The Drug Rediscovery Protocol (DRUP Trial)

Inclusion Criteria:

1. Adult (age >18 years) patient with a histologically-proven locally advanced ormetastatic solid tumor, multiple myeloma or B cell non-Hodgkin lymphomawithsymptomatic disease progression or progression according to RECIST-criteria afterstandard anti-cancer treatment or for whom no such treatment is available orindicated.

• For patients with a primary brain tumor: Histologically confirmed recurrent or denovo primary brain tumor, with unequivocal progression after prior therapy, at least 3months after radiotherapy (either first line chemo-radiotherapy or re-irradiation),and with stable or decreasing dosage of steroids for at least 7 days prior to thebaseline MRI scan.

2. ECOG performance status 0-2
3. Patients must have acceptable organ function as defined below. However, specificinclusion/exclusion criteria specified in the drug-specific study manual will takeprecedence:
4. Absolute neutrophil count ≥ 1.5 x 109/l
5. Hemoglobin > 5.6 mmol/l
6. Platelets > 75 x 109/l
7. Total bilirubin < 2 x ULN
8. AST (SGOT) and ALT (SGPT) < 2.5 x institutional ULN (or < 5 x ULN in patientswith known hepatic metastases)
9. Serum creatinine ≤ 1.5 × ULN or calculated or measured creatinine clearance ≥ 50mL/min/1.73 m2
10. Patients must have objectively measurable disease (by physical or radiographicexamination, according to RECIST v1.1 for patients with solid tumors, or according toIMWG, Lugano, RANO or GCIG criteria, resp., for patients with multiple myeloma,non-Hodgkin lymphoma, glioblastoma or ovarian cancer in case of CA125-based evaluation (please refer to appendices for further details).
11. Results must be available from a tumor genomic or protein expression test. Eligibletests may include any of the following technologies: fluorescence in situhybridization (FISH), polymerase chain reaction (PCR), comparative genomichybridization (CGH), next generation sequencing (NGS) or immunohistochemistry (IHC).The test may have been performed on the primary tumor or a metastatic deposit, in adiagnostic laboratory or within the context of another CPCT study, and must reveal apotentially actionable variant as defined in Section 5. The test results (fullpathology or molecular diagnostics report) must be uploaded in the eCRF.
12. Patients must have a tumor profile for which treatment with one of the FDA and / orEMA approved (or under revision for approval) targeted anti-cancer drugs included inthis study has potential clinical benefit based on preclinical data or clinicalinformation (see section 5).
13. new (obtained ≤2 months before inclusion, and without any type of anti-cancer therapywithin those ≤2 months) fresh frozen tumor biopsy specimen for extensive biomarkertesting is mandatory before the start of treatment with a targeted agent included inthe protocol. Alternatively, fresh frozen tumor tissue acquired in the context of astandard care procedure may be used, provided that no systemic anti-cancer treatmentwas given between the procedure and start of study treatment within DRUP. The following exceptions are made: a. An exception is made for patients with a primary brain tumor, only if the mandatoryDRUP pre-treatment biopsy for biomarker analysis cannot safely be obtained:
14. The fresh frozen tumor biopsy sample may be replaced by fresh frozen tumortissue, obtained earlier from recurrent disease, as part of standard of caresurgical procedure (i.e., performed at progression)
15. If no fresh frozen tumor tissue is available for NGS, and the risk of obtaining anew tumor biopsy is considered too high, no biopsy will be required. In thiscase, the study coordinators must be informed in advance, and there will be noreimbursement for the biopsy procedure. b. In case WGS is performed on tumor tissue outside the context of a clinical trialbefore inclusion, and without any type of anti-cancer therapy between the collectionof tissue and inclusion in DRUP, this can replace the DRUP pre-treatment biopsy,provided that the patient gives consent to use his/her WGS data for biomarker analysisin DRUP. c. An exception is made for patients that underwent an allogeneic hematopoietic stemcell transplantation prior to study enrollment, since this will prevent a correct WGSanalysis due to a mismatch between the biopsy specimen and the required blood sample.
16. Ability to understand and the willingness to sign a written informed consent document.
17. For orally administered drugs, the patient must be able to swallow and tolerate oralmedication and must have no known malabsorption syndrome.
18. Because of the risks of drug treatment to the developing foetus, women ofchild-bearing potential and men must agree to use adequate contraception (hormonal orbarrier method of birth control; abstinence) for the duration of study participation,and for four months following completion of study therapy. Male patients should avoidimpregnating a female partner. Male patients, even if surgically sterilized, (i.e.post-vasectomy) must agree to one of the following: practice effective barriercontraception during the entire study treatment period and through 4 months after thelast dose of study drug, or completely abstain from sexual intercourse.

Exclusion Criteria:

1. Ongoing toxicity > grade 2, other than alopecia.
2. Patient is receiving any other anti-cancer therapy (cytotoxic, biologic, radiation, orhormonal other than for replacement). Required wash out period prior to starting studytreatment is at least two weeks. An exception is made for:

• Patients suffering from CRPC are allowed to continue androgen deprivationtherapy.
• Medications that are prescribed for supportive care but may potentially have ananti-cancer effect (e.g., megestrol acetate, bisphosphonates). These medicationsmust have been started ≥ 1 week prior to enrollment on this study.

3. Patient is pregnant or nursing.
4. Patients with known active progressive brain metastases. Patients with previouslytreated brain metastases are eligible, provided that the patient has not experienced aseizure or had a clinically significant change in neurological status within the 3months prior to registration. All patients with previously treated brain metastasesmust be stable for at least 1 month after completion of treatment and off steroidtreatment prior to study enrollment.

• Additional exclusion criteria specific for glioblastoma patients:

1. Patients who require anti-convulsant therapy must be taking non-enzyme inducingantiepileptic drugs (non-EIAED). EIAED are prohibited. Patients previously onEIAED must be switched to non-EIAED at least 2 weeks prior to randomization.
2. No radiotherapy within the three months prior to the diagnosis of progression.
3. No radiotherapy with a dose over 65 Gy, stereotactic radiosurgery orbrachytherapy unless the recurrence is histologically proven.
4. Patients with clinically significant preexisting cardiac conditions, includinguncontrolled or symptomatic angina, uncontrolled atrial or ventricular arrhythmias, orsymptomatic congestive heart failure are not eligible.
5. Patients with known left ventricular ejection fraction (LVEF) < 40% are not eligible
6. Patients with stroke (including TIA) or acute myocardial infarction within 3 monthsbefore the first dose of study treatment are not eligible
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, orsevere psychiatric illness/social situations. For each drug included in this protocol, specific inclusion and exclusion criteria (basedon the Package Insert or manufacturers recommendations) may also apply. These can be foundin the supplemental information about each agent included in the drug-specific studymanuals. Drug-specific inclusion and exclusion criteria will take precedence over theinclusion/exclusion criteria listed above.