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A CR-UK Phase I Trial of LY3143921

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03096054
Recruitment Status : Recruiting
First Posted : March 30, 2017
Last Update Posted : June 26, 2020
Sponsor:
Information provided by (Responsible Party):
Cancer Research UK

Brief 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

Condition or disease Intervention/treatment Phase
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 Drug: LY3143921 hydrate Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 68 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Cancer Research UK (CR-UK) Phase I Trial of LY3143921 a Cdc7 Inhibitor in Adult Patients With Advanced Solid Tumours
Actual Study Start Date : June 21, 2017
Estimated Primary Completion Date : January 31, 2022
Estimated Study Completion Date : January 31, 2022


Arm Intervention/treatment
Experimental: 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.
Drug: LY3143921 hydrate
LY3143921 hydrate will be administered orally on a daily schedule. Each cycle of treatment will consist of 21 days, and patients may initially receive up to 12 cycles. If the patient is benefitting, they may continue beyond 12 cycles.

Experimental: 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.
Drug: LY3143921 hydrate
LY3143921 hydrate will be administered orally on a daily schedule. Each cycle of treatment will consist of 21 days, and patients may initially receive up to 12 cycles. If the patient is benefitting, they may continue beyond 12 cycles.




Primary Outcome Measures :
  1. Determination of the maximal dose [ Time Frame: 28 days including the single dose on Cycle 1 Day-7 ]
    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 :
  1. Determine the Cmax [ Time Frame: Up to 21 time points from first dose ]
    LY3143921 hydrate levels will be measured in serum by liquid chromatography mass spectrometry (LCMS) according to agreed standard operating procedures (SOPs) and validated methods.

  2. Determine the Tmax [ Time Frame: Up to 21 time points from first dose ]
    LY3143921 hydrate levels will be measured in serum by liquid chromatography mass spectrometry (LCMS) according to agreed standard operating procedures (SOPs) and validated methods.

  3. Determine the area under the curve (AUC) [ Time Frame: Up to 21 time points from first dose ]
    LY3143921 hydrate levels will be measured in serum by liquid chromatography mass spectrometry (LCMS) according to agreed standard operating procedures (SOPs) and validated methods.

  4. Determine the plasma halflife, [ Time Frame: Up to 21 time points from first dose ]
    LY3143921 hydrate levels will be measured in serum by liquid chromatography mass spectrometry (LCMS) according to agreed standard operating procedures (SOPs) and validated methods.

  5. Determine the volume of distribution [ Time Frame: Up to 21 time points from first dose ]
    LY3143921 hydrate levels will be measured in serum by liquid chromatography mass spectrometry (LCMS) according to agreed standard operating procedures (SOPs) and validated methods.

  6. Determine the clearance of LY3143921 hydrate [ Time Frame: Up to 21 time points from first dose ]
    LY3143921 hydrate levels will be measured in serum by liquid chromatography mass spectrometry (LCMS) according to agreed standard operating procedures (SOPs) and validated methods.

  7. Determine the response rate [ Time Frame: Database lock- 4 weeks after the last patient last ]
    Free survival rate of patients treated with LY3143921 hydrate according to the Response

  8. Determine the median progression [ Time Frame: Database lock- 4 weeks after the last patient last ]
    Free survival rate of patients treated with LY3143921 hydrate according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. Histological 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 serous 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): Exclusively for patients with the metastatic CRC and squamous NSCLC.

  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

    INR or PTT** ≤1.5 x ULN Albumin ≥ 80% of the lower limit of normal

    ** 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 for all patients.
  8. Consent for pre and post treatment metastatic site tumour biopsies and skin biopsies must be given for expanded cohorts as applicable.

Exclusion Criteria:

  1. Systemic anti-cancer therapy (with the exception of life-long hormone suppression such as luteinising hormone-releasing hormone (LHRH) 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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03096054


Contacts
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Contact: Richard Wilson, Prof 0044 141 330 3968 Richard.h.wilson@glasgow.ac.uk

Locations
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United Kingdom
Cancer Centre, Belfast City Hospital Recruiting
Belfast, United Kingdom, BT9 7AB
Contact: Vicky Coyle, Dr       v.coyle@qub.ac.uk   
Western General Hospital Recruiting
Edinburgh, United Kingdom, EH4 2XU
Contact: Sally Clive, Dr    0044 1315372263    sally.clive@nhslothian.scot.nhs.uk   
Beatson West of Scotland Cancer Centre Recruiting
Glasgow, United Kingdom, G12 0YN
Contact: Jeff Evans, Prof    0044 1413017116    jeff.evans@ggc.scot.nhs.uk   
Northern Centre for Cancer Care Recruiting
Newcastle Upon Tyne, United Kingdom, NE7 7DN
Contact: Ruth Plummer, Prof       ruth.plummer@newcastle.ac.uk   
Sponsors and Collaborators
Cancer Research UK
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Responsible Party: Cancer Research UK
ClinicalTrials.gov Identifier: NCT03096054    
Other Study ID Numbers: CRUKD/17/004
First Posted: March 30, 2017    Key Record Dates
Last Update Posted: June 26, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Esophageal Neoplasms
Carcinoma, Squamous Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Head and Neck Neoplasms
Esophageal Diseases
Neoplasms, Squamous Cell