Biomarker Trial of Everolimus in Patients With Advanced Renal Cell Carcinoma

• Sponsor: Beth Israel Deaconess Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00827359
• Collaborator: Dana-Farber Cancer Institute (Other), Duke University (Other), Novartis (Industry)
• Enrollment: 25
• Locations: 3
• Arm: 1
• Duration (Months): 111
• Patients Per Site: 8.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if certain features of tumor specimens sampled prior to therapy can predict for the likelihood of responding to everolimus.

Condition or Disease	Intervention/Treatment	Phase
Renal Cell Carcinoma; Renal Cancer	Drug: Everolimus	Phase 2

Detailed Description

• Participants will undergo a CT or ultrasound guided biopsy of an accessible tumor lesion before beginning the study medication.

• Everolimus tablets will be taken orally once a day. Participants will undergo a physical exam and will be asked questions about their general health and specific questions about any problems they might be having. Photographs will be taken of the tumor to assess the response to treatment. This will be done by a CT or MRI scan. Blood tests will be performed every 4 weeks. In addition, blood for research purposes will be done on day 1 of every other cycle. A urine test will be done every 4 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Biomarker Trial of Everolimus in Patients With Advanced Renal Cell Carcinoma
• Study Start Date: Mar 1, 2009
• Actual Primary Completion Date: Jan 1, 2018
• Actual Study Completion Date: Jun 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment This is a single-arm study. All patients will receive everolimus.	Drug: Everolimus; Tablet form taken orally once a day

Outcome Measures

Primary Outcome Measures

1. Difference in Median Progression Free Survival Time Between Favorable and Unfavorable Biomarker Group [Follow-up time was up to 39 months from treatment start date.]

   The biomarkers of interest are pS6 and pAkt. Expression will be classified as low, intermediate, or high based on a composite score of staining intensity and % of tumor cells staining positive. The difference in progression free survival (PFS) time in the "low" to "high" groups is analyzed. PFS is the time from start of treatment to disease progression (PD) or death (estimated by Kaplan Meier method)s. Patients without PD and alive are censored at last date patient is known PD-free. PD is defined by Response Evaluation Criteria In Solid Tumors Criteria 1.1 (RECIST) as follows: >20% increase in the sum of the diameters (SD) of target lesions, referencing the smallest SD on study (including baseline). Must be an increase of >5 mm. New lesions or PD of non-target lesions. Must be represent overall disease status change, not a single lesion increase. Patients with PD at the first on-treatment imaging assessment, will remain on study at investigator discretion until later confirmed.

2. Median Progression Free Survival [Follow-up time was up to 39 months from treatment start date.]

   Progression free survival (PFS) is defined as the time from start of treatment to disease progression (PD) or death from any cause as estimated by Kaplan Meier methods. Patients who have not progressed and are alive are censored at the date the patient is known to be progression-free. Progression is defined by Response Evaluation Criteria In Solid Tumors Criteria 1.1 (RECIST) as follows: - >20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (including baseline if it's the smallest). The sum must also demonstrate an increase of >5 mm. OR -Appearance of new lesions and/or unequivocal progression of non-target lesions. It must be representative of overall disease status change, not a single lesion increase. For patients with PD at the first on-treatment imaging assessment, patients will be allowed to remain on study until confirmation at the next assessment at investigator discretion if patient is benefiting from treatment.

Secondary Outcome Measures

1. Best Overall Response Rate [Evaluated while on treatment. Up to 36 months.]

   The best overall response rate is the percentage of participants achieving complete response (CR) or partial response (PR) as the best response recorded on treatment based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CR and PR must meet the following lesion criteria without having any new lesions as well: Target Lesion: (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Non-Target Lesion: (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Non-CR/Non-Progressive Disease: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have PR in target lesion.

2. Best Overall Response by PI3K-AKT-MTOR Mutation [Evaluated while on treatment. Up to 36 months]

   Next generation sequencing was used to identify participants with PI3K-AKT-MTOR mutations. Best overall response rate was analyzed with mutant versus wild-type pathways. Please see Best Overall Response Rate for response definition.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must have at least one site of disease which in the opinion of the investigator is safely accessible by CT guided biopsy or metastasectomy. Safely accessible metastatic disease will be defined to include those lesions which are palpable with no overlying viscera and are at least 2cm in size. Given the paucity of subcutaneous lesions in RCC, lesions which are felt to be safe to biopsy will also be allowed. These lesions include pleural-based tumors, peripheral liver lesions, kidney lesions and bone lesions with exophytic soft tissue component. As with palpable lesions, these other lesions should be at least 2cm in size with no overlying viscera.

• At least one measurable site of disease, other than the biopsy site, according to RECIST criterial that has not been previously irradiated. Th the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation

• Metastatic renal carcinoma with histologic confirmation by the treating center of either primary or a metastatic lesion. Non-clear cell histologies will be allowed

• 18 years of age or older

• Minimum of four weeks since any major surgery, completion of radiation, or completion of all prior systemic anticancer therapy (adequately recovered from the acute toxicities of any prior therapy)

• ECOG Performance status of 1 or less

• Adequate bone marrow, liver and renal function as outlined in the protocol

• Fasting serum cholesterol < 300mg/dL OR < 7.75 mmol/L AND fasting triglycerides < 2.5 x ULN

• Life expectancy of greater than 6 months

Exclusion Criteria:

• Prior treatment with any investigation drug within the preceding 4 weeks

• Chronic treatment with systemic steroids or another immunosuppressive agent

• Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period

• Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases. Treated brain metastases will be allowed. Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS: Gamma Knife, LINAC or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection performed within 3 months prio to day 1 will be excluded.

• Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin

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

• Uncontrolled diabetes mellitus as defined by a fasting serum > 1.5 x ULN

• A known history of HIV seropositivity.

• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus

• Patients with active, bleeding diathesis or on systemic anticoagulation. Aspirin is permitted.

• Women who are pregnant or breast feeding, or women/men able to conceive and unwilling to practice an effective method of birth control.

• Patients who have received prior treatment with an mTOR inhibitor.

• Patients with known hypersensitivity to everolimus or other rapamycins or to its excipients.

• History of noncompliance to medical regimens

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
3	Duke University Medical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Beth Israel Deaconess Medical Center
• Dana-Farber Cancer Institute
• Duke University
• Novartis

Investigators

• Principal Investigator: David F McDermott, MD, Beth Israel Deaconess Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 3, 2014

More Information

Publications

None provided.

• Responsible Party: David F. McDermott, MD, Director of Biologic Therapy Program, Beth Israel Deaconess Medical Center
• ClinicalTrials.gov Identifier: NCT00827359
• Other Study ID Numbers: 08-313
• First Posted: Jan 22, 2009
• Last Update Posted: Feb 24, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by David F. McDermott, MD, Director of Biologic Therapy Program, Beth Israel Deaconess Medical Center: everolimus
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Kidney Neoplasms; Everolimus

Study Results

Participant Flow

Arm/Group Title	Treatment
Arm/Group Description	This is a single-arm study. All patients will receive everolimus. Everolimus: Tablet form taken orally once a day
Period Title: Overall Study
STARTED	25
Treated	24
COMPLETED	0
NOT COMPLETED	25

Baseline Characteristics

Arm/Group Title	Treatment
Arm/Group Description	This is a single-arm study. All patients will receive everolimus. Everolimus: Tablet form taken orally once a day
Overall Participants	24
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64
Sex: Female, Male (Count of Participants)
Female	8 33.3%
Male	16 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	23 95.8%
Not Hispanic or Latino	0 0%
Unknown or Not Reported	1 4.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 4.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	23 95.8%
More than one race	0 0%
Unknown or Not Reported	0 0%
ECOG Performance Status (Count of Participants)
00	15 62.5%
01	9 37.5%
Prior Lines of Therapy (therapies) [Median (Full Range) ]
Median (Full Range) [therapies]	2
Histology (Count of Participants)
Clear Cell	18 75%
Papillary	4 16.7%
Missing	2 8.3%
Memorial Sloan Kettering Cancer Center Risk Class (Count of Participants)
Favorable (0 risk factors)	4 16.7%
Intermediate (1-2 risk factors)	14 58.3%
High (>=3 risk factors)	6 25%
International Metastatic Renal-Cell Carcinoma Database Consortium Class (Count of Participants)
Favorable (0 risk factors)	5 20.8%
Intermediate (1-2 risk factors)	19 79.2%
High (≥3 risk factors)	0 0%
Prior Nephrectomy (Count of Participants)
Yes, Radical	21 87.5%
Yes, Partial	1 4.2%
No	0 0%
Missing	2 8.3%
Metastatic Sites (Count of Participants)
Bone	4 16.7%
Liver	8 33.3%
Lung	16 66.7%
Brain	0 0%
Renal	6 25%
Pancreas	3 12.5%
Lymph Nodes, Intra-Abdominal	11 45.8%
Lymph Node, Pulmonary	7 29.2%
Adrenal Glands	5 20.8%
Other	15 62.5%

Outcome Measures

1. Primary Outcome

Title	Difference in Median Progression Free Survival Time Between Favorable and Unfavorable Biomarker Group
Description	The biomarkers of interest are pS6 and pAkt. Expression will be classified as low, intermediate, or high based on a composite score of staining intensity and % of tumor cells staining positive. The difference in progression free survival (PFS) time in the "low" to "high" groups is analyzed. PFS is the time from start of treatment to disease progression (PD) or death (estimated by Kaplan Meier method)s. Patients without PD and alive are censored at last date patient is known PD-free. PD is defined by Response Evaluation Criteria In Solid Tumors Criteria 1.1 (RECIST) as follows: >20% increase in the sum of the diameters (SD) of target lesions, referencing the smallest SD on study (including baseline). Must be an increase of >5 mm. New lesions or PD of non-target lesions. Must be represent overall disease status change, not a single lesion increase. Patients with PD at the first on-treatment imaging assessment, will remain on study at investigator discretion until later confirmed.
Time Frame	Follow-up time was up to 39 months from treatment start date.

Outcome Measure Data

Analysis Population Description

Phospho-Akt and phospho-S6 immunohistochemistry analysis was unsuccessful due to the lack of adequate tissue samples and was not pursued further.

Arm/Group Title	Treatment
Arm/Group Description	This is a single-arm study. All patients will receive everolimus. Everolimus: Tablet form taken orally once a day
Measure Participants	0

2. Primary Outcome

Title	Median Progression Free Survival
Description	Progression free survival (PFS) is defined as the time from start of treatment to disease progression (PD) or death from any cause as estimated by Kaplan Meier methods. Patients who have not progressed and are alive are censored at the date the patient is known to be progression-free. Progression is defined by Response Evaluation Criteria In Solid Tumors Criteria 1.1 (RECIST) as follows: - >20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (including baseline if it's the smallest). The sum must also demonstrate an increase of >5 mm. OR -Appearance of new lesions and/or unequivocal progression of non-target lesions. It must be representative of overall disease status change, not a single lesion increase. For patients with PD at the first on-treatment imaging assessment, patients will be allowed to remain on study until confirmation at the next assessment at investigator discretion if patient is benefiting from treatment.
Time Frame	Follow-up time was up to 39 months from treatment start date.

Outcome Measure Data

Analysis Population Description

Twenty-five patients enrolled onto the study between April 2009 and November 2012. One patient became ineligible because of the inability to obtain a pretreatment biopsy sample. A total of 27 tissue samples were successfully obtained from 24 patients, with 3 sets of paired tissues obtained before treatment and while receiving treatment.

Arm/Group Title	Treatment
Arm/Group Description	This is a single-arm study. All patients will receive everolimus. Everolimus: Tablet form taken orally once a day
Measure Participants	24
Median (90% Confidence Interval) [months]	3.8

3. Secondary Outcome

Title	Best Overall Response Rate
Description	The best overall response rate is the percentage of participants achieving complete response (CR) or partial response (PR) as the best response recorded on treatment based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CR and PR must meet the following lesion criteria without having any new lesions as well: Target Lesion: (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Non-Target Lesion: (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Non-CR/Non-Progressive Disease: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have PR in target lesion.
Time Frame	Evaluated while on treatment. Up to 36 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment
Arm/Group Description	This is a single-arm study. All patients will receive everolimus. Everolimus: Tablet form taken orally once a day
Measure Participants	24
Number (90% Confidence Interval) [percentage of participants]	4.2 17.5%

4. Secondary Outcome

Title	Best Overall Response by PI3K-AKT-MTOR Mutation
Description	Next generation sequencing was used to identify participants with PI3K-AKT-MTOR mutations. Best overall response rate was analyzed with mutant versus wild-type pathways. Please see Best Overall Response Rate for response definition.
Time Frame	Evaluated while on treatment. Up to 36 months

Outcome Measure Data

Analysis Population Description

Participants were classified as either "mutations" or "no mutations."

Arm/Group Title	Treatment
Arm/Group Description	This is a single-arm study. All patients will receive everolimus. Everolimus: Tablet form taken orally once a day
Measure Participants	24
Mutation	5.6 23.3%
No Mutations	0 0%

Adverse Events

Time Frame	2 years
Arm/Group Title	Treatment
Arm/Group Description	This is a single-arm study. All patients will receive everolimus. Everolimus: Tablet form taken orally once a day
All Cause Mortality
	Treatment
	Affected / at Risk (%)	# Events
Total	0/24 (0%)
Serious Adverse Events
	Treatment
	Affected / at Risk (%)	# Events
Total	0/24 (0%)
Other (Not Including Serious) Adverse Events
	Treatment
	Affected / at Risk (%)	# Events
Total	5/24 (20.8%)
Gastrointestinal disorders
nausea	5/24 (20.8%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS 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.