Clinical Trials Register

Summary
EudraCT Number:	2016-004633-24
Sponsor's Protocol Code Number:	CRUKD/17/009
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2017-11-02
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2016-004633-24

A.3

Full title of the trial

A Cancer Research UK Phase I/IIa trial of BT1718 (a Bicycle drug conjugate) given intravenously in patients with advanced solid tumours

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Phase I/IIa trial of BT1718 in patients with advanced solid tumours

A.4.1

Sponsor's protocol code number

CRUKD/17/009

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Cancer Research UK
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Cancer Research UK
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	BicycleRD Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Cancer Research UK
B.5.2	Functional name of contact point	Centre for Drug Development
B.5.3	Address:
B.5.3.1	Street Address	2 Redman Place
B.5.3.2	Town/ city	London
B.5.3.3	Post code	E20 1JQ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+4402072420200
B.5.5	Fax number	+4402030147633
B.5.6	E-mail	regulatory@cancer.org.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	BT1718
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	BT1718
D.3.9.4	EV Substance Code	SUB189229
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4.0
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Advanced solid tumours refractory to conventional treatment or for which no conventional therapy exists or is declined by the patient

E.1.1.1

Medical condition in easily understood language

Patients with advanced solid tumours.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10065143
E.1.2	Term	Malignant solid tumour
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Dose escalation phase:
To propose a RP2D for evaluation by establishing the MTD and/or MAD of BT1718 given in patients with advanced solid tumours, at one or more dosing schedules.

Dose escalation & expansion phase:
To assess the safety and toxicity profile of BT1718 in patients with advanced solid tumours.

E.2.2

Secondary objectives of the trial

Dose escalation phase and expansion phase:
To investigate the pharmacokinetic behavior of BT1718 in human.

Dose escalation and expansion phase:
To assess preliminary signals of BT1718 efficacy, including in relevant tumour types with high expression of membrane type 1 matrix metalloproteinase (MT1-MMP) in Phase IIa.

E.2.3

Trial contains a sub-study

E.3

Principal 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:
a. Squamous NSCLC cohort
b. Basket cohort (advanced solid tumours, excluding patients eligible for one of the other recruiting expansion cohorts)
c. Additional expansion cohort(s) may include 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.

Laboratory Test: Value required
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 ≤ 1.5 x ULN)
Alanine amino-transferase (ALT) , aspartate amino-transferase (AST) 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 or calculated creatine clearance (using the Wright or Cockcroft & Gault [C&G] formula or isotope clearance measurement*: serum creatinine ≤1.5 x ULN or GFR ≥50 mL/min (uncorrected value) or GFR ≥50 mL/min (corrected value).
* Isotope clearance result to be used to confirm eligibility if calculated C&G/Wright method results in a glomerular filtration rate (GFR) of =50 mL/min.

6. 16 years or over at the time consent is given.

7. Consent to access and analyse any available archival tissue.

E.4

Principal 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:
a. Congestive heart failure requiring therapy (NYHA III or IV) or known LVEF <40% (moderate to severe)
b. 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)
c. Presence of symptomatic or severe valvular heart disease (severe by local echographic criteria or AHA/ACC Stage C or D)
d. History of a clinically significant cardiac arrhythmia up to six months prior to trial entry (asymptomatic atrial fibrillation or 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.

*Abstinence is only considered to be an acceptable method of contraception when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

E.5 End points

E.5.1

Primary end point(s)

Dose escalation phase:
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 DLT.

Dose escalation and expansion phase:
Determine the frequency and causality of each AE to BT1718 and grade severity according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.02).
The causality of all AE will be assessed by the Investigator.

E.5.1.1

Timepoint(s) of evaluation of this end point

Dose escalation phase:
At the end of the dose escalation phase.

Dose escalation and expansion phase:
For eligible patients, SAE and AE collection and monitoring will commence at the time the patient provides written consent to participate in the trial and will continue until 28 days after the last administration of BT1718 or until the patient starts another cancer therapy.

E.5.2

Secondary end point(s)

Dose escalation and expansion phase:
Measurement of Cmax, AUC, terminal elimination half-life (t½), and other PK parameters of BT1718 in plasma, both as an intact and cleaved molecule.

Dose escalation and expansion phase:
1. 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.
2. Estimate progression-free survival (PFS), progression-free survival rate at six months, and overall survival (OS) (where available).
3. Estimate duration of response.

E.5.2.1

Timepoint(s) of evaluation of this end point

Dose escalation and expansion phase:
PK measurements in plasma up to 24 time points over first two cycles.

Dose escalation and expansion phase:
1. End of trial.
2. End of trial.
3. End of trial.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The 'end of trial' is defined as the date when the last patient has completed the 'off-study' visit or the final follow up visit (whichever is the later). The 'off study' visit is scheduled to take place 28 +/- 7 days after the last dose of BT1718 administration.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

130

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Patients will receive standard of care treatment.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-12-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-01-18

P. End of Trial
P.	End of Trial Status	GB - no longer in EU/EEA

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