Tandutinib in Treating Patients Who Have Undergone Surgery for Metastatic Kidney Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00408902
• Collaborator: (none)
• Enrollment: 10
• Location: 1
• Arm: 1
• Duration (Months): 25
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This phase II trial is studying how well tandutinib works in treating patients who have undergone surgery for metastatic kidney cancer. Tandutinib may stop the growth of kidney cancer by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving tandutinib after surgery may kill any tumor cells that remain after surgery.

Condition or Disease	Intervention/Treatment	Phase
Clear Cell Renal Cell Carcinoma; Recurrent Renal Cell Cancer; Stage IV Renal Cell Cancer	Drug: tandutinib; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the overall efficacy of MLN518 in patients with metastatic clear cell renal carcinoma.

SECONDARY OBJECTIVES:

1. To evaluate the effect of MLN518 on progression-free survival and overall survival in patients with metastatic clear cell renal carcinoma.

2. To evaluate the toxicity of MLN518 in patients with metastatic clear cell renal carcinoma.

3. To evaluate the effects of MLN518 on serum VEGF-A, VEGF-R2, PIGF, and PDGF levels of patients with metastatic renal cell carcinoma receiving MLN518.

4. To determine the VHL gene status, methylation, and pVHL in archived material from the primary nephrectomy specimen of patients receiving MLN518.

5. To evaluate tumor blood flow and vessel permeability based on functional imaging with dynamic contrast enhanced magnetic resonance imaging (dceMRI) in metastatic renal cell carcinoma patients treated with MLN518.

OUTLINE: This is an open-label, nonrandomized study.

Patients receive oral tandutinib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for 4 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of MLN518 in Patients With Metastatic Clear Cell Renal Cell Carcinoma
• Study Start Date: Nov 1, 2006
• Actual Primary Completion Date: Oct 1, 2008
• Actual Study Completion Date: Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TandutinibTreatment Patients receive oral tandutinib 500 mg twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: tandutinib; Given orally, 500 mg bid daily; Other Names: CT53518 MLN518 ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Overall Efficacy, Taking Into Account Both Objective Response and Meaningful Reductions in Tumor Burden That do Not Meet the RECIST Criteria for PR or CR (e.g., 5-30% Reduction in RECIST Defined Tumor Burden) [Up to 4 weeks after completion of study treatment]

   The number of patients that reach complete response (CR)defined as the disappearance of all target lesions or partial response (PR)defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.

Secondary Outcome Measures

1. Overall Survival [Followed until progression or death for approximately 3 years]

   Estimated using the method of Kaplan and Meier.

2. Progression-free Survival [Up to 4 weeks after completion of study treatment]

   Estimated time to progression using the method of Kaplan and Meier.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed RCC of clear cell histology; subjects must have a component of conventional clear cell RCC with or without sarcomatoid features

• Patients must have evidence of metastatic disease and must have had a cytoreductive nephrectomy at least 28 days prior to first day of treatment

• Archival tissue from nephrectomy must be available for correlative studies

• Patients must have measurable disease, defined by RECIST criteria

• Patients must have received at least one prior FDA approved therapy for metastatic renal cell carcinoma with either Sutent, or Nexavar, and may have received up to three prior systemic therapies for metastatic disease; prior cytokine therapy is also permitted

• Prior systemic therapy with other antiangiogenic agents such as Thalidomide, Bevacizumab, or AG013736 is permitted

• Patients must have a life expectancy of >= 3 months

• Patients must have an ECOG performance status of 0-1 (Karnofsky >= 70%)

• Patients must be at least 4 weeks from radiation therapy and recovered from all related toxicity

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Hemoglobin >= 8.5 g/dl

• Total Bilirubin =< 1.5 X institutional upper limit of normal

• AST (SGOT)/ALT (SGPT) =< 3.5 X institutional upper limit of normal

• Alkaline phosphatase =< 2.5 ULN (=< 10 x ULN in presence of bone metastasis)

• Serum calcium of =< 12 mg/dl

• Creatinine =< 1.5 X institutional upper limit of normal

• INR =< 1.5, except for subjects receiving warfarin therapy; for subjects who are receiving warfarin for prophylaxis or treatment of thrombosis, INR values should be carefully monitored while patients are on study

• Electrocardiogram (12-lead) with cQTC < 500 msec using the Bazett's formula

• Absence of significant effusions and/or ascites

• No major surgery requiring general anesthesia within the past 28 days

• Patients may not have had brain metastasis

• Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of MLN518 will be determined following review of their case by the Principal Investigator; because MLN518 is a substrate of the P-glycoprotein (P-gp) drug efflux pump, co- administration of agents that inhibit or induce this mechanism may alter exposure to MLN518

• The effects of MLN518 on the developing human fetus at the recommended therapeutic dose are unknown; for this reason and because receptor tyrosine kinase inhibitors are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; sexually active patients must continue to use contraception for three months after completion of study therapy

• All patients must be informed of the investigational nature of this study and must provide written informed consent in accordance with institutional and federal guidelines; a copy of the informed consent document signed by the patient must be given to the patient

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier

• Patients may not be receiving any other investigational agents

• Patients may not be co-medicated with an agent that causes QTc prolongation

• Patients with a mean QTc > 500 msec using the Bazett's formula taken from the screening electrocardiogram or history of familial long QT syndrome are ineligible

• Left ventricular ejection fraction (LVEF) < 40%

• Myocardial infarction within 6 months of enrollment or New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities

• Ongoing vomiting, or nausea >= grade 2 (NCI CTCAE v3.0)

• Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow pills or absorb oral medications are excluded

• Known or suspected primary muscular or neuromuscular disease (e.g., muscular dystrophy, myasthenia gravis)

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN518 such as Tarceva™, Iressa® and Cardura® XL

• Patients with any CNS metastases or uncontrolled seizure disorder

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infections or psychiatric illness/social situations that would limit compliance with study requirements

• Any malignancy other than a renal cell carcinoma, with the following exceptions:

• Basal or squamous cell carcinomas of the skin

• Carcinoma in-situ of the uterine cervix

• Any malignancy treated with curative intent and in complete remission for > 3 years

• Patients with organ allografts

• Patients with non-clear cell carcinoma i.e., papillary, collecting duct, or chromophobe

• Pregnant women are excluded from this study because MLN518 is a receptor tyrosine kinase inhibitor with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with MLN518, breastfeeding should be discontinued if the mother is treated with MLN518

• HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with MLN518; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated

• Inability to comply with study and/or follow-up procedures

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Case Western Reserve University	Cleveland	Ohio	United States	44106

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jorge Garcia, Case Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00408902
• Other Study ID Numbers: NCI-2012-03014; CASE 10805; CDR0000518799; U01CA062502
• First Posted: Dec 7, 2006
• Last Update Posted: Nov 22, 2017
• Last Verified: Oct 1, 2017

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell

Study Results

Participant Flow

Recruitment Details	Patients were recruited from Cleveland Clinic between November 2006 and August 2007.

Arm/Group Title	TandutinibTreatment
Arm/Group Description	Patients receive oral tandutinib 500 mg twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	10
COMPLETED	0
NOT COMPLETED	10

Baseline Characteristics

Arm/Group Title	TandutinibTreatment
Arm/Group Description	Patients receive oral tandutinib 500 mg twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Participants	10
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.6 (8.3)
Sex: Female, Male (Count of Participants)
Female	2 20%
Male	8 80%
Region of Enrollment (participants) [Number]
United States	10 100%

Outcome Measures

1. Primary Outcome

Title	Overall Efficacy, Taking Into Account Both Objective Response and Meaningful Reductions in Tumor Burden That do Not Meet the RECIST Criteria for PR or CR (e.g., 5-30% Reduction in RECIST Defined Tumor Burden)
Description	The number of patients that reach complete response (CR)defined as the disappearance of all target lesions or partial response (PR)defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.
Time Frame	Up to 4 weeks after completion of study treatment

Outcome Measure Data

Analysis Population Description

Intent to treat

Arm/Group Title	TandutinibTreatment
Arm/Group Description	Patients receive oral tandutinib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	10
Complete Response (CR)	0 0%
Partial Response (PR)	0 0%

2. Secondary Outcome

Title	Overall Survival
Description	Estimated using the method of Kaplan and Meier.
Time Frame	Followed until progression or death for approximately 3 years

Outcome Measure Data

Analysis Population Description

Data was not collected as study closed prior to time period for analysis.

Arm/Group Title	TandutinibTreatment
Arm/Group Description	Patients receive oral tandutinib 500 mg twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. tandutinib: Given orally, 500 mg bid daily laboratory biomarker analysis: Correlative studies
Measure Participants	0

3. Secondary Outcome

Title	Progression-free Survival
Description	Estimated time to progression using the method of Kaplan and Meier.
Time Frame	Up to 4 weeks after completion of study treatment

Outcome Measure Data

Analysis Population Description

Intent to treat

Arm/Group Title	TandutinibTreatment
Arm/Group Description	Patients receive oral tandutinib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	10
Median (Full Range) [months]	1.5

Adverse Events

Time Frame	Adverse events were collected while patients were on treatment and 4 weeks after treatment, up to 12 weeks.
Arm/Group Title	TandutinibTreatment
Arm/Group Description	Patients receive oral tandutinib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. tandutinib: Given orally laboratory biomarker analysis: Correlative studies
All Cause Mortality
	TandutinibTreatment
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	TandutinibTreatment
	Affected / at Risk (%)	# Events
Total	4/10 (40%)
Blood and lymphatic system disorders
Hemolysis	1/10 (10%)
General disorders
Fatigue	3/10 (30%)
Metabolism and nutrition disorders
Hypercalcemia	1/10 (10%)
Other (Not Including Serious) Adverse Events
	TandutinibTreatment
	Affected / at Risk (%)	# Events
Total	10/10 (100%)
Blood and lymphatic system disorders
Hemoglobin	7/10 (70%)
Lymphopenia	2/10 (20%)
Thrombocytopenia	2/10 (20%)
Cardiac disorders
Palpitations	1/10 (10%)
Ear and labyrinth disorders
Hearing w/o monitoring	1/10 (10%)
Endocrine disorders
Hypothyroidism	1/10 (10%)
Eye disorders
Tearing (watery eyes)	1/10 (10%)
Vision-blurred vision	1/10 (10%)
Gastrointestinal disorders
Constipation	1/10 (10%)
Diarrhea patients without colostomy	8/10 (80%)
Gastrointestinal-distention/bloating	2/10 (20%)
Nausea	7/10 (70%)
Retroperitoneal hemorrhage	1/10 (10%)
Vomiting	7/10 (70%)
General disorders
Fatigue (lethargy, malaise, asthenia)	4/10 (40%)
Rigors, chills	3/10 (30%)
Investigations
Creatinine	3/10 (30%)
Hypokalemia	1/10 (10%)
Prolonged QTc interval (QTc > 0.48 seconds)	2/10 (20%)
Metabolism and nutrition disorders
Anorexia	1/10 (10%)
Blood Urea Nitrogen	1/10 (10%)
Hyperkalemia	1/10 (10%)
Hyperuricemia	2/10 (20%)
Hypoalbuminemia	2/10 (20%)
Hypocalcemia	2/10 (20%)
Weight gain	1/10 (10%)
Weight loss	1/10 (10%)
Musculoskeletal and connective tissue disorders
Chest pain (non-cardiac and non-pleuritic)	1/10 (10%)
Muscle weakness (not due to neuropathy)	2/10 (20%)
Pain	3/10 (30%)
Nervous system disorders
Dizziness/lightheadedness	1/10 (10%)
Psychiatric disorders
Depression	1/10 (10%)
Insomnia	2/10 (20%)
Mood alteration-anxiety, agitation	1/10 (10%)
Renal and urinary disorders
Hypouricemia	1/10 (10%)
Protein	1/10 (10%)
Respiratory, thoracic and mediastinal disorders
Cough	2/10 (20%)
Dyspnea (shortness of breath)	3/10 (30%)
Pleural effusion	1/10 (10%)
Voice changes/stridor/larynx (e.g., hoarseness, loss of voice, laryngitis)	1/10 (10%)
Wheezing	1/10 (10%)
Skin and subcutaneous tissue disorders
Dry skin	1/10 (10%)
Sweating (diaphoresis)	1/10 (10%)
Vascular disorders
Edema	5/10 (50%)

Limitations/Caveats

Principal Investigator closed this study due to lack of response and toxicities of drug, therefore overall survival analysis was not done.

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.