The Drug Rediscovery Protocol (DRUP Trial)

Phase 2

Recruiting

• Conditions: Cancer; Tumors; Neoplasm; Neoplasia
• Interventions: Drug: Panitumumab; Drug: Olaparib; Drug: Crizotinib; Drug: Erlotinib; Drug: Alectinib; Drug: Ipilimumab and nivolumab; Drug: Sunitinib; Drug: Trastuzumab and Pertuzumab (combination treatment); Drug: Vemurafenib and Cobimetinib (combination treatment); Drug: Nivolumab; Drug: Dabrafenib and trametinib; Drug: Selpercatinib; Drug: Tepotinib; Drug: Abemaciclib; Drug: Erdafitinib; Drug: Atezolizumab and Bevacizumab; Drug: Dacomitinib; Drug: Dabrafenib; Drug: Nilotinib; Drug: Trametinib; Drug: Vismodegib; Drug: Regorafenib; Drug: Afatinib; Drug: Ribociclib; Drug: Lenvatinib; Drug: Pembrolizumab; Drug: Durvalumab; Drug: Rucaparib; Drug: Axitinib; Drug: Palbociclib; Drug: Cabozantinib; Drug: Entrectinib; Drug: Talazoparib; Drug: Lorlatinib; Drug: Alpelisib; Drug: Niraparib; Drug: Pemigatinib

• Registration Number: NCT02925234
• Lead Sponsor: The Netherlands Cancer Institute

Brief Summary

This is a prospective, non-randomized clinical trial that aims to describe the efficacy and toxicity of commercially available, targeted anticancer drugs\* prescribed for treatment of patients with advanced cancer with a potentially actionable variant as revealed by a genomic or protein expression test. The study also aims to simplify patient access to approved targeted therapies that are contributed to the program by collaborating pharmaceutical companies and to perform next generation sequencing on tumor biopsies for biomarker analyses. Eligible patients have an advanced solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma for which standard treatment options are no longer available and acceptable performance status and organ function. A genomic or protein expression test must have been performed on the tumor and the results must identify at least one potentially actionable molecular variant as defined in the protocol. Results from the molecular profiling test will be used to determine an appropriate drug(s) from among those available in the protocol. The choice of drug will be supported by a list of potential profiles, a molecular tumor board, a knowledge library and by study coordinators for review and approval of the match. The protocol-specified treatment will be administered to the patient once any drug-specific eligibility criteria are confirmed and a fresh pre-treatment biopsy is performed for future genetic studies. All patients who receive treatment with a drug available in the protocol will be followed for standard efficacy outcomes including tumor response, progression-free and overall survival as well as duration of treatment. In addition, treatment related toxicity will be evaluated.

Detailed Description

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.

Study Timeline

• Study Start: 2016-08
• Study First Submitted: 2016-08-26
• Study First Submitted QC: 2016-10-04
• Study First Posted: 2016-10-05
• Status Verified: 2024-01
• Last Update Submitted: 2024-01-22
• Last Update Posted: 2024-01-24
• Primary Completion: 2027-09
• Study Completion: 2027-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1550

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 lymphomawith 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:

   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 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).

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. 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:

   1. 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)
   2. 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.

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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 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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Percentage of patients that are treated based on their molecular tumor profile	6 months after treatment initiation (estimated average)	Primary outcome measure 1 is the percentage of submitted patients, that can be treated based on their molecular tumor profile within the context of this protocol.
Objective tumor response	6 months after treatment initiation (estimated average)	Primary outcome measure 2 is the proportion of study participants with an objective tumor response upon study treatment..
Treatment-related grade≥3 and serious adverse events	6 months after treatment initiation (estimated average)	Primary outcome measure 4 is the proportion of patients that experience treatment-related grade≥3 and /or serious adverse events.
Stable disease	6 months after treatment initiation (estimated average)	Primary outcome measure 3 is the proportion of study participants that has stable disease (SD) during study treatment.

Secondary Outcome Measures

Name	Time	Method
Progression-free survival	Up to 1 year after study completion
Overall survival	Up to 1 year after study completion
Duration of treatment on study (time on drug)	6 months after treatment initiation (estimated average)

Trial Locations

Locations (36)

Meander medisch centrum; 🇳🇱 Amersfoort, Netherlands

Netherlands Cancer Institute; 🇳🇱 Amsterdam, Netherlands

Amsterdam UMC, locatie AMC; 🇳🇱 Amsterdam, Netherlands

Noordwest ziekenhuisgroep Alkmaar (NWZ); 🇳🇱 Alkmaar, Netherlands

Onze Lieve Vrouwe Gasthuis (OLVG); 🇳🇱 Amsterdam, Netherlands

Gelre ziekenhuizen; 🇳🇱 Apeldoorn, Netherlands

Rijnstate ziekenhuis; 🇳🇱 Arnhem, Netherlands

Haga ziekenhuis; 🇳🇱 Den Haag, Netherlands

Amphia Ziekenhuis; 🇳🇱 Breda, Netherlands

Nij Smellinghe Ziekenhuis; 🇳🇱 Drachten, Netherlands

Reiner de Graaf Gasthuis; 🇳🇱 Delft, Netherlands

Maxima Medisch Centrum; 🇳🇱 Eindhoven, Netherlands

Spaarne gasthuis; 🇳🇱 Haarlem, Netherlands

Treant zorggroep; 🇳🇱 Hoogeveen, Netherlands

Elisabeth-TweeSteden Ziekenhuis; 🇳🇱 Tilburg, Netherlands

Isala klinieken; 🇳🇱 Zwolle, Netherlands

Tergooi MC; 🇳🇱 Hilversum, Netherlands

Ziekenhuis Gelderse Vallei; 🇳🇱 Ede, Netherlands

Radboud umc; 🇳🇱 NIjmegen, Netherlands

St. Fransicus Gasthuis; 🇳🇱 Rotterdam, Netherlands

Maastricht University Medical Center; 🇳🇱 Maastricht, Netherlands

Erasmus MC; 🇳🇱 Rotterdam, Netherlands

Bravis ziekenhuis; 🇳🇱 Roosendaal, Netherlands

VieCuri medisch centrum; 🇳🇱 Venlo, Netherlands

Ziekenhuisgroep Twente; 🇳🇱 Almelo, Netherlands

Amsterdam UMC, locatie VUmc; 🇳🇱 Amsterdam, Netherlands

Haaglanden medisch centrum; 🇳🇱 Den Haag, Netherlands

Deventer ziekenhuis; 🇳🇱 Deventer, Netherlands

Zuyderland medisch centrum; 🇳🇱 Geleen, Netherlands

Rivas zorggroep; 🇳🇱 Gorinchem, Netherlands

Martini ziekenhuis; 🇳🇱 Groningen, Netherlands

University Medical Center Groningen; 🇳🇱 Groningen, Netherlands

St. Antonius ziekenhuis; 🇳🇱 Nieuwegein, Netherlands

Medisch Centrum Leeuwaarden; 🇳🇱 Leeuwarden, Netherlands

Leiden University Medical Center; 🇳🇱 Leiden, Netherlands

University Medical Center Utrecht; 🇳🇱 Utrecht, Netherlands