FAP-Familial Adenomatous Polyposis Clinical Trial
Official title:
Erythromycin Treatment for Readthrough of APC Gene Stop Codon Mutation in Familial Adenomatous Polyposis-protocol is Identical to Study No. 0519-10-TLV- Minors' Adjusted Version
Colorectal cancer (CRC) is a leading cause for cancer related mortality in the western world
with a lifetime risk of 6%. Etiology is complex, while genetic background significantly
affects the risk. Around one third of all genetic disorders as well as most cases of
Familial Adenomatous Polyposis (FAP) and a large proportion of all sporadic CRC cases occur
as a result of premature nonsense mutations (creating a stop codon) in an individual's
adenomatous polyposis coli (APC) gene. Nonsense mutations are single-point alterations in
the DNA that prematurely halt the protein translation process, producing a shortened,
nonfunctional protein. In many of these cases, if the cell can be 'persuaded' to ignore the
premature stop codon signal, the resulting protein may be able to ameliorate or stop the
disease.
Recently, members of the aminoglycoside family of antibiotics have been found to induce
ribosomal read-through of nonsense mutations, leading to expression of a full length,
functional protein. Investigators have recently shown that members of the aminoglycoside and
macrolide antibiotic families can induce read-through of the nonsense mutations in the APC
gene and lead to reduced oncogenic phenotypes in CRC cells and in different mice models.
The aim of this project is to determine the ability of the macrolide antibiotic-erythromycin
to induce read-through of the nonsense mutations in the APC gene and to induce expression of
a full length, functional APC protein in patients suffering from FAP and to tests its effect
on adenoma number and size and on desmoid tumors in these patients. The future goal is to
maximize the effect of stop-codon suppressors on APC while minimizing side effects.
In this study investigators will select FAP patients which carry APC nonsense mutations,
treat them with erythromycin PO for 4-6 months and examine colonic and duodenal adenomas as
well as abdominal desmoid tumors, that will be documented before during and after treatment.
In parallel, investigators will test polyp, adenoma and desmoid tissue samples as well as
blood samples from these patients for changes in expression levels of the APC protein and
related oncogenic markers.
Suppression of nonsense mutations within the APC gene should be of benefit for patients
suffering from FAP, attenuated FAP or multiple adenomas and for patients with advanced or
diffuse CRC. Furthermore, given the rapid progress being made in the identification of
different nonsense mutations in human genes that lead to mostly un-curable disease, the
identification of clinically approved compounds that suppress nonsense mutations and that
can be administered long-term without significant side effects would open new venues in the
treatment of genetic human diseases that arise from pre-mature stop codons in important
coding sequences.
Immediate goal: establish the ability of erythromycin to read-through APC nonsense mutation
in FAP patients. The read-through effect of erythromycin will be clinically tested by
counting and measuring the number and size of both colonic and duodenal adenomas before and
over treatment and by measuring the size of known desmoid tumors. Samples of the adenomas
and desmoid tumors will be tested by western blot, immunofluorescence and
immunohistochemistry for restoration of APC expression and changes in oncogenic markers.
These experiments should be conducted within 6 month.
Long term objective:
1. Determine the lowest dose of erythromycin that can inhibit growth of colonic neoplasia
and CRC in patients expressing a truncated APC protein due to nonsense mutations.
2. Examine the ability of a panel of additional macrolide antibiotics to induce APC
nonsense mutation suppression using in-vitro methods. Investigators will focus on
macrolide antibiotics that are currently in clinical use and are administrated for long
terms. These objectives should take around 6 month and will be conducted in parallel.
| Status | Not yet recruiting |
| Enrollment | 15 |
| Est. completion date | December 2017 |
| Est. primary completion date | December 2017 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 10 Years to 17 Years |
| Eligibility |
Inclusion Criteria: - ages: 10-17 years old. - A lack of known sensitivity to ERYTHROMYCIN or other macrolide. - at the relevant subgroup - existence of polyps in the colon or Ileo-anal pouch that classified as adenomas and the size isn't bigger than 10 mm and there's no high grade dysplasia and that not yet need immediate resection of the colon rectal but just a surveillance. - In the relevant subgroup- existence of polyps in the duodenum that do not require surgery and aren't bigger than 10 mm and with out high grade dysplasia. - In the relevant subgroup- a tumor that classified as stomach or pelvic desmoid that not yet need immediate resection and which can be measured by ultrasound or MRI. Exclusion Criteria: - below 10 years old or above 18 years old. - sensitivity to ERYTHROMYCIN or other macrolide. - Ileo-anal pouch without adenomas. - existence of polyps that are classified as adenomas which are bigger than 10 mm and/or with histological of high grade dysplasia. - Taking medicines that have interactions with ERYTHROMYCIN such as: Carbamazepine, Cyclosporine, barbiturate, PHENYTOIN, Disopyramide, Lovastatin, Bromocriptine: it is recommended to keep careful attention over their Concentrations in the blood and to match the dose. - significant personal of familial history of ventricular arrhythmia and/or Long QT interval per ECG, or consumption of drugs that may cause prolonged QT. - Recruitment of children whom suffer from FAP in addition to other diseases is subject to a joint decision of the PI and the study pediatrician. |
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
| Country | Name | City | State |
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| n/a | |||
| Lead Sponsor | Collaborator |
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| michal roll |
Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology. 2010 Jun;138(6):2044-58. doi: 10.1053/j.gastro.2010.01.054. Review. — View Citation
Kerem E, Hirawat S, Armoni S, Yaakov Y, Shoseyov D, Cohen M, Nissim-Rafinia M, Blau H, Rivlin J, Aviram M, Elfring GL, Northcutt VJ, Miller LL, Kerem B, Wilschanski M. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet. 2008 Aug 30;372(9640):719-27. doi: 10.1016/S0140-6736(08)61168-X. Epub 2008 Aug 20. — View Citation
Lai CH, Chun HH, Nahas SA, Mitui M, Gamo KM, Du L, Gatti RA. Correction of ATM gene function by aminoglycoside-induced read-through of premature termination codons. Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15676-81. Epub 2004 Oct 21. Erratum in: Proc Natl Acad Sci U S A. 2004 Nov 30;101(48):16982. — View Citation
Lips DJ, Barker N, Clevers H, Hennipman A. The role of APC and beta-catenin in the aetiology of aggressive fibromatosis (desmoid tumors). Eur J Surg Oncol. 2009 Jan;35(1):3-10. doi: 10.1016/j.ejso.2008.07.003. Epub 2008 Aug 21. Review. — View Citation
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Smith KJ, Johnson KA, Bryan TM, Hill DE, Markowitz S, Willson JK, Paraskeva C, Petersen GM, Hamilton SR, Vogelstein B, et al. The APC gene product in normal and tumor cells. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2846-50. — View Citation
West NJ, Clark SK, Phillips RK, Hutchinson JM, Leicester RJ, Belluzzi A, Hull MA. Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis. Gut. 2010 Jul;59(7):918-25. doi: 10.1136/gut.2009.200642. Epub 2010 Mar 26. — View Citation
Wilschanski M, Yahav Y, Yaacov Y, Blau H, Bentur L, Rivlin J, Aviram M, Bdolah-Abram T, Bebok Z, Shushi L, Kerem B, Kerem E. Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. N Engl J Med. 2003 Oct 9;349(15):1433-41. — View Citation
Zilberberg A, Lahav L, Rosin-Arbesfeld R. Restoration of APC gene function in colorectal cancer cells by aminoglycoside- and macrolide-induced read-through of premature termination codons. Gut. 2010 Apr;59(4):496-507. doi: 10.1136/gut.2008.169805. Epub 2009 Dec 1. — View Citation
* Note: There are 11 references in all — Click here to view all references
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Evaluation of changes in number of adenomas measured by upper endoscopy | Change in number of adenomas from baseline will be measured by endoscopic and histological evaluation. response will be tested by upper and lower endoscopies after 8 ,16-20 weeks and 12 months of treatment. | After 8,16 weeks and 12 months | No |
| Primary | Evaluation of changes in size of adenomas measured by lower endoscopy | Change in number of adenomas from baseline will be measured by endoscopic and histological evaluation. response will be tested by upper and lower endoscopies after 8 ,16-20 weeks and 12 months of treatment. | After 8,16 weeks and 12 months | No |
| Primary | Evaluation of changes in size of desmoid tumors | Desmoids imaging (US or CT or MRI) will be performed to determine the size at the begining of the study and to evaluate the change from baseline after 4-6 months of treatment. | At the begining of the trial (before treatment) and at the end of the treatment (after 4-6 months) | No |
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Recruiting |
NCT02175914 -
Erythromycin Treatment for Readthrough of APC Gene Stop Codon Mutations in Familial Adenomatous Polyposis
|
Phase 4 |