Study to Investigate the Effect of Rifampin and Itraconazole on the Action of Pamiparib in Participants With Cancer

Study Overview
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Brief Summary
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The study was an open-label, parallel-group, fixed-sequence study in male and female cancer patients. The study consists of 2 phases: the Core Phase, which is divided into Part A and Part B, and the Extension Phase. Part A investigated the effect of CYP3A induction by rifampin on the single dose pharmacokinetics (PK) of pamiparib, and Part B investigated the effect of CYP3A inhibition by itraconazole on the single dose PK of pamiparib. Participants were offered participation in the Extension Phase, in which they received pamiparib until progression of disease, unacceptable toxicity, withdrawal of consent, or any other reason for discontinuation.

Official Title
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A Phase 1, Open-label, Parallel-group, Fixed-sequence Study to Investigate the Effect of the CYP3A Inducer Rifampin and the CYP3A Inhibitor Itraconazole on the Pharmacokinetics of Pamiparib (BGB-290) in Cancer Patients

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: pamiparib 60 mg
* Drug: pamiparib 20 mg
* Drug: itraconazole
* Drug: rifampin
* Drug: pamiparib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age ≥ 18 years Histologically or cytologically confirmed advanced or metastatic solid tumors that are refractory or resistant to standard therapy or for which no suitable effective standard therapy exists. Disease that is evaluable per RECIST Version 1.1 or Prostate Cancer Working Group-3 (PCWG-3) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 Life expectancy ≥ 12 weeks Adequate hematologic and end-organ function Key Exclusion Criteria: History of hypersensitivity to rifampin, any rifamycin or any of the components of the rifampin capsule (Part A). History of hypersensitivity to itraconazole or any of the components of the itraconazole capsule (Part B). Prior treatment with a poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor at therapeutic doses is allowed, provided that such treatment was not the most recent therapy (PARP inhibitor must have been discontinued ≥ 3 months prior to the first dose of pamiparib): - Participants who experienced prior severe toxicity to PARP inhibitors that in the opinion of the investigator precludes further treatment with PARP inhibitors should be excluded Diagnosis of Myelodysplastic syndrome (MDS) Active infection requiring systemic treatment Any of the following cardiovascular criteria: Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, ≤ 28 days before Day 1 of pamiparib administration Symptomatic pulmonary embolism ≤ 28 days before Day 1 of pamiparib administration Any history of acute myocardial infarction ≤ 6 months before Day 1 of pamiparib administration Any history of heart failure meeting New York Heart Association Classification III or IV ≤ 6 months before Day 1 of pamiparib - Participants with congestive heart failure or history of heart failure should be excluded from Part B (itraconazole) Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before Day 1 of pamiparib administration Any history of cerebral vascular accident ≤ 6 months before Day 1 of pamiparib administration Previous complete gastric resection or lap-band surgery, chronic diarrhea, active inflammatory gastrointestinal disease, known diverticular disease or any other disease-causing malabsorption syndrome - Gastroesophageal reflux disease under treatment with proton pump inhibitors is allowed Active bleeding disorder, including gastrointestinal bleeding, as evidenced by hematemesis, significant hemoptysis, or melena ≤ 6 months before Day 1 of pamiparib administration Use or anticipated need for food or drugs known to be strong or moderate CYP3A inhibitors or strong CYP3A inducers ≤ 14 days (or ≤ 5 half-lives if half-life is known) prior to Day 1 of pamiparib administration Known history of intolerance to the excipients of the pamiparib capsule Have known hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A (core phase)<br>60 mg pamiparib administered orally on Days 1 and 10 fasting 8 hours pre-dose 600 mg rifampin once a day from days 3 to 11 in the fasted state (at least 2 hours predose) | Drug: pamiparib 60 mg<br>* Single dose of 60 mg pamiparib orally on Days 1 and 10<br>Drug: rifampin<br>* 600 mg rifampin once a day from days 3 to 11<br>|
| Experimental: Part B (core phase)<br>Single dose of 20 mg pamiparib orally in the fasted state (at least 8 hours predose) on days 1 and 7 200 mg itraconazole once a day approximately 30 minutes after completing a meal Day 3 to day 8 | Drug: pamiparib 20 mg<br>* Single dose of 20 mg pamiparib orally on days 1 and 7<br>Drug: itraconazole<br>* 200 mg itraconazole once a day al Day 3 to day 8<br>|
| Experimental: Extension phase<br>60 mg pamiparib orally twice a day in 28-day cycles until progression of disease | Drug: pamiparib<br>* 60 mg pamiparib orally twice a day in 28-day cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Concentration (Cmax) of Pamiparib in Plasma for Part A |  | Part A: from Day -1 (admission) to Day 12 (discharge); 30 min pre-dose, 0.5, 1, 2, 4, 6, 9, 12, 24, and 48 hours post-dose | 
| Maximum Observed Concentration (Cmax) of Pamiparib in Plasma for Part B |  | Part B: from Day -1 (admission) to Day 9 (discharge; ) 30 min pre-dose, 0.5, 1, 2, 4, 6, 9, 12, 24, and 48 hours post-dose | 
| AUC From Time Zero to Time of Last Quantifiable Concentration Post-dose (AUC0-tlast) in Plasma for Part A |  | Part A: from Day -1 (admission) to Day 12 (discharge); 30 min pre-dose, 0.5, 1, 2, 4, 6, 9, 12, 24, and 48 hours post-dose | 
| AUC From Time Zero to Time of Last Quantifiable Concentration Post-dose (AUC0-tlast) in Plasma for Part B |  | Part B: from Day -1 (admission) to Day 9 (discharge) 30 min pre-dose, 0.5, 1, 2, 4, 6, 9, 12, 24, and 48 hours post-dose | 
| AUC From Zero to Infinity (AUC0-inf) of Pamiparib in Plasma for Part A |  | Part A: from Day -1 (admission) to Day 12 (discharge); 30 min pre-dose, 0.5, 1, 2, 4, 6, 9, 12, 24, and 48 hours post-dose | 
| AUC From Zero to Infinity (AUC0-inf) of Pamiparib in Plasma for Part B |  | Part B: from Day -1 (admission) to Day 9 (discharge) 30 min pre-dose, 0.5, 1, 2, 4, 6, 9, 12, 24, and 48 hours post-dose | 
| AUC From Zero to 12 Hours (AUC0-12) of Pamiparib in Plasma for Part A |  | Part A: from Day -1 (admission) to Day 12 (discharge); 30 min pre-dose, 0.5, 1, 2, 4, 6, 9, and 12 hours post-dose | 
| AUC From Zero to 12 Hours (AUC0-12) of Pamiparib in Plasma for Part B |  | Part B: from Day -1 (admission) to Day 9 (discharge); 30 min pre-dose, 0.5, 1, 2, 4, 6, 9, and 12 hours post-dose | 
| AUC From Zero to 9 Hours (AUC0-9) of Pamiparib in Plasma for Part A |  | Part A: from Day -1 (admission) to Day 12 (discharge); 30 min pre-dose, 0.5, 1, 2, 4, 6, and 9 hours post-dose | 
| AUC From Zero to 9 Hours (AUC0-9) of Pamiparib in Plasma for Part B |  | Part B: from Day -1 (admission) to Day 9 (discharge); 30 min pre-dose, 0.5, 1, 2, 4, 6, and 9 hours post-dose | 
| Time of the Maximum Observed Concentration (Tmax) of Pamiparib for Part A |  | Part A: from Day -1 (admission) to Day 12 (discharge); 30 min pre-dose, 0.5, 1, 2, 4, 6, 9, 12 hours post-dose | 
| Time of the Maximum Observed Concentration (Tmax) of Pamiparib for Part B |  | Part B: from Day -1 (admission) to Day 9 (discharge); 30 min pre-dose, 0.5, 1, 2, 4, 6, 9, 12 hours post-dose | 
| Apparent Terminal Elimination Half-life (t1/2) of Pamiparib in Plasma for Part A |  | Part A: from Day -1 (admission) to Day 12 (discharge); 30 min pre-dose, 0.5, 1, 2, 4, 6, 9, 12 hours post-dose | 
| Apparent Terminal Elimination Half-life (t1/2) of Pamiparib in Plasma for Part B |  | Part B: from Day -1 (admission) to Day 9 (discharge); 30 min pre-dose, 0.5, 1, 2, 4, 6, 9, 12 hours post-dose | 
| Apparent Oral Clearance (CL/F) of Pamiparib in Plasma for Part A |  | Part A: from Day -1 (admission) to Day 12 (discharge); 30 min pre-dose, 0.5, 1, 2, 4, 6, 9, 12 hours post-dose | 
| Apparent Oral Clearance (CL/F) of Pamiparib in Plasma for Part B |  | Part B: from Day -1 (admission) to Day 9 (discharge); 30 min pre-dose, 0.5, 1, 2, 4, 6, 9, 12 hours post-dose | 
| Apparent Volume of Distribution (Vz/F) of Pamiparib in Plasma for Part A |  | Part A: from Day -1 (admission) to Day 12 (discharge); 30 min pre-dose, 0.5, 1, 2, 4, 6, 9, 12 hours post-dose | 
| Apparent Volume of Distribution (Vz/F) of Pamiparib in Plasma for Part B |  | Part B: from Day -1 (admission) to Day 9 (discharge); 30 min pre-dose, 0.5, 1, 2, 4, 6, 9, 12 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAE is defined as any AE with an onset date on or after the date of first dose of study medication until the date of last study medication dose plus 30 days. Seriousness of the AE is determined by the investigator based on seriousness criteria. | From the date informed consent has been signed until last study medication dose plus 30 days (up to approximately 26 months) | 
| Number of Participants With Clinically Significant Abnormalities in Laboratory Assessments, Vital Signs, ECG Parameters and Physical Examinations |  | Up to approximately 26 months |