Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Supportive care Active 18 and over NCI URCC-0605 URCC-07004, URCC-06-05, NCT00471445

Objectives

1. 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.

Entry 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)



• No stable systemic metastases and/or bone involvement AND has not received chemotherapy within 3 months of screening assessment
  • Patients receiving ongoing treatment with non-chemotherapy agents (e.g., monoclonal antibodies or hormonal treatment) allowed

Prior/Concurrent Therapy:

• 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

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

Expected Enrollment

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

Outcomes

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

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

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.

Trial Contact Information

Trial Lead Organizations

University of Rochester Cancer Center CCOP Research Base

Supriya Mohile, MD, Protocol chair		Ph: 585-275-5513

U.S.A.
New York
	Rochester
	University of Rochester Cancer Center CCOP Research Base
		Gary Morrow, PhD, MS	Ph:  585-275-5513

Registry Information
Official Title		Assessment of Topical Treatment Response with Amitriptyline and Ketamine: Combination Trial in Chemotherapy Peripheral Neuropathy (ATTRACT-CPN)
Trial Start Date		2007-10-25
Trial Completion Date		2010-12-31 (estimated)
Registered in ClinicalTrials.gov		NCT00471445
Date Submitted to PDQ		2007-04-05
Information Last Verified		2008-12-07

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