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

Launched by CANCER RESEARCH UK · Mar 14, 2023

Keywords

ClinConnect Summary

The DETERMINE Trial is investigating whether a combination of two cancer-fighting drugs, trastuzumab and pertuzumab, can help patients with various types of cancers that have specific changes in their HER2 gene. These changes can make the cancer grow faster. While this treatment is already approved for adult patients with metastatic breast cancer, researchers want to see if it can also be effective for other cancers that share these HER2 characteristics. If the results are promising, the goal is to make this treatment available to more patients through the NHS and the Cancer Drugs Fund.

To be eligible for this trial, participants must be at least 12 years old and have a confirmed diagnosis of cancer with HER2 amplification or an activating mutation. They will also need to undergo a biopsy and meet certain health criteria to ensure their bodies can handle the treatments. Participants will receive the combination of trastuzumab and pertuzumab and be closely monitored for their health and response to the drugs. This trial is an important step in potentially expanding treatment options for patients with rare cancers or specific genetic mutations.

Gender

ALL

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.