Phase 1/2a Two-Arm Dose-Escalation Study of BAX69 in Subjects With Malignant Ascites of Ovarian Cancer

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Refractory Ovarian Cancer With Recurrent Symptomatic Malignant Ascites

Intervention / Treatment
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* Biological: BAX69 Single-Route Arm
* Biological: BAX69 Double-Route Arm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of a signed informed consent Female participants of non-childbearing potential, ≥18 years of age Anticipated life expectancy >3 months at the time of screening Metastatic ovarian epithelial cancer that are platinum-resistant, and has no better option available in the investigator's opinion Recurrent symptomatic malignant ascites having required at least 2 paracenteses within a 45-day interval prior to baseline paracentesis Participants who have an indwelling draining IP catheter (to be drained only under medical supervision) Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2 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 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 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 Adequate venous access Participant is willing and able to comply with the requirements of the protocol Exclusion Criteria: Known central nervous system metastasis that is unstable within the last 2 months 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 Residual AEs >Grade 2 from previous treatment 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) Uncontrolled hypertension defined as systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg confirmed upon repeated measures Left ventricular ejection fraction <50% as determined by echocardiogram (ECHO) performed at screening or within 30 days prior to C1D1 QT/QTc interval >480 msec, before C1D1 treatment administration, as determined by screening electrocardiogram (ECG) 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 Major surgery within 4 weeks (less than 28 days) prior to C1D1 Active joint inflammation or other immune disorder involving joints (osteoarthritis is not exclusionary) Active infection involving IV antibiotics within 2 weeks prior to C1D1 Positive serology test for hepatitis B virus (HBV), hepatitis C virus (HCV), or active tuberculosis Positive serology test for human immunodeficiency virus (HIV) type 1 and 2, or known history of other immunodeficiency disease Participant has received a live vaccine within 2 weeks (less than 14 days) prior to C1D1 Known hypersensitivity to any component of recombinant protein production by Chinese Hamster Ovary (CHO) cells 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 Participant is a family member or employee of the investigator

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single-Route Arm<br>BAX69 administered weekly by intraperitoneal (IP) infusion only | Biological: BAX69 Single-Route Arm<br>* Intraperitoneal (IP) only<br>* Other names: Imalumab;|
| Experimental: Double-Route Arm<br>BAX69 administered weekly by intravenous (IV) infusion + intraperitoneal (IP) infusion | Biological: BAX69 Double-Route Arm<br>* Intravenous (IV) infusion + intraperitoneal (IP) infusion<br>* Other names: Macrophage Migration Inhibitory Factor Antibody (Anti-MIF);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Occurrence of Dose-limiting Toxicity (DLT) | 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 | 4 weeks | 
| The Ratio of Puncture Free Survival (PuFS) Over Puncture-free Interval at Baseline | 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. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio of Time to First Paracentesis Post-treatment Over Puncture-free Interval at Baseline | Time to first paracentesis post-treatment is calculated as the time between the last dose of Imalumab to subsequent first therapeutic paracentesis. | 4 weeks | 
| Change in Ascites Volume Per Unit Time With Treatment | 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. | Up to 4 weeks | 
| Changes in Ascites-related Symptoms | Ascites related symptoms: anorexia, nausea, early satiety, vomiting, abdominal pain, abdominal swelling, dyspnea, fatigue, swollen ankles, heartburn | Baseline, weekly during the treatment period, and every 2 weeks during the safety follow-up period, up to approximately 6 months) | 
| Occurrence of Serious Adverse Events (SAEs) and/or Treatment-emergent Adverse Events (TEAEs), Regardless of Causality or Relationship to Study Drug |  | Throughout the study period of approximately 22 months | 
| Occurrence of Binding and/or Neutralizing Anti-imalumab (BAX69) Antibodies Following Treatment With Imalumab (BAX69) |  | Throughout the study period of approximately 22 months | 
| Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Maximum Observed Concentration (Cmax) |  | Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours | 
| Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Minimum Observed Concentration (Cmin) |  | Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours | 
| Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Area Under the Concentration vs Time Curve (AUC) |  | Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours | 
| Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Half-life (t1/2) |  | Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours | 
| Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Apparent Systemic Clearance (CL) |  | Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours | 
| Imalumab (BAX69) Plasma Pharmacokinetic (PK) Parameter: Volume of Distribution (V) |  | Predose; and post-dose at 1.5, 4, 8, 24, and 72 hours | 
| Quality of Life (QoL) Measure - European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Questionnaire | QoL will be assessed using EORTC QLQ-C30. | Weekly from the baseline visit to the last week of safety follow-up (8 weeks or longer, if additional treatment will be implemented) |