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BT1718 in Patients With Advanced Solid Tumours.

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: NCT03486730
Recruitment Status : Recruiting
First Posted : April 3, 2018
Last Update Posted : November 6, 2018
Sponsor:
Information provided by (Responsible Party):
Cancer Research UK

Brief Summary:
This clinical trial is looking at a drug called BT1718 in adult patients with advanced solid tumours. The main aim of the study is to find the maximum dose of BT1718 that can be given safely to patients; learn more about the potential side effects of BT1718 and how they can be treated and also what happens to BT1718 inside the body.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumours Triple Negative Breast Cancer Non-Small Cell Lung Cancer Non-Small Cell Lung Sarcoma Drug: BT1718 Phase 1

Detailed Description:

BT1718 is a type of drug called a 'bicycle drug conjugate' which is designed to target and inhibit the function of the protein 'membrane type 1 metalloproteinase' (MT1-MMP). MT1-MMP is involved in breaking down the proteins that usually surround a cell; however in cancer cells it can allow a cancer to grow and spread. MT1-MMP is usually found at a low level in normal cells, but can reach higher levels in cancer cells.

BT1718 has been designed to recognise and attach itself to the MT1-MMP protein. Once attached a segment of BT1718 is taken into the cancer cell which causes it to die (DM1 toxin).

This is a first in human clinical study which has two phases. A 'dose escalation' phase where groups of patients will receive increasing doses of BT1718 to find a safe dose that best targets the cancer cells. In this phase it is expected that approximately 50-60 patients with advanced solid tumours will be entered in the study.

An 'expansion phase' where larger groups of patients will receive the selected dose of BT1718 to allow us to find out more about how the drug is working. In this phase it is proposed that approximately 60-70 patients with either Triple Negative Breast Cancer (TNBC), Non-Small Cell Lung Cancer (NSCLC) or Sarcoma will be entered in the study, as these tumour types are commonly known to overexpress MT1-MMP.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Cancer Research UK Phase I/IIa Clinical Trial of BT1718, (A Bicycle Drug Conjugate) Given Intravenously in Patients With Advanced Solid Tumours.
Actual Study Start Date : January 24, 2018
Estimated Primary Completion Date : March 31, 2022
Estimated Study Completion Date : March 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Dose escalation phase
Groups of patients will receive increasing doses of BT1718 to find a safe dose that best targets the cancer cells. In this phase it is expected that approximately 50-60 patients with advanced solid tumours will be entered in the study.
Drug: BT1718
Dose escalation will consist of Stage 1 and 2. Stage 1 patients will receive BT1718 intravenously twice a week (D: 1,4,8,11,15,18) for 3 out of 4 weeks. Starting dose will be 0.6mg/m2. Single patient cohorts will be explored, but it will change to 3 to 6 patients cohorts. Stage 2 patients will receive BT1718 intravenously once a week (D: 1,8,15) for 3 out of 4 weeks. Starting dose will be less than the total weekly dose from Stage 1. This stage will have 3 to 6 patient cohorts until the recommended dose is established. Expansion phase has four sub-parts: Part A, B, C, D. Part A will commence at the twice weekly recommended dose established in Stage 1. This phase may run in parallel to the 'Dose escalation phase', Stage 2. Part B will commence at the once weekly recommended dose established in Stage 2. This phase may run in parallel to the 'Dose escalation phase', Stage 1. C&D will commence once the data from A and B are reviewed.

Experimental: Dose expansion phase
Larger groups of patients will receive the selected dose of BT1718 to allow us to find out more about how the drug is working. In this phase it is proposed that approximately 60-70 patients with either Triple Negative Breast Cancer (TNBC), Non-Small Cell Lung Cancer (NSCLC) or Sarcoma will be entered in the study, as these tumour types are commonly known to overexpress MT1-MMP.
Drug: BT1718
Dose escalation will consist of Stage 1 and 2. Stage 1 patients will receive BT1718 intravenously twice a week (D: 1,4,8,11,15,18) for 3 out of 4 weeks. Starting dose will be 0.6mg/m2. Single patient cohorts will be explored, but it will change to 3 to 6 patients cohorts. Stage 2 patients will receive BT1718 intravenously once a week (D: 1,8,15) for 3 out of 4 weeks. Starting dose will be less than the total weekly dose from Stage 1. This stage will have 3 to 6 patient cohorts until the recommended dose is established. Expansion phase has four sub-parts: Part A, B, C, D. Part A will commence at the twice weekly recommended dose established in Stage 1. This phase may run in parallel to the 'Dose escalation phase', Stage 2. Part B will commence at the once weekly recommended dose established in Stage 2. This phase may run in parallel to the 'Dose escalation phase', Stage 1. C&D will commence once the data from A and B are reviewed.




Primary Outcome Measures :
  1. Determination of the maximum dose [ Time Frame: When sufficient patients have had the opportunity to complete 1 Cycle (28 days). ]
    Determine a dose at which no more than one out of six patients at the same dose level experiences a probable or highly probable BT1718-related dose limiting toxicity (DLT).

  2. Determination of the frequency and causality of each adverse event [ Time Frame: When sufficient patients have had the opportunity to complete 1 Cycle (28 days). ]
    Determine the frequency and causality of each adverse event (AE) to BT1718 and grade severity according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.02.


Secondary Outcome Measures :
  1. Measurement of the maximum observed plasma concentration (Cmax) of BT1718 in plasma, both as an intact and cleaved molecule. [ Time Frame: Up to 24 timepoints from the first dose of BT1718 over the first two cycles (i.e. Cycle 1 and Cycle 2). Each Cycle is 28 days. ]
    Measurement of the maximum observed plasma concentration (Cmax) of BT1718 in plasma, both as an intact and cleaved molecule.

  2. Measurement of the area under the curve (AUC) of BT1718 in plasma, both as an intact and cleaved molecule. [ Time Frame: Up to 24 timepoints from the first dose of BT1718 over the first two cycles (i.e. Cycle 1 and Cycle 2). Each Cycle is 28 days. ]
    Measurement of the area under the curve (AUC) of BT1718 in plasma, both as an intact and cleaved molecule.

  3. Measurement of the terminal elimination half-life (t½) of BT1718 in plasma, both as an intact and cleaved molecule. [ Time Frame: Up to 24 timepoints from the first dose of BT1718 over the first two cycles (i.e. Cycle 1 and Cycle 2). Each Cycle is 28 days. ]
    Measurement of the terminal elimination half-life (t½) of BT1718 in plasma, both as an intact and cleaved molecule.

  4. Measurement of other PK parameters of BT1718 in plasma, both as an intact and cleaved molecule. [ Time Frame: Up to 24 timepoints from the first dose of BT1718 over the first two cycles (i.e. Cycle 1 and Cycle 2). Each Cycle is 28 days. ]
    Measurement of other PK parameters of BT1718 in plasma, both as an intact and cleaved molecule.

  5. Assess anti-tumour response according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 using computerised tomography (CT) or magnetic resonance imaging (MRI) scans. [ Time Frame: Evaluation will be at database lock - 4 weeks after the last patient last visit ]
    Assess anti-tumour response according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 using computerised tomography (CT) or magnetic resonance imaging (MRI) scans.

  6. Estimate progression-free survival [ Time Frame: Evaluation will be at database lock - 4 weeks after the last patient last visit ]
    Estimate progression-free survival

  7. Estimate progression-free survival rate at six months [ Time Frame: Six months ]
    Estimate progression-free survival rate at six months

  8. Estimate overall survival [ Time Frame: Evaluation will be at database lock - 4 weeks after the last patient last visit ]
    Estimate overall survival

  9. Estimate duration of response [ Time Frame: Evaluation will be at database lock - 4 weeks after the last patient last visit ]
    Estimate duration of response



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

Inclusion Criteria:

  1. Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up
  2. Phase I, dose escalation phase (Stages 1 and 2):

    • Histologically or cytologically proven advanced solid tumour, refractory to conventional treatment, or for which no conventional therapy is considered appropriate by the Investigator or is declined by the patient.

    Phase IIa, expansion phase (Parts A, B, C and D):

    • Histologically or cytologically proven advanced solid tumour of particular interest based on pre-clinical and clinical data, refractory to conventional treatment, or for which no conventional therapy is considered appropriate by the Investigator or is declined by the patient. For Part A and Part B, this is currently proposed to be NSCLC or TNBC (with seven NSCLC and seven TNBC in each cohort).
    • At least one measurable lesion according to RECIST criteria Version 1.1, that has had objective radiological progression on or after the last therapy
    • High MT1-MMP expression by IHC assay of archival tumour sample (mandatory fresh tumour samples for those patients without available archival tumour samples).
    • Consent for paired fresh tumour sample at baseline and on treatment in a minimum of six patients.
    • Consent for non-tumour sample at baseline and on treatment (optional) for patients having a paired tumour biopsy.
  3. Life expectancy of at least 12 weeks
  4. World Health Organisation (WHO) performance status of 0 - 1 (Appendix 1)
  5. Haematological and biochemical indices within the ranges shown below. These measurements should be performed to confirm the patient's eligibility.

    Haemoglobin (Hb): ≥9.0 g/L, or ≥10.0 g/L if transfusion within last four weeks Absolute neutrophil count (ANC): ≥1.5 x 10^9/L Platelet count: ≥100 x 10^9/L Bilirubin: ≤1.5 x upper limit of normal (ULN) Alanine amino-transferase (ALT), aspartate amino-transferase (AST) and alkaline phosphatase (ALP): ≤2.5 x ULN (or ≤5 x ULN if has liver metastases) Renal function

    Either:

    Serum creatinine: ≤1.5 x ULN

    Or:

    Calculated creatinine clearance (using the Wright or Cockcroft & Gault [C&G] formula): GFR ≥50 mL/min (uncorrected value)

    Or:

    Isotope clearance measurement: GFR ≥50 mL/min (corrected value)

  6. 16 years or over at the time consent is given
  7. Consent to access and analyse any available archival tissue.

Exclusion Criteria:

  1. Radiotherapy (except for palliative reasons), endocrine therapy, chemotherapy or investigational medicinal products during the previous four weeks (six weeks for nitrosoureas, mitomycin-C) before treatment (or first dose of an immunotherapy during the previous 12 weeks).
  2. Prior bone marrow transplant, myeloablative conditioning, or extensive radiotherapy to greater than 25% of bone marrow, within previous eight weeks of first BT1718 dose.
  3. Ongoing toxic manifestations of previous treatments greater than NCI CTCAE Grade 1. Exceptions to this are alopecia, amenorrhea/oligospermia and any other ongoing toxic manifestation which in the opinion of the Investigator and the Medical Advisor should not exclude the patient.
  4. Any CNS metastases (unless had local therapy and are asymptomatic and radiologically-stable off steroids for the last four weeks).
  5. Current or prior malignancy which could affect compliance with the protocol or interpretation of results. Patients with curatively-treated non-melanoma skin cancer, non-muscle-invasive bladder cancer, or carcinomas-in-situ are generally eligible.
  6. Female patients who are able to become pregnant (or are already pregnant or lactating). However, those patients who have a negative serum or urine pregnancy test before enrolment and agree to use two forms of contraception (one effective form plus a barrier method) [oral, injected or implanted hormonal contraception and condom; intra-uterine device and condom; diaphragm with spermicidal gel and condom] or agree to sexual abstinence8, effective from the first administration of BT1718, throughout 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 a barrier method of contraception [condom plus spermicide] or to sexual abstinence9 effective from the first administration of BT1718, throughout the trial and for six months afterwards. Men with partners of child-bearing potential must also be willing to ensure that their partner uses an effective method of contraception for the same duration for example, hormonal contraception, intrauterine device, diaphragm with spermicidal gel or sexual abstinence). Men with pregnant or lactating partners must be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure of the foetus or neonate.
  8. Surgery from which the patient has not yet recovered.
  9. At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
  10. Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
  11. Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA]) Appendix 3, prior history of cardiac ischaemia or prior history of clinically significant cardiac arrhythmia.
  12. Previous known allergy to one of the constituents or excipients of BT1718.
  13. Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase I/IIa study of BT1718. Participation in an observational trial or interventional clinical trial which does not involve administration of an IMP and which would not place an unacceptable burden on the patient in the opinion of the Investigator and Medical Advisor would be acceptable.
  14. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.

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): NCT03486730


Contacts
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Contact: Udai Banerji, Dr 020 8661 3984 udai.banerji@icr.ac.uk

Locations
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United Kingdom
Royal Marsden Hospital and The Institute of Cancer Research Recruiting
London, United Kingdom, SM2 5PT
Contact: Udai Banerji, Dr       Udai.banerji@icr.ac.uk   
Sponsors and Collaborators
Cancer Research UK

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Responsible Party: Cancer Research UK
ClinicalTrials.gov Identifier: NCT03486730    
Other Study ID Numbers: CRUKD/17/009
First Posted: April 3, 2018    Key Record Dates
Last Update Posted: November 6, 2018
Last Verified: November 2018
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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Triple Negative Breast Neoplasms
Neoplasms
Neoplasms by Site
Breast Neoplasms
Breast Diseases
Skin Diseases