N-acetylcysteine Given IV With Cisplatin and Paclitaxel in Patients With Ovarian Cancer

Sponsor

OHSU Knight Cancer Institute (Other)

Overall Status

Withdrawn

CT.gov ID

NCT01138137

Collaborator

(none)

Enrollment

Location

Arm

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONAL FOR STUDYING IV NAC AS POTENTIAL CHEMOPROTECTANT:

Cisplatin has shown efficacy in the treatment of subjects with epithelial ovarian cancer. Systemic toxicities associated with cisplatin include nephro, oto, and nerve toxicities. It may be possible to reduce the toxicities of cisplatin by administering it in conjunction with IV NAC. NAC may reduce cisplatin related nephro, oto, and nerve toxicities without compromising the effectiveness of the chemotherapy against the ovarian cancer cells. It is possible that this combination of drugs may in the future allow ovarian cancer patients to receive the full series of IP cisplatin-paclitaxel chemotherapy, with fewer side effects and improved survival.

It is hypothesized that the proposed treatment of stage III or IV epithelial ovarian cancer with IP cisplatin and IV/IP paclitaxel in conjunction with IV NAC will limit the neurotoxicity, nephrotoxicity and ototoxicity that is associated with cisplatin administration.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Carcinoma, Stage 3 or 4 Epithelial Ovarian Carcinoma Primary Peritoneal Carcinoma	Drug: Paclitaxel Drug: N-acetylcysteine Drug: Cisplatin	Phase 1

Detailed Description

OBJECTIVES:

PRIMARY:

To determine the Maximum Tolerated Dose (MTD) and assess the toxicity of IV NAC in conjunction with IP cisplatin and IV/IP paclitaxel in subjects with stage 3 or 4 epithelial ovarian cancer that has been surgically debulked

SECONDARY:

To describe tumor response in subjects receiving treatment for previously debulked stage 3 or 4 epithelial ovarian cancer with IP cisplatin, IV/IP paclitaxel , and IV NAC.
To describe the incidence and severity of nephrotoxicity (Creatinine Clearance (CrCl)) in subjects undergoing treatment for stage 3 or 4 epithelial ovarian cancer with IP cisplatin, IV paclitaxel and IV NAC and who have had their disease surgically debulked.
To describe the incidence and severity of hearing loss in subjects undergoing treatment for stage 3 or 4 epithelial ovarian cancer with IP cisplatin, IV/IP paclitaxel and IV NAC and who have had their disease surgically debulked.
To describe the incidence and severity of peripheral and autonomic neuropathy in subjects undergoing treatment for stage 3 or 4 epithelial ovarian cancer with IP cisplatin, IV/IP Taxol and IV NAC and who have had their disease surgically debulked.

OUTLINE:

Subjects will undergo chemotherapy for epithelial ovarian cancer with paclitaxel IV, 135 mg/m2 (Day 1) and IP cisplatin 100 mg/m2 (Day2), followed by Taxol IP, 60 mg/m2 (Day 8) every 3 weeks for 6 courses. Sixty minutes prior to each course of IP cisplatin, IV NAC (starting at 150 mg/kg) will be infused over 30 minutes. A dose escalation schema for NAC will be followed. Toxicity to the therapy will be graded according to the Common Terminology Criteria for Adverse Events.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Dose Escalation Study of N-acetylcysteine (NAC) Administered Intravenously (IV) in Conjunction With Intraperitoneal (IP) Administered Cisplatin and IV/IP Paclitaxel in Patients With Stage III or IV Ovarian Cancer

Study Start Date :

Jun 1, 2010

Actual Primary Completion Date :

Dec 1, 2014

Actual Study Completion Date :

Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: All subjects	Drug: Paclitaxel Dose: 135mg/m2 infused IV on Day 1 of 3 week cycle Dose: 60mg/m2 infused IP on Day 8 of 3 week cycle 6 treatment cycles Drug: N-acetylcysteine A group of 5 subjects will be evaluated at each dose level. On Day 2 of each 3 week cycle, subject receives IV NAC followed by IP cisplatin. 6 treatment cycles Dose escalation schema: Level 1: 150mg/kg Level 2: 300mg/kg Level 3: 600mg/kg Level 4: 800mg/kg Level 5: 1000mg/kg Level 6: 1200mg/kg Other Names: NAC Drug: Cisplatin Dose: 100mg/m2 infused IP on day 2 of each 3 week cycle 60 min after the NAC infusion 6 treatment cycles

Arm

Intervention/Treatment

Experimental: All subjects

Drug: Paclitaxel

Dose: 135mg/m2 infused IV on Day 1 of 3 week cycle Dose: 60mg/m2 infused IP on Day 8 of 3 week cycle 6 treatment cycles

Drug: N-acetylcysteine

A group of 5 subjects will be evaluated at each dose level. On Day 2 of each 3 week cycle, subject receives IV NAC followed by IP cisplatin. 6 treatment cycles Dose escalation schema: Level 1: 150mg/kg Level 2: 300mg/kg Level 3: 600mg/kg Level 4: 800mg/kg Level 5: 1000mg/kg Level 6: 1200mg/kg

Other Names:

NAC

Drug: Cisplatin

Dose: 100mg/m2 infused IP on day 2 of each 3 week cycle 60 min after the NAC infusion 6 treatment cycles

Outcome Measures

Primary Outcome Measures

To determine the MTD and assess the toxicity of IV NAC [4 years]
The MTD of IV NAC will be defined as one dose level below that which produces NCI Common Toxicity Criteria (CTC) grade 3 or 4 non-hematologic toxicity in 20% of subjects. The toxicity of NAC can be differentiated from that of the chemotherapeutic drugs as the half-life of NAC is very short and adverse effects are seen either during or very soon after the administration of NAC.

Secondary Outcome Measures

To describe tumor response [4 years]
To describe the incidence and severity of nephrotoxicity [4 years]
To describe the incidence and severity of hearing loss [4 years]
To describe the incidence and severity of peripheral and autonomic neuropathy [4 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Signed written informed consent in accordance with institutional guidelines
Histologically confirmed diagnosis of stage 3 or 4 epithelial ovarian or primary peritoneal carcinoma
Have had debulking surgery with optimal tumor cytoreduction
Standard treatment offered for ovarian cancer including systemic or intraperitoneal cisplatin with systemic taxane-based chemotherapy
Age ≥ 18 years to ≤ 75 years
Laboratory testing within 14 days of registration:
White blood cell count ≥ 2.5 x 103/mm3
Absolute granulocyte count ≥ 1.2 x 103/mm3
Platelets ≥ 100 x 103/mm3
Creatinine < 1.8
Bilirubin < 2.0
Serum glutamate oxaloacetate transaminase (SGOT)/Serum glutamate pyruvate transaminase (SGPT) < 2.5 x institutional upper limits of normal
Performance status must be Eastern Cooperative Oncology Group (ECOG) < 2 (Karnofsky ≥

Life expectancy of ≥ 60 days from the date of registration

Exclusion Criteria:

Pregnant, positive beta human chorionic gonadotropin (hCG), or lactating
History of clinically significant reactive airway disease
Active significant cardiac disease as evidenced by New York Heart Association Classification for chronic heart failure (CHF), Class III or IV
Uncontrolled (over the last 30 days) clinically significant confounding medical conditions
Allergies or other contraindications to IP cisplatin, IV Taxol, or IV NAC.