Brief Summary
The purpose of this study is to evaluate the safety and tolerability of BAX69 monotherapy given either as intraperitoneal (IP) infusion (Single-Route Arm); or as IP infusion after intravenous (IV) infusion (IV+IP) (Double-Route Arm), and to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) for each Arm separately, in subjects with refractory ovarian cancer and recurrent malignant ascites. In both Arms, the plasma pharmacokinetics (PK) of BAX69 will be characterized, and pharmacodynamics (PD) markers will be explored in plasma and ascites. Two expansion cohorts will further assess the tolerability of the RP2D and explore clinical signs of efficacy.
Brief Title
Phase 1/2a Two-Arm Dose-Escalation Study of BAX69 in Subjects With Malignant Ascites of Ovarian Cancer
Completion Date
Completion Date Type
Actual
Conditions
Refractory Ovarian Cancer With Recurrent Symptomatic Malignant Ascites
Eligibility Criteria
Inclusion Criteria:
1. Provision of a signed informed consent
2. Female participants of non-childbearing potential, ≥18 years of age
3. Anticipated life expectancy \>3 months at the time of screening
4. Metastatic ovarian epithelial cancer that are platinum-resistant, and has no better option available in the investigator's opinion
5. Recurrent symptomatic malignant ascites having required at least 2 paracenteses within a 45-day interval prior to baseline paracentesis
6. Participants who have an indwelling draining IP catheter (to be drained only under medical supervision)
7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2
8. Adequate hematological function, defined as:
* Platelet count ≥100,000/μL
* Prothrombin time (PT) and activated partial thromboplastin time (aPTT) \<1.5 times the upper limit of normal (ULN)
* Absolute neutrophil count ≥1,000/μL
* Hemoglobin ≥9 g/dL, without the need for transfusion in the 2 weeks prior to screening
9. Adequate renal function, defined as serum creatinine ≤2.0 times ULN and creatinine clearance \>50 mL/min or estimated glomerular filtration rate (eGFR) \>50 mL/min/1.73 m\^2
10. Adequate liver function, defined as:
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 times ULN for participants without liver metastases, or ≤5 times ULN in the presence of liver metastases
* Bilirubin ≤2.0 times ULN, unless participant has known Gilbert's syndrome
11. Adequate venous access
12. Participant is willing and able to comply with the requirements of the protocol
Exclusion Criteria:
1. Known central nervous system metastasis that is unstable within the last 2 months
2. Prior malignancy within the past 3 years, with the exception of curatively treated basal or squamous cell carcinoma of the skin, ductal carcinoma in situ of breast, in situ cervical carcinoma, and superficial bladder cancer
3. Residual AEs \>Grade 2 from previous treatment
4. Myocardial infarction within 6 months prior to C1D1 treatment, and/or prior diagnoses of congestive heart failure (New York Heart Association Class III or IV), unstable angina, unstable cardiac arrhythmia requiring medication; and/or the participant is at risk for polymorphic ventricular tachycardia (eg, hypokalemia, family history or long QT syndrome)
5. Uncontrolled hypertension defined as systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg confirmed upon repeated measures
6. Left ventricular ejection fraction \<50% as determined by echocardiogram (ECHO) performed at screening or within 30 days prior to C1D1
7. QT/QTc interval \>480 msec, before C1D1 treatment administration, as determined by screening electrocardiogram (ECG)
8. Received anti-tumor therapy (chemotherapy, investigational product, radiotherapy, retinoid therapy, or hormonal therapy) within 2 weeks (less than 14 days) prior to C1D1 with no residual toxicity \>Grade 1; antibody therapy, molecular targeted therapy within 5 half-lives prior to C1D1
9. Major surgery within 4 weeks (less than 28 days) prior to C1D1
10. Active joint inflammation or other immune disorder involving joints (osteoarthritis is not exclusionary)
11. Active infection involving IV antibiotics within 2 weeks prior to C1D1
12. Positive serology test for hepatitis B virus (HBV), hepatitis C virus (HCV), or active tuberculosis
13. Positive serology test for human immunodeficiency virus (HIV) type 1 and 2, or known history of other immunodeficiency disease
14. Participant has received a live vaccine within 2 weeks (less than 14 days) prior to C1D1
15. Known hypersensitivity to any component of recombinant protein production by Chinese Hamster Ovary (CHO) cells
16. Any disorder or disease, or clinically significant abnormality on laboratory or other clinical test(s) (eg, blood tests and ECG), that in medical judgment of the investigator may impede the participant's participation in the study, pose increased risk to the participant, and/or confound the results of the study
17. Participant is a family member or employee of the investigator
1. Provision of a signed informed consent
2. Female participants of non-childbearing potential, ≥18 years of age
3. Anticipated life expectancy \>3 months at the time of screening
4. Metastatic ovarian epithelial cancer that are platinum-resistant, and has no better option available in the investigator's opinion
5. Recurrent symptomatic malignant ascites having required at least 2 paracenteses within a 45-day interval prior to baseline paracentesis
6. Participants who have an indwelling draining IP catheter (to be drained only under medical supervision)
7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2
8. Adequate hematological function, defined as:
* Platelet count ≥100,000/μL
* Prothrombin time (PT) and activated partial thromboplastin time (aPTT) \<1.5 times the upper limit of normal (ULN)
* Absolute neutrophil count ≥1,000/μL
* Hemoglobin ≥9 g/dL, without the need for transfusion in the 2 weeks prior to screening
9. Adequate renal function, defined as serum creatinine ≤2.0 times ULN and creatinine clearance \>50 mL/min or estimated glomerular filtration rate (eGFR) \>50 mL/min/1.73 m\^2
10. Adequate liver function, defined as:
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 times ULN for participants without liver metastases, or ≤5 times ULN in the presence of liver metastases
* Bilirubin ≤2.0 times ULN, unless participant has known Gilbert's syndrome
11. Adequate venous access
12. Participant is willing and able to comply with the requirements of the protocol
Exclusion Criteria:
1. Known central nervous system metastasis that is unstable within the last 2 months
2. Prior malignancy within the past 3 years, with the exception of curatively treated basal or squamous cell carcinoma of the skin, ductal carcinoma in situ of breast, in situ cervical carcinoma, and superficial bladder cancer
3. Residual AEs \>Grade 2 from previous treatment
4. Myocardial infarction within 6 months prior to C1D1 treatment, and/or prior diagnoses of congestive heart failure (New York Heart Association Class III or IV), unstable angina, unstable cardiac arrhythmia requiring medication; and/or the participant is at risk for polymorphic ventricular tachycardia (eg, hypokalemia, family history or long QT syndrome)
5. Uncontrolled hypertension defined as systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg confirmed upon repeated measures
6. Left ventricular ejection fraction \<50% as determined by echocardiogram (ECHO) performed at screening or within 30 days prior to C1D1
7. QT/QTc interval \>480 msec, before C1D1 treatment administration, as determined by screening electrocardiogram (ECG)
8. Received anti-tumor therapy (chemotherapy, investigational product, radiotherapy, retinoid therapy, or hormonal therapy) within 2 weeks (less than 14 days) prior to C1D1 with no residual toxicity \>Grade 1; antibody therapy, molecular targeted therapy within 5 half-lives prior to C1D1
9. Major surgery within 4 weeks (less than 28 days) prior to C1D1
10. Active joint inflammation or other immune disorder involving joints (osteoarthritis is not exclusionary)
11. Active infection involving IV antibiotics within 2 weeks prior to C1D1
12. Positive serology test for hepatitis B virus (HBV), hepatitis C virus (HCV), or active tuberculosis
13. Positive serology test for human immunodeficiency virus (HIV) type 1 and 2, or known history of other immunodeficiency disease
14. Participant has received a live vaccine within 2 weeks (less than 14 days) prior to C1D1
15. Known hypersensitivity to any component of recombinant protein production by Chinese Hamster Ovary (CHO) cells
16. Any disorder or disease, or clinically significant abnormality on laboratory or other clinical test(s) (eg, blood tests and ECG), that in medical judgment of the investigator may impede the participant's participation in the study, pose increased risk to the participant, and/or confound the results of the study
17. Participant is a family member or employee of the investigator
Inclusion Criteria
Inclusion Criteria:
1. Provision of a signed informed consent
2. Female participants of non-childbearing potential, ≥18 years of age
3. Anticipated life expectancy \>3 months at the time of screening
4. Metastatic ovarian epithelial cancer that are platinum-resistant, and has no better option available in the investigator's opinion
5. Recurrent symptomatic malignant ascites having required at least 2 paracenteses within a 45-day interval prior to baseline paracentesis
6. Participants who have an indwelling draining IP catheter (to be drained only under medical supervision)
7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2
8. Adequate hematological function, defined as:
* Platelet count ≥100,000/μL
* Prothrombin time (PT) and activated partial thromboplastin time (aPTT) \<1.5 times the upper limit of normal (ULN)
* Absolute neutrophil count ≥1,000/μL
* Hemoglobin ≥9 g/dL, without the need for transfusion in the 2 weeks prior to screening
9. Adequate renal function, defined as serum creatinine ≤2.0 times ULN and creatinine clearance \>50 mL/min or estimated glomerular filtration rate (eGFR) \>50 mL/min/1.73 m\^2
10. Adequate liver function, defined as:
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 times ULN for participants without liver metastases, or ≤5 times ULN in the presence of liver metastases
* Bilirubin ≤2.0 times ULN, unless participant has known Gilbert's syndrome
11. Adequate venous access
12. Participant is willing and able to comply with the requirements of the protocol
1. Provision of a signed informed consent
2. Female participants of non-childbearing potential, ≥18 years of age
3. Anticipated life expectancy \>3 months at the time of screening
4. Metastatic ovarian epithelial cancer that are platinum-resistant, and has no better option available in the investigator's opinion
5. Recurrent symptomatic malignant ascites having required at least 2 paracenteses within a 45-day interval prior to baseline paracentesis
6. Participants who have an indwelling draining IP catheter (to be drained only under medical supervision)
7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2
8. Adequate hematological function, defined as:
* Platelet count ≥100,000/μL
* Prothrombin time (PT) and activated partial thromboplastin time (aPTT) \<1.5 times the upper limit of normal (ULN)
* Absolute neutrophil count ≥1,000/μL
* Hemoglobin ≥9 g/dL, without the need for transfusion in the 2 weeks prior to screening
9. Adequate renal function, defined as serum creatinine ≤2.0 times ULN and creatinine clearance \>50 mL/min or estimated glomerular filtration rate (eGFR) \>50 mL/min/1.73 m\^2
10. Adequate liver function, defined as:
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 times ULN for participants without liver metastases, or ≤5 times ULN in the presence of liver metastases
* Bilirubin ≤2.0 times ULN, unless participant has known Gilbert's syndrome
11. Adequate venous access
12. Participant is willing and able to comply with the requirements of the protocol
Gender
Female
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT02540356
Org Class
Industry
Org Full Name
Takeda
Org Study Id
391402
Overall Status
Terminated
Phases
Phase 1
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Phase 1/2a, Open-Label, Parallel, Two-Arm Dose-Escalation Study to Assess the Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of BAX69 in Subjects With Refractory Ovarian Cancer With Malignant Ascites
Primary Outcomes
Outcome Description
DLT is defined as any drug related treatment-emergent adverse event that occurs during the 28-day period after the first dose of Imalumab and that meets any of these criteria: - Any ≥ grade 3 non-hematologic toxicity assessed by the investigator as related to study drug (except: single lab value out of normal range not necessarily translating or considered a feature of clinical diagnosis requiring an intervention per investigator's interpretation and resolves to ≤ Grade 2 with adequate measure in 7 days; Transient grade 3 elevations of hepatic transaminases in the absence of simultaneous increase in serum bilirubin; Alopecia) - Any toxicity resulted in dose delay for ≥14 days - Any grade 4 hematologic toxicity (except lymphopenia) - Grade 3 febrile neutropenia - Grade 3 thrombocytopenia associated with bleeding - Any life-threatening complication/abnormality not covered in the NCICTCAE v4.03
Outcome Measure
The Occurrence of Dose-limiting Toxicity (DLT)
Outcome Time Frame
4 weeks
Outcome Description
PuFS is defined as the time from the last dose of Imalumab to the first therapeutic paracentesis after that, or death, whichever occurs first. Puncture-free interval at baseline is calculated as the time between the last 2 therapeutic paracenteses immediately before the first dose of Imalubmab.
Outcome Measure
The Ratio of Puncture Free Survival (PuFS) Over Puncture-free Interval at Baseline
Outcome Time Frame
4 weeks
Secondary Ids
Secondary Id
2015-003492-29
Secondary Outcomes
Outcome Description
Time to first paracentesis post-treatment is calculated as the time between the last dose of Imalumab to subsequent first therapeutic paracentesis.
Outcome Time Frame
4 weeks
Outcome Measure
Ratio of Time to First Paracentesis Post-treatment Over Puncture-free Interval at Baseline
Outcome Description
The volume of ascites from the last dose of Imalumab to the first post-treatment paracentesis per unit time will be compared to the volume of the last pre-treatment paracentesis per unit time. At each paracentesis, the volume of fluid that can be removed safely (measured by ultrasound-guided paracentesis) to achieve close to dryness should be withdrawn, measured, and documented.
Outcome Time Frame
Up to 4 weeks
Outcome Measure
Change in Ascites Volume Per Unit Time With Treatment
Outcome Description
Ascites related symptoms: anorexia, nausea, early satiety, vomiting, abdominal pain, abdominal swelling, dyspnea, fatigue, swollen ankles, heartburn
Outcome Time Frame
Baseline, weekly during the treatment period, and every 2 weeks during the safety follow-up period, up to approximately 6 months)
Outcome Measure
Changes in Ascites-related Symptoms
Outcome Time Frame
Throughout the study period of approximately 22 months
Outcome Measure
Occurrence of Serious Adverse Events (SAEs) and/or Treatment-emergent Adverse Events (TEAEs), Regardless of Causality or Relationship to Study Drug
Outcome Time Frame
Throughout the study period of approximately 22 months
Outcome Measure
Occurrence of Binding and/or Neutralizing Anti-imalumab (BAX69) Antibodies Following Treatment With Imalumab (BAX69)
Outcome Time Frame
Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours
Outcome Measure
Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Maximum Observed Concentration (Cmax)
Outcome Time Frame
Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours
Outcome Measure
Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Minimum Observed Concentration (Cmin)
Outcome Time Frame
Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours
Outcome Measure
Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Area Under the Concentration vs Time Curve (AUC)
Outcome Time Frame
Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours
Outcome Measure
Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Half-life (t1/2)
Outcome Time Frame
Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours
Outcome Measure
Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Apparent Systemic Clearance (CL)
Outcome Time Frame
Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours
Outcome Measure
Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Volume of Distribution (V)
Outcome Description
QoL will be assessed using EORTC QLQ-C30.
Outcome Time Frame
Weekly from the baseline visit to the last week of safety follow-up (8 weeks or longer, if additional treatment will be implemented)
Outcome Measure
Quality of Life (QoL) Measure - European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Questionnaire
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Gloria Huang
Investigator Email
ghuang@montefiore.org
Investigator Phone
718-405-8082