Erlotinib and Sirolimus for the Treatment of Metastatic Renal Cell Carcinoma

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT00353301
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 25
• Location: 1
• Arm: 1
• Duration (Months): 68
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to test the safety and efficacy of the combination of erlotinib hydrochloride (Tarceva™) and sirolimus (Rapamune™) in the treatment of patients with metastatic kidney cancer.

Condition or Disease	Intervention/Treatment	Phase
Renal Cell Carcinoma	Drug: Erlotinib hydrochloride; Drug: Sirolimus	Phase 2

Detailed Description

Despite recent advances metastatic renal cell carcinoma remains an incurable condition. Currently available treatment with high-dose interleukin-2 can lead to complete responses in a small minority of selected patients but is markedly toxic and not broadly available. FDA-approved multikinase inhibitors (sorafenib and sunitinib malate) often cause partial and transient tumor regression. There is no standard treatment metastatic renal cell carcinoma for patients whose disease progressed on multikinase inhibitors. The kinase mammalian target of rapamycin (mTOR) is overstimulated in a subset of renal cell carcinomas and other malignancies and can be blocked by sirolimus leading to growth arrest. Erlotinib hydrochloride is a drug that blocks the function of the epidermal growth factor receptor (EGFR), often over expressed in kidney cancer. Sirolimus and EGFR inhibitors and been safely used in combination. In vitro experiments show that erlotinib enhances the sirolimus induced growth impairment in a panel of renal cell carcinoma cells. In the present study patients with metastatic renal cell carcinoma whose disease progressed on multikinase inhibitors will be treated with the combination of erlotinib hydrochloride (Tarceva™) and sirolimus (Rapamune™). This is a single arm trial with no placebo or drug-based control arm

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 Single Arm Clinical Trial to Evaluate the Efficacy and Safety of the Combination of Tarceva™ (Erlotinib Hydrochloride) and Rapamune™ (Sirolimus) in the Treatment of Metastatic Renal Cell Carcinoma.
• Study Start Date: Jul 1, 2006
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Erlotinib and Sirolimus Erlotinib hydrochloride (Tarceva) will be self-administered in an open-label unblinded manner to all patients enrolled in the study. During the treatment period, patients will receive single-agent Tarceva, 150 mg/day. Sirolimus (Rapamune) will be self-administered in an open-label unblinded manner to all patients enrolled in the study. Patients will receive a loading dose of 6 mg of Rapamune seven days after beginning treatment with Tarceva™ followed by a dose of 2mg/day.

Drug: Erlotinib hydrochloride; Patients will receive single-agent Tarceva, 150 mg/day; Other Names: Tarceva ; Drug: Sirolimus; Patients will receive a loading dose of 6 mg of Rapamune seven days after beginning treatment with Tarceva™ followed by a dose of 2mg/day.; Other Names: Rapamune

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [Physical exam assessments were performed every 4 weeks during the treatment phase. Survival follow-up information was collected every 4 months following the termination visit until death, loss to follow-up, or study termination up to 275 weeks.]

   Time to progression was defined as the time from beginning of therapy until disease progression or death. For subjects who had not progressed at the time of statistical analysis, progression-free survival was censored at the date of their last tumor assessment. Kaplan-Meier method was used to estimate median progression-free survival. Progression was defined as radiographic progression according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria (year 2000 version), non-compliance in obtaining scans, unequivocal clinical progression or the initiation of another medication for the treatment of renal cell carcinoma.

Secondary Outcome Measures

1. Overall Survival [Survival follow-up information was collected every 4 months following the termination visit until death, loss to follow-up, or study termination up to 275 weeks.]

   For all subjects who had not died at the time of statistical analysis, duration of survival will was censored at the date of last contact. Kaplan-Meier methodology was used to estimate the magnitude of the treatment effect as described for progression-free survival.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Signed informed consent to participate in this study.

• Histological diagnosis of renal cell carcinoma.

• Age greater or equal 18 years.

• Eastern Cooperative Oncology Group (ECOG) Performance status of 2 or better.

• Life expectancy of at least 3 months.

• Failure or intolerance to previous treatment with Sutent® and/or Nexavar®.

• Most recent systemic treatment at least 1 month from the beginning of treatment.

• Most recent local treatment (surgery or irradiation) > 2 weeks from the beginning of treatment.

• At least one site of measurable disease by CT scan or MRI (RECIST criteria).

• Baseline hemoglobin >9 g/dl, platelets > 100,000/mm3, absolute neutrophil count (ANC

1500/mm3.

Exclusion Criteria:

• Previous treatment with Tarceva™, Iressa™, Rapamune™, temsirolimus or everolimus.

• Untreated metastasis to the central nervous system.

• Previous solid organ, bone marrow or stem-cell transplant.

• Known AIDS or HIV infection.

• Symptomatic or poorly controlled chronic heart failure.

• Chronic renal failure requiring dialysis on a regular basis.

• Chronic liver failure.

• Serum aspartate aminotransferase (AST), Alanine Aminotransferase (ALT), alkaline phosphatase or bilirubin >1.5 x the upper limit of normal for the local laboratory.

• Pregnant or breast-feeding women.

• Other invasive malignant diseases within 5 years (other than squamous or basal cell carcinoma of the skin).

• Inability to provide informed consent

• Any other serious and/or unstable medical, psychiatric, or other condition considered by the P.I. to preclude safe or reasonably compliant participation in the protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Hospital	Aurora	Colorado	United States	80010

Sponsors and Collaborators

• University of Colorado, Denver
• Genentech, Inc.

Investigators

• Principal Investigator: Thomas W Flaig, MD, University of Colorado, Denver

Study Documents (Full-Text)

None provided.

More Information

Publications

• Gemmill RM, Zhou M, Costa L, Korch C, Bukowski RM, Drabkin HA. Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma. Br J Cancer. 2005 Jun 20;92(12):2266-77.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT00353301
• Other Study ID Numbers: 05-1135.cc
• First Posted: Jul 18, 2006
• Last Update Posted: Apr 14, 2014
• Last Verified: Mar 1, 2014

• Keywords provided by University of Colorado, Denver: Carcinoma, Renal Cell; Receptor, Epidermal Growth Factor; mTOR protein; Sirolimus; Erlotinib
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Sirolimus; Erlotinib Hydrochloride

Study Results

Participant Flow

Recruitment Details	This was a phase II, single-arm, single-institution trial. A total of 25 patients were enrolled between July 2006 and March 2008 from University of Colorado Cancer Center.
Pre-assignment Detail	Patients with previous treatment with erlotinib, gefitinib, sirolimus, temsirolimus or everolimus, untreated central nervous system metastasis, renal failure requiring dialysis or significant liver dysfunction were excluded from the trial.

Arm/Group Title	Erlotinib and Sirolimus
Arm/Group Description	Erlotinib (Tarceva) therapy was started at 150 mg by mouth daily from day 1 to be taken at least 1 hour before or 2 hours after a meal. Sirolimus was initiated on day 8 (D8) with a loading dose of 6mg by mouth, followed by a daily dose of 2mg by mouth, on the basis of the product prescribing information for low-to-moderate immunologic risk renal transplant patients.
Period Title: Overall Study
STARTED	25
COMPLETED	25
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Erlotinib and Sirolimus
Arm/Group Description	Erlotinib (Tarceva) therapy was started at 150 mg by mouth daily from day 1 to be taken at least 1 hour before or 2 hours after a meal. Sirolimus was initiated on day 8 (D8) with a loading dose of 6mg by mouth, followed by a daily dose of 2mg by mouth, on the basis of the product prescribing information for low-to-moderate immunologic risk renal transplant patients.
Overall Participants	25
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	16 64%
>=65 years	9 36%
Sex: Female, Male (Count of Participants)
Female	5 20%
Male	20 80%
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	0 0%
White	25 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 12%
Not Hispanic or Latino	21 84%
Unknown or Not Reported	1 4%
Region of Enrollment (Number) [Number]
United States	25 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	Time to progression was defined as the time from beginning of therapy until disease progression or death. For subjects who had not progressed at the time of statistical analysis, progression-free survival was censored at the date of their last tumor assessment. Kaplan-Meier method was used to estimate median progression-free survival. Progression was defined as radiographic progression according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria (year 2000 version), non-compliance in obtaining scans, unequivocal clinical progression or the initiation of another medication for the treatment of renal cell carcinoma.
Time Frame	Physical exam assessments were performed every 4 weeks during the treatment phase. Survival follow-up information was collected every 4 months following the termination visit until death, loss to follow-up, or study termination up to 275 weeks.

Outcome Measure Data

Analysis Population Description

Per protocol analysis was used and 25 participants that were enrolled in the study were included in the analysis.

Arm/Group Title	Erlotinib and Sirolimus
Arm/Group Description	Erlotinib (Tarceva) therapy was started at 150 mg by mouth daily from day 1 to be taken at least 1 hour before or 2 hours after a meal. Sirolimus was initiated on day 8 (D8) with a loading dose of 6mg by mouth, followed by a daily dose of 2mg by mouth, on the basis of the product prescribing information for low-to-moderate immunologic risk renal transplant patients.
Measure Participants	25
Median (95% Confidence Interval) [Weeks]	12

2. Secondary Outcome

Title	Overall Survival
Description	For all subjects who had not died at the time of statistical analysis, duration of survival will was censored at the date of last contact. Kaplan-Meier methodology was used to estimate the magnitude of the treatment effect as described for progression-free survival.
Time Frame	Survival follow-up information was collected every 4 months following the termination visit until death, loss to follow-up, or study termination up to 275 weeks.

Outcome Measure Data

Analysis Population Description

Per protocol analysis was used and 25 participants that were enrolled in the study were included in the analysis.

Arm/Group Title	Erlotinib and Sirolimus
Arm/Group Description	Erlotinib (Tarceva) therapy was started at 150 mg by mouth daily from day 1 to be taken at least 1 hour before or 2 hours after a meal. Sirolimus was initiated on day 8 (D8) with a loading dose of 6mg by mouth, followed by a daily dose of 2mg by mouth, on the basis of the product prescribing information for low-to-moderate immunologic risk renal transplant patients.
Measure Participants	25
Median (95% Confidence Interval) [Weeks]	40

Adverse Events

Time Frame	Adverse events were collected throughout the period of active therapy up to 4 weeks.
Adverse Event Reporting Description	Monitoring included patient interview, physical exam, routine laboratory tests (even in absence of symptoms) and appropriate work-up of any new symptoms or laboratorial abnormalities.
Arm/Group Title	Erlotinib and Sirolimus
Arm/Group Description	Erlotinib (Tarceva) therapy was started at 150 mg by mouth daily from day 1 to be taken at least 1 hour before or 2 hours after a meal. Sirolimus was initiated on day 8 (D8) with a loading dose of 6mg by mouth, followed by a daily dose of 2mg by mouth, on the basis of the product prescribing information for low-to-moderate immunologic risk renal transplant patients.
All Cause Mortality
	Erlotinib and Sirolimus
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Erlotinib and Sirolimus
	Affected / at Risk (%)	# Events
Total	2/25 (8%)
General disorders
Hospitalization	1/25 (4%)
Musculoskeletal and connective tissue disorders
Chest pain	1/25 (4%)
Other (Not Including Serious) Adverse Events
	Erlotinib and Sirolimus
	Affected / at Risk (%)	# Events
Total	25/25 (100%)
Blood and lymphatic system disorders
Anaemia	14/25 (56%)
Hypoalbuminaemia	12/25 (48%)
Elevated creatinine	10/25 (40%)
Hypertriglyceridaemia	9/25 (36%)
Hypophosphataemia	7/25 (28%)
Cardiac disorders
Decreased left ventricular ejection fraction	1/25 (4%)
Myocardial infarction	1/25 (4%)
Tachycardia	1/25 (4%)
Anuria	1/25 (4%)
Gastrointestinal disorders
Diarrhoea	12/25 (48%)
Anorexia	9/25 (36%)
Mucositis	9/25 (36%)
Nausea	8/25 (32%)
General disorders
Fatigue	11/25 (44%)
Pain	7/25 (28%)
Chills/cold intolerance	6/25 (24%)
Weight loss	6/25 (24%)
Respiratory, thoracic and mediastinal disorders
Cough	7/25 (28%)
Rhinitis	7/25 (28%)
Pulmonary oedema	1/25 (4%)
Epistaxis	6/25 (24%)
Haemorrhage/bleeding other	6/25 (24%)
Skin and subcutaneous tissue disorders
Rash	24/25 (96%)
Dry skin	8/25 (32%)
Pruritis/pain	6/25 (24%)

Limitations/Caveats

One limitation of this study was the lack of von Hippel-Lindau (VHL) mutational status assessment.

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.