Clinical trial NCT05786716: DETERMINE Trial Treatment Arm 04: Trastuzumab in Combination With Pertuzumab in Adult, Paediatric and Teenage/Young Adult Patients With Cancers With HER2 Amplification or Activating Mutations
Official title: DETERMINE (Determining Extended Therapeutic Indications for Existing Drugs in Rare Molecularly Defined Indications Using a National Evaluation Platform Trial): An Umbrella-Basket Platform Trial to Evaluate the Efficacy of Targeted Therapies in Rare Adult, Paediatric and Teenage/Young Adult (TYA) Cancers With Actionable Genomic Alterations, Including Common Cancers With Rare Actionable Alterations. Treatment Arm 04: Trastuzumab in Combination With Pertuzumab in Adult, Paediatric and Teenage/Young Adult Patients With Cancers With HER2 Amplification or Activating Mutations.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Haematological Malignancy
Colorectal Neoplasms
Urinary Bladder Neoplasm
Gallbladder Neoplasms
Salivary Gland Neoplasm
Lung Neoplasm
Pancreatic Neoplasm
Ovarian Neoplasms
Prostatic Neoplasm
Skin Neoplasm
Solid Tumour
Keywords: Adult
Antibodies, monoclonal
Cancer
Child
Molecular Targeted Therapy
Mutation
Paediatric
Pertuzumab
Precision Medicine
Rare
Receptor, ErbB-2
Targeted
Trastuzumab
Tumour-agnostic
Young adult
Lead sponsor: Cancer Research UK
Sponsor class: OTHER
Collaborators: name: University of Manchester
name: University of Birmingham
name: Royal Marsden NHS Foundation Trust
name: Hoffmann-La Roche
First posted: 2023-03-28
Enrollment: 30
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This clinical trial is looking at a combination of drugs called trastuzumab and pertuzumab. This combination of drugs is approved together as standard of care treatment for adult patients with breast cancer (often with other anti-cancer drugs). 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.

Detailed description: DETERMINE Treatment Arm 04: Trastuzumab in combination with pertuzumab in Adult, Paediatric and TYA patients with rare\* cancers with HER2 amplification or activating mutations and in common cancers where HER2 amplification or activating mutations are considered to be infrequent.

\*Rare is defined generally as incidence less than 6 cases in 100,000 patients (includes paediatric and teenagers/young adult cancers) or common cancers with rare alterations.

This treatment arm has a target sample size of 30 evaluable patients. Sub-cohorts may be defined and further expanded to a target of 30 evaluable patients each.

The ultimate aim is to translate positive clinical findings to the NHS (Cancer Drugs Fund) to provide new treatment options for rare adult, paediatric and TYA cancers.

OUTLINE:

Pre-screening: The Molecular Tumour Board makes a treatment recommendation for the patient based on molecularly-defined cohorts.

Screening: Consenting patients undergo biopsy and collection of blood samples for research purposes.

Treatment: Patients will receive trastuzumab and pertuzumab until disease progression without clinical benefit, unacceptable toxicity or withdrawal of consent. Patients will also undergo collection of blood samples at various intervals while receiving treatment and at End of Treatment (EoT).

After completion of study treatment, patients are followed up every 3 months for 2 years.

THE DETERMINE TRIAL MASTER (SCREENING) PROTOCOL:

Please see DETERMINE Trial Master (Screening) Protocol record (NCT05722886) for information on the DETERMINE Trial Master Protocol and applicable documents.

Eligibility criteria: THE PATIENT MUST FULFIL THE ELIGIBILITY CRITERIA WITHIN THE DETERMINE MASTER PROTOCOL (NCT05722886) AND WITHIN THE TREATMENT ARM 04 (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.

• A HER2 amplification copy number between 5-9 will require an MTB discussion. A HER2 amplification copy number ≥10 will be fast-tracked for an MTB recommendation, unless there are any patient-specific individualities that require MTB discussion.

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 (condom plus spermicide) 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.

All male patients must refrain from donating sperm for the same period.

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

F. ADULT PATIENTS (≥18 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): ≥90 g/L (transfusion allowed)

Absolute neutrophil count (ANC): ≥1.5 × 10\^9L (no granulocyte colony-stimulating factor \[GCSF\] support in preceding 72 hours)

Platelet count: ≥100 × 10\^9L (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 (\<18 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.

Hb: ≥80 g/L (transfusion allowed)

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

ALT and AST: ≤2.5 × ULN or ≤5 × ULN if raised due to metastases

eGFR: ≥60 mL/min (uncorrected value)

Coagulation - PT (or INR) and 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. 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).

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

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

E. Patients who were administered a live, attenuated vaccine within 28 days prior to enrolment, or anticipation of need for such a vaccine during trastuzumab and pertuzumab treatment or within six months after the final dose of trastuzumab and pertuzumab.

F. Patients with clinically significant pre-existing cardiac conditions, including uncontrolled or symptomatic angina, uncontrolled atrial or ventricular arrhythmias (within three months), NYHA class III or IV congestive heart failure.

Left Ventricular Ejection Fraction \<55%.

Patients with a cerebrovascular event (including stroke or transient ischaemic attack \[TIA\]) or cardiovascular event (including acute myocardial infarction \[MI\]) within three months before the first dose of trastuzumab and pertuzumab.

• Patients with primary CNS tumours may be considered unless intra-tumoural bleeding has occurred within 2 weeks of the first dose of trastuzumab and pertuzumab, and patients with punctate CNS haemorrhages \<3 mm may be considered.

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.

I. Known active infections (bacterial, fungal or viral) that would interfere with the assessment of safety or efficacy of trastuzumab and pertuzumab, including human immunodeficiency virus (HIV) positivity. Patients with history of testing positive for HIV infection are eligible provided the each of the following conditions are met:

* CD4 count ≥350/μL;
* undetectable viral load;
* receiving antiretroviral therapy (ART) that does not interact with IMP (patients should be on established ART for at least four weeks); and
* no HIV/ acquired immune deficiency syndrome (AIDS)-associated opportunistic infection in the last 12 months.

Primary outcomes:
measure: Objective Response (OR)
timeFrame: Disease assessments to be performed up to 24 weeks from the start of trial treatment.
measure: Durable Clinical Benefit (DCB)
timeFrame: Disease assessments to be performed up to 24 weeks from the start of trial treatment.
Secondary outcomes:
measure: Duration of response (DR)
timeFrame: Disease assessment every 2 cycles of trastuzumab and pertuzumab (each cycle is 21 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits are every 3 months after last dose for up to 2 years.
measure: Best percentage change in sum of target lesion / index lesion diameters (PCSD)
timeFrame: Disease assessment every 2 cycles of trastuzumab and pertuzumab (each cycle is 21 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits are every 3 months after last dose for up to 2 years.
measure: Time to treatment discontinuation (TTD)
timeFrame: From first dose of trastuzumab and pertuzumab to discontinuation of trial treatment up to 5 years.
measure: Progression-Free Survival time (PFS)
timeFrame: Disease assessment every 2 cycles of trastuzumab and pertuzumab (each cycle is 21 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits are every 3 months after last dose for up to 2 years.
measure: Time to Progression (TTP)
timeFrame: Disease assessment every 2 cycles of trastuzumab and pertuzumab (each cycle is 21 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits are every 3 months after last dose for up to 2 years.
measure: Growth Modulation Index (GMI)
timeFrame: Disease assessment every 2 cycles of trastuzumab and pertuzumab (each cycle is 21 days) and at EoT. After 24 weeks, it can be done every 12 weeks, on discussion with Sponsor. Follow-up visits are every 3 months after last dose for up to 2 years.
measure: Overall Survival time (OS)
timeFrame: Time of death or up to 2 years after the EoT visit.
measure: Occurrence of at least one Suspected Unexpected Serious Adverse Reaction (SUSAR)
timeFrame: From the time of consent until 28 days after last dose of trastuzumab and/or pertuzumab (up to 5 years) or until patient starts another anti-cancer therapy, whichever came first. An average time frame will be presented with results entry.
measure: Occurrence of at least one Grade 3, 4 or 5 trastuzumab and/or pertuzumab related AE
timeFrame: From the time of consent until 28 days after last dose of trastuzumab or pertuzumab (up to 5 years) or until patient starts another anti-cancer therapy, whichever came first. An average time frame will be presented with results entry.
measure: EORTC-QLQ-C30 Standardised Area Under Summary Score Curve (QLQSAUC) in adult patients
timeFrame: QoL surveys performed prior to inclusion, every cycle (each cycle is 21 days) and at EoT visit (up to 5 years).
measure: EQ-5D Standardised Area Under Index Value Curve (EQ5DSAUC) in adult patients
timeFrame: QoL surveys performed prior to inclusion, every cycle (each cycle is 21 days) and at EoT visit (up to 5 years).
measure: Mean change from baseline in the PedsQL 4.0 Standardised Area Under total Scale Score Curve (PedsSAUC) in paediatric patients
timeFrame: QoL surveys performed prior to inclusion, every cycle (each cycle is 21 days) and at EoT visit (up to 5 years).
measure: Mean change from baseline in the PedsQL 4.0 Standardised Area Under total Scale Score Curve (PedsSAUC) in parents of paediatric patients
timeFrame: QoL surveys performed prior to inclusion, every cycle (each cycle is 21 days) and at EoT visit (up to 5 years).
Other outcomes:
Locations:
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Birmingham
country: United Kingdom
facility: University Hospital Birmingham
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre
city: Cardiff
country: United Kingdom
facility: Cardiff Children's Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Glasgow
country: United Kingdom
facility: The Beatson Hospital
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Children Glasgow
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Liverpool
country: United Kingdom
facility: Alder Hey Hospital
city: London Borough of Sutton
country: United Kingdom
facility: The Royal Marsden Hospital
city: London
country: United Kingdom
facility: University College London Hospital
city: London
country: United Kingdom
facility: Guy's Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
city: Manchester
country: United Kingdom
facility: The Christie Hospital
city: Newcastle
country: United Kingdom
facility: Great North Children's Hospital
city: Newcastle
country: United Kingdom
facility: Freeman Hospital
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
city: Sheffield
country: United Kingdom
facility: Sheffield's Children's Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Wirral
country: United Kingdom
facility: Clatterbridge Cancer Centre
Study officials:
affiliation: The Christie Hospital
name: Matthew Krebs, Dr
role: PRINCIPAL_INVESTIGATOR
References: