Uno studio modulare multi-basket per migliorare la medicina personalizzata nei pazienti oncologici (Basket of Baskets)

Eligibilty Criteria (PART A - iPROFILER)

Inclusion Criteria:

1. Subjects must have histologically or cytologically confirmed malignancy that is metastatic or unresectable, who have progressed to standard therapy, who are receiving a standard anticancer treatment, but no subsequent approved treatment would be available upon progression, who are unable to receive standard therapy, or for whom standard therapy does not exist.
2. Patient must have ECOG performance status of 0 or 1.
3. Subjects must be 18-year-old or older.
4. Subjects must have measurable disease according to RECIST 1.1.
5. Subjects must have enough tumour tissue for molecular analysis.

   1. Subjects providing formalin-fixed paraffin embedded tissue (FFPE) must provide a minimum amount of tissue ranging from 28 to 36 slides depending on the sample tumour cellularity. If there is not enough archival tissue to meet this criterion, the patient must undergo a tumour biopsy.
   2. Subjects providing fresh frozen tissue must provide 5 core biopsies or equivalent.

      Fresh frozen tissue must be preferentially collected from a tumour biopsy; hence, subjects must have disease amenable to be biopsied. Otherwise, the patient should have fresh frozen tumour tissue stored in a biobank or biorepository.
   3. Efforts will be made to provide fresh frozen tissue in at least one quarter of the participating subjects. The proportion of subjects that might provide fresh frozen tissue might change based on the results from the molecular analysis.
   4. Since some of the tests are performed in FFPE tissue, subjects providing fresh frozen tissue from a recent biopsy will have part of the sample processed in FFPE as per Laboratory manual.
6. Subjects must have adequate haematological, renal, and hepatic function.
7. For subjects requiring a tumour biopsy: subjects must have adequate coagulation function.
8. Subjects must be willing to participate in a clinical trial with a matched therapy according to the molecular profile of his/her tumour.

Exclusion Criteria:

1. Subjects with leptomeningeal disease should be excluded from this clinical trial.
2. Subjects with known unstable brain metastases should be excluded from this clinical trial. Exception: Subjects who have undergone surgery and/or radiotherapy and in which brain metastases remain stable or decrease in size for six months after having completed therapy.
3. Subjects with spinal cord compression not definitively treated with surgery and/or radiation.
4. Subjects with uncontrolled intercurrent illness including, but not limited to, active infection, symptomatic congestive heart failure, LVEF < 50%, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
5. Subjects with inability to swallow tablets or capsules.
6. Subjects with known HIV, hepatitis B or hepatitis C infection.
7. Subjects with known history of malabsorption.

Eligibilty Criteria (PART B - iBASKET)

Inclusion Criteria:

1. Subjects must have metastatic or unresectable malignant tumour, histologically or cytological confirmed and progressing to current therapy. Tumours must be refractory to standard therapy or for which standard therapy does not exist, or subjects may be unable to receive standard therapy.
2. Patient must have ECOG performance status of 0 or 1.
3. Subjects must be 18-year-old or older.
4. Subjects must have measurable disease according to RECIST 1.1.
5. Subjects must be willing to participate in a clinical trial with a matched therapy according to the molecular profile of his/her tumour.
6. Tumours must harbour the following alterations.
7. Subjects must have adequate hematological, renal, and hepatic function.
8. For subjects requiring a tumour biopsy: subjects must have adequate coagulation function.
9. A woman of childbearing potential must have a negative serum pregnancy test within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy test during the study.
10. A woman must be either of the following:

    1. Not of childbearing potential.
    2. Of childbearing potential and practicing true abstinence during the entire period of the study, including up to 6 months after the last dose of study treatment is given.
    3. Of childbearing potential and practicing 2 methods of contraception, including 1 highly effective user independent method and a second method. Participant must agree to continue contraception throughout the study and through 6 months after the last dose of study treatment.
11. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 6 months after receiving the last dose of study treatment.
12. A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 6 months after receiving the last dose of study treatment.
13. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Pregnant or breastfeeding women. Females of childbearing potential must have a negative serum pregnancy test within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy test during the study.
2. Any approved anticancer therapy, including chemotherapy, hormonal therapy or radiotherapy, within 3 weeks prior to initiation of study treatment; however, the following are allowed:

   1. Hormone-replacement therapy or oral contraceptives.
   2. Somatostatin analogues for the treatment of symptoms related with neuroendocrine tumours.
   3. Gonadotropin-releasing hormone agonists or antiandrogens for prostate cancer.
   4. Palliative radiotherapy for bone metastases > 2 weeks prior to Cycle 1, Day 1.
3. Treatment with an investigational agent within 3 weeks prior to Cycle 1, Day 1 (or within five half-lives of the investigational product, whichever is longer).
4. Patients with recent major surgery or invasive procedure within 15 days before the fist dose of the study drug.
5. Participant has unstable symptomatic brain metastases. A participant with asymptomatic or previously treated and stable brain metastases may participate in this study.

   a. Participants who have received definitive radiation or surgical treatment for symptomatic or unstable brain metastases and have been clinically stable and asymptomatic for at least 2 weeks before enrolment are eligible, provided they have been either off corticosteroid treatment or are stable or tapering doses below 4 mg of dexamethasone.
6. Patients with meningeal or leptomeningeal carcinomatosis.
7. Uncontrolled intercurrent illness including, but not limited to, active infection, cardiovascular disease, or psychiatric illness/social situations that would limit compliance with study requirements.
8. Positive hepatitis B (hepatitis B virus [HBV]) surface antigen (HBsAg). Note: Subjects with a prior history of HBV demonstrated by positive hepatitis B core antibody are eligible if they have at Screening 1) a negative HBsAg and 2) an HBV DNA (viral load) below the lower limit of quantification, per local testing.
9. Positive hepatitis C antibody (anti-HCV). Note: Subjects with a prior history of HCV, who have completed antiviral treatment and have subsequently documented HCV RNA below the lower limit of quantification per local testing are eligible.
10. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class III or greater), myocardial infarction within 3 months prior to Cycle 1, Day 1, unstable angina or unstable clinically meaningful arrhythmias.
11. Another primary malignancy other than disease under study within 2 years prior to Cycle 1 Day 1, unless consider at low risk of relapse at Investigator discretion.
12. Contraindications included in the product information of the drugs used in the study.

Other protocol specified criteria for each module. The study center will determine if criteria for participation are met.