Clinical Trials Register

Summary
EudraCT Number:	2021-006276-16
Sponsor's Protocol Code Number:	CTRIAL-IE-20-27
National Competent Authority:	Ireland - HPRA
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2022-01-11
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

Ireland - HPRA

A.2

EudraCT number

2021-006276-16

A.3

Full title of the trial

PaTcH Trial: A phase 2 study to explore primary and emerging
resistance mechanisms in patients with metastatic refractory pancreatic cancer treated with trametinib and hydroxychloroquine.

A.3.1

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

A phase 2 clinical research study to examine if trametinib and hydroxychloroquine will improve outcomes for patients with advanced pancreatic cancer.

A.3.2

Name or abbreviated title of the trial where available

PaTcH Trial.

A.4.1

Sponsor's protocol code number

CTRIAL-IE-20-27

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 Trials Ireland
B.1.3.4	Country	Ireland
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 Trials Ireland
B.4.2	Country	Ireland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Cancer Trials Ireland
B.5.2	Functional name of contact point	Head of Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	RCSI House, 121 St. Stephen's Green
B.5.3.2	Town/ city	Dublin
B.5.3.3	Post code	D02 H903
B.5.3.4	Country	Ireland
B.5.4	Telephone number	+35316677211
B.5.6	E-mail	info@cancertrials.ie

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	Yes
D.2.1.1.1	Trade name	Mekinist®
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
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	Trametinib
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Trametinib
D.3.9.3	Other descriptive name	TRAMETINIB DIMETHYL SULFOXIDE
D.3.9.4	EV Substance Code	SUB167251
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0.5 to 2
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.IMP: 2
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	Yes
D.2.1.1.1	Trade name	Hydroxychloroquine sulfate
D.2.1.1.2	Name of the Marketing Authorisation holder	Accord-UK Ltd
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Hydroxychloroquine sulfate
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Hydroxychloroquine sulfate
D.3.9.3	Other descriptive name	Hydroxychloroquine sulfate
D.3.9.4	EV Substance Code	SUB02587MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
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

Metastatic refractory pancreatic cancer.

E.1.1.1

Medical condition in easily understood language

Advanced pancreatic cancer.

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	10033605
E.1.2	Term	Pancreatic cancer metastatic
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

To determine the 12-week progression free survival (PFS) of trametinib and hydroxychloroquine in patients with metastatic refractory pancreatic cancer.

E.2.2

Secondary objectives of the trial

SECONDARY OBJECTIVES:
1. To determine the response rate, duration of response& overall survival in patients with metastatic refractory pancreatic cancer treated with trametinib & hydroxychloroquine.
2. To assess the safety & tolerability of this regimen.

EXPLORATORY/TRANSLATIONAL OBJECTIVES:
1. To establish patient-derived organoids from biopsies of patients with pancreatic cancer being treated with trametinib & hydroxychloroquine before treatment & on treatment.
2. To assess efficiency of treatment&potential emerging resistance mechanisms in patient derived organoid cultures from patients with pancreatic cancer treated with trametinib &hydroxychloroquine.
3. To deeply characterise resistance mechanisms&design &test potential rescue therapies in patient-derived organoid cultures from patients with pancreatic cancer treated with trametinib&hydroxychloroquine.
4. To further refine the computational resistance models using new methods of multi-omics data integration.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

The sub-study is part of the main protocol.
This sub-study will include a translational component exploring primary and emerging resistance mechanisms to treatment with trametinib and hydroxychloroquine.

The aims of the sub-study are as follows:

Aim 1: Establish organoids.
Aim 2: Assessment of mechanisms of emerging resistance.
Aim 3: Evaluating potential rescue of resistance.
Aim 4: Refinement of resistance models.

E.3

Principal inclusion criteria

1. Patients must have pathologically confirmed advanced metastatic pancreatic adenocarcinoma or poorly differentiated pancreatic adenocarcinoma that is amenable to tumour biopsy.

2. Patients have received at least one line of systemic therapy for metastatic disease and not be amenable to surgical resection.

3. Patients must have measurable disease by RECIST 1.1 criteria.

4. Age ≥18 years.

5. ECOG performance status ≤ 1

6. Patients must have normal organ and marrow function as defined below:

a. Serum creatinine ≤ 1.5 x ULN.

b. Adequate hepatic function defined by:
o total bilirubin level ≤ 1.5 × ULN,
o an AST, level ≤ 2.5 × ULN, and an ALT level ≤ 2.5 × ULN (or, for subjects with documented metastatic disease to the liver, AST and ALT levels ≤ 5 × ULN)

c. Hematological eligibility parameters:
o Absolute Neutrophil count ≥ 1.5 x 10^9/L
o Platelet count ≥100 x10^9/L
o Hemoglobin ≥ 9 g/dL

7. Ability of subject to understand and the willingness to sign a written informed consent document.

8. Women of child-bearing potential or sexually active males must agree to use highly effective contraceptive measures. This applies from starting treatment until at least 16 weeks after the last study drug administration. The investigator or a designated associate is required to advise the patient how to achieve an adequate birth control. Highly effective contraception is defined in the study as methods that achieve a failure rate of less than 1% per year when used
consistently and correctly. Such methods include:

I. Combined (oestrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation (oral, intravaginal, transdermal).
II. Progestogen-only hormonal contraception associated with inhibition of ovulation
(oral, injectable and implantable).
III. Intrauterine device (IUD).
IV. Intrauterine hormone-releasing system (IUS).
V. Bilateral tubal occlusion.
VI. Successfully vasectomised partner.
VII. Sexual abstinence.

E.4

Principal exclusion criteria

1. Persisting toxicity related to prior therapy (CTCAE Grade > 1); however alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤2 AEs not constituting a safety risk based on
investigator's judgment are acceptable.

2. Prior treatment with a MEK inhibitor.

3. Known history of testing positive for Human Immunodeficiency Virus (HIV) or known acquired
immunodeficiency syndrome.

4. Any significant disease that, in the opinion of the investigator, may impair the patient’s tolerance of study treatment.

5. Patients who are receiving any other investigational agents within 28 days before start of study treatment.

6. Prior organ transplantation including allogenic stem-cell transplantation.

7. Patients with known central nervous system metastases.

8. Active uncontrolled infection, requiring systemic therapy.

9. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious
cardiac arrhythmia requiring medication.

10. Severe left ventricular dysfunction as defined by ejection fraction < 45%.

11. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behaviour; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

12. Known maculopathy of the eye.

13. Known history or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).

14. Screening corrected QT interval by Fridericia (QTcF) > 500 msec.

15. Pregnant women and breastfeeding mothers are excluded due to unknown impact on embryos or infants.

16. Known prior severe hypersensitivity to investigational products or any component in its formulation.

17. Concurrent use of medicines known to induce retinal toxicity (e.g. tamoxifen) or QT interval prolonging agents.

18. Known congenital or documented acquired QT prolongation.

19. Uncorrected hypokalemia and/or hypomagnesemia.

E.5 End points

E.5.1

Primary end point(s)

Anti-tumour efficacy of treatment will be primarily measured as 12-week progression free survival (PFS): that is, the percentage of patients free of progression at 12 weeks from starting treatment into the study as determined by radiographic disease assessments per RECIST version 1.1. Planned efficacy assessments will occur by Computed Tomography Thorax, Abdomen and Pelvis (CT TAP) at baseline, 6 weeks, 12 weeks post starting treatment and then q-8 weekly until disease progression or consent withdrawal.

E.5.1.1

Timepoint(s) of evaluation of this end point

An Interim Analysis will be performed after the first 10 patients have been enrolled and evaluated for radiological/clinical progression.

A Final Analysis will be performed when the trial has been completed.

E.5.2

Secondary end point(s)

SECONDARY ENDPOINTS:

1. Confirmed tumour response rate and duration of response as assessed by RECIST version 1.1.

2. Overall survival

3. To evaluate the safety and tolerability of this regimen as measured by incidence of adverse events reported and toxicity evaluation as per the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

EXPLORATORY ENDPOINTS

1. To establish patient-derived organoids from biopsies of patients with pancreatic cancer being treated with trametinib and hydroxychloroquine before treatment and on treatment.

2. To assess efficiency of treatment and potential emerging resistance mechanisms in patient-derived organoid cultures from patients with pancreatic cancer treated with trametinib and hydroxychloroquine.

3. To deeply characterise resistance mechanisms and design and test potential rescue therapies in patient-derived organoid cultures from patients with pancreatic cancer treated with trametinib and hydroxychloroquine.

4. To further refine the computational resistance models using new methods of multi-omics data integration.

E.5.2.1

Timepoint(s) of evaluation of this end point

A risk assessment will be performed at the beginning of the study and reviewed on an ongoing basis.

The study will be reviewed on a regular basis by the Cancer Trials Ireland Safety Monitoring Committee while patients are on treatment or in the immediate follow-up period (30 days post last dose).

The analysis of the secondary exploratory endpoints will be performed after the required number of tissue samples are available.

An Interim Analysis will be performed after the first 10 patients have been enrolled and evaluated for radiological/clinical progression.

A Final Analysis will be performed when the trial has been completed.

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

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

Yes

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.8.2.4

Number of treatment arms in the trial

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 study is defined as whichever occurs first, when all enrolled patients have completed treatment and follow-up on the study or when the last patient registered has been followed up for 1 year from registration.

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

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)

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)

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

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)

After their participation in the trial has ended, patients will receive the expected normal treatment for their condition.

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

2022-03-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-03-09

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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