Everolimus and Bevacizumab in Advanced Non-Clear Cell Renal Cell Carcinoma (RCC)

• Sponsor: Memorial Sloan Kettering Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01399918
• Collaborator: Novartis Pharmaceuticals (Industry)
• Enrollment: 57
• Locations: 7
• Arm: 1
• Duration (Months): 113.9
• Patients Per Site: 8.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to find out what effects, good and/or bad the combination of two medications, everolimus and bevacizumab, has on kidney cancer. In this clinical trial we are now testing these medications in combination. We think that both together might work better that either drug alone. Importantly, both of these drugs together have been tested in patients with a different type of kidney cancer and patients tolerated the combination well.

Condition or Disease	Intervention/Treatment	Phase
Renal Cell Carcinoma	Drug: everolimus and bevacizumab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 57 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Everolimus and Bevacizumab in Advanced Non-Clear Cell Renal Cell Carcinoma (RCC)
• Study Start Date: Jul 1, 2011
• Actual Primary Completion Date: Dec 28, 2020
• Actual Study Completion Date: Dec 28, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: everolimus and bevacizumab This is a single-institution, single-arm phase II trial of everolimus in combination with bevacizumab in patients with advanced non-clear cell RCC, who have not received prior VEGF-.or mTOR-targeted therapy. A separate cohort of patients with non-clear cell RCC with papillary features will be enrolled in order to gather information regarding the efficacy given the rarity of these entities.

Drug: everolimus and bevacizumab; Cycle length will be defined as 28 days. Treatment will include everolimus 10mg, self administered orally once daily on a continuous schedule (days 1-28), and bevacizumab 10mg/kg, administered intravenously on days 1 and 15 of each cycle. Treatment will be continued until disease progression, major toxicity, or withdrawal from the study for any reason. Dose modification will be permitted based on toxicity. Patients that come off study before 6 months before documented progression/death will be treated as events for the 6 month PFS endpoint.

Outcome Measures

Primary Outcome Measures

1. To Evaluate the Efficacy of Combining Everolimus and Bevacizumab in Patients With Advanced RCC of Non-clear Cell Histology [6 months]

   the percent of patients alive and progression-free after 6 months of therapy.

Secondary Outcome Measures

1. Secondary Endpoint Will be the Overall Response Rate (ORR) [1 year]

   per the international criteria defined by the Response Evaluation Criteria in Solid Tumors Committee

2. Participants Evaluated for Toxicity [2 years]

   Toxicity will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.0 (Gompertz 1825),. Toxicities will be summarized by type and grade using frequencies and rates.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Advanced renal cell carcinoma of non-clear cell histology, histologically with papillary features confirmed by MSKCC pathology. Availability of additional tissue for correlative studies is NOT in inclusion requirement.

• Evidence of unidimensionally measurable disease per RECIST 1.1 (Eisenhauer, Therasse et al. 2009). Resolution of all acute toxic effects of prior radiotherapy or surgical procedures to NCI CTCAE Version 4.0 grade ≤1.

• Adequate organ function as defined by the following criteria:

• Absolute neutrophil count (ANC) ≥1,500/μL

• Platelets ≥100,000/μL

• Hemoglobin ≥9.0 g/dL

• Serum calcium ≤12.0 mg/dL

• Serum creatinine ≤1.5 x ULN

• Total serum bilirubin ≤2.0 x ULN

• Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) ≤2.5 x local laboratory upper limit of normal (ULN), or AST and ALT ≤5 x ULN if liver function abnormalities are due to underlying malignancy

• INR ≤1.5. (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose for >2 weeks at time of study entry.)

• Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.

Karnofsky performance status ≥ 70 %.

• 18 years of age or older.

• Ability to swallow oral medication.

• Signed and dated informed consent document indicating that the subject (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to undergoing study screening procedures.

• Subject's willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

• Patients who have received prior systemic therapy for their RCC with VEGF pathway inhibitor (such as sunitinib, sorafenib, and bevacizumab) or with mTOR inhibitors (such as sirolimus, temsirolimus, everolimus, or deforolimus).

• Patients within 28 days post major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic), open biopsy, or significant traumatic injury to avoid wound healing complications. Minor procedures and percutaneous biopsies or placement of vascular access device without complications require 48 hours prior to study entry.

• Patients who had radiation therapy within 28 days prior to start of study treatment (palliative radiotherapy to bone lesions allowed if completed 2 weeks prior to study treatment start).

Patients with evidence or history of central nervous system (CNS) metastases or spinal cord compression, unless prior treatment with surgery or radiotherapy AND no progression of CNS disease within 6 months prior to enrollment.

• Patients with a history of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess within 6 months prior to study enrollment.

• Patients with proteinuria on screening urinalysis confirmed to be >1g /24h by 24 hour urine collection.

• Patients with inadequately controlled hypertension (defined as a blood pressure of > 150 mmHg systolic and/or > 100 mmHg diastolic on medication), or any prior history of hypertensive crisis or hypertensive encephalopathy.

Patients receiving chronic systemic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisone equivalent) or another immunosuppressive agent. Inhaled and topical steroids are acceptable.

• Patients with a known history of HIV seropositivity.

• Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

• unstable angina pectoris (at any time), symptomatic congestive heart failure (NYHA III, IV) (at any time), serious uncontrolled cardiac arrhythmia (at any time), myocardial infarction, cerebrovascular accidents, or symptomatic left ventricular dysfunction ≤ 6 months prior to first study treatment

• active bleeding diathesis

• known severely impaired lung function defined as spirometry and DLCO ≤ 50% of normal and oxygen saturation at rest ≤ 88% on room air.

• symptomatic intrinsic lung disease requiring oxygen supplementation at baseline

• Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary

• any active (acute or chronic) or uncontrolled infection/disorders that impair the ability to evaluate the patient or for the patient to complete the study

• liver disease such as cirrhosis decompensated liver disease or active and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HBsAg, quantifiable HCV-RNA).

• Patients who have a history of another primary malignancy and are off treatment for ≤ 3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of the uterine cervix.

• Female patients who are pregnant or breast feeding

• Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must use highly effective methods of contraception during the study and 8 weeks after. Highly effective contraception methods include combination of any two of the following:

1. Use of oral, injected or implanted hormonal methods of contraception or;

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

3. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository;

4. Total abstinence or;

5. Male/female sterilization

• Women are 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 have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to randomization. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential.

• Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment

• Patients who are using other investigational agents or who had received investigational drugs ≤ 4 weeks prior to study treatment start.

• Patients who have received attenuated live vaccines within one week of study entry. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines. Known intolerance or hypersensitivity to Everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus).

• Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral Everolimus.

• Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Sloan Kettering at Basking Ridge	Basking Ridge	New Jersey	United States	07920
2	Memorial Sloan Kettering Cancer Center at Basking Ridge	Basking Ridge	New Jersey	United States	07939
3	Memorial Sloan Kettering Monmouth	Middletown	New Jersey	United States	07748
4	Memorial Sloan Kettering Cancer Center @ Suffolk	Commack	New York	United States	11725
5	Memorial Sloan Kettering Westchester	Harrison	New York	United States	10604
6	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
7	Memorial Sloan Kettering at Mercy Medical Center	Rockville Centre	New York	United States

Sponsors and Collaborators

• Memorial Sloan Kettering Cancer Center
• Novartis Pharmaceuticals

Investigators

• Principal Investigator: Darren Feldman, MD, Memorial Sloan Kettering Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 29, 2017

More Information

Additional Information:

• Memorial Sloan Kettering Cancer Center

Publications

None provided.

• Responsible Party: Memorial Sloan Kettering Cancer Center
• ClinicalTrials.gov Identifier: NCT01399918
• Other Study ID Numbers: 10-226
• First Posted: Jul 22, 2011
• Last Update Posted: Feb 1, 2022
• Last Verified: Dec 1, 2020

• Keywords provided by Memorial Sloan Kettering Cancer Center: Kidney; Everolimus; Bevacizumab; 10-226; non-clear cell histology; Advanced
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Bevacizumab; Everolimus

Study Results

Participant Flow

Arm/Group Title	Everolimus and Bevacizumab
Arm/Group Description	This is a single-institution, single-arm phase II trial of everolimus in combination with bevacizumab in patients with advanced non-clear cell RCC, who have not received prior VEGF-.or mTOR-targeted therapy.
Period Title: Overall Study
STARTED	57
COMPLETED	55
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Everolimus and Bevacizumab
Arm/Group Description	This is a single-institution, single-arm phase II trial of everolimus in combination with bevacizumab in patients with advanced non-clear cell RCC, who have not received prior VEGF-.or mTOR-targeted therapy.
Overall Participants	55
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	54
Sex: Female, Male (Count of Participants)
Female	13 23.6%
Male	42 76.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 3.6%
Not Hispanic or Latino	53 96.4%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 7.3%
White	44 80%
More than one race	0 0%
Unknown or Not Reported	7 12.7%
Region of Enrollment (Count of Participants)
United States	55 100%

Outcome Measures

1. Primary Outcome

Title	To Evaluate the Efficacy of Combining Everolimus and Bevacizumab in Patients With Advanced RCC of Non-clear Cell Histology
Description	the percent of patients alive and progression-free after 6 months of therapy.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Everolimus and Bevacizumab
Arm/Group Description	This is a single-institution, single-arm phase II trial of everolimus in combination with bevacizumab in patients with advanced non-clear cell RCC, who have not received prior VEGF-.or mTOR-targeted therapy.
Measure Participants	55
Number [percent of participants]	78 141.8%

2. Secondary Outcome

Title	Secondary Endpoint Will be the Overall Response Rate (ORR)
Description	per the international criteria defined by the Response Evaluation Criteria in Solid Tumors Committee
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Everolimus and Bevacizumab
Arm/Group Description	This is a single-institution, single-arm phase II trial of everolimus in combination with bevacizumab in patients with advanced non-clear cell RCC, who have not received prior VEGF-.or mTOR-targeted therapy.
Measure Participants	55
Number [percent of participants with ORR]	35 63.6%

3. Secondary Outcome

Title	Participants Evaluated for Toxicity
Description	Toxicity will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.0 (Gompertz 1825),. Toxicities will be summarized by type and grade using frequencies and rates.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Everolimus and Bevacizumab
Arm/Group Description	This is a single-institution, single-arm phase II trial of everolimus in combination with bevacizumab in patients with advanced non-clear cell RCC, who have not received prior VEGF-.or mTOR-targeted therapy.
Measure Participants	55
Count of Participants [Participants]	55 100%

Adverse Events

Time Frame	2 years
Arm/Group Title	Everolimus and Bevacizumab
Arm/Group Description	This is a single-institution, single-arm phase II trial of everolimus in combination with bevacizumab in patients with advanced non-clear cell RCC, who have not received prior VEGF-.or mTOR-targeted therapy.
All Cause Mortality
	Everolimus and Bevacizumab
	Affected / at Risk (%)	# Events
Total	43/55 (78.2%)
Serious Adverse Events
	Everolimus and Bevacizumab
	Affected / at Risk (%)	# Events
Total	22/55 (40%)
Cardiac disorders
Palpitations	1/55 (1.8%)
Sinus tachycardia	1/55 (1.8%)
Gastrointestinal disorders
Abdominal Pain	6/55 (10.9%)
Constipation	1/55 (1.8%)
Gastrointestinal disorders - Other, specify	3/55 (5.5%)
Nausea	2/55 (3.6%)
Rectal hemorrhage	1/55 (1.8%)
Vomiting	2/55 (3.6%)
General disorders
Death NOS	3/55 (5.5%)
Fatigue	2/55 (3.6%)
Fever	2/55 (3.6%)
Non-cardiac chest pain	1/55 (1.8%)
Pain	1/55 (1.8%)
Hepatobiliary disorders
Cholecystitis	1/55 (1.8%)
Infections and infestations
Lung infection	1/55 (1.8%)
Investigations
Blood bilirubin increased	1/55 (1.8%)
Creatinine increased	5/55 (9.1%)
Metabolism and nutrition disorders
Anorexia	1/55 (1.8%)
Dehydration	1/55 (1.8%)
Musculoskeletal and connective tissue disorders
Back Pain	3/55 (5.5%)
Flank Pain	10/55 (18.2%)
Muscle weakness lower limb	1/55 (1.8%)
Renal and urinary disorders
Acute kidney injury	2/55 (3.6%)
Hematuria	1/55 (1.8%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	8/55 (14.5%)
Pleural effusion	1/55 (1.8%)
Pneumonitis	2/55 (3.6%)
Vascular disorders
Hematoma	1/55 (1.8%)
Other (Not Including Serious) Adverse Events
	Everolimus and Bevacizumab
	Affected / at Risk (%)	# Events
Total	55/55 (100%)
Gastrointestinal disorders
Mucositis oral	39/55 (70.9%)
Nausea	21/55 (38.2%)
Diarrhea	19/55 (34.5%)
Constipation	11/55 (20%)
Abdominal pain	5/55 (9.1%)
Vomiting	5/55 (9.1%)
General disorders
Fatigue	40/55 (72.7%)
Edema limbs	12/55 (21.8%)
Pain	9/55 (16.4%)
Fever	5/55 (9.1%)
Gen disorders & admin site conditions Other, spec	4/55 (7.3%)
Investigations
Weight loss	10/55 (18.2%)
Alanine aminotransferase increased	5/55 (9.1%)
Alkaline phosphatase increased	4/55 (7.3%)
Aspartate aminotransferase increased	3/55 (5.5%)
Metabolism and nutrition disorders
Anorexia	11/55 (20%)
Hypertriglyceridemia	7/55 (12.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	6/55 (10.9%)
Myalgia	3/55 (5.5%)
Nervous system disorders
Peripheral sensory neuropathy	14/55 (25.5%)
Headache	10/55 (18.2%)
Dysgeusia	6/55 (10.9%)
Psychiatric disorders
Insomnia	3/55 (5.5%)
Renal and urinary disorders
Urinary frequency	6/55 (10.9%)
Renal and urinary disorders - Other, specify	5/55 (9.1%)
Hematuria	4/55 (7.3%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	30/55 (54.5%)
Dyspnea	23/55 (41.8%)
Cough	15/55 (27.3%)
Pneumonitis	8/55 (14.5%)
Sore throat	4/55 (7.3%)
Skin and subcutaneous tissue disorders
Rash acneiform	21/55 (38.2%)
Dry skin	15/55 (27.3%)
Rash maculo-papular	12/55 (21.8%)
Pruritus	8/55 (14.5%)
Palmar-plantar erythrodysesthesia syndrome	4/55 (7.3%)
Skin and subcutaneous tissue disorders - Other, specify	3/55 (5.5%)
Vascular disorders
Hypertension	43/55 (78.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.