MoST Addendum 9 (substudies 21-22): This phase II study is evaluating the effect of a combination of targeted therapies (tucatinib plus trastuzumab) in people with advanced or metastatic solid cancers with HER2 amplifications or mutationsSingle arm, open label, signal seeking, phase II trial of the activity of tucatinib plus trastuzumab in patients with tumours harbouring HER2 amplifications or mutations

Exclusion

1. Contraindications to investigational products.
2. Known history of hypersensitivity to active or inactive components of investigational products.
3. Previous treatment with the same agent or same class of agent e.g. other HER2-directed therapy.
4. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may interact with the investigational product(s)
5. Co-morbidities or conditions that may compromise assessment of key outcomes or in the opinion of the clinician, limit the ability of the patient to comply with the protocol.
6. Primary tumour histology is HER2 amplified breast adenocarcinoma or gastric adenocarcinoma.
7. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment:
a. Radiation therapy, surgery, or tumour embolisation within 14 days prior to the first dose of study treatment. Palliative radiotherapy (for analgesia) is acceptable only if the irradiated field does not include target lesions. Note additional requirements or exceptions in inclusion criteria 10c
b. Immunotherapy within 28 days prior to the first dose of study treatment.
c. Chemotherapy, biologic therapy, or hormonal therapy within 14 days or 5 half-lives of a drug prior to the first dose of study treatment or until recovery from previous therapy (whichever is longer).
8. Administration of any investigational treatment within 30 days or 5 half-lives (whichever is longer) prior to receiving the first dose of study treatment.
9. Use of a strong CYP2C8 inhibitor within 5 half-lives of the inhibitor or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to the first dose of study treatment. Use of sensitive CYP3A substrates should be avoided two weeks before enrolment and during study treatment
10. Ongoing treatment with corticosteroids at a total daily dose of > 2mg dexamethasone daily (or equivalent). Exceptions include use of dexamethasone up to 4mg /day within 14 days of initial treatment for patients with primary brain tumours.
11. Clinically significant cardiopulmonary disease.
12. Any untreated brain lesions >/=2.0 cm in size or any brain lesions requiring immediate local therapy.
13. Known leptomeningeal disease.
14. Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy.
15. Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripheral neuropathy).
16. For non central nervous system (CNS) cancers, patients with symptomatic CNS involvement of his/her cancer are excluded. Subjects with stable neurological function, on stable doses of steroids/anti-epileptics over 4 weeks, and with no evidence of CNS progression within 12 weeks prior to screening are eligible.
17. History of another malignancy within 2 years prior to molecular screening registration are excluded unless adequately treated and determined free of progressive and metastatic disease for at least 6 months. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder can be included.
18. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must have been surgically sterilised or use a (double if required) barrier method of contraception.