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Safety and Efficacy of IV Nerofe™ Followed by Doxorubicin, In Metastatic Ovarian Cancer and Triple Negative Breast Cancer

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ClinicalTrials.gov Identifier: NCT03634150
Recruitment Status : Recruiting
First Posted : August 16, 2018
Last Update Posted : October 19, 2018
Sponsor:
Information provided by (Responsible Party):
Immune System Key Ltd

Brief Summary:
This is a Phase 1b, open-label, non-randomized, Dose Confirmation study. Subjects will be treated, once a week, with IV doses of Nerofe and low dose (20 mg/m2) Doxorubicin (6-8 hours from one another) in consecutive, 28-day cycles.

Condition or disease Intervention/treatment Phase
Metastatic Ovarian Cancer Triple Negative Breast Cancer Biological: Nerofe is a first in class derivative of a human hormon-peptide(TCApF), with Cancer suppressive properties. Phase 1 Phase 2

Detailed Description:
Subjects will be evaluated regularly for safety. Subjects will return for a follow-up visit 30-33 days after the last dosing of study drug. Subjects who tolerate the drug and who do not experience progressive disease, intolerable toxicity, or meet any of the other withdrawal criteria - may continue to receive Nerofe & Doxorubicin for up to 5 cycles, at the discretion of the Principal Investigator. Throughout the trial, oversight will be provided by the Clinical Safety Committee (CSC).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Experimental: IV Nerofe 96 mg\m2 followed by IV Doxorubicin 10mg\m2, once weekly
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b, Open-Label, Dose-Confirmation Study Evaluating the Safety, and Clinical Effects of Intravenously Administered Nerofe™ in Combination With Doxorubicin, In Subjects With Metastatic Ovarian Cancer and Triple Negative Breast Cancer
Actual Study Start Date : September 6, 2018
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : November 2020


Arm Intervention/treatment
Experimental: Single arm Nerofe followed by Doxorubicin
IV treatment of Nerofe 96 mg\m2 followed by IV Doxorubicin 10mg\m2 Once weekly
Biological: Nerofe is a first in class derivative of a human hormon-peptide(TCApF), with Cancer suppressive properties.
Once weekly treatment, with IV doses of Nerofe (96mg\m2) and low dose (20 mg/m2) Doxorubicin 5 or 24 hours from one another) .
Other Name: Doxorubicin or Adriamycin is a registered chemotherapy, which belongs to the Anthracyclines. It slows or stops the growth of cancer cells.




Primary Outcome Measures :
  1. The primary safety endpoint will be the Adverse Events (AE) reported during the combined treatment of Nerofe and low Dose doxorubicin , using the CTCAE score. [ Time Frame: Safety data will be collected weekly during the subjects visits(Weeks 1-20), throughout the study and up to 1 year. ]
    The Adverse Events (AE) reported during the combined treatment of Nerofe and low Dose doxorubicin, using the CTCAE score.

  2. Assessing Change in tumor size from Baseline to End of study [ Time Frame: Imaging would be performed at Baseline and at the end of every 2 cycles(8 weeks), through the study completion, which is estimated to be after 6 months. ]
    Assessing Change in tumor size from Baseline to End of study under combined treatment of Nerofe and Low dose Doxorubicin in Ovarian cancer or triple negative breast cancer. Subject population will be evaluated using Response Evaluation Criteria in Solid Tumors, from Baseline, and every 2 cycles( 8 weeks), and last one- at the end of the study.

  3. Assessing Change in Blood markers from Baseline to End of study [ Time Frame: Blood Markers would be measured at Baseline, and at the end of every cycle(28 Days in each cycle), through the study completion, which is estimated to be after 6 months. ]
    Assessing Change in tumor size from Baseline to End of study, under combined treatment of Nerofe and Low dose Doxorubicin, in Ovarian cancer or triple negative breast cancer. Subject population will be evaluated from Baseline, and every cycle( 28 days each cycle) until the end of the study.


Secondary Outcome Measures :
  1. Pharmacokinetic Profile [ Time Frame: Pharmacokinetic sampling is planned once at Baseline. In Cycle 1(28 Days in each cycle), and Cycle 2 Day 1 visits: pre-dose and following the end of Nerofe infusion: 15 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours ]
    Pharmacokinetic Profile, including area under the curve.

  2. Pharmacokinetic Profile [ Time Frame: Pharmacokinetic sampling is planned once at Baseline. In Cycle 1(28 Days in each cycle), and Cycle 2 Day 1 visits: pre-dose and following the end of Nerofe infusion: 15 min ,1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours. ]
    Pharmacokinetic Profile, including maximum plasma concentration

  3. Pharmacokinetic Profile [ Time Frame: Pharmacokinetic sampling is planned once at Baseline. In Cycle 1(28 Days in each cycle), and Cycle 2 Day 1 visits: pre-dose and following the end of Nerofe infusion: 15 min, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours. ]
    Pharmacokinetic Profile, including trough plasma concentration.

  4. Pharmacokinetic Profile [ Time Frame: Pharmacokinetic sampling is planned once at Baseline. In Cycle 1(28 Days in each cycle), and Cycle 2 Day 1 visits: pre-dose and following the end of Nerofe infusion: 15 min, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours. ]
    Pharmacokinetic Profile, including time to maximum plasma concentration.

  5. Pharmacokinetic Profile [ Time Frame: Pharmacokinetic sampling is planned once at Baseline. In Cycle 1(28 Days in each cycle), and Cycle 2 Day 1 visits: pre-dose and following the end of Nerofe infusion: 15 min, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours. ]
    Pharmacokinetic Profile, including plasma half-life.

  6. Pharmacodynamics profile [ Time Frame: PharmacoDynamics sampling is planned at Baseline, at Day 1, 15, visits of every cycle (28 Days in each cycle), through the study completion which is estimated to be after 6 months.. ]
    PharmacoDynamics profile, including changes in plasma levels of circulating cytokines

  7. Pharmacodynamics profile [ Time Frame: PharmacoDynamics sampling is planned at Baseline, at Day 1, 15, visits of every cycle (28 Days in each cycle), through the study completion which is estimated to be after 6 months. ]
    PharmacoDynamics profile, including changes in plasma levels of soluble T1/ST2 receptor

  8. Pharmacodynamics profile [ Time Frame: PharmacoDynamics sampling is planned at Baseline, at Day 1, 15, visits of every cycle (28 Days in each cycle), through the study completion which is estimated to be after 6 months. ]
    PharmacoDynamics profile, including changes in Peripheral blood mononuclear cells' T1/ST2 receptor expression

  9. Pharmacodynamics profile [ Time Frame: PharmacoDynamics sampling is planned at Baseline, at Day 1, 15, visits of every cycle(28 Days in each cycle), through the study completion which is estimated to be after 6 months. ]
    Immunogenicity of Nerofe, through the analysis of Plasma levels of circulating anti-Nerofe antibodies.



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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Females over18 years of age.
  2. Pathologically confirmed locally advanced and/or metastatic solid tumor, for which, in the judgment of the Principal Investigator, no standard curative therapy exists.
  3. Subjects must have 1 of the following solid tumor types: Ovarian cancer (up to 12 patients), or by Triple-negative breast cancer (up to 12 patients).
  4. Disease that is evaluable, or measurable on imaging by Response Evaluation Criteria in Solid Tumors (RECIST v1.1 Appendix A), and where applicable is characterized by informative tumor marker(s).
  5. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2(Section 6.1.1.6) .
  6. Acceptable clinical laboratory values at screening, as indicated by:

    Absolute neutrophil count ≥ 1,500/mm3; Platelets ≥ 75,000/mm3; Total bilirubin ≤ 5 mg/dL. ASpartate aminoTransferase (SGOT) ≤ 2.5 × the Upper Limit of Normal; ALalanine aminoTransferase (SGPT) ≤ 2.5 × the Upper Limit of Normal; Serum creatinine ≤ 1.5 mg/dL or a measured creatinine clearance higher than 60 mL/min; and Negative serum Beta human chorionic gonadotropin test in women of childbearing potential (defined as women ≤ 50 years of age or history of amenorrhea for ≤ 12 months prior to study entry).

  7. Patients with hepatic metastasis are eligible to enroll, provided that the following criteria are met at Screening:

    Total bilirubin ≤ 5 * mg/dL; ASpartate aminoTransferase and ALalanine aminoTransferase are each ≤ 5 × the Upper Limit of Normal;

  8. Willing and able to provide written Informed Consent and comply with the requirements of the study.
  9. Tumor tissue, taken from either an archival sample or a fresh biopsy, must be available for staining for T1/ST2 receptor, and must be ST2 positive.
  10. Subject has not been previously treated with Doxorubicin or total accumulated dose has never exceeded 240 mg/m2.

Exclusion Criteria:

  1. Any chemotherapy, immunomodulatory drug therapy, anti-neoplastic hormonal therapy (unless dose has been stable for 1 month prior to Baseline and remains stable during the trial), immunosuppressive therapy, corticosteroids > 20 mg/day prednisone or equivalent (unless administered to prevent contrast material reactions during radiographic procedures), or growth factor treatment (eg, erythropoietin) within 14 days prior to initiation of study drug.
  2. Presence of an acute toxicity of prior chemotherapy, with the exception of alopecia or peripheral neuropathy, that has not resolved to ≤ Grade 1, as determined by NCI CTCAE v 4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/About.html).
  3. Receipt of >3 prior regimens of cytotoxic chemotherapy, including any use in the neo-adjuvant, adjuvant, and/or metastatic settings ,Unless more than 1 year elapsed since the Neo-adjuvant treatment was completed
  4. Receipt of Blood Transfusion during 2 weeks prior to Baseline
  5. Life expectancy <12 weeks.
  6. Major surgery or radiation therapy within 28 days prior to initiation of study drug,
  7. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome-related illness.
  8. Patients with history of brain metastasis
  9. Known active hepatitis B or C or other active liver disease (other than malignancy).
  10. Severe liver dysfunction (Child-Pugh Class B or C) and
  11. Patients with a history of esophageal bleeding have varices that have been sclerosed or banded and no bleeding episodes have occurred during the prior 6 months.
  12. Active infection requiring systemic therapy.
  13. Insulin-requiring diabetes mellitus will not be included if, according to the investigator, not stable, during the last 6 months.
  14. History of any of the following within 12 months prior to initiation of study drug:

    Uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4), unstable angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack, or pulmonary embolism (within the last 6 months). Left Ventricular Ejection Fraction <50% .

  15. Uncontrolled arterial hypertension, or anti-hypertensive drugs whose type or dose has been changed within 1 months prior to screening or whose dose is anticipated to change within cycle 1.
  16. Risk of syncope, in the judgment of the Principal Investigator, according to the patient's history of syncope.
  17. History of ongoing cardiac dysrhythmias requiring drug treatment
  18. Malignancies can be a reason for exclusion only if active during the last year or requiring any anti-tumor treatment. Skin non-melanomatous tumors and thyroid carcinomas - can be included. as well as, Previously treated malignancy within the past 2 years that the Principal Investigator deems to be at low risk for recurrence during the course of this trial.
  19. Use of any investigational agents within a minimum of 4 weeks or 5 half-lives of initiation of study drug.
  20. Pregnant or lactating female.
  21. Women of childbearing potential, unless they agree to use dual contraceptive methods which, in the opinion of the Principal Investigator, are effective and adequate for that patient's circumstances while on study drug and for 3 months afterward.
  22. Any severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, may interfere with the informed consent process and/or with compliance with the requirements of the study, or may interfere with the interpretation of study results and, in the investigator's opinion, would make the patient inappropriate for entry into this study.
  23. Any known multiple allergy, or acute allergic reaction within the subject's medical History or General Practitioner's records.

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): NCT03634150


Contacts
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Contact: Gilat Elgar +972546809080 ext +972546809080 gilat.elgar@immunesk.com
Contact: Aviva Fridman +972524798127 aviva.fridman@immunesk.com

Locations
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Israel
Oncologic Institue, Kaplan Recruiting
Reẖovot, Israel, 7661041
Contact: Noa Efrat Ben Baruch, MD    97289441975    noa_b@clalit.org.il   
Contact: Tali Ma-Yafir    97289441729    revitalma1@clalit.org.il   
Sponsors and Collaborators
Immune System Key Ltd
Investigators
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Study Director: Yoram Devary, phd Immune System Key Ltd

Publications of Results:
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Responsible Party: Immune System Key Ltd
ClinicalTrials.gov Identifier: NCT03634150     History of Changes
Other Study ID Numbers: ISK-N103
First Posted: August 16, 2018    Key Record Dates
Last Update Posted: October 19, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Breast Neoplasms
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Doxorubicin
Liposomal doxorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action