Epithelial Ovarian Cancer, Fallopian Tube Cancer, Peritoneum Cancer
Conditions
Brief summary
The investigators hypothesize that tumor cell killing by cytotoxic chemotherapy exposes the immune system to high levels of tumor antigens.The combination of Paclitaxel/Carboplatin and Pembrolizumab may result in deeper and more durable responses compared with standard chemotherapy alone.
Interventions
DRUGPembrolizumab
Pembrolizumab on Day 1 of each cycle.
DRUGPaclitaxel
* NACT: Paclitaxel on Day 1 of each cycle; * ACT: Paclitaxel same as NACT OR; dose-dense option weekly per protocol.
DRUGCarboplatin
Carboplatin IV on Day 1 of each cycle.
Sponsors
Merck Sharp & Dohme LLC
University of Miami
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. No prior treatment for primary advanced (Stage III or IV) high grade epithelial ovarian, primary peritoneal, or fallopian tube carcinoma such as irradiation, chemotherapy, hormonal therapy, immunotherapy, investigational therapy, and/or other concurrent agents or therapies. 2. Patients must undergo diagnostic laparoscopy for disease assessment for tissue biopsies to confirm diagnosis with planned interval tumor reductive surgery after completion of 3-4 cycles of treatment. For those not medically fit to undergo laparoscopy, as determined by the Investigator. (interventional radiology) IR-guided core biopsies may be used. 3. Patients must be appropriate candidates for planned neoadjuvant chemotherapy (NACT) with combination carboplatin and paclitaxel given intravenously (IV) every 3 weeks ( IV Q3W). 4. Tissue from an archival sample or newly obtained core or excisional biopsy of a tumor lesion. 5. Age ≥ 18 years. 6. Life expectancy \> 3 months. 7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 8. Patients must have normal organ and marrow function as defined below: * Hematologic * Absolute neutrophil count (ANC) ≥1,500 /microliter (mcL). * Platelets ≥ 100,000 / mcL. * Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or Erythropoietin (EPO) dependency * Renal * Serum creatinine ≤ 1.5 X upper limit of normal (ULN) OR * Measured or calculated a creatinine clearance ≥60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN (GFR can also be used in place of creatinine or CrCl). Creatinine clearance should be calculated per institutional standard. * Hepatic * Serum total bilirubin ≤ 1.5 X ULN OR * Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN * Aspartate transaminase (AST/SGOT) and Alanine transaminase (ALT/SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases. * Albumin \> 2.5 mg/dL * Coagulation * International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants * Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants. 9. Negative urine or serum pregnancy ≤ 72 hours (i.e. 3 days) prior to receiving the first dose of study medication if not surgically sterilized. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 10. Female subjects of childbearing potential (have not been surgically sterilized or have not been without menses for \> 1 year) should be willing to use 2 methods of birth control at the same time or be surgically sterile, or abstain from heterosexual activity for the course of the study and at least 120 days after the last study dose. 11. Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
1. Patients who are currently in or have participated in a study of an investigational agent or used an investigational device within 4 weeks of the first dose of treatment. 2. Histology showing mucinous or low grade epithelial ovarian cancer. 3. Patients who will not be likely to undergo IDS either secondary to performance status or sites of disease. If at the time of surgery, the patient is deemed to be surgically resectable to no gross residual, the patient will not be eligible for the study. 4. Patients with known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 28 days prior to study treatment. 5. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. 6. Has received prior therapy with an anti-PD1, anti-PDL1, anti-CD137, anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) or anti-PDL2 agent. 7. Uncontrolled intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 8. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. 9. Prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 10. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to previously administered event. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for this study. If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. 11. Has active autoimmune disease that has required systemic treatment in the past two years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 12. Evidence of interstitial lung disease or active, non-infectious pneumonitis. 13. Is pregnant or breastfeeding or expecting to conceive within the projected duration of the study, starting with the pre-screening or screening visit through 120 days after the last dose of study treatment. 14. Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 15. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority. 16. Received live vaccine within 30 days prior to the first dose of study treatment. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed. 17. Patient has active bacillus tuberculosis (TB). 18. Patient with known hypersensitivity to pembrolizumab or any of its excipients (inactive ingredients). 19. Patient receiving concurrent additional biologic therapy. 20. Any other serious medical or psychiatric illness/condition likely in the judgment of the Investigator(s) to interfere or limit compliance with study requirements/treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic Objective Response Rate (pORR) in Participants Receiving Protocol Therapy | Up to 48 months | The pORR will be calculated as the percentage of participants with pathologic complete response (pCR) and pathologic partial response (pPR) overall as best response. For this protocol, pathologic complete response (pCR) will be defined as no residual macroscopic or (viable) microscopic disease. Pathologic partial response (pPR) will be defined as the presence of residual (viable) microscopic tumor, and the size of the largest focus will be provided for possible outcome correlation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Up to 48 months | Progression-Free Survival (PFS) is measured from date of start of treatment to the earliest occurrence of any of the following events: documented disease progression or death from any cause. Patients who are alive and progression-free will be censored at the date of last documented progression-free status which is the date of last tumor assessment according to RECIST v1.1. |
| Number of Participants Experiencing Treatment-related Toxicity | Up to 48 Months | Safety and tolerability of the intervention will be reported as the number of participants experiencing treatment-related toxicity including serious adverse events (SAEs) and adverse events (AEs), as assessed by treating physician. Toxicity will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.0, per physician discretion. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab, Paclitaxel + Carboplatin The following therapy will be administered during each 21-day cycle for a maximum of eight (8) cycles:
* Pembrolizumab 200mg intravenously (IV);
* Paclitaxel 175 mg/m2 IV in a neoadjuvant setting (NACT);
* Paclitaxel same as NACT, OR 80 mg/m2 IV dose dense option in an adjuvant setting (ACT);
* Carboplatin IV area under the curve (AUC) of 6.
Pembrolizumab: Pembrolizumab on Day 1 of each cycle.
Paclitaxel: - NACT: Paclitaxel on Day 1 of each cycle;
\- ACT: Paclitaxel same as NACT OR; dose-dense option weekly per protocol.
Carboplatin: Carboplatin IV on Day 1 of each cycle. | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Pembrolizumab, Paclitaxel + Carboplatin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 11 / 26 |
| other Total, other adverse events | 26 / 26 |
| serious Total, serious adverse events | 6 / 26 |
Outcome results
Primary
Pathologic Objective Response Rate (pORR) in Participants Receiving Protocol Therapy
The pORR will be calculated as the percentage of participants with pathologic complete response (pCR) and pathologic partial response (pPR) overall as best response. For this protocol, pathologic complete response (pCR) will be defined as no residual macroscopic or (viable) microscopic disease. Pathologic partial response (pPR) will be defined as the presence of residual (viable) microscopic tumor, and the size of the largest focus will be provided for possible outcome correlation.
Time frame: Up to 48 months
Population: Participants who received at least one dose of pembrolizumab in combination with paclitaxel and carboplatin will have tissue collected at baseline and at the time interval debulking surgery (IDS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab, Paclitaxel + Carboplatin | Pathologic Objective Response Rate (pORR) in Participants Receiving Protocol Therapy | 60 percentage of participants |
Secondary
Number of Participants Experiencing Treatment-related Toxicity
Safety and tolerability of the intervention will be reported as the number of participants experiencing treatment-related toxicity including serious adverse events (SAEs) and adverse events (AEs), as assessed by treating physician. Toxicity will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.0, per physician discretion.
Time frame: Up to 48 Months
Population: All participants who received at least one dose of pembrolizumab in combination with paclitaxel and carboplatin.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pembrolizumab, Paclitaxel + Carboplatin | Number of Participants Experiencing Treatment-related Toxicity | All Treatment-related SAEs | 3 Participants |
| Pembrolizumab, Paclitaxel + Carboplatin | Number of Participants Experiencing Treatment-related Toxicity | Grade 3 or higher treatment-related SAEs | 1 Participants |
| Pembrolizumab, Paclitaxel + Carboplatin | Number of Participants Experiencing Treatment-related Toxicity | All Treatment-related AEs (excluding SAEs) | 23 Participants |
| Pembrolizumab, Paclitaxel + Carboplatin | Number of Participants Experiencing Treatment-related Toxicity | Grade 3 or higher treatment-related AEs (excluding SAEs) | 10 Participants |
Secondary
Progression-Free Survival (PFS)
Progression-Free Survival (PFS) is measured from date of start of treatment to the earliest occurrence of any of the following events: documented disease progression or death from any cause. Patients who are alive and progression-free will be censored at the date of last documented progression-free status which is the date of last tumor assessment according to RECIST v1.1.
Time frame: Up to 48 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab, Paclitaxel + Carboplatin | Progression-Free Survival (PFS) | 22.5 months |