Matched Paired Pharmacodynamics and Feasibility Study of Durvalumab in Combination With Chemotherapy in Frontline Ovarian Cancer (N-Dur)
Overview
- Phase
- Phase 1
- Intervention
- Carboplatin
- Conditions
- Stage III Fallopian Tube Cancer AJCC v7
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 18
- Locations
- 1
- Primary Endpoint
- Pharmacodynamic Changes Induced by Treatment with Durvalumab in Combination with Paclitaxel and Carboplatin in Women with Advanced Stage, Metastatic Ovarian Cancer Using an Exact Binomial Test
- Status
- Active, not recruiting
- Last Updated
- 4 months ago
Overview
Brief Summary
This phase I/II trial studies how well durvalumab works when given in combination with carboplatin and paclitaxel in treating patients with stage III-IV ovarian, primary peritoneal, or fallopian tube cancer. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving durvalumab in combination with carboplatin and paclitaxel may be a better treatment for ovarian, primary peritoneal, or fallopian tube cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To explore basal levels and effects of durvalumab in combination with chemotherapy on molecular markers in immune-related pathways, including but not limited to, deoxyribonucleic acid (DNA) copy number, mutation, and level of ribonucleic acid (RNA) and protein expression, before and after durvalumab and chemotherapy treatment in women with primary advanced high grade serous ovarian, fallopian tube, or primary peritoneal cancer. SECONDARY OBJECTIVES: I. To evaluate progression-free survival of paclitaxel and carboplatin and durvalumab in patients with advanced stage, metastatic ovarian cancer undergoing neoadjuvant chemotherapy. II. To describe the feasibility of combination therapy and maintenance durvalumab in this population. III. To evaluate the safety, tolerability and pharmacokinetics (PK) of combination and maintenance durvalumab. IV. To report overall survival. EXPLORATORY OBJECTIVES: I. To evaluate circulating lymphoid populations (subsets). II. To determine tissue programmed death-ligand 1 (PD-L1) expression and T-cell infiltration. III. To measure circulating immune-related cytokines/chemokines. IV. To capture patient reported outcomes (symptoms, quality of life, and patient utilities). OUTLINE: NEOADJUVANT CHEMOTHERAPY: Before debulking surgery, patients receive durvalumab and carboplatin intravenously (IV) over 1 hour on day 1, and paclitaxel IV over 3 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo debulking surgery. SURGERY: After 3 courses of chemotherapy, patients undergo debulking laparoscopic surgery. ADJUVANT THERAPY: Beginning after debulking surgery, patients receive carboplatin IV over 1 hour on day 1, paclitaxel IV over 3 hours on days 1, 8, and 15, and durvalumab IV over 1 hour on day 1. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive durvalumab IV over 1 hour on day 1 and 15. Treatment repeats every 28 days for up to 7 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, 2, 3, 4, 6, 8, 9, 10, and 12 months, and then every 6 months thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Written informed consent and any locally-required authorization (e.g., Health Information Portability and Accountability Act \[HIPAA\] in the United States of America \[USA\], European Union \[EU\] Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
- •Histology showing high-grade epithelial non-mucinous ovarian, primary peritoneal, or fallopian tube cancer
- •No prior treatment for primary advanced (stage III or IV) epithelial ovarian, primary peritoneal, or fallopian tube carcinoma such as irradiation, chemotherapy, hormonal therapy, immunotherapy, investigational therapy, surgery, and/or other concurrent agents or therapies
- •A disposition to neoadjuvant chemotherapy with planned interval tumor reductive surgery after 3 complete cycles of treatment
- •Planned chemotherapy with combination carboplatin and paclitaxel given intravenously
- •Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
- •Measurable disease is defined at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded); each target lesion must be \> 20 mm when measured by conventional techniques, including palpation, plain x-ray, computed tomography (CT), and magnetic resonance imaging (MRI), or \> 10 mm when measured by spiral CT
- •Patients with non-measurable but evaluable solid tumors may be deemed eligible contingent upon principal investigator (PI) review; a non-measurable but evaluable solid tumor is defined as either unidimensionally measurable lesions, masses with margins not clearly defined, or lesions with maximal perpendicular diameters \< 10 mm that can still be evaluated for the primary endpoint
- •Peripheral neuropathy grade 0 or 1 by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Exclusion Criteria
- •Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
- •Previous enrollment in the present study
- •Prior treatment for ovarian, fallopian tube, or primary peritoneal cancer
- •Histology showing mucinous or low grade epithelial carcinoma
- •Participation in another clinical study with an investigational product during the last 4 weeks
- •Any previous treatment with a programmed cell death protein 1 (PD1) or programmed cell death ligand 1 (PD-L1) inhibitor, including durvalumab
- •History of another primary malignancy except for: malignancy treated with curative intent and with no known active disease \>= 5 years before the first dose of study drug and of low potential risk for recurrence; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; or adequately treated carcinoma in situ without evidence of disease e.g., cervical cancer in situ
- •Mean QT interval corrected for heart rate (QTc) \>= 470 ms calculated from 3 electrocardiograms (ECGs) using Bazett's correction
- •Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
- •Any unresolved toxicity (\> CTCAE grade 2) from previous anti-cancer therapy; any prior grade \>= 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE \> grade 1
Arms & Interventions
Treatment (durvalumab, carboplatin, paclitaxel, questionnaire)
NEOADJUVANT CHEMOTHERAPY: Before debulking surgery, patients receive durvalumab and carboplatin IV over 1 hour on day 1, and paclitaxel IV over 3 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo debulking surgery. SURGERY: After 3 courses of chemotherapy, patients undergo debulking laparoscopic surgery. ADJUVANT THERAPY: Beginning after debulking surgery, patients receive carboplatin IV over 1 hour on day 1, paclitaxel IV over 3 hours on days 1, 8, and 15, and durvalumab IV over 1 hour on day 1. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive durvalumab IV over 1 hour on day 1 and 15. Treatment repeats every 28 days for up to 7 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Carboplatin
Treatment (durvalumab, carboplatin, paclitaxel, questionnaire)
NEOADJUVANT CHEMOTHERAPY: Before debulking surgery, patients receive durvalumab and carboplatin IV over 1 hour on day 1, and paclitaxel IV over 3 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo debulking surgery. SURGERY: After 3 courses of chemotherapy, patients undergo debulking laparoscopic surgery. ADJUVANT THERAPY: Beginning after debulking surgery, patients receive carboplatin IV over 1 hour on day 1, paclitaxel IV over 3 hours on days 1, 8, and 15, and durvalumab IV over 1 hour on day 1. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive durvalumab IV over 1 hour on day 1 and 15. Treatment repeats every 28 days for up to 7 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Durvalumab
Treatment (durvalumab, carboplatin, paclitaxel, questionnaire)
NEOADJUVANT CHEMOTHERAPY: Before debulking surgery, patients receive durvalumab and carboplatin IV over 1 hour on day 1, and paclitaxel IV over 3 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo debulking surgery. SURGERY: After 3 courses of chemotherapy, patients undergo debulking laparoscopic surgery. ADJUVANT THERAPY: Beginning after debulking surgery, patients receive carboplatin IV over 1 hour on day 1, paclitaxel IV over 3 hours on days 1, 8, and 15, and durvalumab IV over 1 hour on day 1. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive durvalumab IV over 1 hour on day 1 and 15. Treatment repeats every 28 days for up to 7 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Treatment (durvalumab, carboplatin, paclitaxel, questionnaire)
NEOADJUVANT CHEMOTHERAPY: Before debulking surgery, patients receive durvalumab and carboplatin IV over 1 hour on day 1, and paclitaxel IV over 3 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo debulking surgery. SURGERY: After 3 courses of chemotherapy, patients undergo debulking laparoscopic surgery. ADJUVANT THERAPY: Beginning after debulking surgery, patients receive carboplatin IV over 1 hour on day 1, paclitaxel IV over 3 hours on days 1, 8, and 15, and durvalumab IV over 1 hour on day 1. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive durvalumab IV over 1 hour on day 1 and 15. Treatment repeats every 28 days for up to 7 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Paclitaxel
Treatment (durvalumab, carboplatin, paclitaxel, questionnaire)
NEOADJUVANT CHEMOTHERAPY: Before debulking surgery, patients receive durvalumab and carboplatin IV over 1 hour on day 1, and paclitaxel IV over 3 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo debulking surgery. SURGERY: After 3 courses of chemotherapy, patients undergo debulking laparoscopic surgery. ADJUVANT THERAPY: Beginning after debulking surgery, patients receive carboplatin IV over 1 hour on day 1, paclitaxel IV over 3 hours on days 1, 8, and 15, and durvalumab IV over 1 hour on day 1. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive durvalumab IV over 1 hour on day 1 and 15. Treatment repeats every 28 days for up to 7 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Pharmacological Study
Treatment (durvalumab, carboplatin, paclitaxel, questionnaire)
NEOADJUVANT CHEMOTHERAPY: Before debulking surgery, patients receive durvalumab and carboplatin IV over 1 hour on day 1, and paclitaxel IV over 3 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo debulking surgery. SURGERY: After 3 courses of chemotherapy, patients undergo debulking laparoscopic surgery. ADJUVANT THERAPY: Beginning after debulking surgery, patients receive carboplatin IV over 1 hour on day 1, paclitaxel IV over 3 hours on days 1, 8, and 15, and durvalumab IV over 1 hour on day 1. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive durvalumab IV over 1 hour on day 1 and 15. Treatment repeats every 28 days for up to 7 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Quality-of-Life Assessment
Outcomes
Primary Outcomes
Pharmacodynamic Changes Induced by Treatment with Durvalumab in Combination with Paclitaxel and Carboplatin in Women with Advanced Stage, Metastatic Ovarian Cancer Using an Exact Binomial Test
Time Frame: 1 year
Exact binomial test with a 1-sided significance level of 0.05 used to test whether the probability of a biomarker increasing (or decreasing) is \> 0.50.
Pharmacodynamic Changes Induced by Treatment with Durvalumab in Combination with Paclitaxel and Carboplatin in Women with Advanced Stage, Metastatic Ovarian Cancer Using a 2-Sample T-Test
Time Frame: 1 year
A 2-sample t-test with a 2-sided significance level of 0.05 used to compare change in biomarker expression between patients treated with Durvalumab and a control group of 30 untreated patients.
Pharmacodynamic Changes Induced by Treatment with Durvalumab in Combination with Paclitaxel and Carboplatin in Women with Advanced Stage, Metastatic Ovarian Cancer Using Paired T-Test
Time Frame: 1 year
Paired t-test with a 2-sided significance level of 0.05 used to test whether the change in biomarker expression from pre-treatment to post-treatment with Durvalumab is different from 0.
Pharmacodynamic Changes Induced by Treatment with Durvalumab in Combination with Paclitaxel and Carboplatin in Women with Advanced Stage, Metastatic Ovarian Cancer
Time Frame: 1 year
Fisher's exact test with a 1-sided significance level of 0.05 used to compare the proportion of participants treated with Durvalumab who have increasing (or decreasing) expression rates with the corresponding proportion from a historical control group of 30 untreated patients.
Secondary Outcomes
- Feasibility of Treatment with Durvalumab in Combination with Paclitaxel and Carboplatin in Women with Advanced Stage, Metastatic Ovarian Cancer Determined by Methods of Thall et all(126 days)
- Progression-Free Survival with Treatment with Durvalumab in Combination with Paclitaxel and Carboplatin in Women with Advanced Stage, Metastatic Ovarian Cancer(1 year)