A Phase I Trial of LY3143921 Hydrate in Solid Tumours

This clinical study looked at a drug called LY3143921 hydrate (a Cdc7 inhibitor) in adult patients with advanced solid tumours. The main aims were to find out the maximum dose of LY3143921 hydrate that could be given safely to patients, and to assess the potential side effects and how they could be treated.

Inclusion Criteria 1. Histologically proven advanced or metastatic solid tumours, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient. For Phase I Part 1 (dose escalation): Enriched for patients with tumours commonly associated with p53 mutation or loss of function: 1. Colorectal cancer (CRC) 2. High grade serous ovarian cancer 3. Non small-cell lung cancer (NSCLC, squamous variant) 4. Squamous carcinoma of the oesophagus 5. Squamous carcinoma of the head and neck (HPV negative) 6. Urothelial cancer 7. Breast cancer (triple negative type) 8. Pancreatic cancer For Phase I Part 2 (expansion cohorts): Cohort 1: patients with metastatic CRC; Cohort 2: patients with squamous NSCLC and Cohort 3: patients with solid tumours commonly associated with p53 mutation or loss of function (as described above for the Phase 1 Part 1 part of the trial). * Consent for pre-treatment and post-treatment fresh tumour biopsy samples in a minimum of six patients in expansion Cohorts 1 and 3, optional for all other patients. * Consent for pre and post treatment skin punch biopsy in a minimum of six patients in each dose expansion cohort; optional in all remaining patients. 2. Life expectancy of at least 12 weeks. 3. Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up. 4. World Health Organization performance status of 0 or 1 5. Haematological and biochemical indices within the ranges shown below: * Haemoglobin ≥9.0 g/dL (no prior transfusion within last 4 weeks) or ≥10.0 g/dL (transfusion within last 4 weeks) * Absolute neutrophil count ≥1.5 x 10\^9/L * Platelet count ≥100 x 10\^9/L * Serum bilirubin ≤1.5 x upper limit of normal (ULN) * Alanine aminotransferase and aspartate aminotransferase * 2.5 x (ULN) (or ≤5 x ULN in the presence of liver metastasis) * Calculated creatinine clearance (using the Wright or Cockcroft-Gault formula) ≥50 mL/min * Prothrombin time and activated partial thromboplastin time\*\* ≤1.5 x ULN * Albumin ≥80% of the lower limit of normal * Therapeutic International Normalised Ratio values (2.0 - 3.0) are acceptable to confirm eligibility for patients who are taking concomitant warfarin or other anticoagulants. 6. Age 18 years or over. 7. Consent must be given for use of archived tumour samples for all patients. 8. Disease must be either evaluable or measurable using RECIST version 1.1 criteria. Exclusion Criteria: 1. Systemic anti-cancer therapy (with the exception of life-long hormone suppression such as luteinising hormone-releasing hormone agents in prostate cancer) or another investigational agent during the previous 4 weeks (6 weeks for nitrosureas, Mitomycin-C) is not permitted. Previous use of radiotherapy 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. 2. Ongoing toxic manifestations of previous treatments (Grade 2 or greater according to NCI-CTCAE version 4.02) 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. 3. Symptomatic brain metastases or spinal cord compression. 4. Significant baseline hypotension or symptomatic hypotension at any level of BP (\