Medical Summary
This is a phase II multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy and optimal duration of treatment of a new antiemetic compound CJ-11,974, for patients being treated with high dose cisplatin for the treatment of cancer.
Cytotoxic drugs such as cisplatin, cause gastrointestinal cellular damage which may result in the release of serotonin, activating neurons which elicit the vomiting response. Substance P (SP) is a neuropeptide released from sensory neurons in response to chemical or other forms of noxious stimuli. Through binding of the NK-1 receptor, SP may mediate responses such as nausea and vomiting. The SP (NK-1 receptor) antagonist CJ-11,974 has been shown to be active in the control of emesis following a variety of emetogenic stimuli.
Previous human studies have shown that the addition of CJ-11,974 to standard antiemetic treatment for chemotherapy-induced nausea/vomiting had a significant impact on the control of emesis. In studies evaluating CJ-11,974 given as a continuous dose to treat other conditions some subjects (> 3%) experienced headache, fatigue, nausea, dizziness, rash, sleepiness, upset stomach, taste disorder, diarrhea, sore throat, chest pain, and decreased sensitivity to touch. One - 3% of subjects experienced vomiting, pain, dehydration, tremor, back pain, abnormal liver function tests, constipation, arthritis, abnormal vision, weight loss, numbness and tingling, asthma, running or congested nose, itching, ulcerative colitis, joint pain, abnormal thinking, and cough.
The purpose of this study is to evaluate the efficacy of a loading dose and the optimal duration of treatment with CJ-11,974 for the control of high dose cisplatin-induced emesis in combination with standard anti-emetic therapy. Additional objectives include: evaluating the efficacy and safety of CJ 11,974 in successive cycles of cisplatin chemotherapy; the effect of CJ-11,974 on nausea; the effect of the various regimens on the requirement for rescue therapy; and the incidence of complete control of nausea/vomiting.This trial will compare CJ-11,974 plus standard therapy to standard therapy alone in a four armed study with 85 subjects per group .

References:

1. Nakanishi S. Mammalian tachykinin receptors. Ann Rev Neurosci 14: 123-136, 1991.
2. McLean S, Ganong A, Seeger T, et.al., Activity and distribution of binding sites in brain of a nonpeptide substance P (NK1) receptor antagonist. Science 251:437-439, 1991.
3. Roila F, Tonato M, and Del Favero A. Prevention of chemotherapy-induced emesis: The state of the art dig dis 11:343-353, 1993: Kris MG, Gralla RJ, Clark RA, et.al., Phase II trials of the serotonin antagonist GR38032F for the control of vomiting caused by cisplatin. J Natl Cancer Inst 81:42-46, 1989.

Lay Summary
A Some chemotherapeutic anti-cancer drugs, including Cyclophosphamide and Doxorubicin can induce nausea and vomiting (emesis) in a high percentage of patients receiving them. While there are currently some effective anti-nausea/vomiting drugs in use, these are mainly useful in what is known as the acute vomiting phase, that is, vomiting which occurs within the 24 hour period immediately following the chemotherapy. Vomiting which occurs after this period is within the delayed vomiting phase. There is currently no effective drug available to treat delayed vomiting.
This study is designed to test a new anti-emetic compound called CJ-11,974 in patients receiving Cyclophosphamide and Doxorubicin anti-cancer chemotherapy. This compound has been shown in previous studies to significantly improve vomiting in both the acute and delayed phases when given with standard pre-chemotherapy anti-vomiting medication.
Eligible patients will be randomly placed within one of three groups. Each group will receive a different dose of CJ-11,974 for 3 days starting on day 1 of chemotherapy. Each patient will be required to keep a diary of any and all symptoms they experience for a 4 day period starting from day 1 of chemotherapy. This will be repeated for each cycle of chemotherapy. There will be some tests done before and during the study period, including ECG, blood-tests, and brief physical examinations .

1. Subjects who are male or female and at least 18 years of age. Female subjects must be sterile, or post menopausal, or not sexually active, or using effective contraception.
2. Subjects who have a pathological Diagnosis of malignancy confirmed (with the exception of primary CNS malignancy or brain metastases).
3. Subjects who require a chemotherapeutic regimen consisting of cyclophosphamide at a dose >(or =)500 mg/m2 and doxorubicin at a dose >(or =)30 mg/m2. This must be the first cycle of chemotherapy using these agents. Subjects may receive combination therapy, including methotrexate and 5-floroiracil.
4. Subjects who have a Karnofsky performance status 70%
5. Subjects whose laboratory values are acceptable to participate in his/her chemotherapy protocol, as well as within the following parameters:
   a. White blood count >=3500/mm³
   b. Platelet count >=75,000/mm³
   c. SGOT and SGPT <= 2x the ULN
   d. BUN and creatinine <=1.2x the ULN
6. Subjects whose screening ECG is normal or has no clinically significant abnormalities, as noted bythe central ECG reader.
7. Subjects who have given written informed consent.