Overview

DETERMINE Trial Treatment Arm 4: Trastuzumab in Combination With Pertuzumab in Adult, Teenage/Young Adult and Paediatric Patients With Cancers With HER2 Amplification or Activating Mutations

Status:
Recruiting
Trial end date:
2029-10-01
Target enrollment:
0
Participant gender:
All
Summary
This clinical trial is looking at a combination of drugs called trastuzumab and pertuzumab. This combination of drugs is approved as standard of care treatment for adult patients with metastatic breast cancer. This means it has gone through clinical trials and been approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. Trastuzumab and pertuzumab work in patients with these types of cancers which have a molecular alteration called HER2 amplification or HER2 activating mutation. Investigators now wish to find out if it will be useful in treating patients with other cancer types which are also HER2 amplified or HER2 mutated. If the results are positive, the study team will work with the NHS and the Cancer Drugs Fund to see if these drugs can be routinely accessed for patients in the future. This trial is part of a trial programme called DETERMINE. The programme will also look at other anti-cancer drugs in the same way, through matching the drug to rare cancer types or ones with specific mutations.
Phase:
Phase 2/Phase 3
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
Cancer Research UK
Collaborators:
Hoffmann-La Roche
Royal Marsden NHS Foundation Trust
University of Birmingham
University of Manchester
Treatments:
Pertuzumab
Trastuzumab
Criteria
THE PARTICIPANT MUST FULFIL THE ELIGIBILITY CRITERIA WITHIN THE DETERMINE MASTER PROTOCOL
(NCT05722886) AND WITHIN THE TREATMENT ARM 4 (TRASTUZUMAB AND PERTUZUMAB) OUTLINED BELOW*

*When trastuzumab and pertuzumab-specific inclusion/exclusion criteria or precautions below
differ from those specified in the Master Protocol, the trastuzumab and pertuzumab
-specific criteria will take precedence.

Inclusion Criteria:

A. Confirmed diagnosis of a malignancy harbouring HER2 amplification, or an appropriate
activating mutation as defined by the MTB, using an analytically validated method.

B. Age 12 years or above.

C. Women of childbearing potential are eligible provided that they meet the following
criteria:

Have a negative serum or urine pregnancy test before enrolment and;

Agree to use one form of effective birth control method such as:

I. combined (oestrogen and progestogen containing) hormonal contraception associated with
inhibition of ovulation (oral, intravaginal or transdermal):

II. progestogen-only hormonal contraception associated with or without inhibition of
ovulation (oral, injectable or implantable)

III. intrauterine device (IUD)

IV. intrauterine hormone-releasing system (IUS)

V. bilateral tubal occlusion

VI. vasectomised partner

VII. sexual abstinence

VIII. male or female condom with or without spermicide

IX. cap, diaphragm or sponge with spermicide

Effective from the first administration of trastuzumab or pertuzumab (whichever is first),
throughout the trial and for seven months after the last administration of trastuzumab or
pertuzumab (whichever is later).

D. Male patients with partners who are women of childbearing potential are eligible
provided that they agree to the following, from the first administration of trastuzumab or
pertuzumab (whichever is first), throughout the trial and for seven months after the last
administration of trastuzumab or pertuzumab (whichever is later):

- Agree to take measures not to father children by using a barrier method of
contraception or to sexual abstinence.

- Non-vasectomised male patients with partners who are women of childbearing potential
must also be willing to ensure that their partner uses an effective method of
contraception as in C, above.

- Male patients with pregnant or lactating partners must be advised to use barrier
method contraception (e.g. condom) to prevent drug exposure of the foetus or neonate.

E. Patients must be able and willing to undergo a fresh biopsy.

F. ADULT PATIENTS: Adequate organ function as per haematological and biochemical indices
within the ranges shown below. These measurements should be performed to confirm the
patient's eligibility.

Haemoglobin (Hb): ≥90 g/L (transfusion allowed)

Absolute neutrophil count (ANC): ≥1.5x10^9g/L (no GCSF support in preceding 72 hours)

Platelet count: ≥100x10^9g/L (unsupported for 72 hrs)

Bilirubin: <1.5 × upper limit of normal (ULN) Patients with known Gilbert disease: total
bilirubin ≤3 × ULN

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): ≤2.5 × ULN or ≤5 × ULN
if raised due to metastases

Estimated glomerular filtration rate (eGFR): >30 mL/min

Coagulation - prothrombin (PT) (or international normalized ratio [INR]) and activated
partial thromboplastin clotting time (aPTT): <1.5 × ULN (unless patient is on
anticoagulants, e.g. warfarin [INR should be stable and within indicated therapeutic
range], or direct oral anticoagulants [DOAC])

G. PAEDIATRIC PATIENTS aged 12-15 years: Adequate organ function as per haematological and
biochemical indices within the ranges shown below. These measurements should be performed
to confirm the patient's eligibility.

Haemoglobin (Hb): >80 g/L (transfusion allowed)

Absolute neutrophil count (ANC): >0.75×10^9/L (no GCSF support in preceding 72 hours)

Platelet count: ≥75×10^9/L (unsupported for 72 hrs)

Bilirubin: ≤1.5 × ULN for age

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): ≤2.5 × ULN or ≤5 × ULN
if raised due to metastases

Estimated glomerular filtration rate (eGFR): ≥60 mL/min (uncorrected value)

Coagulation - prothrombin (PT) (or international normalized ratio [INR]) and activated
partial thromboplastin clotting time (aPTT): ≤1.5 × ULN for age (unless patient is on
anticoagulants, e.g. warfarin [INR should be stable and within indicated therapeutic
range], or DOAC.

Exclusion Criteria:

A. Diagnosis of HER2-positive early or metastatic breast cancer.

B. Patients with rapidly progressing or symptomatically deteriorating brain metastases.
Patients with previously treated brain metastases are eligible, provided the patient has
not experienced a seizure or had a clinically significant change in neurological status
within the 14 days prior to the start of IMP administration. Such patients must be
nondependent on steroids or on a stable or reducing dose of steroid treatment for at least
14 days (or 7 days for paediatric patients) prior to the start of IMP administration.
Primary brain or central nervous system (CNS) malignancies are allowed providing the
patient is clinically stable (if requiring corticosteroids must be at stable or decreasing
doses for at least 14 days for adults and 7 days for paediatric patients prior to the start
of IMP administration). Patients who have received brain irradiation must have completed
whole-brain radiotherapy and/or stereotactic radiosurgery at least 14 days prior to the
start of IMP administration.

C. Female patients who are pregnant, breastfeeding or planning to become pregnant during
the trial or within seven months following their last dose of trastuzumab or pertuzumab
(whichever is later).

D. Severe dyspnoea at rest due to complications of advanced malignancy or requiring
supplementary oxygen therapy.

E. Known hypersensitivity to trastuzumab or pertuzumab, murine proteins, or to any of the
excipients.

F. Patients with clinically significant pre-existing cardiac conditions, including
uncontrolled or symptomatic angina, uncontrolled atrial or ventricular arrhythmias (within
6 months), NYHA class III or IV congestive heart failure. Patients with a cerebrovascular
event (including stroke or transient ischaemic attack [TIA]) or cardiovascular event
(including acute myocardial infarction [MI]) within six months before the first dose of
trastuzumab and pertuzumab. Left Ventricular Ejection Fraction <55%.

G. Prior treatment with the same class of drug unless genetic profile demonstrates a
mechanism of resistance known to be potentially sensitive to trastuzumab or pertuzumab.

H. Any clinically significant concomitant disease or condition (or its treatment) that
could interfere with the conduct of the trial or absorption of oral medications or that
would, in the opinion of the Investigator, pose an unacceptable risk to the patient in this
trial.