Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer

Condition(s) targeted: Neurotoxicity; Pain; Unspecified Adult Solid Tumor, Protocol Specific

Intervention: ketamine/amitriptyline NP-H cream (Drug); placebo (Other)

Phase: Phase 3

Status: Recruiting

Sponsored by: University of Rochester

Official(s) and/or principal investigator(s):
Supriya Mohile, MD, Study Chair, Affiliation: James P. Wilmot Cancer Center

RATIONALE: Topical cream containing amitriptyline and ketamine may help relieve pain, numbness, tingling, and other symptoms of peripheral neuropathy. It is not yet known whether topical amitriptyline and ketamine cream is more effective than a placebo in treating peripheral neuropathy caused by chemotherapy.

PURPOSE: This randomized phase III trial is studying the side effects and how well topical amitriptyline and ketamine cream work compared with a placebo in treating peripheral neuropathy caused by chemotherapy in patients with cancer.

Official title: Assessment of Topical Treatment Response With Amitriptyline and Ketamine: Combination Trial in Chemotherapy Peripheral Neuropathy (ATTRACT-CPN)

Study design: Supportive Care, Randomized, Double-Blind, Placebo Control

Primary outcome: Change in average daily peripheral neuropathy intensity score from baseline to week 6 in patients treated with amitriptyline and ketamine hydrochloride vs placebo

Secondary outcome:

Percentage of patients treated with amitriptyline and ketamine hydrochloride vs placebo whose CPN intensity decreases by ≥ 30%

Percentage of patients with ≥ 50% reduction in the level of peripheral neuropathy

Percentage of patients with continuous proportion of responder distribution function

Change in average daily pain, numbness, or tingling score from baseline to the end of treatment

Quality of sleep scores

Quality of pain as measured by the European Organization for Research and Treatment of Cancer Quality of Life-Chemotherapy-Induced Peripheral Neuropathy (EORTC QLQ-CIPN20)

Health-related quality of life as measured by the Brief Pain Inventory Interference Scale and Hamilton Anxiety and Depression Scale

Overall assessment of change since beginning of treatment, including changes in pain, side effects, functional status, and overall satisfaction with treatment as measured by the Patient Global Impression of Change Questionnaire

Comparison of proportion of patients in each arm who decide to continue treatment beyond week 6

Detailed description: OBJECTIVES:

- Compare the analgesic properties and safety of topical amitriptyline and ketamine

hydrochloride cream vs placebo in cancer patients with chemotherapy peripheral neuropathy (CPN) who have received taxanes or other cancer chemotherapy agents.

OUTLINE: This is a multicenter, double-blind, randomized, placebo-controlled study. Patients are stratified according to Community Clinical Oncology Program (CCOP) site. Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients apply amitriptyline and ketamine hydrochloride topical analgesic cream

twice daily to areas of pain, numbness, or tingling in the hands and/or feet.

- Arm II: Patients apply a placebo cream twice daily to areas of pain, numbness, or

tingling in the hands and/or feet.

In both arms, treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients may continue treatment for up to a total of 12 weeks.

Patients complete a peripheral neuropathy intensity and quality of sleep diary daily. Patients also complete the European Organization for Research and Treatment of Cancer Quality of Life-Chemotherapy-Induced Peripheral Neuropathy (EORTC QLQ-CIPN20) to assess change in sensory score and the Brief Pain Inventory and Hospital Anxiety and Depression Scale to assess health-related quality of life in week 3 and 6. The VES-13 is administered at baseline to assess level of physical activity and the URCC symptom inventory is administered to track other potentially important symptoms. The Patient Global Impression of Change Questionnaire is administered in week 6 to assess the patient's overall assessment of change since beginning treatment, including changes in pain, side effects, functional status, and overall satisfaction with treatment.

PROJECTED ACCRUAL: A total of 400 patients will be accrued for this study.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- History of cancer

- Pain, numbness, or tingling in the hands or feet beginning in association with a

cancer chemotherapy agent (taxane or other chemotherapeutic agent) and persisting for at least 28 days following the conclusion of chemotherapy

- Pain, numbness, or tingling can be assessed 28 days or more after the conclusion

of chemotherapy

- An average score of ≥ 4 for the 7 daily ratings of the baseline week on the

11-point rating scale of peripheral neuropathy associated with chemotherapy, with a minimum of 5 daily diary ratings completed during the baseline week

- No preexisting or history of peripheral neuropathy due to any cause other than

chemotherapy (e. g., hereditary condition, alcohol, or diabetes)

- Patients with stable systemic metastases and/or bone involvement AND has not received

chemotherapy within 3 months of screening assessment are eligible

- Patients receiving ongoing treatment with non-chemotherapy agents (e. g.,

monoclonal antibodies or hormonal treatment) allowed

- No concuurent active chemotherapy in the adjuvant setting or for progressive systemic

disease

PATIENT CHARACTERISTICS:

- Karnofsky performance status 60-100%

- Creatinine ≤ 2 mg/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Able to adequately understand English

- No allergy or hypersensitivity to ketamine hydrochloride or amitriptyline or any of

the components of study drug

- No clinically significant illness (e. g., endocrine, cardiac, hepatic, renal,

neurologic, hematologic, or skeletal illness) that, in the investigator's clinical judgment, could interfere with the efficacy or safety assessments in this study

- No glaucoma or recurrent urinary retention

- No clinically significant depression or dementia that, in the opinion of the

investigator, may interfere with a patient's adherence to the study protocol and/or the accurate and consistent reporting of CPN

- No open skin lesions in the area where the cream is to be applied

- No HIV positivity

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- At least 30 days since prior unapproved experimental drugs or biological agents

- No prior topical treatment, nerve blocks, implantable therapy, peripheral nerve or

spinal cord stimulation, or neurosurgical procedure for chemotherapy-related peripheral neuropathy (CPN)

- No prior exposure to a peripheral neurotoxin other than chemotherapy

- No concurrent medications (e. g., phenytoin) known to be associated with sensory

neuropathy

- No concurrent selective serotonin reuptake inhibitors (e. g., fluoxetine, paroxetine,

or sertraline), which inhibit CP450 2D6, unless the patient is being treated for depression or another psychiatric disorder and, in the investigator's judgment, the patient's participation in the study can be permitted given the minimal systemic levels of amitriptyline found within the cream

- No concurrent monoamine oxidase inhibitors, barbiturates, anticholinergic agents, or

sympathomimetic drugs, including epinephrine combined with local anesthetics

- Oral inhalers that include any of the drugs listed above are allowed

- Concurrent opioid analgesics, tricyclic or dual reuptake inhibitor antidepressants,

or gabapentin or pregabalin for CPN, or benzodiazepines for sleep allowed, provided dose has been stable for ≥ 2 weeks and the following are true:

- Gabapentin dose must be ≤ 1,800 mg per day

- Pregabalin dose must be ≤ 300 mg per day

- Opioid analgesic dose must be ≤ 60 mg of oxycodone hydrochloride equivalent per

day

- Tricyclic antidepressant dose must be ≤ 75 mg amitriptyline equivalent per day

- Duloxetine dose must be ≤ 60 mg per day

- Venlafaxine dose must be ≤ 150 mg per day

- Tramadol dose must be ≤ 200 mg per day

- Concurrent adjunctive analgesic therapy, such as acupuncture, biofeedback, or herbal

preparations, allowed provided dose has been stable for ≥ 2 weeks

MBCCOP - Hawaii, Honolulu, Hawaii 96813, United States; Recruiting
James Tom, Phone: 808-586-2979

CCOP - Central Illinois, Decatur, Illinois 62526, United States; Recruiting
Peggy Verrill, Phone: 217-876-6618, Email: peggyv@dmhhs.org

CCOP - Evanston, Evanston, Illinois 60201, United States; Recruiting
Michelle Britto, Phone: 847-570-2109

MBCCOP - University of Illinois at Chicago, Chicago, Illinois 60612-7323, United States; Recruiting
Judith Murray, Phone: 312-355-1472, Email: memurray@uic.edu

CCOP - Wichita, Wichita, Kansas 67214-3882, United States; Recruiting
Marge Good, Phone: 316-268-5784, Email: marge_good@via-christi.org

CCOP - Grand Rapids, Grand Rapids, Michigan 49503, United States; Recruiting
Connie Szczepanek, Phone: 616-391-1230

CCOP - Metro-Minnesota, St. Louis Park, Minnesota 55416, United States; Recruiting
Marilee Rose, Phone: 952-993-1516

CCOP - Nevada Cancer Research Foundation, Las Vegas, Nevada 89106, United States; Recruiting
Karen Sartell, Phone: 702-384-0013

CCOP - Hematology-Oncology Associates of Central New York, East Syracuse, New York 13057, United States; Recruiting
Colleen Sweeney, Phone: 315-472-7504 ext. 2129

CCOP - North Shore University Hospital, Manhasset, New York 11030, United States; Recruiting
Nanette Nier-Shoulson, RN, Phone: 516-734-8918, Email: nnier@nshs.edu

CCOP - Southeast Cancer Control Consortium, Winston-Salem, North Carolina 27104-4241, United States; Recruiting
Robin Burgess, Phone: 336-777-3036

CCOP - Columbia River Oncology Program, Portland, Oregon 97225, United States; Recruiting
Mary Brunetti, Phone: 503-216-6262

CCOP - Greenville, Greenville, South Carolina 29615, United States; Recruiting
Lyndon Evans, RN, Phone: 864-404-2045

CCOP - Upstate Carolina, Spartanburg, South Carolina 29303, United States; Recruiting
Nancy Sprouse, Phone: 864-560-6812

CCOP - Northwest, Tacoma, Washington 98405-0986, United States; Recruiting
Karyn Hart, Phone: 253-403-1461, Email: karyn.hart@multicare.org

CCOP - Virginia Mason Research Center, Seattle, Washington 98101, United States; Recruiting
Beth Edelhert, Phone: 206-341-0446

CCOP - Marshfield Clinic Research Foundation, Marshfield, Wisconsin 54449, United States; Recruiting
Cheryl Esselman, Phone: 715-389-5153

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: October 2007
Last updated: August 21, 2009