Improving Public Cancer Care by Implementing Precision Medicine in Norway

Inclusion Criteria:

• Type of Participant and Health status

1. Patient with a pathology-proven locally advanced or metastatic malignant diseasewho is no longer benefitting from standard anti-cancer treatment or for whom, inthe opinion of the investigator, no such treatment is available or indicated.
2. ECOG performance status 0-2.
3. For orally administered drugs, the patient must be able to swallow and tolerateoral medication and must have no known malabsorption syndrome.
4. Patients must have acceptable organ function as defined below. However, as notedabove, drug-specific inclusion/exclusion criteria specified in the drug-specificstudy manuals for each agent will take precedence for this and all inclusioncriteria (exceptions for haematological diagnoses):
5. Absolute neutrophil count ≥ 1.5 x109 / L
6. Hemoglobin > 9 g/dl
7. Platelets > 75,000/µl
8. Total bilirubin < 1.5 x institutional upper limit of normal (ULN)
9. AST (SGOT) and ALT(SGPT) < 2.5 x institutional upper limit of normal (ULN) (or < 5 x ULN in patients with known hepatic metastases)
10. Calculated or measured creatinine clearance ≥ 40 mL/min/1.73 m2.
11. Patients must have measurable or evaluable disease. RECIST v1.1 (10, 18) will beused for patients with solid tumours. For patients with multiple myeloma ornon-Hodgkin lymphoma, IMWG response criteria (19) and CHESON/Lugano guidelines (20) will be used, resp. For glioblastoma patients, RANO criteria will be used (21). iRECIST will be used for immunotherapy-cohorts. IWG response criteria willbe used for haematological cancers. Patients whose disease cannot be objectively measured by physical or radiographicexamination (e.g., elevated serum tumour marker only) are NOT eligible, with theexception of CA-125 for ovarian cancer and PSA for prostate cancer (22).
12. Results must be available from a genomic / molecular test performed in apreapproved laboratory (Section 10.15). The test used to qualify a patient forparticipation in IMPRESS-Norway may have been performed on any specimen of thepatient's tumour obtained at any point during the patient's care at thediscretion of the patient's treating physician. Genomic assays performed oncell-free DNA in plasma ("liquid biopsies") will also be acceptable if thegenomic analysis is performed as defined in Section 10.5. NGS analyses will beperformed on a newly sampled biopsy if possible. Information from these analysesmight be used upon progression, for evaluation of possible new cohort-inclusion.
13. Have a genomic profile for which treatment with one of the approved targetedanti-cancer therapies included in this study has potential clinical benefit seeSection 4.3.5 Note: Eligible genomic tests may include any of the following technologies andequivalent techniques: Immunohistochemistry (IHC), fluorescence in situhybridization (FISH), polymerase chain reaction (PCR) (incl nanostring),array-based copy number analysis (CNV), sanger sequencing (SS), RNA sequencing,gene panels or whole exome sequencing (WES) by next generation sequencing (NGS).The test may have been performed on a fresh (frozen or in RNA-later) orparaffin-embedded specimen of the primary tumour or a metastatic deposit or oncell-free DNA derived from liquid biopsies (like for instance peripheral bloodplasma), as determined by the treating physician, and must reveal a potentiallyactionable genomic variant or protein overexpression as defined in Section 4.3.
14. Patients must meet drug-specific eligibility requirements for the drug selectedby the investigator. Sex and Contraceptive/Barrier Requirements 9.8. Because of the risks of drug treatment tothe developing fetus, women of child-bearing potential and men must agree to use adequatehighly effective methods of contraception for the duration of study participation, and for 4 to 24 months following completion of study therapy as defined in Section 11.4.

10.9. Female participants must have a negative highly sensitive pregnancy test <1 monthprior to inclusion.

11.10. Male patients should avoid impregnating a female partner. Male study patients mustagree to one of the following: practice effective barrier contraception as described undersec. 11.4 during the entire study treatment period and through a certain time after thelast dose of study drug. Details are given in the "Drug specific amendment". Informed Consent 12.11. Ability to understand and the willingness to sign a writteninformed consent/assent document as described in Appendix 1 which includes compliance withthe requirements and restrictions listed in the informed consent form (ICF) and in thisprotocol. Guardians / parents can act on behalf of children.

Exclusion Criteria: A potential participant who meets any of the following criteria will be excluded fromparticipation in this study (other exclusion criteria might apply for specific drugs). Medical Conditions

1. Patients eligible to enter other ongoing trials which have to potential to benefit thepatients equally or more than a IMPRESS-Norway cohort, and for whom access to theongoing trials is manageable (taking geography into consideration).
2. Ongoing toxicity > CTCAE grade 2, other than peripheral neuropathy, related toanti-tumour treatment that was completed within 4 weeks prior to treatment initiation.Patients with ongoing peripheral neuropathy of ≥ CTCAE grade 3. Patients with known progressive brain metastases determined by serial imaging ordeclining neurologic function in the opinion of the treating physician. Patients withpreviously treated / stable brain metastases are eligible. Additional exclusioncriteria specific for GBM patients: a. Patients who require anti-convulsant therapy must be taking non-enzyme inducingantiepileptic drugs (non-EIAED). EIAED are prohibited. Patients previously on EIAEDmust be switched to non-EIAED at least 2 weeks prior to randomization.
3. Patients with the following pre-existing cardiac conditions, uncontrolled angina,uncontrolled atrial or ventricular arrhythmias, or symptomatic congestive heartfailure.
4. Patients with left ventricular ejection fraction (LVEF) known to be < 40%.
5. Patients with stroke (including TIA) or acute myocardial infarction within 4 monthsbefore the first dose of study treatment
6. Patients with acute gastrointestinal bleeding within 1 month of start of treatment
7. Patients with any other clinically significant medical condition which, in the opinionof the treating physician, makes it undesirable for the patient to participate in thestudy or which could jeopardize compliance with study requirements including, but notlimited to: ongoing or active infection, significant uncontrolled hypertension, severepsychiatric illness situations, or anticipated or planned anti-cancer treatment orsurgery.
8. Patients with known allergy/hypersensitivity to the study drug (active substance or toany of the excipients). Prior/Concomitant Therapy 9. Previous treatment with the selected study drug for the samemalignancy. 10. Patient is receiving any other anti-cancer therapy (cytotoxic, biologic,radiation, or hormonal other than for replacement) except for medications that areprescribed for supportive care but may potentially have an anti-cancer effect (e.g.,megestrol acetate, bisphosphonates) or ongoing castration-intent therapy for prostatecancer. These medications must have been started ≥ 1 month prior to enrolment on thisstudy. Patients may be on warfarin, low molecular weight heparin or direct factor Xainhibitors, unless such therapies are prohibited by drug-specific exclusion criteria. Diagnostic assessments 11. If the patient's tumour has a genomic variant known to conferresistance to an anti-cancer agent available in this study, the patient will not beeligible to receive that agent but will be eligible to receive other drugs available inthis study if all inclusion and exclusion criteria are met for that drug. Other Exclusions 12. Female patients who are pregnant or nursing 13. Patients who do notmeet drug-specific eligibility requirements for the drug selected by the investigator Note: For each drug included in this protocol, specific inclusion and exclusion criteria (based on the Summary of Product Characterics (SPC) or manufacturer's recommendations) mayalso apply. These can be found in the supplemental information about each agent included inthe appendices. Drug-specific inclusion and exclusion criteria will take precedence overthe general inclusion/exclusion criteria