Treatment of Radiation and Cisplatin Induced Toxicities with Tempol

Official title

A Double Blind, Placebo Controlled Dose Range Finding Study to Assess the Safety, Pharmacokinetics, and Efficacy of Tempol for the Reduction of Severe Mucositis in Head and Neck Cancer Patients Undergoing Combined Radio- and Chemotherapy

Overview

A 10 week trial to assess the ability of Tempol to prevent and/or reduce toxicities associated with cisplatin and radiation treatment in head and neck cancer patients. Over the course of the 10 week trial, mucositis, nephrotoxicity, and ototoxicity will be monitored and assessed.

Detailed description

One hundred and twenty (120) participants with head and neck cancer are scheduled to undergo combined radio- and chemotherapy (n = 120).

Nearly all (90% to 97%) participants receiving radiotherapy in the head and neck will develop some degree of mucositis. Of these participants treated with radiotherapy with or without chemotherapy, 34% to 43% will present severe mucositis. As a result, the participant's quality of life is affected, hospital admittance rates are higher, the use of total parenteral nutrition is increased and interruption of treatment is more frequent, all of which compromise tumor control. Mucositis causes 9% to 19% of chemotherapy and radiotherapy interruption.

A common chemotherapeutic agent used in head and neck cancer is Cisplatin. Cisplatin (cis- diamminedichloroplatinum(II), CDDP) is an antineoplastic drug used in the treatment of many cancers including testicular cancer, ovarian cancer, bladder cancer, head and neck cancer, esophageal cancer, small and non-small cell lung cancer, breast cancer, cervical cancer, stomach cancer, prostate cancer, brain tumors, neuroblastoma, sarcomas, multiple myeloma, melanoma, mesothelioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, pancreatic cancer, and thyroid cancer. While toxicities include ototoxicity, gastrotoxicity, myelosuppression, and allergic reactions, the main dose-limiting side effect of cisplatin is nephrotoxicity followed by ototoxicity.

Tempol is a piperidine nitroxide. Nitroxides are a class of stable free radical compounds that protects mammalian cells against numerous toxic agents. Tempol protects normal cells from radiation and cisplatin-induced damage; however, in cancerous or tumor cells, Tempol is reduced to its hydroxylamine form that does not and cannot protect the cells from radiation and cisplatin induced damage. This distinction is of particular importance in the setting of cancer treatment, in which both normal and tumor tissue is exposed to radiation and chemotherapy.

Without using Tempol, both normal cells and cancer cells suffer from toxicity. Tempol is the only known compound to possess this functional duality. This compound has the potential to prevent many of the toxicities associated with cisplatin and radiation treatment including the prevention of mucositis, nephrotoxicity, and ototoxicity.

Interventions

• Drug Tempol
  Investigational product is Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) oral solution. Tempol solution is an orange-colored, aqueous solution containing 7% Tempol along with xanthan gum, xylitol, aspartame, acesulfame potassium, sodium saccharin, alcohol, peppermint and wintergreen oils.
• Drug Placebo Solution
  The placebo contains the same excipients as the active product plus FD\&C Yellow #6 for color matching.

Primary outcome measures

• Mucositis [Time frame: 10 weeks]

Secondary outcome measures (4)

• Mucositis [Time frame: 10 weeks]
• Nephrotoxicity [Time frame: 10 weeks]
• Nephrotoxicity [Time frame: 10 weeks]
• Mucositis [Time frame: 10 weeks]

Eligibility criteria

Inclusion criteria

• Be ≥18 years of age with medically diagnosed squamous cell cancer of the head and neck (SCCHN);
• Be scheduled to receive radiotherapy or proton therapy administered with a curative intent;
• If female and of child bearing potential, be using an effective birth-control method with a history of reliability for the individual participant;
• If male and of child bearing potential, adequate methods of contraception must be employed including use of condoms with spermicide. No sperm donation for 90 days until after the conclusion of the study;
• Must be receiving cisplatin for chemotherapy;
• Be properly informed of the nature and risks of the clinical investigation, comply with all clinical investigation-related procedures, and sign an Informed Consent Form prior to entering the clinical investigation;
• Must have a score 2 or less on the ECOG performance status;
• Participant life expectancy ≥ 6 months; and
• Adequate baseline organ function (hematologic, liver, renal, nutritional and metabolic):

Haematology:

Absolute neutrophil count (ANC) ≥1.5 Hemoglobin ≥ 10 g/dL Platelets ≥ 100,000 per microliter of blood

Hepatic:

Total bilirubin ≤ 2 X (Upper limit normal) ULN Alanine amino transferase (ALT) and Aspartate aminotransferase (AST) ≤5 x ULN

Renal:

Serum creatinine ≤ ULN or, if > ULN calculated creatinine clearance (CrCl) ≥ 60 mL/min.

Nutritional and metabolic:

Urine Albumin < 3.0 mg/dl

Exclusion criteria

• Prior radiotherapy of the head and neck;
• Have a clinically significant infection defined as any acute viral, bacterial or fungal infection, which requires specific therapy. Anti-infectious therapy must have been completed within 14 days of starting study treatment;
• Be taking any non-approved therapy for oral mucositis, including β-carotene, tocopherol, laser irradiation, brushing the oral mucosa with silver-nitrate prophylactically, systemic TGF-β (transforming growth factor beta), or systemic KGF (keratinocyte growth factor) during or within 14 days of starting treatment;
• Be taking mugard;
• Be taking prostaglandins, pentoxifylline or leucovorin during or within 14 days of starting treatment;
• Be rinsing with allopurinol, hydrogen peroxide, sucralfate, or chlorhexidine mouthwashes during or within 14 days of starting treatment;
• Have had a recent, serious, non-malignant medical complication that, in the opinion of the investigator, makes the individual unsuitable for study participation;
• Have used an investigational drug within 28 days of the initiation of study treatment;
• Have a history of a positive blood test for HIV;
• At the time of screening, having a significant active medical illness which, in the opinion of the investigator, would preclude completion of the study;
• Participants with a treatment plan consisting of chemoradiation followed by further chemotherapy;
• Participants with body weight less than 35 kg, 77 lbs;
• Women who are pregnant or who are breastfeeding;
• Participants with known intolerance to platin drugs;
• History of insulin-dependent Diabetes Mellitus; and
• Participants with Hepatitis B/C.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

United States · 9 centers

• UCSD — La Jolla
• Mercy Medical Center — Merced
• UCSF Helen Diller Family Comprehensive Cancer Center — San Francisco
• Central Coast Medical Oncology — Santa Maria
• Mission Hope Health Center — Santa Maria
• Montefiore Medical Center-Einstein Campus — The Bronx
• Wake Forest University Health Sciences — Winston-Salem
• Seattle Cancer Care Alliance — Seattle
• … and 1 more center

Publications

• Arany I, Safirstein RL. Cisplatin nephrotoxicity. Semin Nephrol. 2003 Sep;23(5):460-4. doi: 10.1016/s0270-9295(03)00089-5. PMID 13680535
• Ahmed LA, Shehata NI, Abdelkader NF, Khattab MM. Tempol, a superoxide dismutase mimetic agent, ameliorates cisplatin-induced nephrotoxicity through alleviation of mitochondrial dysfunction in mice. PLoS One. 2014 Oct 1;9(10):e108889. doi: 10.1371/journal.pone.0108889. eCollection 2014. PMID 25271439
• Scully C, Sonis S, Diz PD. Oral mucositis. Oral Dis. 2006 May;12(3):229-41. doi: 10.1111/j.1601-0825.2006.01258.x. PMID 16700732
• Hartmann JT, Lipp HP. Toxicity of platinum compounds. Expert Opin Pharmacother. 2003 Jun;4(6):889-901. doi: 10.1517/14656566.4.6.889. PMID 12783586
• Sastry J, Kellie SJ. Severe neurotoxicity, ototoxicity and nephrotoxicity following high-dose cisplatin and amifostine. Pediatr Hematol Oncol. 2005 Jul-Aug;22(5):441-5. doi: 10.1080/08880010590964381. PMID 16020136
• Samuni A, Winkelsberg D, Pinson A, Hahn SM, Mitchell JB, Russo A. Nitroxide stable radicals protect beating cardiomyocytes against oxidative damage. J Clin Invest. 1991 May;87(5):1526-30. doi: 10.1172/JCI115163. PMID 1850756
• Samuni A, Mitchell JB, DeGraff W, Krishna CM, Samuni U, Russo A. Nitroxide SOD-mimics: modes of action. Free Radic Res Commun. 1991;12-13 Pt 1:187-94. doi: 10.3109/10715769109145785. PMID 1649088
• Samuni A, Krishna CM, Mitchell JB, Collins CR, Russo A. Superoxide reaction with nitroxides. Free Radic Res Commun. 1990;9(3-6):241-9. doi: 10.3109/10715769009145682. PMID 2167262

Identifiers

NCT: NCT03480971 · MBI-04-04

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗