Intraperitoneal Infusion of Autologous Monocytes With Sylatron (Peginterferon Alfa-2b) and Actimmune (Interferon Gamma-1b) in Women With Recurrent or Refractory Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer

Background:

* Monocytes can differentiate into classic M1 (classically activated) macrophages inhibiting tumor proliferation and promoting natural killer (NK) cell differentiation.
* Human alpha interferons (interferon alfa, IFN-alpha), interferon gamma (IFN-gamma) and monocytes have strong anti-neoplastic response in vitro and in vivo
* IFN-alpha and IFN-gamma have been shown in early phase clinical trials to be safely administered intraperitoneally.
* Intraperitoneal monocytes alone or activated with IFN-gamma are safe and feasible as demonstrated in phase I clinical studies.
* We have shown that the combination of human monocytes, IFN-alpha2a and IFN-gamma1b, or pegylated IFN-alpha, act synergistically against tumor cells in vitro and in mouse models.

Objectives:

-To identify a maximum tolerated dose of intraperitoneal autologous monocytes and Sylatron(R) (Peginterferon alfa-2b) and Actimmune(R) (Interferon gamma-1b).

Eligibility:

* Advanced metastatic or unresectable epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer that is relapsed and resistant or refractory to prior platinum-based standard care systemic regimen.
* Patients must be off prior chemotherapy, radiation therapy, hormonal therapy or biological therapy for at least 4 weeks.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1 and adequate organ and marrow function.

Design:

* This is an open label single arm phase I trial to determine the maximum tolerated dose of intraperitoneal monocytes and Sylatron(R) (Peginterferon alfa-2b) and Actimmune(R) (Interferon gamma-1b).
* Autologous monocytes obtained through apheresis will be mixed with Sylatron(R) (Peginterferon alfa-2b) and Actimmune(R) (Interferon gamma-1b) in a 3 + 3 dose escalation and administered intraperitoneally once every 28 days. A new product will be manufactured for each treatment cycle.
* Once the maximum tolerated dose is obtained, an expansion cohort will be enrolled to better quantify response rate and time to disease progression.
* Research samples including peripheral blood and ascites will be obtained prior to the initiation of study therapy andprior to the start of each cycle. Tissue biopsies will be obtained in the dose expansion phase to characterize the immune infiltration.
* Patients will be evaluated every 2 cycles for response using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and every cycle for safety using Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

• Autologous Monocytes + ACTIMMUNE + SYLATRON (Biological): The autologous monocytes cell product in 250ml total volume of investigational combination (monocytes + ACTIMMUNE + SYLATRON) is infused via the intraperitoneal catheter over 30-60 min +/- 10 min every 28 days +/- 7 days until disease progression, limiting toxicity, intercurrent medical issues, or patient withdrawal. Dosing is based on a dose escalation design including an expansion cohort at the maximum tolerated dose (MTD).

Primary outcomes

• Overall Maximum Tolerated Dose of Intraperitoneal Autologous Monocytes [Cycle 1 Day 28]: Maximum Tolerated Dose of intraperitoneal autologous monocytes.
• Overall Maximum Tolerated Dose of Sylatron (Peginterferon Alpha-2b) [Cycle 1 Day 28]: Maximum Tolerated Dose of Sylatron (Peginterferon alpha-2b).
• Overall Maximum Tolerated Dose of Actimmune (Interferon Gamma-1b) [Cycle 1 Day 28]: Maximum Tolerated Dose of Actimmune (Interferon gamma-1b).

Secondary outcomes

• Number of Participants With a Response [Participants were evaluated for response by radiographic imaging every 8 weeks, up to 80 weeks]: Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.
• Time to Disease Progression [Participants were assessed every 4 weeks by physical exam and 8 weeks by radiographic imaging for disease progression, up to 10 months.]: Time to disease progression is defined as the time from registration to progression, censored at date last known progression-free for those who have not progressed. Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study

Other outcomes

• Number of Participants With Serious or Non-serious (Any) Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) [Date treatment consent signed to date off study, approximately 10 months and 11 days for dose level 1,12 months and 1 day for dose level 2, 11 months and 4 days for dose level 3, and 12 months and 6 days for dose level 4.]: Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
• Number of Participants With a Grade 3 or Higher Dose-Limiting Toxicity (DLT) [Cycle 1 Day 28]: DLT is defined as an laboratory abnormality or adverse drug reaction (ADR) according to the Common Terminology Criteria for Adverse Events (CTCAE), such as any grade 4 immune mediated adverse event attributed to local tumor response, any grade ≥3 colitis, grade 3 or 4 noninfectious pneumonitis, and any > grade 2 cardiac toxicity which dose not resolve to grade 1 within 3 days of initiation of maximum supportive care that is possibly, probably, or definitely related to the combination of drug. Grade 3 adverse event is severe or medically significant but not immediately life-threatening, Grade 4 is life-threatening, and Grade 5 is death related to adverse event.

Sex: Female, ages: 18 Years to any

* INCLUSION CRITERIA:
* Patients must have histologically or cytologically confirmed advanced metastatic or unresectable epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer that is relapsed and resistant (recurred less than 6 months after chemotherapy) or refractory (progressed on chemotherapy) to prior platinum- and taxane-based standard care systemic regimen. Or patients who are eligible for aditional platinum therapy. Histopathologic diagnosis must be confirmed in the Laboratory of Pathology (LP), National Cancer Institute (NCI).
* Patients must have measurable or evaluable disease. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral computed tomography (CT) scan.
* Patients must be at least 4 weeks from previous therapy (chemotherapy, hormonal therapy, and radiation therapy, immunotherapy and monoclonal antibodies, alternative therapy or investigational therapeutic agents). There is no limitation on the amount of prior therapies allowed. Patients with ovarian cancer 4 weeks from previous therapy have been found to have normal monocyte function (unpublished).
* Patients who have had cranial radiation therapy need to have completed it greater than or equal to 8 weeks prior to enrollment.
* Patients are permitted to receive investigational imaging agents while on study.
* Patients who have had major surgery must be fully recovered and require a recovery period of greater than or equal to 4 weeks prior to enrolling on study.
* Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of intraperitoneal monocytes, interferon (IFN)-alpha 2 or IFN-gamma in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 (Karnofsky greater than or equal to 70%).
* Adequate renal function, defined as serum creatinine less than or equal to 1.5 X upper limit of normal (ULN), or measured creatinine clearance greater than or equal to 60 mL/min/1.73m\^2.
* Adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels less than or equal to 3 X ULN and total bilirubin < 1.5 X ULN, unless known diagnosis of Gilbert's syndrome, where bilirubin less than or equal to 5 mg/dl will be permitted. Gilbert's syndrome will be defined as elevated unconjugated bilirubin, with conjugated (direct) bilirubin within the normal range and less than 20% of the total. Total bilirubin will be permitted up to 5 mg/dl, if patients have historical readings consistent with the definition of Gilbert's syndrome prior to entering study.
* Adequate bone marrow function, defined as absolute neutrophil (ANC) greater than or equal to 1,500/mm\^3 (greater than or equal to 1.5 X106/L), platelet count greater than or equal to 75,000/mm\^3 (greater than or equal to 75 X10\^6/L), and hemoglobin greater than or equal to 8 g/dL (transfusion to obtain hemoglobin greater than or equal to 8 g/dL is allowed).
* The effects of intraperitoneal monocytes, IFN-alpha 2, and IFN-gamma on the developing human fetus are unknown. For this reason and because interferons based on animal data may cause fetal harm, women of child-bearing potential (excludes women with recurrent ovarian cancer) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.
* Ability of subject to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

* Patients who are receiving any other investigational agents (with exception of imaging agents as indicated above in the inclusion criteria).
* Patients cannot have previously been treated with interferons (e.g., for chronic active hepatitis).
* Lack of recovery of prior adverse events to Grade less than or equal to 1 severity (National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] v 4.03) (except alopecia) due to therapy administered prior to the initiation of study drug dosing. Stable persistent grade 2 peripheral neuropathy may be allowed as determined on a case-bycase basis at the discretion of the Investigator as interferon has not been shown to cause or exacerbate peripheral neuropathy.
* Patients with active infection will not be eligible, but may become eligible once infection has resolved and at least 7 days have elapsed after antibiotics use was completed.
* Concomitant chronic (daily or almost daily for greater than or equal to 1 month prior) use of steroids or non-steroidal anti-steroidal anti-inflammatory drugs (NSAIDS).
* Patients with a recent history (within last 5 years) of autoimmune disease or inflammatory diseases will be excluded, because interferons may worsen these conditions. Exceptions will be allowed for vitiligo and hypothyroidism that has been stable on thyroid replacement medications for >6 weeks.
* Impaired cardiac function or clinically significant cardiac disease including the following:

  * New York Heart Association class III or IV congestive heart failure
  * Myocardial infarction within the last 12 months
  * Subjects known to have impaired left ventricular ejection fraction (LVEF) according to institutional standards
* History of allergic reactions attributed to compounds of chemical or biologic composition similar to interferons or other agents used in the study.
* 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 within the last 12 months that would limit compliance with study requirements. Patients with history of neuropsychiatric disorders or Major Depressive Disorder (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM 5) definition: http://dsm.psychiatryonline.org/doi/full/10.1176/appi.books.9780890425596.dsm04) requiring medical treatment will not be eligible to enroll, based on the black box warning (SYLATRON (peginterferon alfa-2b) for injection, for subcutaneous use. Merck Sharp \& Dohme Corp., a subsidiary of Merck \& Co., Inc., Whitehouse Station, NJ). Exception to this is if patients experienced transient post-partum depression that resolved and patient has been off treatment for >10 years. Patients who are taking oral anti-depressants for normal sadness, bereavement, or grief will not be excluded.
* Pregnant women are excluded from this study because interferons based on animal data may cause fetal harm. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with interferons, breastfeeding should be discontinued if the mother is treated with intraperitoneal interferons. These potential risks may also apply to other agents used in this study.
* Patients on combination antiretroviral therapy for the treatment of HIV are ineligible because of the potential for pharmacokinetic interactions with interferons alfa and gamma.
* Patients receiving any medications or substances that are potent inhibitors or inducers of Cytochrome P450 1A2 (CYP1A2) or Cytochrome P450 2D6 (CYP2D6) are ineligible.

Participant flow

Outcome results

• Overall Maximum Tolerated Dose of Intraperitoneal Autologous Monocytes (Primary), Number, Cells: All Participants On Dose Level 1 Through Dose Level 4 750000000
• Overall Maximum Tolerated Dose of Sylatron (Peginterferon Alpha-2b) (Primary), Number, mcg: All Participants On Dose Level 1 Through Dose Level 4 250
• Overall Maximum Tolerated Dose of Actimmune (Interferon Gamma-1b) (Primary), Number, mcg: All Participants On Dose Level 1 Through Dose Level 4 50
• Number of Participants With a Response (Secondary), Count of participants, Participants: Dose Level 1 - Sylatron 25µg (0.1 µg/ml); Actimmune 5mg (0.02µg/ml) 0; Dose Level 2 - Monocytes (75x10^6); Sylatron 25µg (0.1µg/ml); Actimmune 5mg (0.02µg/ml) 0; Dose Level 3 - Monocytes (750x10^6); Sylatron 25µg (0.1µg/ml); Actimmune 5mg (0.02µg/ml) 0; Dose Level 4 - Monocytes (750x10^6); Sylatron 250µg (1µg/ml); Actimmune 50mg (0.2µg/ml) 0
• Time to Disease Progression (Secondary), Median, Months: Dose Level 1 - Sylatron 25µg (0.1 µg/ml); Actimmune 5mg (0.02µg/ml) 3.7 (1 to 8); Dose Level 2 - Monocytes (75x10^6); Sylatron 25µg (0.1µg/ml); Actimmune 5mg (0.02µg/ml) 3.2 (1 to 10); Dose Level 3 - Monocytes (750x10^6); Sylatron 25µg (0.1µg/ml); Actimmune 5mg (0.02µg/ml) 2.0 (1 to 3); Dose Level 4 - Monocytes (750x10^6); Sylatron 250µg (1µg/ml); Actimmune 50mg (0.2µg/ml) 3.7 (1 to 10)
• Number of Participants With Serious or Non-serious (Any) Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) (Other pre specified), Count of participants, Participants: Dose Level 1 - Sylatron 25µg (0.1 µg/ml); Actimmune 5mg (0.02µg/ml) 3; Dose Level 2 - Monocytes (75x10^6); Sylatron 25µg (0.1µg/ml); Actimmune 5mg (0.02µg/ml) 6; Dose Level 3 - Monocytes (750x10^6); Sylatron 25µg (0.1µg/ml); Actimmune 5mg (0.02µg/ml) 3; Dose Level 4 - Monocytes (750x10^6); Sylatron 250µg (1µg/ml); Actimmune 50mg (0.2µg/ml) 6
• Number of Participants With a Grade 3 or Higher Dose-Limiting Toxicity (DLT) (Other pre specified), Count of participants, Participants: Dose Level 1 - Sylatron 25µg (0.1 µg/ml); Actimmune 5mg (0.02µg/ml) 0; Dose Level 2 - Monocytes (75x10^6); Sylatron 25µg (0.1µg/ml); Actimmune 5mg (0.02µg/ml) 1; Dose Level 3 - Monocytes (750x10^6); Sylatron 25µg (0.1µg/ml); Actimmune 5mg (0.02µg/ml) 0; Dose Level 4 - Monocytes (750x10^6); Sylatron 250µg (1µg/ml); Actimmune 50mg (0.2µg/ml) 0

Adverse events

Time frame: Date treatment consent signed to date off study, approximately 10 months and 11 days for dose level 1,12 months and 1 day for dose level 2, 11 months and 4 days for dose level 3, and 12 months and 6 days for dose level 4.

Serious adverse events by term

Other adverse events by term

14 more terms not shown.

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• Phase 1 study of intraperitoneal infusion of autologous monocytes with peginterferon alfa-2b and interferon gamma-1b in women with recurrent or refractory ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. By: Nunes, Ana Tablante; Green, Daniel; Ekwede, Irene; et al. Conference: 53rd Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Location: Chicago, IL Date: JUN 02-06, 2017 Sponsor(s): Amer Soc Clin Oncol JOURNAL OF CLINICAL ONCOLOGY Volume: 35 Supplement: 15 Meeting Abstract: TPS3092 Published: MAY 20 2017
• Production of autologous monocytes stimulated ex vivo with peg-interferon alfa 2b and interferon gamma 1b for intraperitoneal administration in phase I clinical trial. By: Duemler, Anna; Green, Daniel S.; Highfill, Steven L.; et al. Conference: ASCO-SITC Clinical Immuno-Oncology Symposium Location: San Francisco, CA Date: FEB 28-MAR 02, 2019 Sponsor(s): ASCO; SITC JOURNAL OF CLINICAL ONCOLOGY Volume: 37 Issue: 8 Supplement: S Meeting Abstract: 5 Published: MAR 10 2019
• Green DS, Nunes AT, David-Ocampo V, Ekwede IB, Houston ND, Highfill SL, Khuu H, Stroncek DF, Steinberg SM, Zoon KC, Annunziata CM. A Phase 1 trial of autologous monocytes stimulated ex vivo with Sylatron(R) (Peginterferon alfa-2b) and Actimmune(R) (Interferon gamma-1b) for intra-peritoneal administration in recurrent ovarian cancer. J Transl Med. 2018 Jul 16;16(1):196. doi: 10.1186/s12967-018-1569-5. PMID 30012146
• Green DS, Nunes AT, Tosh KW, David-Ocampo V, Fellowes VS, Ren J, Jin J, Frodigh SE, Pham C, Procter J, Tran C, Ekwede I, Khuu H, Stroncek DF, Highfill SL, Zoon KC, Annunziata CM. Production of a cellular product consisting of monocytes stimulated with Sylatron(R) (Peginterferon alfa-2b) and Actimmune(R) (Interferon gamma-1b) for human use. J Transl Med. 2019 Mar 14;17(1):82. doi: 10.1186/s12967-019-1822-6. PMID 30871636
• Results publication: First-in-human phase I study of intraperitoneally administered interferon-activated autologous monocytes in platinum-resistant or refractory ovarian cancer By: Cole, Christopher Browning; Annunziata, Christina M. Conference: ASCO-SITC Clinical Immuno-Oncology Symposium Location: Orlando, FL Date: FEB 06-08, 2020 Sponsor(s): Amer Soc Clin Oncol; Soc Immunotherapy Canc JOURNAL OF CLINICAL ONCOLOGY Volume: 38 Issue: 5 Supplement: S Meeting Abstract: 1 Published: FEB 10 2020
• Results publication: Kamat K, Krishnan V, Berek JS, Dorigo O. Cell-based immunotherapy in gynecologic malignancies. Curr Opin Obstet Gynecol. 2021 Feb 1;33(1):13-18. doi: 10.1097/GCO.0000000000000676. PMID 33278077

• Study Protocol and Statistical Analysis Plan (PDF, 2025-12-04)
• Informed Consent Form (PDF, 2020-06-24)

• Stanley Lipkowitz, M.D., Principal investigator, National Cancer Institute (NCI)