Vorinostat and Bevacizumab in Treating Patients With Unresectable or Metastatic Kidney Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00324870
• Collaborator: (none)
• Enrollment: 37
• Locations: 3
• Arm: 1
• Duration (Months): 93
• Patients Per Site: 12.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase I/II trial is studying the side effects and best dose of vorinostat when given together with bevacizumab and to see how well they work in treating patients with unresectable or metastatic kidney cancer. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of kidney cancer by blocking blood flow to the tumor. Giving vorinostat together with bevacizumab may kill more tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Clear Cell Renal Cell Carcinoma; Recurrent Renal Cell Cancer; Stage III Renal Cell Cancer; Stage IV Renal Cell Cancer	Drug: vorinostat; Drug: bevacizumab	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine the safety and tolerability of vorinostat (SAHA) in combination with bevacizumab in patients with unresectable or metastatic renal cell carcinoma. (Phase I) II. Determine the recommended dosing in patients treated with this regimen. (Phase I) III. Determine the proportion of patients who are progression-free at 6 months after receiving this regimen. (Phase II) IV. Determine the clinical response rate in patients treated with this regimen. (Phase II)

SECONDARY OBJECTIVES:

1. Determine the toxicity of this regimen in these patients. (Phase II) II. Determine time to progression and duration of progression-free and overall survival in patients treated with this regimen. (Phase II) III. Determine the pharmacodynamic effects in peripheral blood mononuclear cells and tumors before and after treatment with this regimen in these patients. (Phase II) IV. Determine the antiproliferative and apoptotic effects of this regimen in these patients. (Phase II) V. Determine the antiangiogenic effects of this regimen in these patients. (Phase II) VI. Determine the modulation of tumor metabolism and tumor blood flow in patients treated with this regimen. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of vorinostat (SAHA) followed by a phase II study.

PHASE I: Patients receive oral SAHA twice daily on days 1-14 and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD.

PHASE II: Patients receive SAHA at the MTD determined in phase I and bevacizumab as in phase I.

After completion of study treatment, patients are followed at 4 weeks and then every 3 months thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Study of Suberoylanilide Hydroxamic Acid (SAHA) in Combination With the VEGF Inhibitor Bevacizumab in Patients With Metastatic Renal Cell Carcinoma
• Study Start Date: Feb 1, 2006
• Actual Primary Completion Date: Jun 1, 2013
• Actual Study Completion Date: Nov 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Arm I Phase I: Patients receive oral SAHA twice daily on days 1-14 and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD. Phase II: Patients receive SAHA at the MTD determined in phase I and bevacizumab as in phase I.

Drug: vorinostat; Given orally; Other Names: L-001079038 SAHA suberoylanilide hydroxamic acid Zolinza ; Drug: bevacizumab; Given IV; Other Names: anti-VEGF humanized monoclonal antibody anti-VEGF monoclonal antibody Avastin rhuMAb VEGF

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival Assessed by Response Evaluation Criteria for Solid Tumors (RECIST) (Phase II) [At 6 months]

   Estimated by Kaplan-Meier method

Other Outcome Measures

1. Maximum Tolerated Dose [18 months from first patient dosing]

   Determine the maximum tolerated dose of SAHA

2. Clinical Response Rate of SAHA and Bevacizumab [7 years]

   To determine the clinical response rate of SAHA and Bevacizumab in patients with metastatic renal cell carcinoma.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• No known CNS metastasis

• ECOG performance status 0-2

• Life expectancy > 6 months

• LVEF ≥ 45%

• Absolute neutrophil count ≥ 1,500/mm3

• Platelet count ≥ 100,000/mm3

• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

• AST/ALT ≤ 2.5 times ULN

• Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 50 mL/min

• PT/INR ≤ 1.5

• Urine protein < 1+ by urinalysis OR < 1 g by 24-hour urine collection

• Not pregnant

• No nursing during and for 6 months after completion of study treatment

• Negative pregnancy test

• Fertile patients must use effective contraception for 2 weeks prior, during, and for 6 months after completion of study treatment

• No other currently active malignancy defined as > 30% risk of relapse upon completion of anticancer therapy, except nonmelanoma skin cancer

• No history of allergic reaction attributed to compounds of similar chemical or biologic composition to vorinostat (SAHA)

• No hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies

• No evidence of bleeding diathesis or coagulopathy

• No active bleeding or pathological conditions that carry high risk of bleeding (i.e., tumor involving major vessels or known varices)

• No ongoing, active infection

• No New York Heart Association class II-IV congestive heart failure

• No angina pectoris requiring nitrate therapy

• No cardiac arrhythmia

• No myocardial infarction within the past 6 months

• No history of cerebrovascular accident within the past 6 months

• No uncontrolled hypertension (defined as systolic blood pressure (BP) > 160 mm Hg and/or diastolic BP > 90 mm Hg on medication)

• No history of peripheral vascular disease

• No psychiatric illness or social situation that would preclude study compliance

• No other uncontrolled illness

• No serious nonhealing wound, ulcer, or bone fracture

• No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days

• No significant traumatic injury in the past 28 days

• At least 4 weeks since prior major surgery or open biopsy

• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)

• More than 4 weeks since prior radiotherapy

• At least 2 weeks since prior tyrosine kinase inhibitor

• Prior palliative radiotherapy to metastatic lesions allowed provided ≥ 1 measurable and/or evaluable lesion has not been irradiated

• No more than 2 prior systemic treatments for metastatic disease, including immunotherapy, receptor tyrosine kinase inhibitor therapy, chemotherapy, or investigational therapy

• No prior therapy with bevacizumab, vascular endothelial growth factor-trap, or histone deacetylase inhibitors, including valproic acid

• No core biopsy within 1 week prior to day 1 of study treatment

• No planned major surgery during study treatment

• No concurrent combination antiretroviral therapy for HIV-positive patients

• No other concurrent investigational agents

• Concurrent stable-dose prophylactic anticoagulation (i.e., warfarin or low molecular weight heparin) allowed provided requirements for INR are met

• Histologically confirmed renal cell carcinoma, clear cell component, unresectable or metastatic disease (patients with a primary tumor in place who are eligible for surgery are strongly encouraged to undergo a nephrectomy prior to study entry to increase potential survival)

• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm with spiral CT scan

• The following histologies are not allowed:

• Papillary, sarcomatoid carcinoma

• Chromophobe carcinoma

• Oncocytoma

• Collecting duct tumor

• Transitional cell carcinoma

• WBC ≥ 3,000/mm^3

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
2	Peninsula Oncology and Hematology PA	Salisbury	Maryland	United States	21801
3	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Michael Carducci, Johns Hopkins University/Sidney Kimmel Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00324870
• Other Study ID Numbers: NCI-2009-00093; NCI-2009-00093; NA 00001107; NCI-6884; JHOC-J0570; CDR0000467800; 6884; JHOC-00001107; J0570; IRB #NA 00001107, SKCCC J0570; 6884; P30CA006973; U01CA062491; U01CA070095
• First Posted: May 11, 2006
• Last Update Posted: Jan 13, 2016
• Last Verified: Oct 1, 2013

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Bevacizumab; Antineoplastic Agents, Immunological; Vorinostat; Antibodies; Immunoglobulins; Antibodies, Monoclonal

Study Results

Participant Flow

Arm/Group Title	Arm I
Arm/Group Description	Phase I: Patients receive oral SAHA twice daily on days 1-14 and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD. Phase II: Patients receive SAHA at the MTD determined in phase I and bevacizumab as in phase I. vorinostat: Given orally bevacizumab: Given IV
Period Title: Overall Study
STARTED	37
COMPLETED	37
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Arm I
Arm/Group Description	Phase I: Patients receive oral SAHA twice daily on days 1-14 and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD. Phase II: Patients receive SAHA at the MTD determined in phase I and bevacizumab as in phase I. vorinostat: Given orally bevacizumab: Given IV
Overall Participants	37
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	20 54.1%
>=65 years	17 45.9%
Sex: Female, Male (Count of Participants)
Female	6 16.2%
Male	31 83.8%
Region of Enrollment (participants) [Number]
United States	37 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival Assessed by Response Evaluation Criteria for Solid Tumors (RECIST) (Phase II)
Description	Estimated by Kaplan-Meier method
Time Frame	At 6 months

Outcome Measure Data

Analysis Population Description

Progression free survival was summarized for the entire sample (n=37). The median survival times and 6-month survival rates are estim. based on the KP curve,w/ corresp. 95% confidence intervals using the log-log method. Conducted in SAS v9.3(Cary, NC). Progr.free survival time is calc. from date of first tx until date of progres./death or last fu.

Arm/Group Title	Arm I
Arm/Group Description	Phase I: Patients receive oral SAHA twice daily on days 1-14 and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD. Phase II: Patients receive SAHA at the MTD determined in phase I and bevacizumab as in phase I. vorinostat: Given orally bevacizumab: Given IV
Measure Participants	37
Number (95% Confidence Interval) [percent]	48.6

2. Other Pre-specified Outcome

Title	Maximum Tolerated Dose
Description	Determine the maximum tolerated dose of SAHA
Time Frame	18 months from first patient dosing

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Other Pre-specified Outcome

Title	Clinical Response Rate of SAHA and Bevacizumab
Description	To determine the clinical response rate of SAHA and Bevacizumab in patients with metastatic renal cell carcinoma.
Time Frame	7 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	7 years
Adverse Event Reporting Description	Adverse events were assessed through a regular investigator assessment
Arm/Group Title	Arm I
Arm/Group Description	Phase I: Patients receive oral SAHA twice daily on days 1-14 and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD. Phase II: Patients receive SAHA at the MTD determined in phase I and bevacizumab as in phase I. vorinostat: Given orally bevacizumab: Given IV
All Cause Mortality
	Arm I
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	3/37 (8.1%)
Blood and lymphatic system disorders
thrombocytopenia	1/37 (2.7%)	1
Nervous system disorders
dizziness	1/37 (2.7%)	1
Respiratory, thoracic and mediastinal disorders
pulmonary embolism	1/37 (2.7%)	1
Other (Not Including Serious) Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	22/37 (59.5%)
Gastrointestinal disorders
nausea	17/37 (45.9%)	17
anorexia	16/37 (43.2%)	16
diarrhea	13/37 (35.1%)	13
Hepatobiliary disorders
elevated creatinine	13/37 (35.1%)	13
Nervous system disorders
fatigue	22/37 (59.5%)	22

Limitations/Caveats

[Not Specified]

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.