DETERMINE (Determining Extended Therapeutic Indications for Existing Drugs in Rare Molecularly Defined Indications Using a National Evaluation Platform Trial) - Master Screening Protocol

THE PARTICIPANT MUST FULFIL THE ELIGIBILITY CRITERIA OUTLINED BELOW AND WITHIN THE SPECIFICTREATMENT ARM APPENDIX TO WHICH THEY ARE ENROLLED. Core Inclusion Criteria

1. Any patient with histologically proven locally advanced or metastatic cancer (solidtumour or haematological malignancy) who has:
2. exhausted (or declined) standard-of-care treatment options.
3. or for whom no effective standard treatment is available*. *In exceptionalcircumstances where upfront treatment on the CRUKD/21/004 DETERMINE trial isconsidered the best choice for the patient in the opinion of the Investigator,due to risk of considerable harm from standard treatment (e.g. where thisinvolves mutilating surgery or is unacceptable due to patient age or geneticvulnerability such as CMMRD).
4. and whose disease has progressed, or is refractory.
5. Diagnosis of a rare cancer harbouring an actionable genomic alteration, or commoncancer types with rare actionable genomic alterations, that have been identified usinga validated sequencing technique and for which there is a relevant open treatment armwithin the DETERMINE trial.
6. Life expectancy of at least three months.
7. Patients are able to provide written (signed and dated) informed consent and becapable of co-operating with treatment and follow-up. For patients under 16 years ofage, the parent or legal guardian will be asked to provide written informed consentand the patient will be asked to provide age-appropriate assent (written or verbal,commensurate with age and level of understanding).
8. Patients with objectively evaluable or measurable disease, according to an assessmentmethod appropriate for their cancer type.
9. Patients must provide a fresh tissue biopsy at baseline and blood samples fortranslational research.
10. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (ECOG performancestatus 2 may be considered on an individual basis) (≥ 16 years), Karnofsky score ≥ 50% (12 years to 15 years) or Lansky Play scales ≥ 50% (<12 years). Please see specifictreatment arm appendices for any variations on this criterion. Note: Patients <16years: patients with Central Nervous System (CNS) tumours and a neurological deficitmay be eligible with a performance status below 50%, at the discretion of theInvestigator. In such cases, the deficit must be stable for at least 7 days prior totrial enrolment, be due to tumour or due to a post-surgical adverse event that isdeemed by the local Investigator.
11. Women of childbearing potential are eligible provided that they meet the followingcriteria:

• Have a negative serum or urine pregnancy test before enrolment and
• Agree to the birth control methods and duration of use of those methods, asspecified in each treatment arm appendix.

9. Male patients with partners of childbearing potential are eligible provided that theyagree to the birth control methods and duration of use of those methods, as specifiedin each treatment arm appendix.

Core exclusion criteria:

1. Ongoing AEs >Common Terminology Criteria of Adverse Events (CTCAE) Grade 2attributable to previous anti-cancer treatments. Exceptions to this are any ongoingtoxic manifestation, which in the opinion of the Investigator should not exclude thepatient.
2. At high medical risk, in the opinion of the Investigator, because of non-malignantsystemic disease (including active uncontrolled infection).
3. Female patients who are pregnant, breastfeeding or planning to become pregnant or malepatients with a partner who is a woman of childbearing potential and is planning tobecome pregnant during the trial or following the last dose of IMP, as specified ineach treatment arm appendix.
4. Is (or plans to be) a participant in another interventional clinical trial, whilsttaking part in this trial. Participation in an observational trial which does notinvolve administration of an Investigational Medicinal Product (IMP) and which, in theopinion of the local Investigator, would not place an unacceptable burden on thepatient would be acceptable e.g. sample collection* or Quality of Life (QoL) studies. *for paediatric patients participating in other studies involving tissue/circulatingtumour (ct) DNA/other blood collection, consideration would need to be given to thetotal blood volumes collected (as per the European Medicines Agency blood volumelimits for children).
5. Co-administration of anti-cancer therapies other than those administered in thistrial.
6. Radiotherapy (except for palliative reasons) or chemotherapy, endocrine therapy,nitrosoureas, mitomycin-C, immunotherapy and molecularly targeted agents or otherinvestigational medicinal products within 4 weeks or 5 half-lives (whichever is theshorter).
7. Rapidly progressing or symptomatically deteriorating brain metastases. Patients withpreviously treated brain metastases are eligible, provided the patient has notexperienced a seizure or had a clinically significant change in neurological statuswithin the two weeks prior to registration. Such patients must be non-dependent onsteroids or on a stable or reducing dose of steroid treatment for at least 14 days (or 7 days for paediatric patients) prior to trial enrolment. Primary brain or CNSmalignancies are allowed providing the patient is clinically stable (if requiringcorticosteroids must be at stable or decreasing doses for at least 14 days for adultsand 7 days for paediatric patients prior to the start of IMP administration). Patientswho have received brain irradiation must have completed whole-brain radiotherapyand/or stereotactic radiosurgery at least 14 days prior to the start of IMPadministration.
8. Any other condition which, in the opinion of the local Investigator, would not be inthe best interests of the patient.