Clinical trial NCT03994211: Study to Investigate the Effect of Rifampin and Itraconazole on the Action of Pamiparib in Participants With Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumor
Lead sponsor: BeiGene
Sponsor class: INDUSTRY
First posted: 2019-06-21
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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.


Eligibility criteria: Key Inclusion Criteria:

1. Age ≥ 18 years
2. 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.
3. Disease that is evaluable per RECIST Version 1.1 or Prostate Cancer Working Group-3 (PCWG-3)
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
5. Life expectancy ≥ 12 weeks
6. Adequate hematologic and end-organ function

Key Exclusion Criteria:

1. History of hypersensitivity to rifampin, any rifamycin or any of the components of the rifampin capsule (Part A).
2. History of hypersensitivity to itraconazole or any of the components of the itraconazole capsule (Part B).
3. 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
4. Diagnosis of Myelodysplastic syndrome (MDS)
5. Active infection requiring systemic treatment
6. Any of the following cardiovascular criteria:

   1. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, ≤ 28 days before Day 1 of pamiparib administration
   2. Symptomatic pulmonary embolism ≤ 28 days before Day 1 of pamiparib administration
   3. Any history of acute myocardial infarction ≤ 6 months before Day 1 of pamiparib administration
   4. 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)
   5. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before Day 1 of pamiparib administration
   6. Any history of cerebral vascular accident ≤ 6 months before Day 1 of pamiparib administration
7. 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
8. Active bleeding disorder, including gastrointestinal bleeding, as evidenced by hematemesis, significant hemoptysis, or melena ≤ 6 months before Day 1 of pamiparib administration
9. 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
10. Known history of intolerance to the excipients of the pamiparib capsule
11. Have known hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Maximum Observed Concentration (Cmax) of Pamiparib in Plasma for Part A
timeFrame: 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
measure: Maximum Observed Concentration (Cmax) of Pamiparib in Plasma for Part B
timeFrame: 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
measure: AUC From Time Zero to Time of Last Quantifiable Concentration Post-dose (AUC0-tlast) in Plasma for Part A
timeFrame: 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
measure: AUC From Time Zero to Time of Last Quantifiable Concentration Post-dose (AUC0-tlast) in Plasma for Part B
timeFrame: 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
measure: AUC From Zero to Infinity (AUC0-inf) of Pamiparib in Plasma for Part A
timeFrame: 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
measure: AUC From Zero to Infinity (AUC0-inf) of Pamiparib in Plasma for Part B
timeFrame: 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
measure: AUC From Zero to 12 Hours (AUC0-12) of Pamiparib in Plasma for Part A
timeFrame: 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
measure: AUC From Zero to 12 Hours (AUC0-12) of Pamiparib in Plasma for Part B
timeFrame: 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
measure: AUC From Zero to 9 Hours (AUC0-9) of Pamiparib in Plasma for Part A
timeFrame: 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
measure: AUC From Zero to 9 Hours (AUC0-9) of Pamiparib in Plasma for Part B
timeFrame: 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
measure: Time of the Maximum Observed Concentration (Tmax) of Pamiparib for Part A
timeFrame: 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
measure: Time of the Maximum Observed Concentration (Tmax) of Pamiparib for Part B
timeFrame: 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
measure: Apparent Terminal Elimination Half-life (t1/2) of Pamiparib in Plasma for Part A
timeFrame: 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
measure: Apparent Terminal Elimination Half-life (t1/2) of Pamiparib in Plasma for Part B
timeFrame: 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
measure: Apparent Oral Clearance (CL/F) of Pamiparib in Plasma for Part A
timeFrame: 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
measure: Apparent Oral Clearance (CL/F) of Pamiparib in Plasma for Part B
timeFrame: 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
measure: Apparent Volume of Distribution (Vz/F) of Pamiparib in Plasma for Part A
timeFrame: 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
measure: Apparent Volume of Distribution (Vz/F) of Pamiparib in Plasma for Part B
timeFrame: 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 outcomes:
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From the date informed consent has been signed until last study medication dose plus 30 days (up to approximately 26 months)
measure: Number of Participants With Clinically Significant Abnormalities in Laboratory Assessments, Vital Signs, ECG Parameters and Physical Examinations
timeFrame: Up to approximately 26 months
Other outcomes:
Locations:
city: Tbilisi
country: Georgia
facility: Arensia Exploratory Medicine Llc
city: Chiinu
country: Moldova, Republic of
facility: Republican Clinical Hospital, Oncology Department
city: Warszawa
country: Poland
facility: Szpital Luxmed
city: Bratislava
country: Slovakia
facility: Summit Clinical Research, Sro
Study officials:
affiliation: BeiGene
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Mu S, Lin C, Skrzypczyk-Ostaszewicz A, Bulat I, Maglakelidze M, Skarbova V, Andreu-Vieyra C, Sahasranaman S. The pharmacokinetics of pamiparib in the presence of a strong CYP3A inhibitor (itraconazole) and strong CYP3A inducer (rifampin) in patients with solid tumors: an open-label, parallel-group phase 1 study. Cancer Chemother Pharmacol. 2021 Jul;88(1):81-88. doi: 10.1007/s00280-021-04253-x. Epub 2021 Mar 27.