Ovarian Neoplasms, Peritoneal Neoplasms
Conditions
Keywords
Pressurized intraperitoneal aerosol chemotherapy, platinum-resistant recurrent, ovarian cancer, paclitaxel
Brief summary
The purpose of this study is to evaluate the tolerance, safety, efficacy, and pharmacokinetics of pressurized intraperitoneal aerosol chemotherapy (PIPAC) with paclitaxel in patients with platinum-resistant recurrent ovarian cancer and peritoneal carcinomatosis.
Detailed description
The Study Design is an interventional, non-randomized, sequential Phase 1/2a trial, where patients with platinum-resistant recurrent ovarian cancer(PROC) and radiologically confirmed peritoneal carcinomatosis will be enrolled. All patients included in this study will receive PIPAC, laparoscopic aerosolization of paclitaxel under 12 mmHg pressure at 6-week intervals (up to 9 cycles) for treating PROC with peritoneal metastasis.
Interventions
DRUGPressurized intraperitoneal aerosol chemotherapy (PIPAC) using paclitaxel
All patients enrolled in this study receive PIPAC using paclitaxel under 12 mmHg at 6 weeks intervals (up to 9 cycles) 1. Phase 1 Design 1. Dose Escalation: Standard 3+3 design across 5 paclitaxel cohorts (20 → 40 → 67 → 100 → 140 mg/m²) using modified Fibonacci increments (100%, 67%, 50%, 40%). 2. Maximum tolerated dose(MTD) Determination * If ≥2/6 patients in cohort χ experience dose limiting toxicities(DLTs; Grade ≥3 toxicity per CTCAE v5.0, excluding manageable pain) and ≤1/6 in cohort χ-1, MTD = χ-1. * If no DLTs at 140 mg/m², Phase 1 concludes. 3. Dose Reduction * DLTs in 20 mg/m² trigger de-escalation to 10 mg/m². * If ≤1/6 DLTs in 10 mg/m² → RP2D; ≥2/6 DLTs → trial termination. 2. Phase 2 Design : Evaluates efficacy/safety of PIPAC at the RP2D in 23 patients, adjusting for 5-17% laparoscopic access failure.
Sponsors
Seoul National University Hospital
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
19 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Age: Women aged 19-85 years. 2. Diagnosis: Histologically confirmed ovarian, fallopian tube, or peritoneal cancer. 3. Platinum Status: * Refractory: Disease progression during platinum-based chemotherapy. * Resistant: Progression within 6 months (24 weeks) post-platinum therapy. 4. Prior Therapies: ≥2 prior intravenous chemotherapies (may include paclitaxel). 5. Treatment Options: Unresponsive to/ineligible for standard therapies (e.g., intolerance, hypersensitivity) and ineligible for surgical resection. 6. Measurable Disease: ≥1 measurable/evaluable peritoneal lesion per RECIST 1.1. 7. Metastasis: ≤1 asymptomatic distant metastasis (excluding retroperitoneal lymph nodes, pleural effusion, localized skin metastases). 8. Imaging Confirmation: Peritoneal carcinomatosis confirmed by PET-CT/CT. 9. Performance Status: ECOG 0-2. 10. Pregnancy/Contraception: * Non-pregnant/non-lactating. * Contraception: Effective methods (IUD, sterilization) for 6 months post-PIPAC (childbearing potential only). 11. Organ Function: * Bone Marrow: ANC \>1,500/mm³, platelets \>100,000/mm³, hemoglobin \>8.0 g/dL. * Liver: Bilirubin ≤1.5×ULN, AST/ALT ≤1.5×ULN. * Kidney: Creatinine ≤1.5×ULN, creatinine clearance \>60 mL/min. * Lungs: FVC/FEV1 ≥70% predicted. * Coagulation: INR ≤1.5, aPTT ≤1.5×ULN. 12. Consent: Signed informed consent.
Exclusion criteria
1. ≥2 distant metastases (excluding retroperitoneal lymph nodes, pleural effusion, and localized skin metastases). 2. Contraindications to paclitaxel per approved domestic labeling. 3. Hypersensitivity history to paclitaxel or PIPAC devices. 4. Uncontrolled comorbidities per investigator judgment: * NYHA Class ≥II heart failure * Clinically significant cardiovascular disease (e.g., arrhythmia, myocardial infarction) * Immunosuppressive conditions (AIDS, autoimmune diseases, immunosuppressive therapy) * Active HBV/HCV infection * Uncontrolled hypertension (systolic \>160 mmHg or diastolic \>100 mmHg) * Uncontrolled diabetes (HbA1c \>8%) * Radiographic/clinical bowel obstruction. 5. IV chemotherapy within 4 weeks prior to Cycle 1 PIPAC. 6. Life expectancy \<3 months. 7. Prior PIPAC therapy. 8. Medically unfit for general anesthesia or laparoscopic surgery. 9. Refusal of contraception: \- Medically acceptable methods: * Intrauterine device (failure rate \<1%) * Surgical sterilization (tubal ligation, hysterectomy, vasectomy; failure rate \<0.5%). 10. Participation in another clinical trial within 1 month of screening. 11. Other exclusionary factors per investigator discretion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose limiting toxicities | Till 6 weeks after the first PIPAC in phase 1 study | Dose limiting toxicities |
| Maximum tolerated dose | During phase 1 study (up to 6 weeks) | We consider dose escalation if 3 consecutive DLTs do not occur, or less than 1 in 6 DLTs occur, per standard 3+3 design. If DLT occurs in 2 or more of 6, the lower dose is considered the MTD if 1 or fewer DLTs are identified. In addition, the highest dose (140 mg/m2) is considered the MTD when 3 to 0 DLTs or 6 to 1 DLTs are identified at the highest dose. On the other hand, if the initial dose (20 mg/m2) is reduced to 10 mg/m2 to account for DLT, it is considered the MTD if no more than 1 in 6 develop DLT at that reduced dose. |
| Recommended Phase 2 Dose | During phase 1 study | Recommended Phase 2 Dose determined by dose limiting toxicities |
| Disease control rate | During phase 2 study | Disease control rate at the 9-week time point |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival | During phase 1 and 2a studies | Time from the treatment start of pressurized intraperitoneal aerosol chemotherapy to the identification of progressive disease or the end of the study |
| Overall survival | During phase 1 and 2a studies | Time from the treatment start of pressurized intraperitoneal aerosol chemotherapy to cancer-related death or the end of the study |
| Peritoneal cancer index | During phase 1 and 2a studies | Peritoneal cancer index scores identified during pressurized intraperitoneal aerosol chemotherapy, which range from 0 to 39 |
| Peritoneal Regression Grading Score | During phase 1 and 2a studies | Peritoneal Regression Grading Score examined by pathologic review; Peritoneal Regression Grading Score 1, complete response: Peritoneal Regression Grading Score 2, major response: Peritoneal Regression Grading Score 3, minor response; Peritoneal Regression Grading Score 4, no response |
| Changes in ascites volume | During phase 1 and 2a studies | Changes in ascites volume measured during pressurized intraperitoneal aerosol chemotherapy |
| Maximum concentration (Cmax) | During phase 1 study | Cmax on pharmacokinetic evaluation of paclitaxel administered via pressurized intraperitoneal aerosol chemotherapy |
| human epididymis protein 4 (HE4) | Assessed at every visit during the study period | Serum HE4 levels, which are related to disease progression when more than 140 pmol/L |
| The Risk of Ovarian Malignancy Algorithm (ROMA) score | Assessed at every visit during the study period | ROMA score using serum CA-125 and HE4 levels, which are related to disease progression when more than 30% |
| EORTC QLQ-C30 questionnaire | During phase 1 and 2a studies | EORTC QLQ-C30 questionnaires measured during the study. The evaluation range for each item is from 0 to 100. |
| EORTC QLQ-OV28 questionnaire measured during the study | During phase 1 and 2a studies | EORTC QLQ-OV28 questionnaire measured during the study. The evaluation range for each item is from 0 to 100. |
| Safety evaluation | During phase 1 and 2a studies | Safety evaluation per CTCAE v5.0, including treatment-related adverse events and surgical complications. The evaluation range for each item is from grade 1 to grade 5. |
| CA-125 | Assessed at every visit during the study period | Seum CA-125 levels, which are related to disease progression when more than 35 U/ml |
| Time at which Cmax is observed (Tmax) | During phase 1 study | Tmax on pharmacokinetic evaluation of paclitaxel administered via pressurized intraperitoneal aerosol chemotherapy |
| Area under the curve (AUC) | During phase 1 study | AUC on pharmacokinetic evaluation of paclitaxel administered via pressurized intraperitoneal aerosol chemotherapy |
| Disease control rate | During phase 1 study | Disease control rate at the 9-week time point |
Contacts
Primary ContactHee Seung Kim, MD, PhD
Outcome results
None listed