The Drug Rediscovery Protocol (DRUP Trial)

Problem description: evidence is building that matching targeted agents to tumor characteristics can improve outcomes. Such reports have fueled interest among patients and physicians to use molecular testing for treatment planning when standard treatment options have been exhausted. When oncologists aim to provide such personalized treatment to their patients though, obtaining the drugs can be challenging since off-label prescribing, while legal, is generally not reimbursed by insurance companies. Furthermore, outcomes of off-label treatment in routine clinical practice are not systematically recorded. As a result, the research and clinical communities have limited insight in these outcomes, leading to repetitive use of ineffective treatment for some tumor types, while effective treatment strategies might be missed for others. The latter is especially relevant for 'orphan diseases', that are too rare to conduct formal phase II and III trials. In summary, there is a lack of access to potentially effective therapy on one hand, and a lack of knowledge on broader use of such therapies on the other, altogether leading to sub-optimal use of available resources.

Envisioned solution and study aim: creation of a drug-access program, in which patients are treated with registered targeted therapy matched to their molecular tumor profile, and in which the outcomes of such therapies are recorded systematically, per tumor profile and tumor type (this is important since it is becoming increasingly clear that the tissue of origin is an important determinant of outcome of genetic abnormalities). We hereby aim to improve and broaden the use of registered targeted therapy, whilst facilitating patient access to such therapy.

Plan of investigation: patients will be treated with approved targeted agents, selected based on results of a molecular profiling test of the patient's tumor. Eligible patients will have exhausted standard treatment options, and their tumor must harbor a potentially actionable molecular variant as defined in the protocol. The study will provide a tumor board to help physicians understand the profiling test results and treatment options, and will enable insights about the utility of this approach. In addition, next generation sequencing will be performed on fresh tumor biopsies for additional biomarker discovery. Patients from the Netherlands and the USA will be included in two similar though independent protocols (DRUP and TAPUR), allowing data-exchange and empowering of both trials.

Expected outcome: early signs of clinical activity of approved drugs outside their label, providing effective personalized treatment options, improved patient outcomes and access to targeted therapy.

• Cancer
• Tumors
• Neoplasm
• Neoplasia

• Drug: Panitumumab
  Panitumumab treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of panitumumab might be expected based on their molecular tumor profile.
  Other Name: Vectibix
• Drug: Olaparib
  Olaparib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of olaparib might be expected based on their molecular tumor profile.
  Other Name: Lynparza
• Drug: Dabrafenib
  Dabrafenib treatment for patients with an mutated advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of dabrafenib might be expected based on their molecular tumor profile.
  Other Name: Tafinlar
• Drug: Nilotinib
  Nilotinib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of nilotinib might be expected based on their molecular tumor profile.
  Other Name: Tasigna
• Drug: Trametinib
  Trametinib treatment for patients with an mutated advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of trametinib might be expected based on their molecular tumor profile.
  Other Name: Mekinist
• Drug: Erlotinib
  Erlotinib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of erlotinib might be expected based on their molecular tumor profile.
  Other Name: Tarceva
• Drug: Trastuzumab and Pertuzumab (combination treatment)
  Trastuzumab and Pertuzumab treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of trastuzumab + pertuzumab might be expected based on their molecular tumor profile.
  Other Name: Herceptin + Perjeta
• Drug: Vemurafenib and Cobimetinib (combination treatment)
  Vemurafenib + Cobimetinib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of Vemurafenib + Cobimetinib might be expected based on their molecular tumor profile.
  Other Name: Zelboraf + Cotellic
• Drug: Vismodegib
  Vismodegib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of vismodegib might be expected based on their molecular tumor profile.
  Other Name: Erivedge
• Drug: Regorafenib
  Regorafenib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of vismodegib might be expected based on their molecular tumor profile.
  Other Name: Stivarga
• Drug: Nivolumab
  Nivolumab treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of nivolumab might be expected based on their molecular tumor profile.
  Other Name: Opdivo
• Drug: Afatinib
  Afatinib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of Afatinib might be expected based on their molecular tumor profile.
  Other Name: Giotrif
• Drug: Dabrafenib and trametinib
  Dabrafenib + trametinib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of Dabrafenib + Trametinib might be expected based on their molecular tumor profile.
  Other Name: Tafinlar and Mekinist
• Drug: Ribociclib
  Ribociclib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of Ribociclib might be expected based on their molecular tumor profile.
  Other Name: Kisqali
• Drug: Lenvatinib
  Lenvatinib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of Lenvatinib might be expected based on their molecular tumor profile.
  Other Name: Lenvima
• Drug: Pembrolizumab
  Pembrolizumab treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of Pembrolizumab might be expected based on their molecular tumor profile.
  Other Name: Keytruda
• Drug: Durvalumab
  Durvalumab treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of Durvalumab might be expected based on their molecular tumor profile.
  Other Name: MEDI4736
• Drug: Rucaparib
  Rucaparib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of Rucaparib might be expected based on their molecular tumor profile.
  Other Name: Rubraca
• Drug: Axitinib
  Axitinib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of Axitinib might be expected based on their molecular tumor profile.
  Other Name: Inlyta
• Drug: Palbociclib
  Palbociclib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of Palbociclib might be expected based on their molecular tumor profile.
  Other Name: Ibrance
• Drug: Crizotinib
  Crizotinib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of Crizotinib might be expected based on their molecular tumor profile.
  Other Name: Xalkori
• Drug: Sunitinib
  Sunitinib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of Sunitinib might be expected based on their molecular tumor profile.
  Other Name: Sutent
• Drug: Cabozantinib
  Cabozantinib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of Cabozantinib might be expected based on their molecular tumor profile.
• Drug: Abemaciclib
  Abemaciclib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of Abemaciclib might be expected based on their molecular tumor profile.
• Drug: Alectinib
  Alectinib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of Alectinib might be expected based on their molecular tumor profile.
• Drug: Atezolizumab and Bevacizumab
  Atezolizumab + Bevacizumab treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of Atezolizumab + Bevacizumab might be expected based on their molecular tumor profile.
• Drug: Ipilimumab and nivolumab
  Ipilimumab+nivolumab treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of ipilimimab + nivolumab might be expected based on their molecular tumor profile.
• Drug: Entrectinib
  Entrectinib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of entrectinib might be expected based on their molecular tumor profile.
• Drug: Talazoparib
  Talazoparib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of talazoparib might be expected based on their molecular tumor profile.
• Drug: Dacomitinib
  Dacomitinib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of dacomitinib might be expected based on their molecular tumor profile.
• Drug: Lorlatinib
  Lorlatinib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of lorlatinib might be expected based on their molecular tumor profile.
• Drug: Erdafitinib
  Erdafitinib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of erdafitinib might be expected based on their molecular tumor profile.
• Drug: Alpelisib
  Alpelisib treatment for patients with an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma, who are not eligible for on-label treatment but for whom anti-tumor activity of alpelisib might be expected based on their molecular tumor profile.

• Experimental: Panitumumab
  Panitumumab for patients with a molecular tumor profile that can potentially be targeted by Panitumumab.
  Intervention: Drug: Panitumumab
• Experimental: Olaparib
  Olaparib for patients with a molecular tumor profile that can potentially be targeted by Olaparib.
  Intervention: Drug: Olaparib
• Experimental: Dabrafenib
  Dabrafenib for patients with a molecular tumor profile that can potentially be targeted by Dabrafenib.
  Intervention: Drug: Dabrafenib
• Experimental: Nilotinib
  Nilotinib for patients with a molecular tumor profile that can potentially be targeted by nilotinib.
  Intervention: Drug: Nilotinib
• Experimental: Trametinib
  Trametinib for patients with a molecular tumor profile that can potentially be targeted by trametinib.
  Intervention: Drug: Trametinib
• Experimental: Erlotinib
  Erlotinib for patients with a molecular tumor profile that can potentially be targeted by erlotinib.
  Intervention: Drug: Erlotinib
• Experimental: Trastuzumab & Pertuzumab (combination)
  Trastuzumab and Pertuzumab (combination treatment) for patients with a molecular tumor profile that can potentially be targeted by Trastuzumab and Pertuzumab.
  Intervention: Drug: Trastuzumab and Pertuzumab (combination treatment)
• Experimental: Vemurafenib & Cobimetinib (combination)
  Vemurafenib and Cobimetinib (combination treatment) for patients with a molecular tumor profile that can potentially be targeted by Vemurafenib and Cobimetinib.
  Intervention: Drug: Vemurafenib and Cobimetinib (combination treatment)
• Experimental: Vismodegib
  Vismodegib for patients with a molecular tumor profile that can potentially be targeted by vismodegib.
  Intervention: Drug: Vismodegib
• Experimental: Regorafenib
  Regorafenib for patients with a molecular tumor profile that can potentially be targeted by regorafenib.
  Intervention: Drug: Regorafenib
• Experimental: Nivolumab
  Nivolumab for patients with a molecular tumor profile that can potentially be targeted by nivolumab.
  Intervention: Drug: Nivolumab
• Experimental: Afatinib
  Afatinib for patients with a molecular tumor profile that can potentially be targeted by Afatinib.
  Intervention: Drug: Afatinib
• Experimental: Dabrafenib & trametinib (combination)
  Dabrafenib and trametinib (combination treatment) for patients with a molecular tumor profile that can potentially be targeted by Dabrafenib and trametinib.
  Intervention: Drug: Dabrafenib and trametinib
• Experimental: Ribociclib
  Ribociclib for patients with a molecular tumor profile that can potentially be targeted by Ribociclib.
  Intervention: Drug: Ribociclib
• Experimental: Lenvatinib
  Lenvatinib for patients with a molecular tumor profile that can potentially be targeted by Lenvatinib.
  Intervention: Drug: Lenvatinib
• Experimental: Pembrolizumab
  Pembrolizumab for patients with a molecular tumor profile that can potentially be targeted by Pembrolizumab.
  Intervention: Drug: Pembrolizumab
• Experimental: Durvalumab
  Durvalumab for patients with a molecular tumor profile that can potentially be targeted by Durvalumab.
  Intervention: Drug: Durvalumab
• Experimental: Rucaparib
  Rucaparib for patients with a molecular tumor profile that can potentially be targeted by Rucaparib.
  Intervention: Drug: Rucaparib
• Experimental: Axitinib
  Axitinib for patients with a molecular tumor profile that can potentially be targeted by Axitinib.
  Intervention: Drug: Axitinib
• Experimental: Palbociclib
  Palbociclib for patients with a molecular tumor profile that can potentially be targeted by Palbociclib.
  Intervention: Drug: Palbociclib
• Experimental: Crizotinib
  Crizotinib for patients with a molecular tumor profile that can potentially be targeted by Crizotinib.
  Intervention: Drug: Crizotinib
• Experimental: Sunitinib
  Sunitinib for patients with a molecular tumor profile that can potentially be targeted by Sunitinib.
  Intervention: Drug: Sunitinib
• Experimental: Cabozantinib
  Cabozantinib for patients with a molecular tumor profile that can potentially be targeted by Cabozantinib.
  Intervention: Drug: Cabozantinib
• Experimental: Abemaciclib
  Abemaciclib for patients with a molecular tumor profile that can potentially be targeted by Abemaciclib.
  Intervention: Drug: Abemaciclib
• Experimental: Alectinib
  Alectinib for patients with a molecular tumor profile that can potentially be targeted by Alectinib.
  Intervention: Drug: Alectinib
• Experimental: Atezolizumab/bevacizumab
  Atezolizumab and bevacizumab (combination treatment) for patients with a molecular tumor profile that can potentially be targeted by Atezolizumab and bevacizumab.
  Intervention: Drug: Atezolizumab and Bevacizumab
• Experimental: Ipilimumab/nivolumab
  Ipilimumab and nivolumab (combination treatment) for patients with a molecular tumor profile that can potentially be targeted by Ipilimumab and nivolumab.
  Intervention: Drug: Ipilimumab and nivolumab
• Experimental: Entrectinib
  Entrectinib for patients with a molecular tumor profile that can potentially be targeted by entrectinib.
  Intervention: Drug: Entrectinib
• Experimental: Talazoparib
  Talazoparib for patients with a molecular tumor profile that can potentially be targeted by talazoparib.
  Intervention: Drug: Talazoparib
• Experimental: dacomitinib
  Dacomitinib for patients with a molecular tumor profile that can potentially be targeted by dacomitinib.
  Intervention: Drug: Dacomitinib
• Experimental: Lorlatinib
  Lorlatinib for patients with a molecular tumor profile that can potentially be targeted by lorlatinib.
  Intervention: Drug: Lorlatinib
• Experimental: Erdafitinib
  Erdafitinib for patients with a molecular tumor profile that can potentially be targeted by erdafitinib.
  Intervention: Drug: Erdafitinib
• Experimental: Alpelisib
  Alpelisib for patients with a molecular tumor profile that can potentially be targeted by alpelisib.
  Intervention: Drug: Alpelisib

Inclusion Criteria:

1. Adult (age >18 years) patient with a histologically-proven locally advanced or metastatic solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma who is no longer benefitting from standard anti-cancer treatment or for whom no such treatment is available or indicated.

   * For GBM patients: Histologically confirmed recurrent or de novo glioblastoma (primary), with unequivocal first progression after radiotherapy and concurrent/adjuvant chemotherapy, at least 3 months after the concomitant part of the chemo-radiotherapy, 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:

   1. Absolute neutrophil count ? 1.5 x 109/l
   2. Hemoglobin > 5.6 mmol/l
   3. Platelets > 75 x 109/l
   4. Total bilirubin < 2 x ULN
   5. AST (SGOT) and ALT (SGPT) < 2.5 x institutional ULN (or < 5 x ULN in patients with known hepatic metastases)
   6. 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) [16, 17].
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 single agent treatment with one of the EMA approved 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.

   *For GBM patients:

   The mandatory fresh frozen tumor biopsy sample can be obtained through standard-of-care surgical procedures (i.e., performed at progression, for cytoreduction, to proof progressive disease, or to reduce mass effect on the surrounding brain tissue). Thus, surgical procedures are standard-of-care and not part of trial participation. Fresh frozen tumor tissue must have been obtained ?2 months before inclusion, and without any type of anti-cancer therapy within those ?2 months. After surgical procedures, patients must meet the following inclusion criteria:

   i. Surgery must have confirmed the recurrence. ii. A post-surgery MRI should be available within 48 hours following surgery, and must show residual and measurable disease.

   iii. Craniotomy or intracranial biopsy site must be adequately healed free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of study inclusion.

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.

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) except for 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 glioblastoma patients:

   1. 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.
   2. No radiotherapy within the three months prior to the diagnosis of progression.
   3. 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.

• Amgen
• AstraZeneca
• Bayer
• Bristol-Myers Squibb
• Novartis
• Roche Pharma AG
• Merck Sharp & Dohme Corp.
• Boehringer Ingelheim
• Ipsen
• Eisai Inc.
• Pfizer
• Clovis Oncology, Inc.
• Eli Lilly and Company
• Janssen, LP