BT1718 in Patients With Advanced Solid Tumours.
BT1718 in Patients With Advanced Solid Tumours.
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.
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 at the optimal
 dose/schedule(s), patients will be enrolled with tumour types known to commonly overexpress
 MT1-MMP and where MT1-MMP overexpression is confirmed during prospective selection at
 enrolment (i.e. squamous non-small cell lung cancer). It is expected that up to an additional
 70 patients will be required to complete this phase.
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:

 -  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. Phase IIa expansion cohorts will be:

 1. Squamous NSCLC cohort

 2. Basket cohort (advanced solid tumours, excluding patients eligible for one
 of the other recruiting expansion cohorts)

 3. Additional expansion cohort(s) of squamous oesophageal cancer if confirmed
 as recruiting by the Sponsor.

 -  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 using archival tumour sample (mandatory
 fresh tumour samples for those patients without available archival tumour samples
 or additional analysis is deemed necessary).

 -  Consent for pre-treatment and post-treatment fresh tumour biopsy sample in a
 minimum of eight patients in the squamous NSCLC cohort, squamous oesophageal
 cohort (if confirmed as recruiting by the Sponsor) and all patients in the basket
 cohort.

 -  Consent for pre-treatment and post-treatment non-tumour sample (optional) for
 patients having a pre and post treatment tumour biopsy.

 -  Consent for pre and post treatment skin punch biopsy (optional).

 3. Life expectancy of at least 12 weeks.

 4. World Health Organisation (WHO) performance status of 0 - 1.

 5. Haematological and biochemical indices within the ranges shown below. These
 measurements should be performed to confirm the patient's eligibility.

 Haemoglobin (Hb): ≥90.0 g/L, or ≥100.0 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). NB: >1.5 ULN, acceptable if conjugated
 bilirubin is ≤1.5x ULN Alanine amino-transferase (ALT), aspartate amino-transferase
 (AST) and alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) : ≤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), systemic anti-cancer therapy (with the
 exception of life-long hormone suppression such as LHRH agents in prostate cancer) 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 abstinence, 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 abstinence 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. Patients with significant cardiovascular disease are excluded as defined by:

 1. Current congestive heart failure requiring therapy (NYHA III or IV - Appendix 3)
 or known LVEF <40% (moderate to severe)

 2. History of unstable angina pectoris or myocardial infarction up to six months
 prior to trial entry, or of current poorly controlled angina (symptoms weekly or
 more)

 3. Presence of symptomatic or severe valvular heart disease (severe by local
 echographic criteria or AHA/ACC Stage C or D - Appendix 4)

 4. History of a clinically significant cardiac arrhythmia up to six months prior to
 trial entry (asymptomatic atrial fibrillation or asymptomatic first-degree heart
 block are permitted)

 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.