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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

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ClinicalTrials.gov Identifier: NCT02948426
Recruitment Status : Recruiting
First Posted : October 28, 2016
Last Update Posted : February 14, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Ovarian cancer is a leading cause of cancer death in women. Monocytes are white blood cells that slow tumor growth. Interferons (IFNs) are molecules that help immune cells fight cancer. Researchers want to stimulate monocytes with IFNs. They want to test if these stimulated monocytes combined with the drugs Sylatron and Actimmune can shrink tumors and slow the progression of cancer.

Objective:

To test how well IFN stimulated monocytes, with Sylatron and Actimmune, kill tumor cells.

Eligibility:

Women ages 18 and older with certain ovarian, fallopian tube, or peritoneal cancers

Design:

Participants will be screened with:

Medical history

Physical exam

Blood and urine tests

Scan

Results or sample from previous biopsy

Participants may have a tumor sample taken.

Participants who do not have a port will have a catheter placed inside the abdominal cavity. It will be used to give the treatment.

Participants will have visits for 4 days of each 28-day cycle. This includes overnight observation.

Participants with ascites fluid in their abdominal cavity will have it sampled twice.

Each cycle, participants will have:

Blood tests

Leukapheresis. Some blood is removed and put through a machine that separates out the monocytes. The rest of the blood is returned to the body.

Infusion of the monocytes and study drugs

Participants will have weekly phone calls in Cycle 1 and scans every 2 cycles.

Participants will continue treatment until they can no longer tolerate it or their cancer gets worse.

Participants will have a visit about 1 month after stopping treatment, then monthly phone calls.


Condition or disease Intervention/treatment Phase
Fallopian Tube Cancer Ovarian Cancer Primary Peritoneal Cancer Biological: Autologous Monocytes + ACTIMMUNE + SYLATRON Phase 1

Detailed Description:

Background:

  • Monocytes can differentiate into classic M1 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.
  • 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 RECIST v1.1 and every cycle for safety using CTCAE v4.0.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Study of 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
Study Start Date : October 27, 2016
Estimated Primary Completion Date : July 31, 2018
Estimated Study Completion Date : July 1, 2019


Arm Intervention/treatment
Experimental: ES1 Phase 1 Dose Escalation Arm
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.
Biological: Autologous Monocytes + ACTIMMUNE + SYLATRON
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 MTD.
Experimental: EX1 Dose Expansion Arm
10 additional patients will be treated at the MTD
Biological: Autologous Monocytes + ACTIMMUNE + SYLATRON
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 MTD.



Primary Outcome Measures :
  1. Maximum Tolerated Dose of intraperitoneal autologous monocytes and Sylatron (Peginterferon alpha-2b) and Actimmune (Interferon gamma-1b). [ Time Frame: Cycle 1 Day 28 ]
    Maximum Tolerated Dose of intraperitoneal autologous monocytes and Sylatron (Peginterferon alpha-2b) and Actimmune (Interferon gamma-1b).


Secondary Outcome Measures :
  1. Response rate [ Time Frame: Every 2 cycles ]
    overall response rate including complete response and partial response

  2. Time to progression [ Time Frame: Date of disease progression ]
    time from the date of start of treatment to progression of disease



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria
  • 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), 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 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, 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.
  • 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 AST and 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/mm3 (greater than or equal to 75 X10^6/L), and hemoglobin greater than or equal to 10 g/dL (transfusion to obtain hemoglobin greater than or equal to 10 g/dL within 24 hours prior to dosing 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).
  • Patients with metastasis outside of the abdominal cavity as we are only giving intraperitoneal therapy and we are unsure whether our therapy would be beneficial to patients with other metastatic disease except

    --Disease outside of the abdomen that is non-measurable by Recist criteria will be allowed.

  • 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 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 (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 CYP1A2 or CYP2D6 are ineligible.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02948426


Contacts
Contact: Irene Ekwede, R.N. (240) 760-6126 ekwedeib@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Christina M Annunziata, M.D. National Cancer Institute (NCI)

Additional Information:
Publications:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02948426     History of Changes
Other Study ID Numbers: 170011
17-C-0011
First Posted: October 28, 2016    Key Record Dates
Last Update Posted: February 14, 2018
Last Verified: December 6, 2017

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Immunotherapy
Adoptive Cell Therapy
Carcinomatosis
CA125

Additional relevant MeSH terms:
Ovarian Neoplasms
Fallopian Tube Neoplasms
Peritoneal Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Fallopian Tube Diseases
Abdominal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Peritoneal Diseases
Interferons
Peginterferon alfa-2b
Interferon-alpha
Interferon-gamma
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs