Safety Study of rhuMAb 2C4 to Treat Advanced Solid Tumors

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I, Open-Label, Multicenter, Dose-Escalation Study of the Safety and Pharmacokinetics of a Recombinant Humanized Antibody to Her2 (rhuMAb 2C4) Administered Every 3 Weeks to Subjects With Advanced Solid Malignancies

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: rhuMAb 2C4


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: rhuMAb 2C4|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Adverse Event (AE), Serious Adverse Event (SAE), or Death | 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. | 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) | 
| Number of Participants With Dose-Limiting Toxicities (DLTs) | 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. | Day 1 of Cycles 1 and 2, and 24 hours after Cycle 2 infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Measurement of Area Under the Curve (AUC) | 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. | 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 | 
| Pharmacokinetic Measurement of Systemic Clearance (CL) | 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. | 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) | 
| Pharmacokinetic Measurement of Volume of Central Compartment (Vc) | 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. | 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) | 
| Pharmacokinetic Measurement of Steady-State Volume of Distribution (Vss) | 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. | 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) | 
| Pharmacokinetic Measurement of Initial Distribution Half-Life (t1/2 Initial) | 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. | 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) | 
| Pharmacokinetic Measurement of Terminal Half-Life (t1/2 Terminal) in Days | 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. | 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) |