The Drug Rediscovery Protocol (DRUP Trial)

Cancer Clinical Trial

— DRUP  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02925234
• Other study ID #: M15DRU
• Status: Recruiting
• Phase: Phase 2
• Start date: August 2016
• Est. completion date: December 2027

Study information

• Verified date: January 2024
• Source: The Netherlands Cancer Institute
• Contact: E.E. Voest, prof.
• Phone: 0031205129111
• Email: DRUP[@]nki.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1550
• Est. completion date: December 2027
• Est. primary completion date: September 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cancer
• Neoplasia
• Neoplasm
• Neoplasms
• Tumors

Intervention

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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Niraparib
Niraparib 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 niraparib might be expected based on their molecular tumor profile.
• Pemigatinib
Pemigatinib 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 pemigatinib might be expected based on their molecular tumor profile.
• Selpercatinib
Selpercatinib 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 selpercatinib might be expected based on their molecular tumor profile.
• Tepotinib
Tepotinib 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 tepotinib might be expected based on their molecular tumor profile.

Locations

Country	Name	City	State
Netherlands	Noordwest ziekenhuisgroep Alkmaar (NWZ)	Alkmaar
Netherlands	Ziekenhuisgroep Twente	Almelo
Netherlands	Meander medisch centrum	Amersfoort
Netherlands	Amsterdam UMC, locatie AMC	Amsterdam
Netherlands	Amsterdam UMC, locatie VUmc	Amsterdam
Netherlands	Netherlands Cancer Institute	Amsterdam
Netherlands	Onze Lieve Vrouwe Gasthuis (OLVG)	Amsterdam
Netherlands	Gelre ziekenhuizen	Apeldoorn
Netherlands	Rijnstate ziekenhuis	Arnhem
Netherlands	Amphia Ziekenhuis	Breda
Netherlands	Reiner de Graaf Gasthuis	Delft
Netherlands	Haaglanden medisch centrum	Den Haag
Netherlands	Haga ziekenhuis	Den Haag
Netherlands	Deventer ziekenhuis	Deventer
Netherlands	Nij Smellinghe Ziekenhuis	Drachten
Netherlands	Ziekenhuis Gelderse Vallei	Ede
Netherlands	Maxima Medisch Centrum	Eindhoven
Netherlands	Zuyderland medisch centrum	Geleen
Netherlands	Rivas zorggroep	Gorinchem
Netherlands	Martini ziekenhuis	Groningen
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Spaarne gasthuis	Haarlem
Netherlands	Tergooi MC	Hilversum
Netherlands	Treant zorggroep	Hoogeveen
Netherlands	Medisch Centrum Leeuwaarden	Leeuwarden
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Maastricht University Medical Center	Maastricht
Netherlands	St. Antonius ziekenhuis	Nieuwegein
Netherlands	Radboud umc	NIjmegen
Netherlands	Bravis ziekenhuis	Roosendaal
Netherlands	Erasmus MC	Rotterdam
Netherlands	St. Fransicus Gasthuis	Rotterdam
Netherlands	Elisabeth-TweeSteden Ziekenhuis	Tilburg
Netherlands	University Medical Center Utrecht	Utrecht
Netherlands	VieCuri medisch centrum	Venlo
Netherlands	Isala klinieken	Zwolle

Sponsors (19)

Lead Sponsor	Collaborator
The Netherlands Cancer Institute	Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology - Pharma and, Dutch Cancer Society, Eisai Inc., Eli Lilly and Company, GlaxoSmithKline, Incyte Corporation, Ipsen, Janssen, LP, Merck Sharp & Dohme LLC, Novartis, Pfizer, Roche Pharma AG, Stelvio for Life

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Concordance between pre-treatment and historic mutational tumor profile	Sequencing results of fresh pre-treatment biopsies will be available within 2 months after treatment initiation.	2 months after treatment initiation (estimated average)
Primary	Percentage of patients that are treated based on their molecular tumor profile	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.	6 months after treatment initiation (estimated average)
Primary	Objective tumor response	Primary outcome measure 2 is the proportion of study participants with an objective tumor response upon study treatment..	6 months after treatment initiation (estimated average)
Primary	Stable disease	Primary outcome measure 3 is the proportion of study participants that has stable disease (SD) during study treatment.	6 months after treatment initiation (estimated average)
Primary	Treatment-related grade=3 and serious adverse events	Primary outcome measure 4 is the proportion of patients that experience treatment-related grade=3 and /or serious adverse events.	6 months after treatment initiation (estimated average)
Secondary	Progression-free survival		Up to 1 year after study completion
Secondary	Overall survival		Up to 1 year after study completion
Secondary	Duration of treatment on study (time on drug)		6 months after treatment initiation (estimated average)