Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT01791387




Registration number
NCT01791387
Ethics application status
Date submitted
8/01/2013
Date registered
15/02/2013
Date last updated
3/02/2015

Titles & IDs
Public title
1st-line Activity of Dovitinib and Correlation With Genetic Changes in RCC
Scientific title
Dovitinib In 1st-Line Renal Cell Carcinoma, an Investigation Into Tumour GENe Status and Correlation With Efficacy - 1st Exploratory Study
Secondary ID [1] 0 0
ACTRN12612000140853
Secondary ID [2] 0 0
CTKI258AAU02T
Universal Trial Number (UTN)
Trial acronym
DILIGENCE-1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Clear Cell Renal Cell Carcinoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Non melanoma skin cancer
Cancer 0 0 0 0
Kidney

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Dovitinib

Experimental: Dovitinib - Dovitinib 500 mg taken orally once daily 5 days on / 2 days off, until disease progression


Treatment: Drugs: Dovitinib
Patients will be treated with dovitinib (500 mg orally, once daily 5 days on/2 days off) until disease progression, intolerability, patient refusal, death or study drug discontinuation for any other reason. Dovitinib should be ingested at least 1 hour prior to a meal or at least 2 hours following a meal at approximately the same time each day.
If patients cannot tolerate the protocol-specified dosing schedule, dose reductions or treatment interruptions are permitted. When necessary, dovitinib may be reduced to 400 mg for 5 days on/2 days off. If an additional dose reduction is required, dovitinib may be reduced to 300 mg dose 5 days on/2 days off. Once dose is reduced due to an adverse event, it cannot be re-escalated. Patients are allowed only 2 dose reductions.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression-free survival (PFS) as assessed by RECIST 1.1.
Timepoint [1] 0 0
From baseline until documented disease progression, estimated to be up to 65 weeks
Secondary outcome [1] 0 0
Response rate (RR) using RECIST 1.1.
Timepoint [1] 0 0
Change from baseline until disease progression, estimated to be up to 65 weeks
Secondary outcome [2] 0 0
Proportion of subjects who are FGFR-1,-2,-3 amplified using gene analysis by Fluorescent in-situ hybridization
Timepoint [2] 0 0
Baseline
Secondary outcome [3] 0 0
Efficacy (PFS, RR, OS) by FGFR gene amplification status as measured by Spearman's rho correlation coefficient
Timepoint [3] 0 0
Baseline until documented disease progression, estimated to be up to 65 weeks
Secondary outcome [4] 0 0
Safety profile of dovitinib (specifically in this first-line patient population) using NCI CTCAE v4.0
Timepoint [4] 0 0
8 months
Secondary outcome [5] 0 0
Safety profile of dovitinib (specifically in this first-line patient population) using NCI CTCAE v4.0
Timepoint [5] 0 0
Baseline until documented disease progression, estimated to be up to 65 weeks
Secondary outcome [6] 0 0
Proportion of subjects who are FGFR-1,-2,-3 amplified using gene analysis by Fluorescent in-situ hybridization
Timepoint [6] 0 0
Disease progression, estimated to be up to 65 weeks.
Secondary outcome [7] 0 0
Safety profile of dovitinib (specifically in this first-line patient population) using NCI CTCAE v4.0
Timepoint [7] 0 0
12 months
Secondary outcome [8] 0 0
Safety profile of dovitinib (specifically in this first-line patient population) using NCI CTCAE v4.0
Timepoint [8] 0 0
24 months
Secondary outcome [9] 0 0
Safety profile of dovitinib (specifically in this first-line patient population) using NCI CTCAE v4.0
Timepoint [9] 0 0
From documented disease progression up to 2 years.

Eligibility
Key inclusion criteria
- Advanced renal cell (clear cell) carcinoma confirmed histologically, including either
distant metastases or locally advanced disease that is not resectable or potentially
resectable following response. Sarcomatoid change is allowed if clear cell
predominant. Histological variants, papillary, chromophobe and collecting duct
carcinoma are not allowed.

- Availability of FFPE tissue for gene status analysis. If unavailable, an image-guided
biopsy of a metastatic disease site is required.

- Evaluable disease by RECIST 1.1 criteria

- ECOG (WHO) performance status 0 or 1

- Age = 18 years

- Absolute neutrophil count = 1.5 x 109/L; platelets = 100 x 109/L; haemoglobin > 9
g/dL; serum total bilirubin = 1.5 x ULN; ALT and AST = 3.0 x ULN; serum creatinine =
1.5 x ULN or creatinine clearance >35 ml/min by Cockcroft and Gault.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Uncontrolled brain metastases. For know brain metastases, definitive treatment with
either surgery, stereotactic radiotherapy or whole brain radiotherapy is required.
Patients must be neurologically stable for > 4 weeks after CNS treatment ends, and
either be off corticosteroids or receiving a low daily dose.

- Another primary malignancy within 3 years prior to starting study treatment, except
for adequately treated basal cell carcinoma, squamous cell carcinoma or other
non-melanomatous skin cancer, or in-situ carcinoma of the uterine cervix. If another
primary tumour was noted within this period, a metastatic disease site biopsy is
required to confirm renal origin.

- Prior systemic anticancer treatment for renal carcinoma. Prior bisphosphonates are
allowed.

- Radiotherapy = 4 weeks prior to starting the study drug or non-recovery from related
toxicities. Palliative radiotherapy for bone lesions = 2 weeks prior to starting study
drug is allowed.

- Major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic) = 4 weeks prior
to starting study treatment or non-recovery from surgical side effects.

- History of pulmonary embolism or untreated deep venous thrombosis within the past 6
months. If a history of PE or DVT within the past 6 months is present, patients must
be clinically stable on appropriate doses of anticoagulation as per thrombosis
specialist advice.

- Impaired cardiac function or clinically significant cardiac diseases, including
history of serious uncontrolled ventricular arrhythmias; clinically significant
resting bradycardia; LVEF assessed by 2-D echocardiogram < 50% or lower limit of
normal (whichever is higher) or multiple gated acquisition scan < 45% or lower limit
of normal (whichever is higher). Within 6 months prior to starting study drug:
myocardial infarction, severe/unstable angina, coronary artery bypass graft,
congestive heart failure, cerebrovascular accident, transient ischemic attack;
uncontrolled hypertension defined by a SBP = 160 mm Hg and/or DBP = 90 mm Hg, with or
without anti-hypertensive medication. Initiation or adjustment of antihypertensive
medication is allowed before study entry.

- Impaired gastrointestinal function or GI disease that may significantly alter
dovitinib absorption, e.g. ulcerative diseases, uncontrolled nausea, vomiting,
diarrhoea, malabsorption syndrome, or small bowel resection.

- Cirrhosis, chronic active hepatitis or chronic persistent hepatitis

- Known diagnosis of human immunodeficiency virus infection (testing is not mandatory)

- Current full dose anticoagulation treatment with therapeutic doses of warfarin,
dabigatran or anti-platelet therapy. Treatment with = 100mg acetylsalicyclic acid
daily is allowed as are therapeutic or prophylactic doses of low molecular weight
heparin, provided there is no recent evidence of bleeding.

- Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.
infection, diabetes) that could cause unacceptable safety risks or compromise protocol
compliance.

- Pregnant or breast-feeding women

- Women of child-bearing potential or fertile males not using effective contraception.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Unknown status
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/03/2012
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/06/2015
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
New Zealand
State/province [1] 0 0
Auckland

Funding & Sponsors
Primary sponsor type
Other
Name
Auckland District Health Board
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
University of Auckland, New Zealand
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
IGENZ, Ltd., Auckland
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Commercial sector/Industry
Name [3] 0 0
Novartis
Address [3] 0 0
Country [3] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
The main purpose of this study is to find out how useful dovitinib is when given as the
initial treatment to participants with advanced kidney cancer, that has spread to other parts
of the body. The usefulness of dovitinib will be assessed by: how long the disease is
controlled while participants are receiving the drug, the proportion of participants who get
a reduction in the size of their tumours and how long participants live (both while on
dovitinib and on any subsequent therapy they may receive).

If participants have secondary disease in the bones, the study will evaluate how useful
dovitinib is in controlling this site of disease. In addition, this study will look for
changes in the genetic makeup of tumour cells and see if some of these changes are associated
with a benefit from dovitinib. The study will also compare and contrast the genetic changes
in the primary tumour cells with cells from secondary tumour specimens, and with cells from
tumour specimens taken if a participant's disease has worsened. The purpose of the latter is
to identify possible ways in which the tumour becomes resistant to the study drug.
Trial website
https://clinicaltrials.gov/ct2/show/NCT01791387
Trial related presentations / publications
Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev. 2008 May;34(3):193-205. doi: 10.1016/j.ctrv.2007.12.001. Epub 2008 Mar 4.
Chow WH, Devesa SS, Warren JL, Fraumeni JF Jr. Rising incidence of renal cell cancer in the United States. JAMA. 1999 May 5;281(17):1628-31. doi: 10.1001/jama.281.17.1628.
Hollingsworth JM, Miller DC, Daignault S, Hollenbeck BK. Five-year survival after surgical treatment for kidney cancer: a population-based competing risk analysis. Cancer. 2007 May 1;109(9):1763-8. doi: 10.1002/cncr.22600.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009 Aug 1;27(22):3584-90. doi: 10.1200/JCO.2008.20.1293. Epub 2009 Jun 1.
Sibilia M, Fleischmann A, Behrens A, Stingl L, Carroll J, Watt FM, Schlessinger J, Wagner EF. The EGF receptor provides an essential survival signal for SOS-dependent skin tumor development. Cell. 2000 Jul 21;102(2):211-20. doi: 10.1016/s0092-8674(00)00026-x.
Arteaga CL. The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J Clin Oncol. 2001 Sep 15;19(18 Suppl):32S-40S.
Cohen P. Protein kinases--the major drug targets of the twenty-first century? Nat Rev Drug Discov. 2002 Apr;1(4):309-15. doi: 10.1038/nrd773.
Collett MS, Erikson RL. Protein kinase activity associated with the avian sarcoma virus src gene product. Proc Natl Acad Sci U S A. 1978 Apr;75(4):2021-4. doi: 10.1073/pnas.75.4.2021.
Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 1995 Sep 15;55(18):3964-8.
Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Muller C, Gruning W, Kratz-Albers K, Serve S, Steur C, Buchner T, Kienast J, Kanakura Y, Berdel WE, Serve H. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood. 2000 Dec 1;96(12):3907-14.
Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood. 2000 Nov 15;96(10):3343-56. No abstract available.
Dvorak HF. Rous-Whipple Award Lecture. How tumors make bad blood vessels and stroma. Am J Pathol. 2003 Jun;162(6):1747-57. doi: 10.1016/s0002-9440(10)64309-x. No abstract available.
Auguste P, Javerzat S, Bikfalvi A. Regulation of vascular development by fibroblast growth factors. Cell Tissue Res. 2003 Oct;314(1):157-66. doi: 10.1007/s00441-003-0750-0. Epub 2003 Jul 8.
Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005 Oct;8(4):299-309. doi: 10.1016/j.ccr.2005.09.005.
Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest. 2003 May;111(9):1287-95. doi: 10.1172/JCI17929.
Zhang W, Stoica G, Tasca SI, Kelly KA, Meininger CJ. Modulation of tumor angiogenesis by stem cell factor. Cancer Res. 2000 Dec 1;60(23):6757-62.
Dowlati A, Haaga J, Remick SC, Spiro TP, Gerson SL, Liu L, Berger SJ, Berger NA, Willson JK. Sequential tumor biopsies in early phase clinical trials of anticancer agents for pharmacodynamic evaluation. Clin Cancer Res. 2001 Oct;7(10):2971-6.
Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF; American Society of Clinical Oncology/College of American Pathologists. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2007;131(1):18-43. doi: 10.5858/2007-131-18-ASOCCO.
Tsimafeyeu I, Demidov L, Stepanova E, Wynn N, Ta H. Overexpression of fibroblast growth factor receptors FGFR1 and FGFR2 in renal cell carcinoma. Scand J Urol Nephrol. 2011 Apr;45(3):190-5. doi: 10.3109/00365599.2011.552436. Epub 2011 Feb 18.
Rini BI. Metastatic renal cell carcinoma: many treatment options, one patient. J Clin Oncol. 2009 Jul 1;27(19):3225-34. doi: 10.1200/JCO.2008.19.9836. Epub 2009 May 26.
Gronwald J, Storkel S, Holtgreve-Grez H, Hadaczek P, Brinkschmidt C, Jauch A, Lubinski J, Cremer T. Comparison of DNA gains and losses in primary renal clear cell carcinomas and metastatic sites: importance of 1q and 3p copy number changes in metastatic events. Cancer Res. 1997 Feb 1;57(3):481-7.
Velickovic M, Delahunt B, Storkel S, Grebem SK. VHL and FHIT locus loss of heterozygosity is common in all renal cancer morphotypes but differs in pattern and prognostic significance. Cancer Res. 2001 Jun 15;61(12):4815-9.
Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2009 May 1;27(13):2278-87. doi: 10.1200/JCO.2008.20.0766. Epub 2009 Mar 30.
Chen M, Ye Y, Yang H, Tamboli P, Matin S, Tannir NM, Wood CG, Gu J, Wu X. Genome-wide profiling of chromosomal alterations in renal cell carcinoma using high-density single nucleotide polymorphism arrays. Int J Cancer. 2009 Nov 15;125(10):2342-8. doi: 10.1002/ijc.24642.
Pantuck AJ, Seligson DB, Klatte T, Yu H, Leppert JT, Moore L, O'Toole T, Gibbons J, Belldegrun AS, Figlin RA. Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy. Cancer. 2007 Jun 1;109(11):2257-67. doi: 10.1002/cncr.22677.
Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol. 2009 Oct;10(10):992-1000. doi: 10.1016/S1470-2045(09)70240-2.
Wrobel CN, Debnath J, Lin E, Beausoleil S, Roussel MF, Brugge JS. Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture. J Cell Biol. 2004 Apr 26;165(2):263-73. doi: 10.1083/jcb.200309102.
El-Hariry I, Powles T, Lau MR, Sternberg CN, Ravaud A, von der Maase H, Zantl N, Harper P, Rolland F, Audhuy B, Barthel F, Machiels JP, Patel P, Kreuser ED, Hawkins RE. Amplification of epidermal growth factor receptor gene in renal cell carcinoma. Eur J Cancer. 2010 Mar;46(5):859-62. doi: 10.1016/j.ejca.2010.01.011. Epub 2010 Feb 16.
Weber K, Doucet M, Kominsky S. Renal cell carcinoma bone metastasis--elucidating the molecular targets. Cancer Metastasis Rev. 2007 Dec;26(3-4):691-704. doi: 10.1007/s10555-007-9090-y.
Tang SW, Chang WH, Su YC, Chen YC, Lai YH, Wu PT, Hsu CI, Lin WC, Lai MK, Lin JY. MYC pathway is activated in clear cell renal cell carcinoma and essential for proliferation of clear cell renal cell carcinoma cells. Cancer Lett. 2009 Jan 8;273(1):35-43. doi: 10.1016/j.canlet.2008.07.038. Epub 2008 Sep 21.
Thomas RK, Baker AC, Debiasi RM, Winckler W, Laframboise T, Lin WM, Wang M, Feng W, Zander T, MacConaill L, Lee JC, Nicoletti R, Hatton C, Goyette M, Girard L, Majmudar K, Ziaugra L, Wong KK, Gabriel S, Beroukhim R, Peyton M, Barretina J, Dutt A, Emery C, Greulich H, Shah K, Sasaki H, Gazdar A, Minna J, Armstrong SA, Mellinghoff IK, Hodi FS, Dranoff G, Mischel PS, Cloughesy TF, Nelson SF, Liau LM, Mertz K, Rubin MA, Moch H, Loda M, Catalona W, Fletcher J, Signoretti S, Kaye F, Anderson KC, Demetri GD, Dummer R, Wagner S, Herlyn M, Sellers WR, Meyerson M, Garraway LA. High-throughput oncogene mutation profiling in human cancer. Nat Genet. 2007 Mar;39(3):347-51. doi: 10.1038/ng1975. Epub 2007 Feb 11. Erratum In: Nat Genet. 2007 Apr;39(4):567. Macconnaill, Laura E [corrected to MacConaill, Laura].
MacConaill LE, Campbell CD, Kehoe SM, Bass AJ, Hatton C, Niu L, Davis M, Yao K, Hanna M, Mondal C, Luongo L, Emery CM, Baker AC, Philips J, Goff DJ, Fiorentino M, Rubin MA, Polyak K, Chan J, Wang Y, Fletcher JA, Santagata S, Corso G, Roviello F, Shivdasani R, Kieran MW, Ligon KL, Stiles CD, Hahn WC, Meyerson ML, Garraway LA. Profiling critical cancer gene mutations in clinical tumor samples. PLoS One. 2009 Nov 18;4(11):e7887. doi: 10.1371/journal.pone.0007887. Erratum In: PLoS One. 2010;5(9). doi: 10.1371/annotation/3a0c8fee-57ef-43ed-b6c2-55b503e6db5e. PLoS One. 2010;5(9). doi: 10.1371/annotation/613c7509-e4c9-42ac-82fb-fc504400d9e0.
Broom R, Du H, Clemons M, Eton D, Dranitsaris G, Simmons C, Ooi W, Cella D. Switching breast cancer patients with progressive bone metastases to third-generation bisphosphonates: measuring impact using the Functional Assessment of Cancer Therapy-Bone Pain. J Pain Symptom Manage. 2009 Aug;38(2):244-57. doi: 10.1016/j.jpainsymman.2008.08.005. Epub 2009 Apr 11.
Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, Eigl BJ, Ruether JD, Cheng T, North S, Venner P, Knox JJ, Chi KN, Kollmannsberger C, McDermott DF, Oh WK, Atkins MB, Bukowski RM, Rini BI, Choueiri TK. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009 Dec 1;27(34):5794-9. doi: 10.1200/JCO.2008.21.4809. Epub 2009 Oct 13.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):115-24. doi: 10.1056/NEJMoa065044.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-55. No abstract available.
Public notes

Contacts
Principal investigator
Name 0 0
Reuben Broom, MBChB, FRACP
Address 0 0
Auckland Hospital
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT01791387