Safety Study of rhuMAb 2C4 to Treat Advanced Solid Tumors

Phase 1

Completed

Conditions: Neoplasms

Registration Number: NCT00027027

Lead Sponsor: Genentech, Inc.

Brief Summary: The purpose of this Phase I study is to test the safety of rhuMAb 2C4 to see what effects (good and bad) it has on patients with certain types of cancer, and also to find the highest dose of rhuMAb that can be given without causing severe side effects. All study participants will be assigned to specific group to evaluate different dosages of rhuMAb 2C4. The study is scheduled to run for up to one year depending on how patients respond to the study treatment.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 21

Inclusion Criteria

Signed informed consent
Age >=18 years old
ECOG performance status of 0 or 1 (see Appendix F)
Life expectancy of >=12 weeks
Histologically documented, incurable, locally advanced or metastatic solid malignancies
Disease progression on or after standard effective therapy or a malignancy for which there is no standard therapy
At least one bi-dimensionally measurable lesion (>=2 cm [>=1 cm on spiral CT scan])
HER2-negative status as defined by fluorescence in situ hybridization (FISH) testing (only for subjects with breast cancer)
Use of an effective means of contraception for women of childbearing potential
Granulocyte count of >=1500/uL, platelet count of >=100,000/uL, and hemoglobin of >=9 g/dL
Serum bilirubin less than or equal to the upper limit of normal (ULN) and alkaline phosphatase, AST, and ALT <=2.5x ULN (ALT and AST <=5x ULN for subjects with liver metastases; alkaline phosphatase <=5x ULN for subjects with liver or bone metastases)
Serum creatinine less than or equal to ULN or creatinine clearance of >=60 mL/min
International normalized ratio (INR) of <1.3 and activated partial thromboplastin time (aPTT) of <1.5x ULN

Exclusion Criteria

Pleural effusions, ascites, or bone lesions as the only manifestation of the current cancer
Symptomatic or untreated brain metastases
Prior chemotherapy, hormonal therapy (except for androgen-deprivation therapy for subjects with prostate cancer), radiotherapy, or immunotherapy within 4 weeks of Day 1 (within 6 weeks for nitrosoureas or mitomycin)
Prior treatment with Herceptin
Prior cumulative doxorubicin dose of >360 mg/m2 or the equivalent
History of other malignancies within 5 years of Day 1 except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer
History of significant cardiac disease, unstable angina, congestive heart failure, myocardial infarction, or ventricular arrhythmia requiring medication
Ejection fraction of <50% or below the lower limit of normal determined by ECHO (Subjects who are unable to have ejection fraction evaluated by ECHO may have ejection fraction evaluated by a MUGA scan, although this must be discussed with the Medical Monitor prior to enrollment.)
Active infection requiring IV antibiotics
Uncontrolled hypercalcemia (>11.5 mg/dL)
Clinically important history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
Known human immunodeficiency virus (HIV) infection
Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the subject at high risk from treatment complications
Major surgery or significant traumatic injury within 3 weeks of Day 1
Pregnancy or lactation
Inability to comply with study and follow-up procedures

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
Number of Participants With Dose-Limiting Toxicities (DLTs)	Day 1 of Cycles 1 and 2, and 24 hours after Cycle 2 infusion	Incidence of DLTs defined as any Grade 3 or 4 major organ toxicity according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) Version 2 or any subjectively intolerable toxicity felt by the investigator to be related to rhuMAb 2C4. One participant in the 15.0 mg/kg dose group experienced a gastrointestinal hemorrhage on Day 16. This event was judged by the investigator to be related to study drug. The participant recovered in 3 days and continued to receive rhuMAb 2C4 beyond Cycle 2.This was the only DLT reported during the first two treatment cycles.
Number of Participants With an Adverse Event (AE), Serious Adverse Event (SAE), or Death	Days 1, 2, 5, 8, and 15 of Cycle 1; Days 1, 8, and Week 3, of Cycles 2 and beyond up to 1 year and at the follow-up visit (4 weeks after last infusion)	For this protocol, an AE is defined any untoward medical occurrence (e.g., sign, symptom, disease, syndrome, intercurrent illness, abnormal laboratory finding) that emerges or worsens relative to pretreatment baseline during the treatment or post-treatment periods, regardless of the suspected cause. For this protocol an SAE was defined as any AE that occurred at any dose if: * It resulted in death (i.e., the AE caused or led to death), * It was life threatening, * It required or prolonged inpatient hospitalization, * It was disabling, * It resulted in a congenital anomaly/birth defect, * It may have jeopardized the participant or may have required medical or surgical intervention to prevent one of the outcomes listed above. The primary cause of death for all reported cases was disease progression, and all of the deaths occurred following study discontinuation, with one death occurring within 4 weeks of the last treatment day.

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetic Measurement of Systemic Clearance (CL)	Days 1 (predose, 89 minutes from infusion start, at 1.5, 4, and 8 hours postdose), 2, 5, 8 and 15 of Cycle 1; Days 1 (predose, 29 minutes from infusion start) and 8 of Cycles 2 and beyond until the follow-up visit (4 weeks after the last infusion)	A one-compartment model was used for the 0.5 mg/kg dose group, and a two-compartment model was used for the 2-15 mg/kg dose groups.
Pharmacokinetic Measurement of Volume of Central Compartment (Vc)	Days 1 (predose, 89 minutes from infusion start, at 1.5, 4, and 8 hours postdose), 2, 5, 8 and 15 of Cycle 1; Days 1 (predose, 29 minutes from infusion start) and 8 of Cycles 2 and beyond until the follow-up visit (4 weeks after the last infusion)	A one-compartment model was used for the 0.5 mg/kg dose group, and a two-compartment model was used for the 2-15 mg/kg dose groups.
Pharmacokinetic Measurement of Initial Distribution Half-Life (t1/2 Initial)	Days 1 (predose, 89 minutes from infusion start, at 1.5, 4, and 8 hours postdose), 2, 5, 8 and 15 of Cycle 1; Days 1 (predose, 29 minutes from infusion start) and 8 of Cycles 2 and beyond until the follow-up visit (4 weeks after the last infusion)	A one-compartment model was used for the 0.5 mg/kg dose group, and a two-compartment model was used for the 2-15 mg/kg dose groups.
Pharmacokinetic Measurement of Area Under the Curve (AUC)	Days 1 (predose, 89 minutes following start of infusion and at 1.5, 4, and 8 hours postdose) 2, 5, 8 and 15 of Cycle 1; Days 1 (predose and 29 minutes following start of infusion) and 8 of Cycle 2	Mean rhuMAb 2C4 serum concentrations versus nominal time profiles for the first two treatment cycles are presented for AUC micrograms per milliliters (ug/mL) by day. A one-compartment model was used for the 0.5 mg/kg dose group, and a two-compartment model was used for the 2-15 mg/kg dose groups.
Pharmacokinetic Measurement of Steady-State Volume of Distribution (Vss)	Days 1 (predose, 89 minutes from infusion start, at 1.5, 4, and 8 hours postdose), 2, 5, 8 and 15 of Cycle 1; Days 1 (predose, 29 minutes from infusion start) and 8 of Cycles 2 and beyond until the follow-up visit (4 weeks after the last infusion)	A one-compartment model was used for the 0.5 mg/kg dose group, and a two-compartment model was used for the 2-15 mg/kg dose groups.
Pharmacokinetic Measurement of Terminal Half-Life (t1/2 Terminal) in Days	Days 1 (predose, 89 minutes from infusion start, at 1.5, 4, and 8 hours postdose), 2, 5, 8 and 15 of Cycle 1; Days 1 (predose, 29 minutes from infusion start) and 8 of Cycles 2 and beyond until the follow-up visit (4 weeks after the last infusion)	A one-compartment model was used for the 0.5 mg/kg dose group, and a two-compartment model was used for the 2-15 mg/kg dose groups.