Safety Study of rhuMAb 2C4 to Treat Advanced Solid Tumors

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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00027027

Enrollment

Registered

2001-11-16

Start date

2001-11-30

Completion date

2003-08-31

Last updated

2015-07-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neoplasms

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.

Interventions

DRUGrhuMAb 2C4

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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.
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.

Secondary

Measure	Time frame	Description
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 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 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 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.
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 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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
rhuMAb 2C4: 0.5 mg/kg rhuMAb 2C4 0.5 mg/kg was administered once every 3 weeks as an IV infusion until PD or unacceptable toxicity occurred for up to a maximum of 1 year.	3
rhuMAb 2C4: 2 mg/kg rhuMAb 2C4 2 mg/kg was administered once every 3 weeks as an IV infusion until PD or unacceptable toxicity occurred for up to a maximum of 1 year.	3
rhuMAb 2C4: 5 mg/kg rhuMAb 2C4 5 mg/kg was administered once every 3 weeks as an IV infusion until PD or unacceptable toxicity occurred for up to a maximum of 1 year.	4
rhuMAb 2C4: 10 mg/kg rhuMAb 2C4 10 mg/kg was administered once every 3 weeks as an IV infusion until PD or unacceptable toxicity occurred for up to a maximum of 1 year.	3
rhuMAb 2C4: 15 mg/kg rhuMAb 2C4 15 mg/kg was administered once every 3 weeks as an IV infusion until PD or unacceptable toxicity occurred for up to a maximum of 1 year.	8
Total	21

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004
Overall Study	Admitted for Signs of PD	0	0	0	0	1
Overall Study	Adverse Event	0	0	1	0	1
Overall Study	Clinical Symptoms Progression not PD	1	0	0	0	0
Overall Study	PD Requiring Surgery	0	0	1	0	0
Overall Study	Physician Decision Due To PD	2	3	2	3	5
Overall Study	Withdrawal by Subject	0	0	0	0	1

Baseline characteristics

Characteristic	rhuMAb 2C4: 0.5 mg/kg	rhuMAb 2C4: 2 mg/kg	rhuMAb 2C4: 5 mg/kg	rhuMAb 2C4: 10 mg/kg	rhuMAb 2C4: 15 mg/kg	Total
Age, Continuous	58 years STANDARD_DEVIATION 20.4	55 years STANDARD_DEVIATION 13.6	48 years STANDARD_DEVIATION 13.8	61 years STANDARD_DEVIATION 17.1	60 years STANDARD_DEVIATION 8.2	56.7 years STANDARD_DEVIATION 12.7
Sex: Female, Male Female	2 Participants	1 Participants	3 Participants	0 Participants	6 Participants	12 Participants
Sex: Female, Male Male	1 Participants	2 Participants	1 Participants	3 Participants	2 Participants	9 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	3 / 3	3 / 3	4 / 4	3 / 3	8 / 8
serious Total, serious adverse events	3 / 3	1 / 3	2 / 4	0 / 3	5 / 8

Outcome results

Primary

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.

Time frame: 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)

Population: All enrolled participants

Arm	Measure	Group	Value (NUMBER)
rhuMAb 2C4: 0.5 mg/kg	Number of Participants With an Adverse Event (AE), Serious Adverse Event (SAE), or Death	Adverse events	3 participants
rhuMAb 2C4: 0.5 mg/kg	Number of Participants With an Adverse Event (AE), Serious Adverse Event (SAE), or Death	Serious adverse events	3 participants
rhuMAb 2C4: 0.5 mg/kg	Number of Participants With an Adverse Event (AE), Serious Adverse Event (SAE), or Death	Death	3 participants
rhuMAb 2C4: 2 mg/kg	Number of Participants With an Adverse Event (AE), Serious Adverse Event (SAE), or Death	Death	1 participants
rhuMAb 2C4: 2 mg/kg	Number of Participants With an Adverse Event (AE), Serious Adverse Event (SAE), or Death	Adverse events	3 participants
rhuMAb 2C4: 2 mg/kg	Number of Participants With an Adverse Event (AE), Serious Adverse Event (SAE), or Death	Serious adverse events	1 participants
rhuMAb 2C4: 5 mg/kg	Number of Participants With an Adverse Event (AE), Serious Adverse Event (SAE), or Death	Adverse events	4 participants
rhuMAb 2C4: 5 mg/kg	Number of Participants With an Adverse Event (AE), Serious Adverse Event (SAE), or Death	Serious adverse events	2 participants
rhuMAb 2C4: 5 mg/kg	Number of Participants With an Adverse Event (AE), Serious Adverse Event (SAE), or Death	Death	2 participants
rhuMAb 2C4: 10 mg/kg	Number of Participants With an Adverse Event (AE), Serious Adverse Event (SAE), or Death	Adverse events	3 participants
rhuMAb 2C4: 10 mg/kg	Number of Participants With an Adverse Event (AE), Serious Adverse Event (SAE), or Death	Serious adverse events	0 participants
rhuMAb 2C4: 10 mg/kg	Number of Participants With an Adverse Event (AE), Serious Adverse Event (SAE), or Death	Death	0 participants
rhuMAb 2C4: 15 mg/kg	Number of Participants With an Adverse Event (AE), Serious Adverse Event (SAE), or Death	Adverse events	8 participants
rhuMAb 2C4: 15 mg/kg	Number of Participants With an Adverse Event (AE), Serious Adverse Event (SAE), or Death	Death	1 participants
rhuMAb 2C4: 15 mg/kg	Number of Participants With an Adverse Event (AE), Serious Adverse Event (SAE), or Death	Serious adverse events	5 participants

Primary

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.

Time frame: Day 1 of Cycles 1 and 2, and 24 hours after Cycle 2 infusion

Population: All enrolled participants who completed at least 2 cycles of study treatment.

Arm	Measure	Value (NUMBER)
rhuMAb 2C4: 0.5 mg/kg	Number of Participants With Dose-Limiting Toxicities (DLTs)	3 participants
rhuMAb 2C4: 2 mg/kg	Number of Participants With Dose-Limiting Toxicities (DLTs)	1 participants
rhuMAb 2C4: 5 mg/kg	Number of Participants With Dose-Limiting Toxicities (DLTs)	2 participants
rhuMAb 2C4: 10 mg/kg	Number of Participants With Dose-Limiting Toxicities (DLTs)	0 participants
rhuMAb 2C4: 15 mg/kg	Number of Participants With Dose-Limiting Toxicities (DLTs)	6 participants

Secondary

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.

Time frame: 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

Population: All enrolled participants

Arm	Measure	Value (MEAN)	Dispersion
rhuMAb 2C4: 0.5 mg/kg	Pharmacokinetic Measurement of Area Under the Curve (AUC)	43.057 ug*hr/mL	Standard Deviation 17.77
rhuMAb 2C4: 2 mg/kg	Pharmacokinetic Measurement of Area Under the Curve (AUC)	569.433 ug*hr/mL	Standard Deviation 168.995
rhuMAb 2C4: 5 mg/kg	Pharmacokinetic Measurement of Area Under the Curve (AUC)	1478.000 ug*hr/mL	Standard Deviation 349.396
rhuMAb 2C4: 10 mg/kg	Pharmacokinetic Measurement of Area Under the Curve (AUC)	3959.333 ug*hr/mL	Standard Deviation 1110.113
rhuMAb 2C4: 15 mg/kg	Pharmacokinetic Measurement of Area Under the Curve (AUC)	4502.625 ug*hr/mL	Standard Deviation 1245.289

Secondary