The Drug Rediscovery Protocol (DRUP trial)
A Dutch National Study on behalf of the Center for Personalized Cancer Treatment (CPCT) to Facilitate Patient Access to Commercially Available, Targeted Anti-cancer Drugs to determine the Potential Efficacy in Treatment of Advanced Cancers with a Known Molecular Profile

INCLUSION CRITERIA:
1. Adult (age >18 years) patient with a histologically-proven locally advanced
or metastatic solid tumor, multiple myeloma or non-Hodgkin lymphoma with
symptomatic disease progression or progression according to RECIST-criteria
after standard anti-cancer treatment or for whom no such treatment is available
or indicated.
For patients with a primary brain tumor:
Histologically confirmed recurrent or de novo primary brain tumor, with
unequivocal progression after prior therapy, at least 3 months 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 the
baseline MRI scan.
2. ECOG performance status 0-2
3. Patients must have acceptable organ function as defined below. However,
specific inclusion/exclusion criteria specified in the drug-specific study
manual will take precedence:
a. Absolute neutrophil count >= 1.5 x 109/l
b. Hemoglobin > 5.6 mmol/l
c. Platelets > 75 x 109/l
d. Total bilirubin < 2 x ULN
e. AST (SGOT) and ALT (SGPT) < 2.5 x institutional ULN (or < 5 x ULN in
patients with known hepatic metastases)
f. Serum creatinine <= 1.5 × ULN or calculated or measured creatinine clearance
>= 50 mL/min/1.73 m2
4. Patients must have objectively evaluable or measurable disease (by physical
or radiographic examination, according to RECIST v1.1 for patients with solid
tumors, or according to IMWG, 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) [15, 16].
5. Results must be available from a tumor genomic or protein expression test.
Eligible tests may include any of the following technologies: fluorescence in
situ hybridization (FISH), polymerase chain reaction (PCR), comparative genomic
hybridization (CGH), next generation sequencing (NGS) or immunohistochemistry
(IHC). The test may have been performed on the primary tumor or a metastatic
deposit, in a diagnostic laboratory or within the context of another CPCT
study, and must reveal a potentially actionable variant as defined in Section
5. The test results (full pathology or molecular diagnostics report) must be
uploaded in the eCRF.
6. Patients must have a tumor profile for which treatment with one of the FDA
and / or EMA approved (or under revision for approval) targeted anti-cancer
drugs included in this study has potential clinical benefit based on
preclinical data or clinical information (see section 5).
7. A new (obtained <=2 months before inclusion, and without any type of
anti-cancer therapy within those <=2 months) fresh frozen tumor biopsy specimen
for extensive biomarker testing is mandatory before the start of treatment with
a targeted agent included in the protocol. Alternatively, fresh frozen tumor
tissue acquired in the context of a standard care procedure may be used,
provided that no systemic anti-cancer treatment was 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
mandatory DRUP pre-treatment biopsy for biomarker analysis cannot safely be
obtained:
i) The fresh frozen tumor biopsy sample may be replaced by fresh frozen tumor
tissue, obtained earlier from recurrent disease, as part of standard of care
surgical procedure (i.e., performed at progression)
ii) If no fresh frozen tumor tissue is available for NGS, and the risk of
obtaining a new tumor biopsy is considered too high, no biopsy will be
required. In this case, the study coordinators must be informed in advance, and
there will be no reimbursement for the biopsy procedure.
b. In case WGS is performed on tumor tissue outside the context of a clinical
trial before inclusion, and without any type of anti-cancer therapy between the
collection of 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 analysis in DRUP.
c. An exception is made for patients that underwent an allogeneic hematopoietic
stem cell transplantation prior to study enrollment, since this will prevent a
correct WGS analysis due to a mismatch between the biopsy specimen and the
required blood sample.
8. Ability to understand and the willingness to sign a written informed consent
document.
9. For orally administered drugs, the patient must be able to swallow and
tolerate oral medication and must have no known malabsorption syndrome.10.
Because of the risks of drug treatment to the developing foetus, women of
child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) for the duration of
study participation, and for four months following completion of study
therapy. Male patients should avoid impregnating a female partner. Male
patients, even if surgically sterilized, (i.e. post-vasectomy) must agree to
one of the following: practice effective barrier contraception during the
entire study treatment period and through 4 months after the last dose of study
drug, or completely abstain from sexual intercourse.

For each drug included in this protocol, specific inclusion and exclusion
criteria (based on the Package Insert or manufacturers recommendations) may
also apply. These can be found in the supplemental information about each agent
included in the drug-specific study manuals. Drug-specific inclusion and
exclusion criteria will take precedence over the inclusion/exclusion criteria
listed above.

EXCLUSION CRITERIA:
1. Ongoing toxicity > grade 2, other than alopecia.
2. Patient is receiving any other anti-cancer therapy (cytotoxic, biologic,
radiation, or hormonal other than for replacement). Required wash out period
prior to starting study treatment is at least two weeks. An exception is made
for:
• Patients suffering from CRPC are allowed to continue androgen deprivation
therapy.
• Medications that are prescribed for supportive care but may potentially have
an anti-cancer effect (e.g., megestrol acetate, bisphosphonates). These
medications must 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
previously treated brain metastases are eligible, provided that the patient has
not experienced a seizure or had a clinically significant change in
neurological status within the 3 months prior to registration. All patients
with previously treated brain metastases must be stable for at least 1 month
after completion of treatment and off steroid treatment prior to study
enrollment.
Additional exclusion criteria specific for GBM patients:
a. Patients who require anti-convulsant therapy must be taking non-enzyme
inducing antiepileptic drugs (non-EIAED). EIAED are prohibited. Patients
previously on EIAED must be switched to non-EIAED at least 2 weeks prior to
randomization.
b. No radiotherapy within the three months prior to the diagnosis of
progression.
c. No radiotherapy with a dose over 65 Gy, stereotactic radiosurgery or
brachytherapy unless the recurrence is histologically proven.
5. Patients with clinically significant preexisting cardiac conditions,
including uncontrolled or symptomatic angina, uncontrolled atrial or
ventricular arrhythmias, or symptomatic congestive heart failure are not
eligible.
6. Patients with known left ventricular ejection fraction (LVEF) < 40% are not
eligible
7. Patients with stroke (including TIA) or acute myocardial infarction within 3
months before the first dose of study treatment are not eligible
8. Patients with any other clinically significant medical condition which, in
the opinion of the treating physician, makes it undesirable for the patient to
participate in the study or which could jeopardize compliance with study
requirements including, but not limited to: ongoing or active infection,
significant uncontrolled hypertension, or severe psychiatric illness/social
situations.

For each drug included in this protocol, specific inclusion and exclusion
criteria (based on the Package Insert or manufacturers recommendations) may
also apply. These can be found in the supplemental information about each agent
included in the drug-specific study manuals. Drug-specific inclusion and
exclusion criteria will take precedence over the inclusion/exclusion criteria
listed above.