Clinical trial NCT02925234: The Drug Rediscovery Protocol (DRUP Trial)
Official title: A Dutch National Study on Behalf of the 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Cancer
Tumors
Neoplasm
Neoplasia
Keywords: Molecular tumor profile
Multidisciplinary tumor board
Antitumor drugs
Molecular Targeted Therapy
Drug Repositioning
Off-Label Use
Sequence Analysis, DNA
Lead sponsor: The Netherlands Cancer Institute
Sponsor class: OTHER
Collaborators: name: Amgen
name: AstraZeneca
name: Bayer
name: Bristol-Myers Squibb
name: Novartis
name: Roche Pharma AG
name: Merck Sharp & Dohme LLC
name: Boehringer Ingelheim
name: Ipsen
name: Eisai Inc.
name: Pfizer
name: Clovis Oncology - Pharma and
name: Eli Lilly and Company
name: Janssen, LP
name: GlaxoSmithKline
name: Incyte Corporation
name: Dutch Cancer Society
name: Stelvio for Life
First posted: 2016-10-05
Enrollment: 1550
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

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.

Primary outcomes:
measure: Percentage of patients that are treated based on their molecular tumor profile
timeFrame: 6 months after treatment initiation (estimated average)
measure: Objective tumor response
timeFrame: 6 months after treatment initiation (estimated average)
measure: Stable disease
timeFrame: 6 months after treatment initiation (estimated average)
measure: Treatment-related grade≥3 and serious adverse events
timeFrame: 6 months after treatment initiation (estimated average)
Secondary outcomes:
measure: Progression-free survival
timeFrame: Up to 1 year after study completion
measure: Overall survival
timeFrame: Up to 1 year after study completion
measure: Duration of treatment on study (time on drug)
timeFrame: 6 months after treatment initiation (estimated average)
Other outcomes:
measure: Concordance between pre-treatment and historic mutational tumor profile
timeFrame: 2 months after treatment initiation (estimated average)
Locations:
city: Alkmaar
country: Netherlands
facility: Noordwest ziekenhuisgroep Alkmaar (NWZ)
city: Almelo
country: Netherlands
facility: Ziekenhuisgroep Twente
city: Amersfoort
country: Netherlands
facility: Meander medisch centrum
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, locatie VUmc
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, locatie AMC
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwe Gasthuis (OLVG)
city: Apeldoorn
country: Netherlands
facility: Gelre ziekenhuizen
city: Arnhem
country: Netherlands
facility: Rijnstate ziekenhuis
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Delft
country: Netherlands
facility: Reiner de Graaf Gasthuis
city: Den Haag
country: Netherlands
facility: Haaglanden medisch centrum
city: Den Haag
country: Netherlands
facility: Haga ziekenhuis
city: Deventer
country: Netherlands
facility: Deventer ziekenhuis
city: Drachten
country: Netherlands
facility: Nij Smellinghe Ziekenhuis
city: Ede
country: Netherlands
facility: Ziekenhuis Gelderse Vallei
city: Eindhoven
country: Netherlands
facility: Maxima Medisch Centrum
city: Geleen
country: Netherlands
facility: Zuyderland medisch centrum
city: Gorinchem
country: Netherlands
facility: Rivas zorggroep
city: Groningen
country: Netherlands
facility: Martini ziekenhuis
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Haarlem
country: Netherlands
facility: Spaarne gasthuis
city: Hilversum
country: Netherlands
facility: Tergooi MC
city: Hoogeveen
country: Netherlands
facility: Treant zorggroep
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwaarden
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Nieuwegein
country: Netherlands
facility: St. Antonius ziekenhuis
city: NIjmegen
country: Netherlands
facility: Radboud umc
city: Roosendaal
country: Netherlands
facility: Bravis ziekenhuis
city: Rotterdam
country: Netherlands
facility: St. Fransicus Gasthuis
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Tilburg
country: Netherlands
facility: Elisabeth-TweeSteden Ziekenhuis
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
city: Venlo
country: Netherlands
facility: VieCuri medisch centrum
city: Zwolle
country: Netherlands
facility: Isala klinieken
Study officials:
affiliation: The Netherlands Cancer Institute
name: E.E. Voest, prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: van Berge Henegouwen JM, van der Wijngaart H, Zeverijn LJ, Hoes LR, Meertens M, Huitema ADR, Devriese LA, Labots M, Verheul HMW, Voest EE, Gelderblom H. Efficacy and toxicity of vemurafenib and cobimetinib in relation to plasma concentrations, after administration via feeding tube in patients with BRAF-mutated thyroid cancer: a case series and review of literature. Cancer Chemother Pharmacol. 2022 Jul;90(1):97-104. doi: 10.1007/s00280-022-04437-z. Epub 2022 May 22.
citation: Nakauma-Gonzalez JA, Rijnders M, van Riet J, van der Heijden MS, Voortman J, Cuppen E, Mehra N, van Wilpe S, Oosting SF, Rijstenberg LL, Westgeest HM, Zwarthoff EC, de Wit R, van der Veldt AAM, van de Werken HJG, Lolkema MPJ, Boormans JL. Comprehensive Molecular Characterization Reveals Genomic and Transcriptomic Subtypes of Metastatic Urothelial Carcinoma. Eur Urol. 2022 Apr;81(4):331-336. doi: 10.1016/j.eururo.2022.01.026. Epub 2022 Jan 25.