Rational Therapeutics Based on Matched Tumor and Normal Tissue

If you agree to take part in this study, your tumor tissue and blood samples will be tested
for molecular profiling. Molecular profiling is the classification of tissue based on the
expression of certain genes within a tumor compared to normal tissue. This may be used to
predict how the tumor responds to therapy. Your doctor may use the results of the molecular
profiling to help decide which treatment might be the most beneficial for the disease.

Study Procedures:

Blood (about 2 teaspoons) will be drawn and you will have a tumor biopsy and a biopsy of
normal tissue when you enroll in this study. Blood (about 2 teaspoons) will be drawn again
about 2-3 weeks after you begin treatment. The type of biopsy you have will depend on the
type of disease you have. The risks of this procedure will be discussed in more detail with
you.

If there is not enough tissue with which the study doctor can perform the study tests
(described below), you may need to have a second biopsy. The study staff will discuss this
with you if it is needed.

Treatment Arms:

A series of tests to find which gene mutations you have, if any, will be performed. Depending
on the results of your molecular testing, you may be enrolled on 1 of 2 arms.

If your molecular profile shows that you have a gene mutation that may benefit from study
drugs that are believed to target your gene mutation, you will be enrolled in Arm A and will
receive these targeted drugs.

If your molecular profile shows that you do not have a gene mutation, you will be enrolled in
Arm B. In Arm B, the doctor will choose a therapy based on other studies rather than gene
mutation.

Length of Study:

This study will last about 2 years. Your participation on this study will be complete after
the last blood draw and tumor biopsy is collected.

Inclusion Criteria:

1. Informed consent

2. Any histologic type of metastatic cancer, (except for lung and brain at US sites), in
which histologic normal counterpart can be obtained. See list of cancer types included
in the trial in Appendix 1.

3. Progression by RECIST (Response Evaluation Criteria In Solid Tumors) or other criteria
on at least one prior regimen for advanced disease

4. Ability to undergo a biopsy or surgical procedure to obtain fresh tumor biopsy paired
with its normal counterpart

5. Age from 18 years

6. Life expectancy of at least 3 months

7. ECOG Performance status of 0 to 1

8. Measurable or evaluable disease according to RECIST 1.1 criteria

9. For US sites only: advanced cancer patients that have exhausted all effective therapy
for their disease and have progressed after previous line of therapy (documented
disease progression under last treatment received) and conventional methods of
assigning new therapy would not be expected to increase survival by more than 3
months.

Exclusion Criteria:

1. For US sites only: Any patient that might require a lung or brain biopsy are excluded

2. Alteration of organ function or hematopoietic function as defined by the following
criteria:

1. Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) >2.5 x
upper limit of normal (ULN), except for patients with liver metastases, for which
AST and ALT > 5.0 ULN is the exclusion criteria.

2. Bilirubin > 2.0 ULN to allow for Gilberts

3. Polynuclear neutrophil < 1.5 x 109/L

4. Platelets < 100 x 10 9/L

5. Hemoglobin < 90 g/L

6. Creatinine > 1.5 ULN

i. Calcemia > 1.5 ULN g. Phosphatemia > 1.5 ULN

3. Coagulation abnormality prohibiting a biopsy

4. Symptomatic or progressive brain metastases detected by radio imaging, or meningeal

5. Patient who received a personalized therapeutic treatment based on molecular anomaly
during the treatment period immediately prior to the WINTHER directed treatment
(defining the PFS1). Hormonal therapy may be continued during WINTHER suggested
therapy. The exclusion of prior matched targeted therapy includes but is not limited
to all targeted therapeutics that are EMA approved and genomically matched to
patients. If there are questions about whether or not a prior therapy is a matched
targeted treatment it will be agreed on by discussion between PIs who are also
Clinical Management Committee members; the resolution should take place prior to
starting Winther directed treatment.