/min - PT and aPTT =1.5 x ULN - Albumin = 80% of the lower limit of normal - Amylase = ULN - Lipase = 1.2 ULN
Exclusion criteria
Exclusion criteria: Current exclusion criteria as of 12/02/2025: 1. Anti-cancer therapy consisting of endocrine therapy, immunotherapy, chemotherapy or another investigational agent during the previous 4 weeks (6 weeks for nitrosureas, Mitomycin-C) is not permitted with the exception of LHRH agonists for treated/biochemically-stable, organ-confined prostate cancer in the preceding 3 years. Previous use of palliative radiotherapy within the preceding 4 weeks is permitted except where there has been a large volume of bone marrow irradiated or where the irradiated lesion is the only one suitable for RECIST measurability or biopsy. Previous short course or long course radiotherapy more than 4 weeks before trial registration for rectal cancer is permitted provided the criteria for RECIST measurability and biopsy are met. 2. Major surgery within 4 weeks of trial registration 3. Ongoing toxic manifestations of previous treatments that are = Grade 2 according to NCI-CTCAE v5.0 with the exception of alopecia or certain Grade 2 toxicities, which in the opinion of the investigator and Sponsor should not exclude the patient – these should be discussed on a case by case basis 4. Symptomatic brain metastases or spinal cord compression. Participants with brain metastases that have been radiologically stable post treatment over an 8-week period may be included (provided corticosteroid use is equal to or less than 10mg/day prednisolone equivalent) 5. Uncontrolled hypertension (>160 mmHg systolic or >100 mmHg diastolic in a relaxed, temperate setting with patient quiet and seated with their arm outstretched and supported) 6. Participants with a known left ventricular ejection fraction (LVEF) =470 msec). 11.6. Presence of complete Left Bundle Branch Block or 3rd degree heart block 12. Known to be serologically positive for Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV) (mandatory testing not required) 13. Pregnant or breast-
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The maximal dose of ASTX660 which can be administered in combination with mFOLFOX6 for which toxicity rate is closest to target toxicity rate of 25%. This will be defined the maximum tolerated dose (MTD) determined by dose limiting toxicities as measured by clinical and laboratory toxicities (NCI-CTC AE version 5) during the first 2 - 2 weekly cycles of treatment. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Toxicity of the combination which will be measured by clinical and laboratory toxicities (NCI-CTC AE version 5) for patients throughout the duration of their treatment and for 30 days following completion of their study treatment 2. Objective response rate (defined as the proportion of patients with a complete response or partial response according to RECIST v1.1) 3. Progression free survival (determined as the time from patient registration to subsequent radiological disease progression according to RECIST v1.1) 4. Pharmacokinetic profile of ASTX660 in patients with metastatic colorectal cancer (Cmax, Tmax, AUC, T1/2, volume of distribution, and clearance of ASTX660 (through measurement of plasma concentration of ASTX660)) | — |
Countries
England, Northern Ireland, Scotland, United Kingdom
Outcome results
None listed