SIGNATURE: Dovitinib for Patients With Tumor Pathway Activations Inhibited by Dovitinib

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01831726
• Collaborator: (none)
• Enrollment: 80
• Locations: 49
• Arm: 1
• Duration (Months): 28
• Patients Per Site: 1.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this signal seeking study was to determine whether treatment with dovitinib (TKI258) demonstrated sufficient efficacy in select pathway-activated solid tumors and/or hematologic malignancies to warrant further study.

Condition or Disease	Intervention/Treatment	Phase
Tumor Pathway Activations Inhibited by Dovitinib	Drug: Dovitinib (TKI258)	Phase 2

Detailed Description

This was a phase II, open label study to determine the efficacy and safety of treatment with dovitinib (TKI258) in patients with a diagnosis of select solid tumors or hematological malignancies that have been pre-identified (prior to study consent) to have mutations, translocations or amplifications and whose disease has progressed on or after standard treatment.

Genomic profiling is becoming more accessible to patients and their physicians. As such, more patients have been identified with potentially-actionable mutations, translocations or amplifications but do not have access to targeted drug treatment. This is a signal-seeking study to match patients with tumor pathway activations inhibited by dovitinib to the RTK inhibitor dovitinib. Pre-identification of mutations, translocations, or amplifications will be performed locally at a CLIA certified laboratory prior to participation on the trial.

For the purpose of this study, genomic profiling is not considered part of screening. Informed consent must be signed before any screening activities take place. Once eligibility (screening criteria met) has been confirmed by Novartis, the patient will initiate therapy with dovitinib single-agent. The patient may not receive any additional anti-cancer therapy during treatment with dovitinib.

Patients received study treatment until disease progression (assessed by investigator per RECIST 1.1 or appropriate hematologic response criteria), unacceptable toxicity, death or discontinuation from study treatment for any other reason (e.g., withdrawal of consent, start of a new anti-neoplastic therapy or at the discretion of the investigator), otherwise known as End of Treatment. All patients who discontinue from study treatment due to disease progression must have their progression clearly documented.

Disease assessment (by RECIST 1.1 or appropriate hematological response criteria) will be performed every 8 weeks (±4 days) after first dose of study drug (Day 1 of every odd cycle), until disease progression or end of treatment, whichever occurs first. The frequency of disease assessment may be reduced to every 12 weeks for patients who have at least 4 post-baseline disease assessments and are clinically stable (except AML patients). Scans was assessed locally by the investigator. After discontinuation of treatment, patients, regardless of reason for treatment discontinuation, will be followed for safety for 30 days after the last dose.

All patients will be followed for survival status every 3 months for 2 years after the last patient has enrolled in the study,regardless of treatment discontinuation reason (except if consent is withdrawn or patient is lost to follow-up)

Study Design

• Study Type: Interventional
• Actual Enrollment: 80 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Modular Phase II Study to Link Targeted Therapy to Patients With Pathway Activated Tumors: Module 2 - Dovitinib for Patients With Tumor Pathway Activations Inhibited by Dovitinib Including Tumors With Mutations or Translocations of FGFR, PDGFR, VEGF, cKIT, FLT3, CSFR1, Trk and RET
• Study Start Date: Aug 1, 2013
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TKI258 Dovitinib (TKI) will be dosed on a flat scale of 500 mg on a 5 days on/2 days off dosing schedule.	Drug: Dovitinib (TKI258); Dovitinib (TKI) will be dosed on a flat scale of 500 mg on a 5 days on/2 days off dosing schedule.

Outcome Measures

Primary Outcome Measures

1. Clinical Benefit Rate (CBR) [Week 16]

   CBR determined by investigator assessment for each tumor assessment & defined as responses of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) ≥ 16 wks. Confirmed CR/PR or SD prior to 16 wks,but discontinued prior to 16 wks for reasons other than progressive disease,will have their clinical benefit defined non-evaluable; confirmed CR/PR or SD prior to 16 wks,but progressed prior to 16 wks,will be considered not achieving clinical benefit;if CR/PR/SD occurred prior to 16 wks,but progressed at or after 16 wks without evidence of CR/PR/SD at or after 16 wks,will also be considered not achieving clinical benefit. CBR will be analyzed by comparing achieved CBR with a historical control rate of each tumor type,& if there is at least 90% probability that the response rate in a tumor type exceeds the historical rate,then the tumor type will be considered a success. CBR: CR+PR+SD the assessment criteria was RECIST 1.1

Secondary Outcome Measures

1. Overall Response (OR) of Partial Response (PR) or Greater [Week 16]

   Overall Response (OR) of Partial Response (PR) or greater based on local investigator assessment. For patients with solid tumors, the assessment criteria will be RECIST 1.1 and will include responses of CR and/or PR. For hematologic tumors other appropriate hematological response criteria will apply and are included in the appendices. ORR: CR+PR

2. Progression-Free Survival (PFS) [36 months]

   Progression free survival (PFS) is defined as the time from the date of first dose to the date of first documented disease progression or relapse or death due to any cause.

3. Overall Survival (OS) [36 months]

   Overall survival (OS) is defined as the time from the date of first dose to the date of death due to any cause. If a patient is not known to have died, survival time will be censored at the date of the last contact

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

Patients eligible for inclusion in this study had to meet all of the following criteria:

1. Patient's age was ≥ 18 years of age at the time of signing informed consent.

2. Patient had a confirmed diagnosis of a selected solid tumor (except for primary diagnosis of urothelial tumors, hepatocellular carcinoma (HCC), endometrial carcinoma, metastatic breast cancer (mBC), squamous NSCLC, and renal cell carcinoma (RCC)) or hematologic malignancies (except for primary diagnosis of FLT3 AML and multiple myeloma). Additional tumor types could be excluded during the course of the study in the case of early futility or success based upon an interim analysis or at the discretion of Novartis.

3. Patient was in need of treatment because of progression or relapse defined as:

• radiological progression for solid tumor and lymphoma

• for hematologic malignancies, measureable progression or relapse by appropriate criteria

1. Patients had pre-identified tumor with a mutation and/or translocation of one of the known kinase targets of dovitinib. The qualifying alteration were assessed and reported by a CLIA-certified laboratory. The mutations included:

2. FGFR 1-3 (amplifications were also allowed)

3. PDGFRα or PDGFRβ

4. VEGFR1-2 (KDR)

5. FLT3, cKIT (amplifications are also allowed),

6. RET, TrkA (NTRK1), or CSF-1R

7. Patient had archival tissue available for submission to allow for molecular testing related to pathway activation. If the tissue was not available or not of sufficient quantity the patient was willing to undergo a fresh tumor biopsy to allow for this analysis. The sample was submitted prior to first study dose unless agreed upon between Novartis and the investigator.

8. Patient received at least one prior treatment for recurrent, metastatic and /or locally advanced disease and for whom no standard therapy options were anticipated to result in a durable remission.

9. Diffuse large B cell lymphoma only: Patient received or was ineligible for autologous or allogeneic stem cell transplant. This did not apply to patients with Mantle cell lymphoma or follicular lymphoma

10. Patients with measurable disease as per appropriate guidelines:

1. Solid Tumors: by RECIST 1.1

1. Lymphoma: Patient had at least one measurable nodal lesion (≥2 cm) according to Cheson criteria (Cheson 2007). In case where the patient had no measurable nodal lesions ≥ 2 cm in the long axis at screening, then the patient had at least one measurable extra-nodal lesion.

2. Leukemia only: Relapsed/refractory leukemia for which no standard therapy options were anticipated to result in a durable remission:

3. Acute myelogenous leukemia (AML) by World Health Organization (WHO) classification (except FLT3) or acute lymphoblastic leukemia (ALL) relapsed or refractory to standard chemotherapy; unsuitable for standard chemotherapy or unwilling to undergo standard chemotherapy. Philadelphia chromosome (Ph) positive ALL eligible if failed prior tyrosine-kinase inhibitor therapy.

4. Age > 60 years with AML (except FLT3) not candidates for or have refused standard chemotherapy, excluding patients with acute promyelocytic leukemia (APL) or with favorable cytogenetic abnormalities.

5. For patients with Chronic Myeloid Leukemia (CML) only accelerated and blast phase CML were allowed.

6. Patient with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

7. Patient with a life expectancy of at least 16 weeks

8. All Patients were having adequate bone marrow as described below:

9. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L (not applicable for leukemia patients).

10. Platelets (PLT) ≥ 75 x 109/L (no platelet transfusion within past 14 days) (not applicable for leukemia patients).

11. Hemoglobin (Hgb) ≥ 9 g/dl (not applicable for leukemia patients).

12. International Normalized Ratio (INR) ≤ 1.5.

13. Serum amylase and lipase ≤ upper limit of normal (ULN).

14. All patients had adequate organ function defined as described below:

15. Potassium, calcium (corrected for serum albumin) and magnesium within normal limits (WNL). Supplementation was allowed to meet eligibility requirements. Bisphosphonates to treat malignant hypercalcemia WERE NOT allowed.

16. Serum creatinine ≤ 1.5 x ULN or Serum creatinine >1.5 - 3 x ULN if

• creatinine clearance by 24-hr urine was ≥ 30 mL/min/1.73m2 (≥50 mL/min/1.73m2 in the presence of proteinuria as defined by inclusion criterion #16 or

• calculated creatinine clearance (CrCl) was ≥ 30 mL/min using the Cockroft- Gault equation CrCl = (140 - age in years) x (weight in kg) / (72 x serum creatinine in mg/dL) (if female, multiply the number by 0.85)

1. Alanine aminotransferase (AST) and/or aspartate aminotransferase (ALT) ≤ 3.0 x upper limit of normal range (ULN)

2. Total serum bilirubin within normal range (or ≤ 1.5 x ULN)

3. Urine dipstick reading: Negative for proteinuria or, if documentation of +1 results for protein on dipstick reading, then total urinary protein ≤ 500 mg and measured creatinine clearance ≥ 50 mL/min/1.73m2 from a 24 hour urine collection.

4. For Leukemia patients, peripheral blast counts < 50,000 blasts/mm3

Key Exclusion Criteria:

Patients eligible for this study did not meet any of the following criteria:

1. Patients who received prior treatment with dovitinib (TKI258).

2. Patients with a known hypersensitivity to dovitinib (TKI258) or to its excipients.

3. Patients with brain metastasis or history of brain metastasis or leptomeningeal carcinomatosis.

4. Patients with diarrhea ≥ CTCAE grade 2.

5. Patients with neuropathy ≥ CTCAE grade 2.

6. Patients with acute or chronic pancreatitis.

7. Patients with external biliary drains.

8. Patients with a history of pulmonary embolism (PE), or untreated deep venous thrombosis (DVT) ≤ 6 months prior to starting study drug. Note: Patients with recent DVT who were treated with therapeutic anti-coagulant agents for at least 6 weeks are eligible.

9. Patients with impaired cardiac function or clinically significant cardiac diseases, including any of the following:

10. History or presence of serious uncontrolled ventricular arrhythmias.

11. Clinically significant resting bradycardia.

12. LVEF assessed by either 2-D echocardiogram (ECHO) < 50% or lower limit of normal (whichever was the higher), or 2-D multiple gated acquisition scan (MUGA) < 45% or lower limit of normal (whichever was the higher).

13. Any of the following within 6 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, coronary artery bypass graft (CABG), congestive heart failure (CHF), cerebrovascular accident (CVA), transient ischemic Attack (TIA).

14. Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg, with or without anti-hypertensive medication(s). Initiation or adjustment of antihypertensive medication(s) was allowed prior to study entry.

15. Patients with uncontrolled diabetes mellitus.

16. Patients with clinical evidence of active CNS leukemia.

17. Patient who received Allogeneic stem cell transplant and/or had active has graft-versus host disease (GVHD).

18. Patient received Autologous stem cell transplant within last 4 weeks.

19. Impairment of GI function or GI disease that could significantly alter the absorption of dovitinib (e.g. severe ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

20. Any other condition that was, in the Investigator's judgment, contraindicate patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g. infection/inflammation, intestinal obstruction, unable to swallow oral medication, social/psychological complications.

21. Patients who were treated with any hematopoietic colony-stimulating growth factors (e.g.,G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, could be continued. Restriction was not applicable for patients with Leukemia.

22. Patient who received chemotherapy or other anticancer therapy ≤ 4 weeks (6 weeks for nitrosourea, monoclonal antibodies or mitomycin-C) prior to starting study drug or who had not recovered to a grade 1 from side effects of such therapy (except for alopecia and neuropathy). Patients with leukemia could receive therapy with hydroxyurea and/or steroids for the purpose of cytoreduction but must discontinue use prior to first dose of study drug.

23. Patients who received the last administration of an anticancer small molecule therapy (e.g. sunitinib, sorafenib, pazopanib, axitinib, everolimus, temsirolimus, ridaforolimus) ≤ 2 weeks prior to starting study drug, or who had not recovered from the side effects of such therapy.

24. Patients not able to discontinue their current anti-cancer therapy prior to first dose of study drug.

25. Patients who received radiotherapy ≤ 4 weeks prior to starting the study drug or who had not recovered from radiotherapy-related toxicities (note: palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study drug is allowed).

26. Patients who had undergone major surgery (e.g., intra-thoracic, intra-abdominal, intrapelvic) ≤ 4 weeks prior to starting study treatment or who had not recovered from side effects of such surgery.

27. Patient was currently receiving antiplatelet therapy of prasugrel or clopidogrel, or full dose anticoagulation treatment with therapeutic doses of warfarin. However, treatment with low doses of warfarin (e.g., ≤ 2 mg/day) or locally accepted low doses of acetylsalicylic acid (up to 100 mg daily) to prevent cardiovascular events or strokes was allowed.

28. Patients with another primary malignancy within 3 years prior to starting study treatment, with the exception of adequately treated basal cell carcinoma, squamous cell carcinoma or other non-melanomatous skin cancer, or in-situ carcinoma of the uterine cervix.

29. Cirrhosis of the liver or known hepatitis B or C infection that was either acute or was considered chronic because the virus did not become undetectable:

30. Hepatitis C Virus (HCV) infection: acute or chronic infection as depicted by a positive HCV RNA testing (note: in a patient with known anti-HCV but with a negative test for HCV RNA, re-testing for HCV RNA 4-6 months later was requested to confirm the resolution of HCV infection).

31. Hepatitis B Virus (HBV) infection: acute infection (HBsAg+ with or without HBeAg+ or detectable serum HBV DNA), HBV carriers as evidence by ongoing presence of HBsAg and detectable serum HBV DNA levels.

32. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing was not mandatory).

33. Patients who received investigational agents within ≤ 5t1/2 of the agent (or ≤ 4 weeks when half-life was unknown) prior to starting study drug.

34. Patient with history of non-compliance to medical regimen.

35. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.

36. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they were using highly effective methods of contraception (defined below). Highly effective contraception had to be used by both sexes (female patients and their male partners) during study treatment and for 30 days after the last doseof study medication.

Highly effective contraception methods included:

• Total abstinence (when this was in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post- ovulation methods) and withdrawal were not acceptable methods of contraception

• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment.

In case of oophorectomy alone, only when the reproductive status of the woman was confirmed by follow up hormone level assessment

• Male sterilization (at least 6 months prior to screening). For female patients on the study the vasectomized male partner was the sole partner for that subject.

• Combination of the following (a+b):

1. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

2. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

3. Oral, implantable, or injectable hormone contraceptives might be affected by cytochrome P450 interactions, and were therefore not considered effective for this study Women of child-bearing potential (sexually mature women) who had not undergone a hysterectomy or who were not naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months), were required to have a negative serum pregnancy test ≤ 14 days prior to starting study drug.

4. Post-menopausal women were allowed to participate in this study. Women were considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks prior to entry in the study. In the case of oophorectomy alone, only when the reproductive status of the woman was confirmed by follow up hormone level assessment, then she was considered not of child bearing potential.

5. Fertile males not willing to use contraception. Fertile males must use condom with spermicide. Highly effective contraception, as defined above, was to be used by both sexes (male patients and their female partners) during study treatment and for 90 days after the last dose of study medication and was not to father a child in this period. A condom was required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alabama Oncology	Birmingham	Alabama	United States	35211
2	Highlands Oncology Group SC	Fayetteville	Arkansas	United States	72703
3	PCR Oncology	Pismo Beach	California	United States	93449
4	Sarcoma Oncology Center	Santa Monica	California	United States	90403
5	Rocky Mountain Cancer Centers Rocky Mountain Cancer Centers	Greenwood Village	Colorado	United States
6	Whittingham Cancer Center Norwalk Hospital	Norwalk	Connecticut	United States	06856
7	Memorial Cancer Institute Memorial Healthcare System	Hollywod	Florida	United States	33021
8	Cancer Specialists of North Florida Cancer Specialists (2)	Jacksonville	Florida	United States	32256
9	Florida Hospital Cancer Institute	Orlando	Florida	United States	32804
10	Space Coast Medical Associates Space Coast Cancer Center	Titusville	Florida	United States	32796
11	University Cancer & Blood Center, LLC	Athens	Georgia	United States	30607
12	NorthWest Georgia Oncology Centers NW Georgia Oncology	Marietta	Georgia	United States	30060
13	Lurie Children's Hospital of Chicago Developmental Therapeutics	Chicago	Illinois	United States	60611
14	Illinois Cancer Care	Peoria	Illinois	United States	61615-7828
15	Indiana University Indiana Univ. - Purdue Univ.	Indianapolis	Indiana	United States	46202
16	Horizon Oncology Center Horizon Oncology Ctr.	Lafayette	Indiana	United States	47905
17	St. Agnes Hospital St. Agnes Hospital (2)	Baltimore	Maryland	United States	21229
18	University of Michigan Int. Medicine Oncology	Ann Arbor	Michigan	United States	48109
19	Minnesota Oncology Hematology, P.A. Minnesota Oncology Hematology	Minneapolis	Minnesota	United States	55404
20	Billings Clinic Onc Dept	Billings	Montana	United States	59107
21	Southeast Nebraska Oncology Cancer Center	Lincoln	Nebraska	United States	68510
22	Comprehensive Cancer Centers of Nevada CCC of Nevada- Southwest (2)	Las Vegas	Nevada	United States	89109
23	Waverly Hematology Oncology	Cary	North Carolina	United States	27518
24	Oncology Hematology Care, Inc. Oncology Hematology Care (2)	Cincinnati	Ohio	United States	45242
25	Cleveland Clinic Foundation Cleveland Clinic (19)	Cleveland	Ohio	United States	44195
26	St. Charles Cancer Center	Bend	Oregon	United States	97701
27	Oregon Health & Science University OHSU Knight Cancer Institute	Portland	Oregon	United States	97239
28	University of Pittsburgh Cancer Institute	Pittsburgh	Pennsylvania	United States	15232-1305
29	Rhode Island Hospital Rhode Island Hosp. (2)	Providence	Rhode Island	United States	02903
30	Gibbs Cancer Center & Research Institute Spartanburg Reg. Healthcare	Spartanburg	South Carolina	United States	29303
31	Chattanooga Oncology and Hematology Assoicates, PC Chattanooga Oncology	Chattanooga	Tennessee	United States	37404
32	The West Clinic	Memphis	Tennessee	United States	38120
33	Sarah Cannon Research Institute Tennessee Oncology	Nashville	Tennessee	United States	37203
34	Austin Cancer Centers Austin Cancer Center (2)	Austin	Texas	United States	78759
35	Texas Oncology Texas Oncology - Sammons	Dallas	Texas	United States	75246
36	Texas Oncology Midtown Texas Oncology	Dallas	Texas	United States	75251
37	The Center for Cancer and Blood Disorders	Fort Worth	Texas	United States	76104
38	Oncology Consultants Oncology Group	Houston	Texas	United States	77024
39	MD Anderson Cancer Center/University of Texas MD Anderson Cancer Center (3)	Houston	Texas	United States	77030
40	Tyler Cancer Center	Tyler	Texas	United States	75702
41	Intermountain Medical Center Intermountain Healthcare	Murray	Utah	United States	84157
42	Virginia Cancer Specialists Virginia Cancer Specialists	Fairfax	Virginia	United States	22031
43	Providence Regional Cancer Partnership Providence Reg. Cancer (2)	Everett	Washington	United States	98201
44	Evergreen Hematology & Oncology	Spokane	Washington	United States	99218
45	Northwest Medical Specialties Hematology/Oncology	Tacoma	Washington	United States	98405
46	Wenatchee Valley Medical Center Wenatchee Valley	Wenatchee	Washington	United States	98801
47	Yakima Valley Memorial Hospital North Star Lodge Cancer Center	Yakima	Washington	United States	98902
48	Aurora Research Institute	Milwaukee	Wisconsin	United States	53226
49	Medical College of Wisconsin Cancer Ctr.-Froedtert Hospital	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01831726
• Other Study ID Numbers: CTKI258AUS26
• First Posted: Apr 15, 2013
• Last Update Posted: Mar 20, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by Novartis Pharmaceuticals: Solid tumor malignancy; hematologic malignancy; mutation; translocations; FGFR; PDGFR; VEGF; cKIT; FLT3; CSR1; Trk; RET; TKI258; dovitinib; signature; AML; acute myelogenous leukemia; GIST; gastrointestinal stromal tumor; Head and Neck cancer; Melanoma; NSCLC; non-small cell lung carcinoma; lung cancer; ovarian cancer; thyroid cancer; amplification
• Additional relevant MeSH terms: Neoplasms

Study Results

Participant Flow

Arm/Group Title	TKI258
Arm/Group Description	Dovitinib (TKI) will be dosed on a flat scale of 500 mg on a 5 days on/2 days off dosing schedule.
Period Title: Overall Study
STARTED	80
COMPLETED	0
NOT COMPLETED	80

Baseline Characteristics

Arm/Group Title	TKI258
Arm/Group Description	Dovitinib (TKI) will be dosed on a flat scale of 500 mg on a 5 days on/2 days off dosing schedule.
Overall Participants	80
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.3 (11.62)
Sex: Female, Male (Count of Participants)
Female	40 50%
Male	40 50%

Outcome Measures

1. Primary Outcome

Title	Clinical Benefit Rate (CBR)
Description	CBR determined by investigator assessment for each tumor assessment & defined as responses of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) ≥ 16 wks. Confirmed CR/PR or SD prior to 16 wks,but discontinued prior to 16 wks for reasons other than progressive disease,will have their clinical benefit defined non-evaluable; confirmed CR/PR or SD prior to 16 wks,but progressed prior to 16 wks,will be considered not achieving clinical benefit;if CR/PR/SD occurred prior to 16 wks,but progressed at or after 16 wks without evidence of CR/PR/SD at or after 16 wks,will also be considered not achieving clinical benefit. CBR will be analyzed by comparing achieved CBR with a historical control rate of each tumor type,& if there is at least 90% probability that the response rate in a tumor type exceeds the historical rate,then the tumor type will be considered a success. CBR: CR+PR+SD the assessment criteria was RECIST 1.1
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all patients who received at least one dose of study drug. FAS was used for the analysis of efficacy endpoints.

Arm/Group Title	TKI258
Arm/Group Description	Dovitinib (TKI) will be dosed on a flat scale of 500 mg on a 5 days on/2 days off dosing schedule.
Measure Participants	80
Complete response (CR)	0 0%
Partial response (PR)	1 1.3%
Stable disease (SD)	10 12.5%
Clinical benefit rate (CBR)	11 13.8%

2. Secondary Outcome

Title	Overall Response (OR) of Partial Response (PR) or Greater
Description	Overall Response (OR) of Partial Response (PR) or greater based on local investigator assessment. For patients with solid tumors, the assessment criteria will be RECIST 1.1 and will include responses of CR and/or PR. For hematologic tumors other appropriate hematological response criteria will apply and are included in the appendices. ORR: CR+PR
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all patients who received at least one dose of study drug. FAS was used for the analysis of efficacy endpoints.

Arm/Group Title	TKI258
Arm/Group Description	Dovitinib (TKI) will be dosed on a flat scale of 500 mg on a 5 days on/2 days off dosing schedule.
Measure Participants	80
Complete response (CR)	0 0%
Partial response (PR)	1 1.3%
Overall response rate (ORR)	1 1.3%

3. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	Progression free survival (PFS) is defined as the time from the date of first dose to the date of first documented disease progression or relapse or death due to any cause.
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all patients who received at least one dose of study drug. FAS was used for the analysis of efficacy endpoints.

Arm/Group Title	TKI258
Arm/Group Description	Dovitinib (TKI) will be dosed on a flat scale of 500 mg on a 5 days on/2 days off dosing schedule.
Measure Participants	80
Median (95% Confidence Interval) [months]	2.4

4. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival (OS) is defined as the time from the date of first dose to the date of death due to any cause. If a patient is not known to have died, survival time will be censored at the date of the last contact
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all patients who received at least one dose of study drug. FAS was used for the analysis of efficacy endpoints.

Arm/Group Title	TKI258
Arm/Group Description	Dovitinib (TKI) will be dosed on a flat scale of 500 mg on a 5 days on/2 days off dosing schedule.
Measure Participants	80
Median (95% Confidence Interval) [months]	13.5

Adverse Events

Arm/Group Title	TKI258
Arm/Group Description	Dovitinib (TKI) will be dosed on a flat scale of 500 mg on a 5 days on/2 days off dosing schedule.
All Cause Mortality
	TKI258
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	TKI258
	Affected / at Risk (%)	# Events
Total	32/80 (40%)
Blood and lymphatic system disorders
Anaemia	1/80 (1.3%)
Febrile neutropenia	2/80 (2.5%)
Neutropenia	1/80 (1.3%)
Thrombocytopenia	2/80 (2.5%)
Cardiac disorders
Cardiac arrest	1/80 (1.3%)
Gastrointestinal disorders
Abdominal pain	2/80 (2.5%)
Diarrhoea	1/80 (1.3%)
Dysphagia	1/80 (1.3%)
Gastrointestinal haemorrhage	1/80 (1.3%)
Nausea	2/80 (2.5%)
Small intestinal obstruction	1/80 (1.3%)
Stomatitis	1/80 (1.3%)
Vomiting	5/80 (6.3%)
General disorders
Chest pain	2/80 (2.5%)
Fatigue	1/80 (1.3%)
Pyrexia	2/80 (2.5%)
Hepatobiliary disorders
Bile duct obstruction	1/80 (1.3%)
Gallbladder obstruction	1/80 (1.3%)
Infections and infestations
Cellulitis	1/80 (1.3%)
Peritonitis	1/80 (1.3%)
Pneumonia	1/80 (1.3%)
Urinary tract infection	1/80 (1.3%)
Wound infection	1/80 (1.3%)
Injury, poisoning and procedural complications
Spinal fracture	1/80 (1.3%)
Subdural haematoma	1/80 (1.3%)
Investigations
Blood alkaline phosphatase increased	1/80 (1.3%)
Blood bilirubin increased	2/80 (2.5%)
Platelet count decreased	1/80 (1.3%)
Metabolism and nutrition disorders
Dehydration	4/80 (5%)
Hyponatraemia	1/80 (1.3%)
Musculoskeletal and connective tissue disorders
Back pain	1/80 (1.3%)
Neck pain	1/80 (1.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma	1/80 (1.3%)
Nervous system disorders
Cerebral thrombosis	1/80 (1.3%)
Encephalopathy	1/80 (1.3%)
Lethargy	1/80 (1.3%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/80 (1.3%)
Cough	1/80 (1.3%)
Dyspnoea	2/80 (2.5%)
Pleural effusion	1/80 (1.3%)
Pneumothorax	1/80 (1.3%)
Pulmonary embolism	4/80 (5%)
Skin and subcutaneous tissue disorders
Angioedema	1/80 (1.3%)
Vascular disorders
Deep vein thrombosis	1/80 (1.3%)
Hypertension	1/80 (1.3%)
Other (Not Including Serious) Adverse Events
	TKI258
	Affected / at Risk (%)	# Events
Total	78/80 (97.5%)
Blood and lymphatic system disorders
Anaemia	8/80 (10%)
Lymphopenia	4/80 (5%)
Thrombocytopenia	8/80 (10%)
Cardiac disorders
Sinus tachycardia	4/80 (5%)
Eye disorders
Lacrimation increased	5/80 (6.3%)
Gastrointestinal disorders
Abdominal pain	12/80 (15%)
Abdominal pain upper	4/80 (5%)
Constipation	26/80 (32.5%)
Diarrhoea	51/80 (63.8%)
Dry mouth	6/80 (7.5%)
Dyspepsia	8/80 (10%)
Dysphagia	4/80 (5%)
Gastrooesophageal reflux disease	4/80 (5%)
Haemorrhoids	4/80 (5%)
Nausea	47/80 (58.8%)
Vomiting	35/80 (43.8%)
General disorders
Asthenia	13/80 (16.3%)
Fatigue	56/80 (70%)
Mucosal inflammation	4/80 (5%)
Oedema peripheral	5/80 (6.3%)
Pain	7/80 (8.8%)
Pyrexia	7/80 (8.8%)
Infections and infestations
Pneumonia	4/80 (5%)
Upper respiratory tract infection	7/80 (8.8%)
Urinary tract infection	7/80 (8.8%)
Investigations
Alanine aminotransferase increased	16/80 (20%)
Amylase increased	8/80 (10%)
Aspartate aminotransferase increased	19/80 (23.8%)
Blood alkaline phosphatase increased	23/80 (28.8%)
Blood bilirubin increased	7/80 (8.8%)
Blood creatinine increased	4/80 (5%)
Gamma-glutamyltransferase increased	17/80 (21.3%)
Lipase increased	8/80 (10%)
Platelet count decreased	4/80 (5%)
Weight decreased	18/80 (22.5%)
White blood cell count decreased	6/80 (7.5%)
Metabolism and nutrition disorders
Decreased appetite	34/80 (42.5%)
Dehydration	17/80 (21.3%)
Hypercholesterolaemia	5/80 (6.3%)
Hyperglycaemia	6/80 (7.5%)
Hyperkalaemia	4/80 (5%)
Hypertriglyceridaemia	27/80 (33.8%)
Hypoalbuminaemia	8/80 (10%)
Hypocalcaemia	5/80 (6.3%)
Hypokalaemia	4/80 (5%)
Hypomagnesaemia	9/80 (11.3%)
Hyponatraemia	12/80 (15%)
Hypophosphataemia	4/80 (5%)
Musculoskeletal and connective tissue disorders
Arthralgia	6/80 (7.5%)
Back pain	12/80 (15%)
Muscular weakness	6/80 (7.5%)
Musculoskeletal pain	5/80 (6.3%)
Myalgia	6/80 (7.5%)
Pain in extremity	9/80 (11.3%)
Nervous system disorders
Dizziness	10/80 (12.5%)
Dysgeusia	9/80 (11.3%)
Headache	15/80 (18.8%)
Neuropathy peripheral	5/80 (6.3%)
Psychiatric disorders
Anxiety	4/80 (5%)
Insomnia	4/80 (5%)
Renal and urinary disorders
Proteinuria	4/80 (5%)
Respiratory, thoracic and mediastinal disorders
Cough	14/80 (17.5%)
Dyspnoea	19/80 (23.8%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform	4/80 (5%)
Dry skin	5/80 (6.3%)
Night sweats	4/80 (5%)
Palmar-plantar erythrodysaesthesia syndrome	6/80 (7.5%)
Pruritus	8/80 (10%)
Rash	11/80 (13.8%)
Rash maculo-papular	6/80 (7.5%)
Vascular disorders
Hypertension	14/80 (17.5%)
Hypotension	8/80 (10%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.