Clinical trial NCT02540356: Phase 1/2a Two-Arm Dose-Escalation Study of BAX69 in Subjects With Malignant Ascites of Ovarian Cancer
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Refractory Ovarian Cancer With Recurrent Symptomatic Malignant Ascites
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2015-09-03
Enrollment: 2
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: The Occurrence of Dose-limiting Toxicity (DLT)
timeFrame: 4 weeks
measure: The Ratio of Puncture Free Survival (PuFS) Over Puncture-free Interval at Baseline
timeFrame: 4 weeks
Secondary outcomes:
measure: Ratio of Time to First Paracentesis Post-treatment Over Puncture-free Interval at Baseline
timeFrame: 4 weeks
measure: Change in Ascites Volume Per Unit Time With Treatment
timeFrame: Up to 4 weeks
measure: Changes in Ascites-related Symptoms
timeFrame: Baseline, weekly during the treatment period, and every 2 weeks during the safety follow-up period, up to approximately 6 months)
measure: Occurrence of Serious Adverse Events (SAEs) and/or Treatment-emergent Adverse Events (TEAEs), Regardless of Causality or Relationship to Study Drug
timeFrame: Throughout the study period of approximately 22 months
measure: Occurrence of Binding and/or Neutralizing Anti-imalumab (BAX69) Antibodies Following Treatment With Imalumab (BAX69)
timeFrame: Throughout the study period of approximately 22 months
measure: Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Maximum Observed Concentration (Cmax)
timeFrame: Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours
measure: Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Minimum Observed Concentration (Cmin)
timeFrame: Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours
measure: Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Area Under the Concentration vs Time Curve (AUC)
timeFrame: Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours
measure: Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Half-life (t1/2)
timeFrame: Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours
measure: Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Apparent Systemic Clearance (CL)
timeFrame: Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours
measure: Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Volume of Distribution (V)
timeFrame: Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours
measure: Quality of Life (QoL) Measure - European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Questionnaire
timeFrame: Weekly from the baseline visit to the last week of safety follow-up (8 weeks or longer, if additional treatment will be implemented)
Other outcomes:
Locations:
city: Miami
country: United States
facility: University of Miami Miller School of Medicine
state: Florida
city: Augusta
country: United States
facility: Georgia Regents University
state: Georgia
city: Silver Spring
country: United States
facility: Women's Health Specialists
state: Maryland
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center at The University of Oklahoma
state: Oklahoma
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Shire
name: Study Director
role: STUDY_DIRECTOR
References: