RAPAMYCIN FOR KIDNEY ANGIOMYOLIPOMAS

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase II Multi-Center Study of Rapamycin for Treating Kidney Angiomyolipomas in TSC or LAM Patients

Conditions
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Nonmalignant Neoplasm, Tuberous Sclerosis, Lymphangioleimyomatosis, Kidney Angiomyolipoma

Intervention / Treatment
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* Drug: Rapamycin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ramaycin<br>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. | Drug: Rapamycin<br> <br> * Other names: Sirolimus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. | On treatment, patients were evaluated radiologically for response to therapy up to 52 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade 3 or More Treatment-Related Lymphopenia | All participants reporting maximum grade 3 or more lymphopenia adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv3 on case report forms were counted. | Assessed on treatment up to 52 weeks. | 
| Number of Participants With no Change Are Observed Changes That Occur in Other TSC Lesions | TSC lesions are tubers, subependymal giant cell astrocytomas, facial angiofibromas, kidney cysts. | Data collected at week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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angiomyolipoma