RAPAMYCIN FOR KIDNEY ANGIOMYOLIPOMAS

NCT ID: NCT00126672

Last Updated: 2022-04-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 36 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-12-20
• Study Completion Date: 2010-04-30

Brief Summary

This research study is evaluating a drug called rapamycin as a possible treatment for the lumps (or tumors) that form in the kidneys, called angiomyolipomas, in people who have either TSC or LAM. Kidney angiomyolipomas are tumors that are made up of blood vessels, muscle and fat. Rapamycin has been approved to treat other diseases, but it is investigational for treating kidney angiomyolipomas.

Investigational means that it is being as a possible treatment for kidney angiomyolipomas but is not currently approved by the U.S. Food and Drug Administration (FDA) for treating this disease.

Detailed Description

This research study is a Phase ll clinical trial. Phase II clinical trials test the effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is still being studied and that research doctors are trying to find out more about it-such as the safest dose to use, the side effects it may cause, and if the drug is effective for treating different types of diseases. It also means that the FDA (the U.S. Food and Drug Administration) has not yet approved this drug for this type of disease.

The purpose of this research study is to see if the drug, rapamycin, is effective in treating kidney angiomyolipomas. Rapamycin is a drug that may decrease the size of tumors. This drug has been used in treating other diseases and cancers in humans and information from those other research studies suggests that rapamycin may help to shrink tumors in this research study.

The investigators will also be looking at the safety of this drug in people with TSC or LAM. In addition, the investigators will also look at whether this drug is effective for treating other conditions that occur in people that have TSC or LAM (tubers, subependymal giant cell astrocytomos, facial angiofibromas, kidney cysts in TSC, or symptoms of cough, breathing trouble or other symptoms of lung problems in people with LAM).

Although these tumors (kidney angiomyolipomas) may not change for many years, they do not go away on their own. They often grow larger and may bleed. The standard of care for treating these tumors is to take pictures of them using ultrasound, CT or MRI (called kidney imaging) every 1-3 years to see if they are getting larger or if they are bleeding. If they do grow larger or bleed, removing them by surgery or cutting off the blood supply to the tumor (vascular embolization) may be recommended.

This research study is being done because there are no medicines available at this time that can treat kidney angiomyolipomas. However, recent studies in the laboratory have shown that the drug, rapamycin, maybe effective in treating these tumors. Because rapamycin is approved by the FDA for treating other medical conditions, we know what doses are safe to use based on guidelines that have been approved by the FDA.

Conditions

Nonmalignant Neoplasm; Tuberous Sclerosis; Lymphangioleimyomatosis; Kidney Angiomyolipoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Ramaycin

Rapamycin treatment was initiated with a loading dose of 6 mg by mouth on day 1 followed by 2 mg by mouth daily. The dose was then adjusted to maintain a target blood level of 3-9 ng/ml for the first 16 weeks. After week 16, the dose of Rapamycin was increased to a target level of 9-15 ng/ml unless there was evidence for a partial response or complete response by kidney MRI. Trough Rapamycin levels were checked every 8-12 weeks (at 24 weeks, 32 weeks, 40 weeks, and 52 weeks) in all patients until the 12-month (week 52) study visit. If the Rapamycin dose was below target, the dose was increased by 1-2 mg until the target trough level was achieved. Rapamycin levels were checked every 2-3 weeks while the dose was adjusted. Amendment 20 (Jan 2009) permitted additional Rapamycin treatment during months 12-24 if the treating site investigator judged that this was in the best interest of the study participant.

Group Type: EXPERIMENTAL

Rapamycin

Intervention Type: DRUG

Interventions

Rapamycin

Intervention Type: DRUG

Other Intervention Names

Rapamune; Sirolimus

Eligibility Criteria

Inclusion Criteria

• Age 3-65 years old (females of reproductive age must not be pregnant or breastfeeding)
• Kidney ANGIOMYOLIPOMA 2 cm or greater on baseline MRI (a CT scan may be used for patients who cannot undergo MRI imaging)
• No evidence of severe LAM (not on continuous oxygen)
• Informed consent, including consent for submission of blood, urine and tissue samples as described in the appendix.
• Adequate renal and liver function (eGFR of 30 or higher, SGOT, SGPT, TBili, Alk Phos all<2x normal)
• HCT>27%
• ANC > 1500 and platelet count >100,000
• Diagnosis of TSC or LAM (diagnosis of TSC using revised diagnostic criteria [45], diagnosis of LAM made by chest CT scan and reviewed by a pulmonologist).
• Fertility/Reproductive issues: The effects of rapamycin on the developing fetus at the doses used in this study are unknown. For this reason, rapamycin should not be taken during pregnancy. Participants who are fertile must maintain adequate contraception while they are taking rapamycin and for twelve weeks after stopping the drug. Acceptable contraceptive measures include prior hysterectomy, oophorectomy or tubal ligation, complete abstinence, barrier methods which include both a cervical diaphragm and spermicidal jelly, and progestin based contraceptives. Pregnancy tests will be obtained at enrollment and during study visits at 8 weeks, 16 weeks, 24 weeks, 32 weeks, 40 weeks, and 52 weeks.

• Note: Eligibility requirement of ECOG PS of 0 or 1 has been removed to allow participation of those subjects with TSC who are classified as ECOG PS of 2,3, or 4 because of cognitive impairment rather than progressive disease. This change allows site Pl's to individualize decision making on whether or not to enroll such subjects after discussing details of the study with prospective participant and legal guardian. The decision to enroll individuals with ECOG PS of 2,3, or 4 will be at the discretion of the Principal Investigator.

Exclusion Criteria

• Unstable seizures (defined as changes in anti-epileptics OR increase in frequency and/or severity or seizures in the 60 days prior to study entry)
• Significant bleed associated with kidney angiomyolipoma(s) (defined as bleed associated with shock OR requiring a blood transfusion in the 30 days prior to study entry)
• Severe LAM (defined as dependent on continuous supplemental oxygen)
• Evidence for accelerating renal dysfunction or acute renal failure
• Diagnosis of Renal Cell Cancer that has not been treated (additional clarification: individuals with a prior history of renal cancer who have had appropriate surgery and have no evidence of metastatic disease can be enrolled)
• Active infection
• Patients will be excluded if they have been treated with any investigational agent in the 30 days prior to study entry
• Patients may not be treated with other investigational agents while on study
• Prior history of coronary artery disease
• Vascular embolization for treatment of kidney angiomyolipoma(s) within 6 months
• Patients who must take diltiazem, ketoconazole or rifampin chronically will be excluded because of known drug interactions. Both diltiazem and ketoconazole are strong inhibitors of CYP3A4 and are known to increase rapamycin levels. Rifampin is a known CYP3A4 and P-glycoprotein inducer and is known to significantly reduce rapamycin levels.

• Minimum Eligible Age: 3 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Wyeth is now a wholly owned subsidiary of Pfizer

INDUSTRY

Sponsor Role: collaborator

Tuberous Sclerosis Alliance

OTHER

Sponsor Role: collaborator

Dana-Farber Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sandra Dabora, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Dana-Farber/Brigham and Women's Cancer Center

Locations

Loma Linda University School of Medicine

Loma Linda, California, United States

Connecticut Children's Medical Center

Hartford, Connecticut, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

New York University Medical Center

New York, New York, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

University of Pennsylvania Medical Center

Philadelphia, Pennsylvania, United States

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, United States

Countries

United States

References

Malinowska IA, Lee N, Kumar V, Thiele EA, Franz DN, Ashwal S, Sagalowsky A, Dimario FJ Jr, Cutler D, Krueger D, Camposano S, Paolini J, Dabora SL. Similar trends in serum VEGF-D levels and kidney angiomyolipoma responses with longer duration sirolimus treatment in adults with tuberous sclerosis. PLoS One. 2013;8(2):e56199. doi: 10.1371/journal.pone.0056199. Epub 2013 Feb 20.

Reference Type: DERIVED

PMID: 23437092 (View on PubMed)

Dabora SL, Franz DN, Ashwal S, Sagalowsky A, DiMario FJ Jr, Miles D, Cutler D, Krueger D, Uppot RN, Rabenou R, Camposano S, Paolini J, Fennessy F, Lee N, Woodrum C, Manola J, Garber J, Thiele EA. Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease. PLoS One. 2011;6(9):e23379. doi: 10.1371/journal.pone.0023379. Epub 2011 Sep 6.

Reference Type: DERIVED

PMID: 21915260 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

R01CA107164

Identifier Type: NIH

Identifier Source: secondary_id

View Link

P30CA006516

Identifier Type: NIH

Identifier Source: secondary_id

View Link

04-298

Identifier Type: -

Identifier Source: org_study_id