Clinical Trials /

A CR-UK Phase I Trial of LY3143921

NCT03096054

Description:

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

Related Conditions:
  • Breast Carcinoma
  • Colorectal Carcinoma
  • Esophageal Squamous Cell Carcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Non-Small Cell Lung Carcinoma
  • Ovarian Carcinoma
  • Pancreatic Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A CR-UK Phase I Trial of LY3143921
  • Official Title: A Cancer Research UK (CR-UK) Phase I Trial of LY3143921 a Cdc7 Inhibitor in Adult Patients With Advanced Solid Tumours

Clinical Trial IDs

  • ORG STUDY ID: CRUKD/17/004
  • NCT ID: NCT03096054

Conditions

  • a. Colorectal Cancer
  • b. High Grade Serous Ovarian Cancer
  • c. Non Small-cell Lung Cancer (Squamous Cell Variant)
  • d. Squamous Carcinoma of the Oesophagus
  • e. Squamous Carcinoma of the Head and Neck (HPV Negative)
  • f. Urothelial Cancer
  • g. Breast Cancer (Triple Negative Type)
  • h. Pancreatic Cancer

Interventions

DrugSynonymsArms
LY3143921 hydratePart 1 a dose escalation

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Part 1 a dose escalationExperimentalPhase 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.
  • LY3143921 hydrate
Part 2 an expansionExperimentalPhase 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.
  • LY3143921 hydrate

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determination of the maximal dose
Time Frame:28 days including the single dose on Cycle 1 Day-7
Safety Issue:
Description:Determining the maximal dose at which no more than one patient out of up to six patients at the same dose level experience a highly probably or probably drug related DLT and determining the schedule of administration at which the MTD is established Determining the maximal dose at which no more than one patient out of up to six patients at the same dose level experience a highly probably or probably drug related DLT and determining the schedule of administration at which the MTD is established

Secondary Outcome Measures

Measure:Determine the Cmax
Time Frame:Up to 21 time points from first dose
Safety Issue:
Description:LY3143921 hydrate levels will be measured in serum by liquid chromatography mass spectrometry (LCMS) according to agreed standard operating procedures (SOPs) and validated methods.
Measure:Determine the Tmax
Time Frame:Up to 21 time points from first dose
Safety Issue:
Description:LY3143921 hydrate levels will be measured in serum by liquid chromatography mass spectrometry (LCMS) according to agreed standard operating procedures (SOPs) and validated methods.
Measure:Determine the area under the curve (AUC)
Time Frame:Up to 21 time points from first dose
Safety Issue:
Description:LY3143921 hydrate levels will be measured in serum by liquid chromatography mass spectrometry (LCMS) according to agreed standard operating procedures (SOPs) and validated methods.
Measure:Determine the plasma halflife,
Time Frame:Up to 21 time points from first dose
Safety Issue:
Description:LY3143921 hydrate levels will be measured in serum by liquid chromatography mass spectrometry (LCMS) according to agreed standard operating procedures (SOPs) and validated methods.
Measure:Determine the volume of distribution
Time Frame:Up to 21 time points from first dose
Safety Issue:
Description:LY3143921 hydrate levels will be measured in serum by liquid chromatography mass spectrometry (LCMS) according to agreed standard operating procedures (SOPs) and validated methods.
Measure:Determine the clearance of LY3143921 hydrate
Time Frame:Up to 21 time points from first dose
Safety Issue:
Description:LY3143921 hydrate levels will be measured in serum by liquid chromatography mass spectrometry (LCMS) according to agreed standard operating procedures (SOPs) and validated methods.
Measure:Determine the response rate
Time Frame:Database lock- 4 weeks after the last patient last
Safety Issue:
Description:Free survival rate of patients treated with LY3143921 hydrate according to the Response
Measure:Determine the median progression
Time Frame:Database lock- 4 weeks after the last patient last
Safety Issue:
Description:Free survival rate of patients treated with LY3143921 hydrate according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Cancer Research UK

Last Updated

June 9, 2017