ADC ID	DRG0BBYHA
ADC Name	Bivatuzumab mertansine
Synonyms	bivatuzumab mertansine; BIWI 1; BIWI1    Click to Show/Hide
Organization	Boehringer Ingelheim (Top20 MNC) (Originator)
Drug Status	Phase 1 (discontinued)
Drug-to-Antibody Ratio	3 to 4
Structure
				2D MOL
Antibody Name	Bivatuzumab					Antibody Info
Antigen Name	CD44 antigen (CD44)					Antigen Info
Payload Name	DM1					Payload Info
Therapeutic Target	Microtubule (MT)					Target Info
Linker Name	N-succinimidyl 4-(2-pyridyldithio) pentanoate (SPP)					Linker Info
Conjugate Type	Random Lysines
Combination Type	mertansine

Standard Type	Value	Units	Description	Reference
Area Under the Concentration-Time Curve (AUC)	19.9	(ug*h/mL)/ (mg/m2)	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 1.	[1]
Area Under the Concentration-Time Curve (AUC)	20.2	(ug*h/mL)/ (mg/m2)	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 2.	[1]
Area Under the Concentration-Time Curve (AUC)	20.4	(ug*h/mL)/ (mg/m2)	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 3.	[1]
Maximum Observed Concentration (Cmax)	0.568	(ug/mL)/ (mg/m2)	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 1.	[1]
Maximum Observed Concentration (Cmax)	0.564	(ug/mL)/ (mg/m2)	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 2.	[1]
Maximum Observed Concentration (Cmax)	0.559	(ug/mL)/ (mg/m2)	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 3.	[1]
Time to Maximum Concentration (Tmax)	0.75	h	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 1.	[1]
Time to Maximum Concentration (Tmax)	0.783	h	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 2.	[1]
Time to Maximum Concentration (Tmax)	0.875	h	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 3.	[1]
Area Under the Concentration-Time Curve (AUC)	22.2	(ug*h/mL)/ (mg/m2)	Pharmacokinetic parameters of bivatuzumab mertansine in 24 patients: noncompartmental analysis, AUCinf.	[2]
Area Under the Concentration-Time Curve (AUC)	20.5	(ug*h/mL)/ (mg/m2)	Pharmacokinetic parameters of bivatuzumab mertansine in 24 patients: noncompartmental analysis, AUC0-168.	[2]
Maximum Observed Concentration (Cmax)	0.567	(ug/mL)/ (mg/m2)	Pharmacokinetic parameters of bivatuzumab mertansine in 24 patients: noncompartmental analysis.	[2]
Time to Maximum Concentration (Tmax)	0.833	h	Pharmacokinetic parameters of bivatuzumab mertansine in 24 patients: noncompartmental analysis.	[2]

Standard Type	Value	Units	Description	Reference
Area Under the Concentration-Time Curve (AUC)	19.9	(ug*h/mL)/ (mg/m2)	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 1.	[1]
Area Under the Concentration-Time Curve (AUC)	20.2	(ug*h/mL)/ (mg/m2)	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 2.	[1]
Area Under the Concentration-Time Curve (AUC)	20.4	(ug*h/mL)/ (mg/m2)	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 3.	[1]
Volume of Distribution (Vd)	5.25	L	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 3.	[1]
Area Under the Concentration-Time Curve (AUC)	22.2	(ug*h/mL)/ (mg/m2)	Pharmacokinetic parameters of bivatuzumab mertansine in 24 patients: noncompartmental analysis, AUCinf.	[2]
Area Under the Concentration-Time Curve (AUC)	20.5	(ug*h/mL)/ (mg/m2)	Pharmacokinetic parameters of bivatuzumab mertansine in 24 patients: noncompartmental analysis, AUC0-168.	[2]
Volume of Distribution (Vd)	4.54	L	Pharmacokinetic parameters of bivatuzumab mertansine in 24 patients: noncompartmental analysis.	[2]

Standard Type	Value	Units	Description	Reference
Area Under the Concentration-Time Curve (AUC)	19.9	(ug*h/mL)/ (mg/m2)	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 1.	[1]
Area Under the Concentration-Time Curve (AUC)	20.2	(ug*h/mL)/ (mg/m2)	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 2.	[1]
Area Under the Concentration-Time Curve (AUC)	20.4	(ug*h/mL)/ (mg/m2)	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 3.	[1]
Area Under the Concentration-Time Curve (AUC)	22.2	(ug*h/mL)/ (mg/m2)	Pharmacokinetic parameters of bivatuzumab mertansine in 24 patients: noncompartmental analysis, AUCinf.	[2]
Area Under the Concentration-Time Curve (AUC)	20.5	(ug*h/mL)/ (mg/m2)	Pharmacokinetic parameters of bivatuzumab mertansine in 24 patients: noncompartmental analysis, AUC0-168.	[2]

Standard Type	Value	Units	Description	Reference
Area Under the Concentration-Time Curve (AUC)	19.9	(ug*h/mL)/ (mg/m2)	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 1.	[1]
Area Under the Concentration-Time Curve (AUC)	20.2	(ug*h/mL)/ (mg/m2)	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 2.	[1]
Area Under the Concentration-Time Curve (AUC)	20.4	(ug*h/mL)/ (mg/m2)	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 3.	[1]
Elimination Half-Life (t1/2)	42.1	h	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 1.	[1]
Elimination Half-Life (t1/2)	40.2	h	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 2.	[1]
Elimination Half-Life (t1/2)	69.1	h	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 3.	[1]
Clearance (CL)	1.51	mL/min	Descriptive statistics of noncompartmental pharmacokinetic variables of bivatuzumab mertansine after a 3-week once weekly infusion regimen, week 3.	[1]
Area Under the Concentration-Time Curve (AUC)	22.2	(ug*h/mL)/ (mg/m2)	Pharmacokinetic parameters of bivatuzumab mertansine in 24 patients: noncompartmental analysis, AUCinf.	[2]
Area Under the Concentration-Time Curve (AUC)	20.5	(ug*h/mL)/ (mg/m2)	Pharmacokinetic parameters of bivatuzumab mertansine in 24 patients: noncompartmental analysis, AUC0-168.	[2]
Elimination Half-Life (t1/2)	69.6	h	Pharmacokinetic parameters of bivatuzumab mertansine in 24 patients: noncompartmental analysis.	[2]
Clearance (CL)	1.29	mL/min	Pharmacokinetic parameters of bivatuzumab mertansine in 24 patients: noncompartmental analysis.	[2]

Standard Type	NCT Number	Clinical Status	Clinical Trial Description
Undisclosed	NCT02254044	PHASE1	An Open Phase I Dose Escalation Study of Bivatuzumab Mertansine Administered Intravenously Once Per Week for Three Weeks in Patients With Advanced Squamous Cell Carcinoma of the Head and Neck or Esophagus With Repeated Administration Courses in Patients With Clinical Benefit    Click to Show/Hide
Undisclosed	NCT02254005	PHASE1	An Open Phase I Single Dose Escalation Study of Bivatuzumab Mertansine Administered Intravenously in Female Patients With CD44v6 Positive Metastatic Breast Cancer With Repeated Administration in Patients With Clinical Benefit    Click to Show/Hide
Undisclosed	NCT02254031	PHASE1	An Open Phase I Dose Escalation Study of Bivatuzumab Mertansine Administered Intravenously Once Per Week for Three Weeks in Female Patients With CD44v6 Positive Recurrent or Metastatic Breast Cancer With Repeated Administration Courses in Patients With Clinical Benefit    Click to Show/Hide
Undisclosed	NCT02254018	PHASE1	An Open Phase I Single Dose Escalation Study of Bivatuzumab Mertansine Administered Intravenously in Patients With Advanced Squamous Cell Carcinoma of the Head and Neck With Repeated Administration in Patients With Clinical Benefit    Click to Show/Hide
Objective Response Rate (ORR)	NCT02254005	Phase 1	An open phase 1 single dose escalation study of bivatuzumab mertansine administered intravenously in female patients with CD44v6 positive metastatic breast cancer with repeated administration in patients with clinical benefit.    Click to Show/Hide
Undisclosed	NCT02254044	Phase 1	An open phase 1 dose escalation study of bivatuzumab mertansine administered intravenously once per week for three weeks in patients with advanced squamous cell carcinoma of the head and neck or esophagus with repeated administration courses in patients with clinical benefit.    Click to Show/Hide
Undisclosed	NCT02254044	Phase 1	An open phase 1 dose escalation study of bivatuzumab mertansine administered intravenously once per week for three weeks in patients with advanced squamous cell carcinoma of the head and neck or esophagus with repeated administration courses in patients with clinical benefit.    Click to Show/Hide
Undisclosed	NCT02254031	Phase 1	An open phase 1 dose escalation study of bivatuzumab mertansine administered intravenously once per week for three weeks in female patients with CD44V6 positive recurrent or metastatic breast cancer with repeated administration courses in patients with clinical.    Click to Show/Hide
Undisclosed	NCT02254005	Phase 1	An open phase 1 single dose escalation study of bivatuzumab mertansine administered intravenously in female patients with CD44v6 positive metastatic breast cancer with repeated administration in patients with clinical benefit.    Click to Show/Hide
Undisclosed	NCT02254018	Phase 1	An open phase 1 single dose escalation study of bivatuzumab mertansine administered intravenously in patients with advanced squamous cell carcinoma of the head and neck with repeated administration in patients with clinical benefit.    Click to Show/Hide

Experiment 1 Reporting the Activity Date of This ADC					[3]
Patients Enrolled	Eligible patients (18-80 years) must have histologically confirmed recurrent/metastatic head/neck or esophageal squamous cell carcinoma refractory to standard treatments, measurable disease, ECOG &le;2, and life expectancy &ge;3 months. Key exclusions include antibody hypersensitivity, active infections, untreated brain metastases, grade &ge;2 neuropathy, significant hematologic/hepatic/renal dysfunction (ANC <1500/mm <sup>3</sup>, platelets <100K/mm <sup>3</sup>, bilirubin >1.5mg/dl, AST/ALT >3&times;ULN, creatinine >1.5mg/dl), recent anticancer therapy (<4 weeks), pregnancy, or protocol non-compliance.    Click to Show/Hide
Administration Dosage	.
Related Clinical Trial
NCT Number	NCT02254044	Clinical Status	PHASE1
Clinical Description	An Open Phase I Dose Escalation Study of Bivatuzumab Mertansine Administered Intravenously Once Per Week for Three Weeks in Patients With Advanced Squamous Cell Carcinoma of the Head and Neck or Esophagus With Repeated Administration Courses in Patients With Clinical Benefit
Primary Endpoint	The primary objective is to determine the maximum tolerated dose (MTD) of the investigational drug within a 6-month observation period.
Other Endpoint	Safety evaluations include monitoring adverse events (graded by CTC criteria), clinically significant lab/vital sign abnormalities, and HAHA development for 14 days post-treatment. Pharmacokinetic parameters (AUC0-168, AUC0-tz, AUC0-∞, Cmax, tmax, t1/2, MRT, CL, Vss, Vz, Cpre,ss, Cmin,ss, LI, RA) are assessed for 14 days post-dosing. Tumor response is evaluated per RECIST criteria.    Click to Show/Hide
Experiment 2 Reporting the Activity Date of This ADC					[4]
Patients Enrolled	Eligible patients are women &ge;18 years with CD44v6+ (&ge;50% tumor cells) metastatic breast cancer refractory to anthracyclines/taxanes, measurable lesions (MRI/CT), ECOG &le;2, and life expectancy &ge;6 months. Exclusions include antibody hypersensitivity, active infections, untreated brain metastases, grade &ge;2 neuropathy, hematologic/organ dysfunction (ANC <1500/mm <sup>3</sup>, platelets <100K/mm <sup>3</sup>, bilirubin >1.5mg/dl, AST/ALT >3&times;ULN, creatinine >1.5mg/dl), recent anticancer therapy (<4 weeks), pregnancy, or protocol non-compliance.    Click to Show/Hide
Administration Dosage	.
Related Clinical Trial
NCT Number	NCT02254005	Clinical Status	PHASE1
Clinical Description	An Open Phase I Single Dose Escalation Study of Bivatuzumab Mertansine Administered Intravenously in Female Patients With CD44v6 Positive Metastatic Breast Cancer With Repeated Administration in Patients With Clinical Benefit
Primary Endpoint	The study aims to determine the maximum tolerated dose (MTD) of bivatuzumab mertansine within a 21-day evaluation period.
Other Endpoint	Safety assessments (AEs, lab abnormalities, vital signs) and pharmacokinetic markers (drug concentration, anti-CD44v6-IgG, HAHA development) are monitored for 21 days. Tumor response is evaluated per RECIST criteria over 1 year.
Experiment 3 Reporting the Activity Date of This ADC					[5]
Patients Enrolled	Eligible patients are women &ge;18 years with CD44v6+ (&ge;50% tumor cells) locally recurrent/metastatic breast cancer refractory to anthracyclines/taxanes, having measurable lesions (MRI/CT), ECOG &le;2, and &ge;6 months life expectancy. Key exclusions include antibody hypersensitivity, active infections, untreated brain metastases, grade &ge;2 neuropathy, significant hematologic/organ dysfunction, recent anticancer therapies (<4 weeks), pregnancy/lactation, or protocol non-compliance.    Click to Show/Hide
Administration Dosage	.
Related Clinical Trial
NCT Number	NCT02254031	Clinical Status	PHASE1
Clinical Description	An Open Phase I Dose Escalation Study of Bivatuzumab Mertansine Administered Intravenously Once Per Week for Three Weeks in Female Patients With CD44v6 Positive Recurrent or Metastatic Breast Cancer With Repeated Administration Courses in Patients With Clinical Benefit
Primary Endpoint	The primary objective is to determine the maximum tolerated dose (MTD) of the study drug, with evaluation up to 6 months from treatment initiation.
Other Endpoint	Secondary outcomes include safety assessments (adverse events graded by CTC criteria, lab abnormalities, vital signs, and HAHA development) and comprehensive pharmacokinetic parameters (AUC, Cmax, tmax, clearance rates, volume of distribution) measured within 14 days post-treatment. Tumor response will be evaluated per RECIST criteria during this same timeframe.    Click to Show/Hide
Experiment 4 Reporting the Activity Date of This ADC					[6]
Patients Enrolled	Enrollment criteria: Adults (&ge;18 years) with histologically confirmed, measurable recurrent/metastatic disease (MRI/CT), ECOG &le;2, &ge;6-month life expectancy, and no active infections/brain metastases. Excluded: hypersensitivity to immunoconjugates, significant cytopenias/organ dysfunction, recent anticancer therapies (<3-4 weeks), pregnancy, or protocol non-adherence.    Click to Show/Hide
Administration Dosage	.
Related Clinical Trial
NCT Number	NCT02254018	Clinical Status	PHASE1
Clinical Description	An Open Phase I Single Dose Escalation Study of Bivatuzumab Mertansine Administered Intravenously in Patients With Advanced Squamous Cell Carcinoma of the Head and Neck With Repeated Administration in Patients With Clinical Benefit
Primary Endpoint	The primary endpoint is determining the maximum tolerated dose (MTD) of bivatuzumab mertansine within a 21-day evaluation period in patients with treatment-refractory head and neck squamous cell carcinoma.
Other Endpoint	Secondary assessments include safety profiles (CTC-graded adverse events, lab/vital sign abnormalities, HAHA development) and efficacy (RECIST tumor response monitored for 1 year), along with pharmacokinetic measurements (drug and anti-CD44v6-IgG concentrations) during the 21-day treatment course.
Experiment 5 Reporting the Activity Date of This ADC					[7]
Efficacy Data	Objective Response Rate (ORR)	0%
Patients Enrolled	Metastatic breast cancer (MBC) that expresses CD44v6 in at least 50% of tumor cells in primary tumor tissue as assessed by immunohistochemistry, pretreatment with anthracyclines and taxanes, tumor metastases measurable by computed tomography (CT) or magnetic resonance imaging (MRI), life expectancy of at least 6 months, no chemotherapy, radiotherapy or immunotherapy within the last 4 weeks before study entry, adequate organ function, Eastern Cooperative Oncology Group performance score 2.    Click to Show/Hide
Administration Dosage	One single intravenous infusion over 30 min, dose was escalated in 25 mg/m2 increments up to the maximum tolerated dose (MTD).
Related Clinical Trial
NCT Number	NCT02254005	Clinical Status	Phase 1
Clinical Description	An open phase 1 single dose escalation study of bivatuzumab mertansine administered intravenously in female patients with CD44v6 positive metastatic breast cancer with repeated administration in patients with clinical benefit.
Primary Endpoint	The MTD in this trial could not be determined.
Other Endpoint	No objective responses were observed. Disease stabilization was achieved in 50.00% of patients independently of dose level.
Experiment 6 Reporting the Activity Date of This ADC					[8]
Patients Enrolled	Ecurrent or metastatic head and neck squamous cell carcinoma (HNSCC) not amenable to established treatments, an ECOG score 2, and an estimated life expectancy of at least 6 months, a tumor diameter of at least 1 cm in CT or MRI scans was also required.
Administration Dosage	Starting with 25 mg/m2, the dose was escalated in steps of 25 mg/m2 until dose limiting toxicity was observed, intravenously.
Related Clinical Trial
NCT Number	NCT02254044	Clinical Status	Phase 1
Clinical Description	An open phase 1 dose escalation study of bivatuzumab mertansine administered intravenously once per week for three weeks in patients with advanced squamous cell carcinoma of the head and neck or esophagus with repeated administration courses in patients with clinical benefit.
Primary Endpoint	The MTD was 300 mg/m2.
Other Endpoint	Due to the premature discontinuation of the trial efficacy complying with the study plan could not be assessed. In 3 patients,a partial response at doses of 2.00, 2.75 and 3.25 mg/m2.
Experiment 7 Reporting the Activity Date of This ADC					[9]
Related Clinical Trial
NCT Number	NCT02254044	Clinical Status	Phase 1
Clinical Description	An open phase 1 dose escalation study of bivatuzumab mertansine administered intravenously once per week for three weeks in patients with advanced squamous cell carcinoma of the head and neck or esophagus with repeated administration courses in patients with clinical benefit.
Experiment 8 Reporting the Activity Date of This ADC					[10]
Related Clinical Trial
NCT Number	NCT02254031	Clinical Status	Phase 1
Clinical Description	An open phase 1 dose escalation study of bivatuzumab mertansine administered intravenously once per week for three weeks in female patients with CD44V6 positive recurrent or metastatic breast cancer with repeated administration courses in patients with clinical.
Experiment 9 Reporting the Activity Date of This ADC					[11]
Related Clinical Trial
NCT Number	NCT02254005	Clinical Status	Phase 1
Clinical Description	An open phase 1 single dose escalation study of bivatuzumab mertansine administered intravenously in female patients with CD44v6 positive metastatic breast cancer with repeated administration in patients with clinical benefit.
Experiment 10 Reporting the Activity Date of This ADC					[12]
Related Clinical Trial
NCT Number	NCT02254018	Clinical Status	Phase 1
Clinical Description	An open phase 1 single dose escalation study of bivatuzumab mertansine administered intravenously in patients with advanced squamous cell carcinoma of the head and neck with repeated administration in patients with clinical benefit.

Ref 1	A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus
Ref 2	Safety and pharmacokinetics of bivatuzumab mertansine in patients with CD44v6-positive metastatic breast cancer: final results of a phase I study
Ref 3	Dose Escalation of Bivatuzumab Mertansine in Patients With Advanced Squamous Cell Carcinoma of the Head and Neck or Esophagus
Ref 4	Single Dose Escalation Study of Bivatuzumab Mertansine in Female Patients With CD44v6 Positive Metastatic Breast Cancer
Ref 5	Dose Escalation of Bivatuzumab Mertansine in Female Patients With CD44v6 Positive Recurrent or Metastatic Breast Cancer
Ref 6	Single Dose Escalation Study of Bivatuzumab Mertansine in Patients With Advanced Squamous Cell Carcinoma of the Head and Neck
Ref 7	Safety and pharmacokinetics of bivatuzumab mertansine in patients with CD44v6-positive metastatic breast cancer: final results of a phase I study. Anticancer Drugs. 2007 Apr;18(4):477-85.
Ref 8	Phase I trial with the CD44v6-targeting immunoconjugate bivatuzumab mertansine in head and neck squamous cell carcinoma. Oral Oncol. 2008 Sep;44(9):823-9.
Ref 9	An Open Phase I Dose Escalation Study of Bivatuzumab Mertansine Administered Intravenously Once Per Week for Three Weeks in Patients With Advanced Squamous Cell Carcinoma of the Head and Neck or Esophagus With Repeated Administration Courses in Patients With Clinical Benefit
Ref 10	An Open Phase I Dose Escalation Study of Bivatuzumab Mertansine Administered Intravenously Once Per Week for Three Weeks in Female Patients With CD44v6 Positive Recurrent or Metastatic Breast Cancer With Repeated Administration Courses in Patients With Clinical Benefit
Ref 11	An Open Phase I Single Dose Escalation Study of Bivatuzumab Mertansine Administered Intravenously in Female Patients With CD44v6 Positive Metastatic Breast Cancer With Repeated Administration in Patients With Clinical Benefit
Ref 12	An Open Phase I Single Dose Escalation Study of Bivatuzumab Mertansine Administered Intravenously in Patients With Advanced Squamous Cell Carcinoma of the Head and Neck With Repeated Administration in Patients With Clinical Benefit