Bevacizumab for Treatment of Recurrent Respiratory Papillomatosis (RRP)

Recurrent Respiratory Papillomatosis Clinical Trial

Official title:

A Pilot Study to Evaluate the Effects of Antiangiogenic Factor as an Adjunct Treatment After Photoangiolysis in Patients With Bilateral Recurrent Respiratory Papillomatosis of the Vocal Fold

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01020747
• Other study ID #: VC-P001
• Status: Completed
• Phase: Phase 1
• First received: November 13, 2009
• Last updated: December 18, 2012
• Start date: November 2009
• Est. completion date: March 2011

Study information

• Verified date: December 2012
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This phase I single center open labeled study is planned to assess the safety and tolerability of bevacizumab for treating patients with bilateral Recurrent Respiratory Papillomatosis (RRP). Approximately 20 patients will receive bevacizumab directly injected into the vocal folds. Patients who enroll in the protocol will be injected with bevacizumab in one vocal fold that represents the more diseased of the two folds. A sham injection with saline will be administered to the other vocal fold as the control. This therapy will be administered once every 6 ± 1 week for 6 months, with the same vocal fold selected for the initial treatment always getting the drug injection. The investigator will also treat lesions by laser photoangiolysis of both vocal folds using the 532 nm potassium-titanyl-phosphate (KTP) laser.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: March 2011
• Est. primary completion date: March 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• Male or female patients with dysphonia that have been diagnosed with Recurrent Respiratory Papillomatosis (RRP) of the vocal folds

• Age between 18 and 60 years old

• Female patients must be surgically sterilized, postmenopausal, or employ adequate contraception. Criteria for menopause are surgical menopause (hysterectomy, oophorectomy) or age > 45 years with absence of menses for greater than 12 months and an elevated serum Hormone, follicle-stimulating (FSH) (> 25 mIU/mL). Tubal ligation with menses within the past 12 months is not considered to be surgical sterilization.

• Have bilateral glottal papillomatosis (i.e., involving both the right and left vocal folds)

• Willing and able to comply with the investigational nature of the study and able to communicate well with investigators.

• Ability to comprehend and willingness to provide written informed consent in accordance with institutional and regulatory guidelines.

Exclusion Criteria:

• Have known sensitivity to bevacizumab

• Have been treated systemically with bevacizumab within 4 months (approximately 6 half-lives).

• Have hematocrits < 30, elevated PT or PTT levels more than 1.2 X the upper limit of normal (ULN) or absolute platelet counts below the lower limit of normal (LLN).

• Have absolute neutrophil counts below 1500

• Have urine dipsticks positive for =3+ proteinuria will have spot urine collections and those patients with urine protein to urine creatinine ratios greater than 1.5.

• Have a history of congestive heart failure, angina that remains symptomatic despite medications, myocardial infarction or coronary artery disease-related procedure within the past 6 months (including angioplasty, stent placement, bypass graft surgery) or who have prosthetic heart valves.

• Have significant uncontrolled hypertension (systolic blood pressure above 160 and/or diastolic blood pressure above 100).

• Have had surgeries within 1 month of enrollment or who have un-healed surgical incisions at screening.

• Have a history of thromboembolic events, gastro-intestinal (GI) ulcer or bleeding, or with a history of wound dehiscence.

• Female patients that are pregnant, nursing or plan to nurse during the up to 18 months of treatment period.

• Patients with a history of bleeding disorders, documented platelet dysfunction, current use of anti-platelet drugs, or abnormal prothrombin time (PT) or activated partial thromboplastin timea (PTT) laboratory values as defined in number 3 above.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Papilloma
• Papillomavirus Infections
• Recurrent Respiratory Papillomatosis
• Respiratory Tract Infections

Intervention

Drug:
• Avastin® (bevacizumab)
Bevacizumab injections (~7.5-12.5mg in 0.3 - 0.5 c.c.) into diseased vocal folds in conjunction with 532 nm pulsed-KTP laser photoangiolysis, administered every 6 ±1 weeks, for a total of 5 treatments. No patient will have an injection volume exceed 0.5 cc. for any single treatment. If initial results indicate a benefit, as described below, an extension of the active treatment period will be permitted up to a total treatment duration of 18 months.
• Saline
A sham injection with saline (0.3-0.5 cc) has been administered to the other vocal fold as the control. This therapy will be administered once every 6 ± 1 week for 6 months, with the same vocal fold selected for the initial treatment always getting the drug injection.

Locations

Country	Name	City	State
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Massachusetts General Hospital

Country where clinical trial is conducted

United States, 

References & Publications (23)

Anderson RR, Parrish JA. Selective photothermolysis: precise microsurgery by selective absorption of pulsed radiation. Science. 1983 Apr 29;220(4596):524-7. — View Citation

Armstrong LR, Derkay CS, Reeves WC. Initial results from the national registry for juvenile-onset recurrent respiratory papillomatosis. RRP Task Force. Arch Otolaryngol Head Neck Surg. 1999 Jul;125(7):743-8. — View Citation

Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2006 Mar;113(3):363-372.e5. Epub 2006 Feb 3. — View Citation

Burns JA, Zeitels SM, Akst LM, Broadhurst MS, Hillman RE, Anderson R. 532 nm pulsed potassium-titanyl-phosphate laser treatment of laryngeal papillomatosis under general anesthesia. Laryngoscope. 2007 Aug;117(8):1500-4. — View Citation

Dedo HH, Yu KC. CO(2) laser treatment in 244 patients with respiratory papillomas. Laryngoscope. 2001 Sep;111(9):1639-44. — View Citation

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Folkman J. Angiogenesis. Annu Rev Med. 2006;57:1-18. Review. — View Citation

Franco RA Jr, Zeitels SM, Farinelli WA, Anderson RR. 585-nm pulsed dye laser treatment of glottal papillomatosis. Ann Otol Rhinol Laryngol. 2002 Jun;111(6):486-92. — View Citation

Fung AE, Rosenfeld PJ, Reichel E. The International Intravitreal Bevacizumab Safety Survey: using the internet to assess drug safety worldwide. Br J Ophthalmol. 2006 Nov;90(11):1344-9. Epub 2006 Jul 19. — View Citation

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. — View Citation

Kernt M, Neubauer AS, Kampik A. Intravitreal bevacizumab (Avastin) treatment is safe in terms of intraocular and blood pressure. Acta Ophthalmol Scand. 2007 Feb;85(1):119-20. — View Citation

Meert AP, Feoli F, Martin B, Ninane V, Sculier JP. Angiogenesis in preinvasive, early invasive bronchial lesions and micropapillomatosis and correlation with EGFR expression. Histopathology. 2007 Feb;50(3):311-7. — View Citation

Mounts P, Shah KV, Kashima H. Viral etiology of juvenile- and adult-onset squamous papilloma of the larynx. Proc Natl Acad Sci U S A. 1982 Sep;79(17):5425-9. — View Citation

Parsons DS, Bothwell MR. Powered instrument papilloma excision: an alternative to laser therapy for recurrent respiratory papilloma. Laryngoscope. 2001 Aug;111(8):1494-6. — View Citation

Rahbar R, Vargas SO, Folkman J, McGill TJ, Healy GB, Tan X, Brown LF. Role of vascular endothelial growth factor-A in recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol. 2005 Apr;114(4):289-95. — View Citation

Ratner M. Genentech discloses safety concerns over Avastin. Nat Biotechnol. 2004 Oct;22(10):1198. — View Citation

Sachdev JC, Jahanzeb M. Evolution of bevacizumab-based therapy in the management of breast cancer. Clin Breast Cancer. 2008 Oct;8(5):402-10. doi: 10.3816/CBC.2008.n.048. Review. — View Citation

Shehab N, Sweet BV, Hogikyan ND. Cidofovir for the treatment of recurrent respiratory papillomatosis: a review of the literature. Pharmacotherapy. 2005 Jul;25(7):977-89. Review. — View Citation

Spaide RF, Laud K, Fine HF, Klancnik JM Jr, Meyerle CB, Yannuzzi LA, Sorenson J, Slakter J, Fisher YL, Cooney MJ. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina. 2006 Apr;26(4):383-90. — View Citation

Steinberg BM, DiLorenzo TP. A possible role for human papillomaviruses in head and neck cancer. Cancer Metastasis Rev. 1996 Mar;15(1):91-112. Review. — View Citation

Strong MS, Vaughan CW, Cooperband SR, Healy GB, Clemente MA. Recurrent respiratory papillomatosis: management with the CO2 laser. Ann Otol Rhinol Laryngol. 1976 Jul-Aug;85(4 Pt 1):508-16. — View Citation

Wu L, Martínez-Castellanos MA, Quiroz-Mercado H, Arevalo JF, Berrocal MH, Farah ME, Maia M, Roca JA, Rodriguez FJ; Pan American Collaborative Retina Group (PACORES). Twelve-month safety of intravitreal injections of bevacizumab (Avastin): results of the Pan-American Collaborative Retina Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol. 2008 Jan;246(1):81-7. Epub 2007 Aug 3. — View Citation

Zeitels, S.M. (2001). In Atlas of Phonomicrosurgery and Other Endolaryngeal Procedures for Benign and Malignant Disease (San Diego).

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The Primary Activity Variable Was the Recurrence of Recurrent Respiratory Papillomatosis (RRP) in Bevacizumab Treated and the Un-treated Vocal Fold in the Same Patient During and at the End of the 6-month Treatment Period.	Prior to each treatment,the area of reappearance of disease was measured and the % change from baseline was calculated. The change was then added to the % change from the previous treatment to generate a cumulative total % change of reappearance of RRP from baseline. The additive nature of this parameter resulted in % greater than 100% if the area of vocal fold affected by the RRP increased over the baseline measurement.	6 months	No

External Links

•   Avastin package insert and information from the Genentech website.
•   International RRP ISA site
•   RRP Foundation website