Intraperitoneal Natural Killer Cells and INCB024360 for Recurrent Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
Primary Purpose
Ovarian Cancer, Fallopian Tube Carcinoma, Primary Peritoneal Carcinoma
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Fludarabine
Cyclophosphamide
NK cells
IL-2
INCB024360
Sponsored by
About this trial
This is an interventional treatment trial for Ovarian Cancer focused on measuring Ovarian cancer, Fallopian cancer, Primary peritoneal cancer
Eligibility Criteria
Inclusion Criteria:
- Diagnosis of recurrent epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer that has failed or progressed after at least 1 prior salvage chemotherapy regimen directed at recurrent/metastatic disease.
- Measurable disease per disease specific RECIST version 1.1- patients with bone as their only site of disease will not be eligible
- If history of brain metastases must be stable for at least 3 months after treatment - A brain CT scan will only be required in subjects with known brain metastases at the time of enrollment or in subjects with clinical signs or symptoms suggestive of brain metastases.
- Available related HLA-haploidentical NK cell donor by at least Class I serologic typing at the A&B locus
- Age 18 years or older
- GOG Performance Status ≥ 2 - refer to appendix III
Adequate organ function as determined by the following criteria within 14 days of the start of the preparative regimen, unless otherwise noted:
- Bone marrow: platelets ≥ 80,000 x 109/L and hemoglobin ≥ 9 g/dL, unsupported by transfusions; absolute neutrophil count (ANC) ≥ 1000 x 109/L, unsupported by G-CSF or granulocytes
- Renal function: estimated glomerular filtration rate (GFR) of ≥ 50 ml/min (based on the Fairview Laboratories formula at time of screening)
- Liver function: total bilirubin < 1.5 times upper limit of institutional normal; AST, ALT, and alkaline phosphatase < 3 times upper limit of institutional normal
- Cardiac: Left ventricular ejection fraction > 40% (within 28 days of treatment start)
- Pulmonary function: > 50% corrected DLCO and FEV1, if presence of pleural effusion due to metastatic disease > 40% corrected DLCO and FEV1 is acceptable (within 28 days of treatment start)
- Able to be off prednisone or other immunosuppressive medications other than that prescribed per protocol for at least 3 days prior to Day 0
- At least 14 days must lapse between last prior anti-cancer treatment and 1st day of preparative regimen
- Not pregnant or lactating - The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. Participants of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy and agree to use adequate birth control during study treatment.
- Able to tolerate intraperitoneal (IP) port placement and IP treatment administration in the opinion of the enrolling investigator
- Voluntary written consent
Exclusion Criteria:
- Active infection - must be afebrile and off antibiotics
- Receiving monoamine oxidase inhibitors (MAOI)s or drug which as significant MAOI activity (meperidine, linezolid, methylene blue) within 21 days of 1st dose of fludarabine
- Requiring potent CYP3A4 inducers or inhibitors
- Have ever had Serotonin Syndrome after receiving one or more serotonergic drugs
- Prior therapy with anti-CTLA-4 antibody, anti PD-1, or an experimental immune system-targeted therapy
- Use of any UGT1A9 inhibitor including: diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid from screening through follow-up period.
- Undergone an organ transplant(s) including allogeneic stem cell or bone marrow transplants.
- Unstable cardiovascular disease (eg, uncontrolled hypertension, peripheral vascular disease, congestive heart failure, cardiac arrhythmia, or acute coronary syndrome) within 6 months of starting study treatment.
- Any gastrointestinal condition causing malabsorption or obstruction (eg, celiac sprue, gastric bypass surgery, strictures, adhesions, history of small bowel resection, blind loop syndrome). Unable or unwilling to swallow tablets BID.
- Active autoimmune process (eg rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease, etc.) or who have been receiving therapy for an autoimmune or inflammatory disease. Vitiligo, thyroiditis, or eczema is permitted if patient is otherwise eligible
- Known HIV-positivity
History of hepatitis or positive serology as follows:
- Hepatitis B (HepB) screening testing required:
- HepB SAg (hepatitis B surface antigen);
- Anti-HepB SAg (antibody against hepatitis B surface antigen);
- Anti-Hepatitis B core IgG (antibody against hepatitis B core antigen).
Hepatitis B core IgM antibody
- Hepatitis C screening testing required:
- HCV-antibody (antibody against hepatitis C virus);
- HCV-RNA (serum test for circulating virus, based on detecting RNA)
Sites / Locations
- University of Minnesota Masonic Cancer Center
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment
Arm Description
Haploidentical donor NK cells and IL-2 are infused intraperitoneally (IP) after a non-myeloablative preparative regimen of cyclophosphamide and fludarabine. INCB024360, at the assigned dose, begins 2 days before the NK cell infusion and continues twice daily for 90 days.
Outcomes
Primary Outcome Measures
Maximum tolerated dose of INCB024360
To determine the maximum tolerated dose (MTD) of INCB024360 when administered with intraperitoneal haploidentical donor NK cells/IL-2 after a nonmyeloablative cyclophosphamide/fludarabine (Cy/Flu) preparative regimen in patients with recurrent ovarian, fallopian tube, and primary peritoneal cancer
Secondary Outcome Measures
Initial tumor response
The proportion of patients with initial tumor response (CR or PR)
Duration of tumor response
Duration of tumor response
Progression-free survival
Average time to progression.
Overall survival
Average length of survival after treatment
Full Information
NCT ID
NCT02118285
First Posted
March 26, 2014
Last Updated
December 3, 2017
Sponsor
Masonic Cancer Center, University of Minnesota
Collaborators
Incyte Corporation
1. Study Identification
Unique Protocol Identification Number
NCT02118285
Brief Title
Intraperitoneal Natural Killer Cells and INCB024360 for Recurrent Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
Official Title
Indoleamine-2,3-dioxygenase (IDO) Inhibition With INCB024360 and Intraperitoneal Delivery of Allogeneic Natural Killer Cells for Women With Recurrent Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
December 2017
Overall Recruitment Status
Completed
Study Start Date
July 28, 2014 (Actual)
Primary Completion Date
November 12, 2015 (Actual)
Study Completion Date
November 12, 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Masonic Cancer Center, University of Minnesota
Collaborators
Incyte Corporation
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This is a single center phase I trial designed to determine the maximum tolerated dose (MTD) of the oral IDO inhibitor INCB024360 when administered as part of a larger regimen of intraperitoneal (IP) delivery of haploidentical donor NK cells and IL-2 after a non-myeloablative cyclophosphamide/fludarabine (Cy/Flu) preparative regimen for the treatment of recurrent ovarian, fallopian tube, and primary peritoneal cancer.
Detailed Description
Haploidentical donor NK cells and the 1st dose of IL-2 are infused intraperitoneally (IP) after a non-myeloablative preparative regimen of cyclophosphamide and fludarabine. IP IL-2 continues three times a week for 5 additional doses. INCB024360, at the assigned dose, begins 2 days before the NK cell infusion (on day -2) and continues twice daily for 90 days.
Follow-up for disease response and survival is for 1 year from the NK cell infusion with the possibility of re-treatment for patients who experience at least a clinical benefit for a minimum of 6 months prior to disease progression.
The MTD of INCB024360 will be determined using the continual reassessment method (CRM). The 1st 2 patients will be enrolled at dose level 1 (50 mg bid) of INCB024360. Each new cohort of 2 patients will be sequentially assigned to most appropriate dose by the study statistician based on the updated toxicity profile. Up to 4 dose levels of INCB024360 will be tested (50, 100, 200, and 300 mg bid) with a dose level -1 (25 mg bid) used in the event that 50 mg bid proves to be too toxic. The MTD will be identified when the total sample size of 20 patients is exhausted.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ovarian Cancer, Fallopian Tube Carcinoma, Primary Peritoneal Carcinoma
Keywords
Ovarian cancer, Fallopian cancer, Primary peritoneal cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
2 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Treatment
Arm Type
Experimental
Arm Description
Haploidentical donor NK cells and IL-2 are infused intraperitoneally (IP) after a non-myeloablative preparative regimen of cyclophosphamide and fludarabine. INCB024360, at the assigned dose, begins 2 days before the NK cell infusion and continues twice daily for 90 days.
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara
Intervention Description
Fludarabine 25 mg/m^2 IV on days -6 through -2 from NK cell infusion
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Endoxan, Cytoxan, Neosar, Procytox, Revimmune
Intervention Description
Cyclophosphamide 30 mg/kg IV on days -5 and -4 from NK cell infusion
Intervention Type
Biological
Intervention Name(s)
NK cells
Other Intervention Name(s)
Natural Killer Cells
Intervention Description
CD3-/CD19- selected NK cells administered by intraperitoneal (IP) infusion on day 0
Intervention Type
Biological
Intervention Name(s)
IL-2
Other Intervention Name(s)
Interleukin 2
Intervention Description
IL-2 at 6 million units/dose IP 3 times a week x 6 doses with the 1st dose given immediately after the NK cell infusion
Intervention Type
Drug
Intervention Name(s)
INCB024360
Intervention Description
INCB024360 at assigned dose by mouth twice a day begin day -2 and continue for 90 days (+/- 3 days)
Primary Outcome Measure Information:
Title
Maximum tolerated dose of INCB024360
Description
To determine the maximum tolerated dose (MTD) of INCB024360 when administered with intraperitoneal haploidentical donor NK cells/IL-2 after a nonmyeloablative cyclophosphamide/fludarabine (Cy/Flu) preparative regimen in patients with recurrent ovarian, fallopian tube, and primary peritoneal cancer
Time Frame
90 days
Secondary Outcome Measure Information:
Title
Initial tumor response
Description
The proportion of patients with initial tumor response (CR or PR)
Time Frame
90 days
Title
Duration of tumor response
Description
Duration of tumor response
Time Frame
1 year
Title
Progression-free survival
Description
Average time to progression.
Time Frame
5 years
Title
Overall survival
Description
Average length of survival after treatment
Time Frame
5 years
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Diagnosis of recurrent epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer that has failed or progressed after at least 1 prior salvage chemotherapy regimen directed at recurrent/metastatic disease.
Measurable disease per disease specific RECIST version 1.1- patients with bone as their only site of disease will not be eligible
If history of brain metastases must be stable for at least 3 months after treatment - A brain CT scan will only be required in subjects with known brain metastases at the time of enrollment or in subjects with clinical signs or symptoms suggestive of brain metastases.
Available related HLA-haploidentical NK cell donor by at least Class I serologic typing at the A&B locus
Age 18 years or older
GOG Performance Status ≥ 2 - refer to appendix III
Adequate organ function as determined by the following criteria within 14 days of the start of the preparative regimen, unless otherwise noted:
Bone marrow: platelets ≥ 80,000 x 109/L and hemoglobin ≥ 9 g/dL, unsupported by transfusions; absolute neutrophil count (ANC) ≥ 1000 x 109/L, unsupported by G-CSF or granulocytes
Renal function: estimated glomerular filtration rate (GFR) of ≥ 50 ml/min (based on the Fairview Laboratories formula at time of screening)
Liver function: total bilirubin < 1.5 times upper limit of institutional normal; AST, ALT, and alkaline phosphatase < 3 times upper limit of institutional normal
Cardiac: Left ventricular ejection fraction > 40% (within 28 days of treatment start)
Pulmonary function: > 50% corrected DLCO and FEV1, if presence of pleural effusion due to metastatic disease > 40% corrected DLCO and FEV1 is acceptable (within 28 days of treatment start)
Able to be off prednisone or other immunosuppressive medications other than that prescribed per protocol for at least 3 days prior to Day 0
At least 14 days must lapse between last prior anti-cancer treatment and 1st day of preparative regimen
Not pregnant or lactating - The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. Participants of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy and agree to use adequate birth control during study treatment.
Able to tolerate intraperitoneal (IP) port placement and IP treatment administration in the opinion of the enrolling investigator
Voluntary written consent
Exclusion Criteria:
Active infection - must be afebrile and off antibiotics
Receiving monoamine oxidase inhibitors (MAOI)s or drug which as significant MAOI activity (meperidine, linezolid, methylene blue) within 21 days of 1st dose of fludarabine
Requiring potent CYP3A4 inducers or inhibitors
Have ever had Serotonin Syndrome after receiving one or more serotonergic drugs
Prior therapy with anti-CTLA-4 antibody, anti PD-1, or an experimental immune system-targeted therapy
Use of any UGT1A9 inhibitor including: diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid from screening through follow-up period.
Undergone an organ transplant(s) including allogeneic stem cell or bone marrow transplants.
Unstable cardiovascular disease (eg, uncontrolled hypertension, peripheral vascular disease, congestive heart failure, cardiac arrhythmia, or acute coronary syndrome) within 6 months of starting study treatment.
Any gastrointestinal condition causing malabsorption or obstruction (eg, celiac sprue, gastric bypass surgery, strictures, adhesions, history of small bowel resection, blind loop syndrome). Unable or unwilling to swallow tablets BID.
Active autoimmune process (eg rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease, etc.) or who have been receiving therapy for an autoimmune or inflammatory disease. Vitiligo, thyroiditis, or eczema is permitted if patient is otherwise eligible
Known HIV-positivity
History of hepatitis or positive serology as follows:
Hepatitis B (HepB) screening testing required:
HepB SAg (hepatitis B surface antigen);
Anti-HepB SAg (antibody against hepatitis B surface antigen);
Anti-Hepatitis B core IgG (antibody against hepatitis B core antigen).
Hepatitis B core IgM antibody
Hepatitis C screening testing required:
HCV-antibody (antibody against hepatitis C virus);
HCV-RNA (serum test for circulating virus, based on detecting RNA)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Melissa Geller, MD
Organizational Affiliation
University of Minnesota
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Minnesota Masonic Cancer Center
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Intraperitoneal Natural Killer Cells and INCB024360 for Recurrent Ovarian, Fallopian Tube, and Primary Peritoneal Cancer
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