RAPAMYCIN FOR KIDNEY ANGIOMYOLIPOMAS

NCT00126672 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: 04-298R01CA107164P30CA006516
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 7

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.

Conditions

Nonmalignant Neoplasm; Tuberous Sclerosis; Lymphangioleimyomatosis; Kidney Angiomyolipoma

Keywords

angiomyolipoma

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Number of Participants With Grade 3 or More Treatment-Related Lymphopenia

  Assessed on treatment up to 52 weeks.

• Number of Participants With no Change Are Observed Changes That Occur in Other TSC Lesions

  Data collected at week 52

Study Arms (1)

Ramaycin

EXPERIMENTAL

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

Interventions

Rapamycin DRUG

Also known as: Rapamune, Sirolimus

Ramaycin

Eligibility Criteria

• Age: 3 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• National Cancer Institute (NCI): collaborator
• Wyeth is now a wholly owned subsidiary of Pfizer: collaborator
• Tuberous Sclerosis Alliance: collaborator

Study Sites (7)

Loma Linda University School of Medicine

Loma Linda, California, 92350, United States

Location

Connecticut Children's Medical Center

Hartford, Connecticut, 06106, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

New York University Medical Center

New York, New York, 10016, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229-3039, United States

Location

University of Pennsylvania Medical Center

Philadelphia, Pennsylvania, 19104, United States

Location

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, 75390, United States

Location

Related Publications (2)

• 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.

  PMID: 23437092 DERIVED

• 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.

  PMID: 21915260 DERIVED

MeSH Terms

Conditions

Neoplasms; Tuberous Sclerosis; Angiomyolipoma

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Hamartoma; Neoplasms, Multiple Primary; Neoplastic Syndromes, Hereditary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Nervous System Diseases; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Neoplasms, Adipose Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Perivascular Epithelioid Cell Neoplasms

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Dabora Sandra L MD
• Organization: Dana-Farber Cancer Institute

sandy.dabora@gmail.com

(617) 732-5500

Study Officials

• Sandra Dabora, MD, PhD

  Dana-Farber/Brigham and Women's Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 2, 2005
• First Posted: August 4, 2005
• Study Start: December 20, 2005
• Primary Completion: April 1, 2010
• Study Completion: April 1, 2010
• Last Updated: April 25, 2022
• Results First Posted: April 25, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)