Patient case: 49-year-old female with Pancreatic adenocarcinoma. Genetic variant: KRAS, TP53. Other conditions: None.

Clinical trial: A CR-UK Phase I Trial of LY3143921

Summary: This clinical study is looking at a drug called LY3143921 hydrate (a Cdc7 inhibitor) in adult patients with advanced solid tumours. The main aims are to find out the maximum dose of LY3143921 hydrate that can be given safely to patients, more about the potential side effects and how they can be treated

Detailed description: This clinical study is looking at a drug called LY3143921 hydrate (a Cdc7 inhibitor). Cdc7 helps our cells replicate correctly. In normal cells, Cdc7 is usually found at a low level, but can reach higher levels in cancer cells. This is often the case in certain types of solid tumour cancers, which we will focus on in this study. It is thought that giving LY3143921 hydrate will block the function of Cdc7 and will affect cancer cells by stopping their replication and causing them to die. LY3143921 hydrate looks promising in laboratory studies and studies in animals.
  This clinical study has two parts:
  Part 1 - a 'dose escalation' phase where groups of patients will receive increasing doses of LY3143921 hydrate to find a safe dose and a dose that best targets the cancer cells.
  Part 2 - an 'expansion' phase where a larger group of patients will receive the highest dose of LY3143921 hydrate considered to be safe from Part 1, to find out more about how the drug is working.

Eligibility: Inclusion Criteria
  1. Histological or cytological diagnosis of incurable, advanced/metastatic cancer For Phase Ia (dose escalation): Enriched for patients with tumours associated with p53 mutation or loss of function:
  1. Colorectal cancer (CRC)
  2. High grade serious ovarian cancer (HGSOC)
  3. Non small-cell lung cancer (NSCLC, squamous cell 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 Ib (expansion cohorts): These will exclusively be CRC/mCRC, HGSOC and/or squamous NSCLC patients.
  2. Life expectancy of at least 12 weeks.
  3. Written (signed and dated) informed consent and be capable of complying with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.
  4. World Health Organisation (WHO) performance status of 0 or 1
  5. Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week before the patient starts study treatment (single dose given C1D-6 to C1D-11):
  Laboratory Test Value required
  Haemoglobin (Hb) ≥9.0 g/dL (no prior transfusion) 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 amino-transferase (ALT) and aspartate amino-transferase (AST) ≤ 2.5 x (ULN) (or ≤5 x ULN in the presence of liver metastasis)
  Either:
  Calculated creatinine clearance (using the Wright or C&G formula) > 50 mL/min
  Or: Isotope clearance measurement** ≥ 50 mL/min (uncorrected) INR or PTT*** ≤1.5 x ULN Albumin ≥ 80% of the lower limit of normal
  ** Isotope clearance result to be used to confirm eligibility if calculated C&G/Wright method results in GFR of = 50 mL/min.
  *** Therapeutic INR values (2.0-3.0) are acceptable to confirm eligibility for patients who are taking concomitant warfarin
  6. Age 18 years or over.
  7. Consent must be given for use of archived tumour samples, pre and post treatment skin biopsies and hair follicle collection in all patients.
  8. Consent for pre and post treatment metastatic site tumour biopsies must be given for expanded cohorts but is optional for dose escalation cohorts.
  Exclusion Criteria:
  1. Radiotherapy (except for control of symptoms where irradiated lesions will not be followed for response), endocrine therapy, immunotherapy or chemotherapy during the previous 4 weeks (6 weeks for nitrosureas, Mitomycin-C).
  2. Ongoing toxic manifestations of previous treatments (Grade 2 or greater according to NCI-CTCAE v4.02) 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 (patients must be stable for >3 months post RT treatment) or spinal cord compression.
  4. Significant baseline hypotension (<90mmgHg systolic or <50 mmHg diastolic).
  5. Uncontrolled hypertension (>160mmHg/100mmHg).
  6. Ability to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom, have a intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible.
  7. Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception [condom plus spermicide] during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (e.g. condom plus spermicidal gel) to prevent exposure to the foetus or neonate.
  8. Patients must have recovered from effects or major surgery, no major surgery within 4 weeks prior to the patient receiving Cycle 1 Day 7 (for dose escalation) or C1 Day1 (for dose expansion). If minor surgery has been performed within 2 weeks of the start of trial treatment then the sponsor and CI should be notified of the nature of this and agree to patient inclusion.
  9. Co-existing active infection or serious concurrent medical condition.
  10. Known to be serologically positive for Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV) (mandatory testing not required).
  11. History of allergy or auto-immune disease.
  12. Significant cardiovascular disease as defined by:
  1. History of congestive heart failure requiring therapy
  2. History of unstable angina pectoris or myocardial infarction up to 6 months prior to trial entry
  3. Presence of severe valvular heart disease
  4. Presence of a ventricular arrhythmia requiring treatment
  13. Concurrent hypotension defined as baseline supine blood pressure systolic <90 mmHg.
  14. Past history of corneal ulceration, dry eye syndrome, glaucoma. Contact lenses should also be avoided during participation in the trial.
  15. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
  16. Participation in any other clinical study within the 4 weeks previous to start of trial treatment.

Relevance to patient case: not relevant