DETERMINE Trial Treatment Arm 04: Trastuzumab in Combination With Pertuzumab in Adult, Teenage/Young Adult and Paediatric Patients With Cancers With HER2 Amplification or Activating Mutations

Study Overview
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Brief Summary
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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.

Detailed Description
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DETERMINE Treatment Arm 04: Trastuzumab in combination with pertuzumab in Adult, Teenage/Young adult and Paediatric 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 where promising activity is identified 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 participant based on molecularly-defined cohorts. Screening: Consenting participants undergo biopsy and collection of blood samples for research purposes. Treatment: Participants will receive trastuzumab and pertuzumab until disease progression, unacceptable toxicity or withdrawal of consent. Participants will also undergo collection of blood samples at various intervals while receiving treatment and at 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.

Official Title
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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, Teenage/Young Adult and Paediatric Patients With Cancers With HER2 Amplification or Activating Mutations.

Conditions
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Lung Neoplasm, Solid Tumor, Haematological Malignancy, Salivary Gland Neoplasm, Pancreatic Neoplasm, Ovarian Neoplasms, Prostatic Neoplasm, Skin Neoplasm, Colorectal Neoplasms, Urinary Bladder Neoplasm, Gallbladder Neoplasms

Intervention / Treatment
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* Drug: Trastuzumab
* Drug: Pertuzumab


Participation Criteria
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Eligibility Criteria
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THE PARTICIPANT 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. 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.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm 04: trastuzumab in combination with pertuzumab<br>This trastuzumab and pertuzumab treatment arm is for adult, TYA and paediatric participants with malignancies with HER2 amplification or activating mutations. | Drug: Trastuzumab<br>* An initial loading dose of 8 mg/kg body weight administered intravenously every 21 days followed thereafter by a maintenance dose of 6 mg/kg body weight.<br>* Other names: Herceptin;Drug: Pertuzumab<br>* An initial loading dose of 14 mg/kg administered intravenously every 21 days followed thereafter by a maintenance dose of 7 mg/kg.<br>* Other names: Perjeta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response (OR) | An OR is defined as the confirmed occurrence of either a Complete Response (CR) or Partial Response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 criteria (or immune related (ir)-RECIST or standard imaging criteria for specific disease e.g. Response Evaluation in Neuro Oncology criteria (RANO)). In patients with leukaemia, OR will be defined as the occurrence of CR , CRi (CR incomplete neutrophil recovery) or CRp (CR with incomplete platelet recovery). The trial will report the proportion of patients with an OR and 95% credible interval. | Disease assessments to be performed up to 24 weeks from the start of trial treatment. | 
| Durable Clinical Benefit (DCB) | DCB is defined as the absence of disease progression for at least 24 weeks from the start of trial treatment according to RECIST Version 1.1 criteria (or ir-RECIST or standard imaging criteria for specific disease e.g. RANO criteria). Alternative definitions of DCB based on different time points may be pre-specified for particular sub-cohorts if 24 weeks is not clinically relevant. The trial will report the proportion of patients with a DCB and 95% credible interval. | Disease assessments to be performed up to 24 weeks from the start of trial treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DR) | Duration of response, is defined as the time from the date of the first confirmed CR or PR according to RECIST 1.1 or ir-RECIST or standard imaging criteria for specific disease e.g. RANO criteria to the date of disease progression. The trial will report the median DR and 95% credible interval. | 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 3 cycles, on discussion with Sponsor. Follow-up visits are every 12 weeks after last dose for up to 2 years. | 
| Best percentage change in sum of target lesion / index lesion diameters (PCSD) | PCSD is defined as the greatest decrease or least increase in the sum of target lesion diameters (RECIST) or index lesion diameters (irRECIST) as a percentage compared to the baseline measurement. The trial will report the mean PCSD and 95% credible interval. | Disease assessment performed every 2 cycles (each cycle is 21 days). After 24 weeks, disease assessments can be repeated every 3 cycles, on discussion with Sponsor. Follow-up visits are every 12 weeks following last dose for a period of up to 2 years. | 
| Time to treatment discontinuation (TTD) | TTD is defined as the time from date of starting trial treatment to date of discontinuing trial treatment, in days estimated by the median of the posterior inverse gamma probability distribution. The trial will report the median TTD and 95% credible interval. | From first dose of trastuzumab and pertuzumab to discontinuation of trial treatment up to 5 years. | 
| Progression-Free Survival time (PFS) | PFS is defined as the time from date of starting trial treatment to date of progression or date of death without a previous progression recorded estimated by the median of the posterior inverse gamma probability distribution. | Disease assessment every 2 cycles (each cycle is 21 days). After 24 weeks, it can be done every 3 cycles, on discussion with Sponsor. Follow-up visits occur every 12 weeks following last dose of trastuzumab and pertuzumab for a period of up to 2 years. | 
| Time to Progression (TTP) | TTP is defined as the time from date of starting trial treatment to date of progression or date of death without recorded progression censored rather than events. The trial will report the median TTP and 95% credible interval. | Disease assessment every 2 cycles (each cycle is 21 days). After 24 weeks, it can be done every 3 cycles, on discussion with Sponsor. Follow-up visits occur every 12 weeks following last dose of trastuzumab and pertuzumab for a period of up to 2 years. | 
| Growth Modulation Index (GMI) | GMI is defined as the ratio of TTP with the trial protocol treatment to TTP on the most recent prior line of therapy. The trial will report the mean GMI and 95% credible interval. | Disease assessment every 2 cycles (each cycle is 21 days). After 24 weeks, it can be done every 3 cycles, on discussion with Sponsor. Follow-up visits occur every 12 weeks following last dose of trastuzumab and pertuzumab for a period of up to 2 years. | 
| Overall Survival time (OS) | OS is defined as the time from date of starting trial treatment to date of death from any cause estimated by the median of the posterior normal probability distribution. | Time of death or up to 2 years after the End of Treatment (EoT) visit. | 
| Occurrence of at least one Suspected Unexpected Serious Adverse Event (SUSAR) | The trial will report the number of patients who experience at least one SUSAR to trastuzumab and pertuzumab. | 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. | 
| Occurrence of at least one Grade 3, 4 or 5 trastuzumab and pertuzumab related AE | Number of patients who experience at least one trastuzumab and pertuzumab related Grade 3, 4 or 5 AE according to NCI CTCAE Version 5.0. | 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. | 
| EORTC-QLQ-30 Standardised Area Under Summary Score Curve (QLQSAUC) in adult participants | For adult populations, multiple measures of QoL will be generated from patient completion of the European Organisation for Research and Treatment of Cancer QLQC30 (EORTC-QLQC30) questionnaire (30 measures). For each patient the Summary Score from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean QLQSAUC and 95% credible interval. | QoL surveys performed at baseline every 2 cycles during treatment (each cycle is 21 days) and immediately after interrupting treatment (up to 5 years). | 
| EQ-5D Standardised Area Under Index Value Curve (EQ5DSAUC) in adult participants | For adult populations, two measures of QoL will be generated from patient completion of the EQ-5D-5L questionnaire. For each measure, scores based on responses from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean EQ5DSAUC and 95% credible interval. | QoL surveys performed prior to inclusion, every 2 cycles (each cycle is 21 days) and at EoT visit (up to 5 years). | 
| Mean change from baseline in the PedsQL 4.0 Standardised Area Under total Scale Score Curve (PedsSAUC) in paediatric participants | For paediatric populations multiple measures of QoL will be generated from patient completion of the, PedsQL 4.0 (4 measures). The Summary Score from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean PedsSAUC and 95% credible interval. | QoL surveys performed prior to inclusion, every 2 cycles (each cycle is 21 days) and at EoT visit (up to 5 years). | 
| Mean change from baseline in the PedsQL 4.0 Standardised Area Under total Scale Score Curve (PedsSAUC) in parents from paediatric participants | For paediatric populations multiple measures of QoL will be generated from patient's parent completion of the, PedsQL 4.0 (4 measures). The Summary Score from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean PedsSAUC and 95% credible interval. | QoL surveys performed prior to inclusion, every 2 cycles (each cycle is 21 days) and at EoT visit (up to 5 years). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antibodies, monoclonal, Cancer, Child, Molecular Targeted Therapy, Mutation, Paediatric, Pertuzumab, Precision Medicine, Rare, Receptor, ErbB-2, Targeted, Trastuzumab, Tumour-agnostic, Young adult, Adult