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NK Cell Infusions With Trastuzumab for Patients With HER2+ Breast and Gastric Cancer

Primary Purpose

Breast Cancer, Gastric Cancer

Status
Unknown status
Phase
Phase 1
Locations
Singapore
Study Type
Interventional
Intervention
Trastuzumab + NK cells
Sponsored by
National University Hospital, Singapore
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Cancer focused on measuring NK cells, trastuzumab, immunotherapy

Eligibility Criteria

21 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age 18-65
  2. Histologically confirmed diagnosis of HER2-positive breast or gastric cancer (defined as IHC 3+ or HER2 FISH amplification ratio >2.2)
  3. Metastatic disease
  4. Presence of measurable tumour by RECIST 1.1 criteria
  5. Must have failed at least two lines of trastuzumab-containing systemic therapy (documented relapse while receiving adjuvant or neoadjuvant trastuzumab for HER2 positive breast cancer is eligible)
  6. At least two weeks since receipt of any biological therapy, chemotherapy, and/or radiation therapy
  7. Left ventricular ejection fraction ≥50%
  8. Adequate organ function ANC ≥ 1500/µL Platelet count ≥ 100,000/µL Creatinine clearance ≥60ml/minute Total bilirubin ≤ 1.5 x upper limit normal (ULN) AST ≤ 2 x upper limit normal ALT ≤ 2 x upper limit normal
  9. ECOG performance status of 0-1
  10. Life expectancy of at least 60 days
  11. Negative serum or urine pregnancy test result within 14 days prior to enrolment for women who are of childbearing potential
  12. Ability to provide informed consent. Otherwise, a legally authorized representative (LAR) must be present throughout the consent process and is allowed to give consent on the patient's behalf.
  13. Patients with reproductive potential must agree to use an approved contraceptive method
  14. Ability to comply with study procedures

Exclusion Criteria:

  1. Treatment within the last 30 days with any investigational drug
  2. Concurrent administration of any other tumor therapy, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy
  3. Major surgery within 28 days of study drug administration
  4. Active infection that in the opinion of the investigator would compromise the patient's ability to tolerate therapy
  5. Lactating or pregnant.

  6. Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator; serious cardiac illness or medical conditions including but not limited to:

    • Patients with dyspnea at rest.
    • History of documented congestive heart failure
    • High risk uncontrolled arrhythmias
    • Angina pectoris requiring a medicinal product
    • Clinically significant valvular disease
    • Evidence of transmural infarction on ECG
    • Poorly controlled hypertension
  7. Second primary malignancy that is clinically detectable at the time of consideration for study enrolment
  8. Symptomatic brain metastases
  9. Receipt of steroids during time period of 3 days prior to expanded NK cell infusion to 30 days after infusion (i.e. day -3 to day +30).

Sites / Locations

  • National University HospitalRecruiting
  • National University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Trastuzumab + NK cells

Arm Description

During cycle 1, Day 1 patient will receive intravenous trastuzumab and subcutaneous IL-2 on day 1, followed by NK cell infusion on day 2, followed by subcutaneous IL-2 for an additional 5 doses three times a week to support NK cell viability and expansion in vivo. From cycles 2-4, patient will receive trastuzumab monotherapy alone every 21 days, except for patients who achieve objective tumor response after 2 cycles of therapy, who will then receive an additional infusion of NK cells along with trastuzumab during cycle 4 therapy at the same dose and schedule as in cycle 1. Patients will be taken off study after cycle 4, unless the patient has objective tumor response after 4 cycles of therapy with only stable disease after cycle 2, in which case the patient will be given another 2 cycles of trastuzumab with an additional NK cell infusion during cycle 6 therapy at the same dose and schedule as in cycle 1.

Outcomes

Primary Outcome Measures

Number of Participants with Serious and Non-Serious Adverse Events
During cycle 1 (21 days) and for at least 21 days following a second NK cell infusion if administered: - Patients will be reviewed twice a week with Limited physical examination to include blood pressure, heart rate, weight Full blood count, renal function and liver function tests Toxicity rating using the NCI CTC scale Concomitant medication notation and number of units required for transfusions Any significant abnormalities or significant toxicities have to be followed until recovery to baseline or 30 days after patient withdraws from the study, whichever occurs later. During other cycles when only trastuzumab is administered (without NK cells infusion or IL-2) Patients will be reviewed once every cycle of every 3-weekly cycle
Duration of Tumor Response Measure
Among tumor responders, the duration of tumor response is measured from the date of enrolment until the first date of documented disease progression or death due to any cause, whichever occurs first. Duration of tumor response will be censored at the date of the last follow-up visit for tumor responders who are still alive and who have not progressed.
Time-to-Event Outcome Measure
Time to documented disease progression is defined as the time from the date of enrolment to the first date of documented disease progression. Time to documented disease progression will be censored at the date of death for patients who have not had documented disease progression. For patients who are still alive at the time of analysis and who have not had documented disease progression, time to documented disease progression will be censored at the date of the last follow-up visit.

Secondary Outcome Measures

Full Information

First Posted
January 7, 2014
Last Updated
June 21, 2016
Sponsor
National University Hospital, Singapore
Collaborators
National University of Singapore
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1. Study Identification

Unique Protocol Identification Number
NCT02030561
Brief Title
NK Cell Infusions With Trastuzumab for Patients With HER2+ Breast and Gastric Cancer
Official Title
Phase I/II Study of Expanded, Activated Autologous Natural Killer Cell Infusions With Trastuzumab for Patients With HER2+ Breast and Gastric Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
June 2016
Overall Recruitment Status
Unknown status
Study Start Date
January 2014 (undefined)
Primary Completion Date
August 2017 (Anticipated)
Study Completion Date
August 2018 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National University Hospital, Singapore
Collaborators
National University of Singapore

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study will determine the safety and efficacy of expanded activated autologous NK cells administered after Trastuzumab in patients with HER2-positive breast or gastric cancer. It will also provide valuable insights of the role of NK cell infusions in adult solid tumors.
Detailed Description
Recently, targeted immunotherapies have become part of the therapeutic arsenal in adult solid tumors, and have shown promising activity in melanomas and prostate cancers. Trastuzumab is a monoclonal antibody that targets HER2 and is used routinely in combination with chemotherapy in HER2 over-expressing breast and gastric cancer. Trastuzumab is known to induce antibody dependent cell cytotoxicity (ADCC), among its various mechanisms for tumor cell kill. As such, trastuzumab may suitably be combined with immunotherapy as a strategy to harness the host's immune system against HER2-positive tumor cells.There is mounting evidence that natural killer (NK) cells have powerful anti-cancer activity. In patients with leukemia undergoing allogeneic hematopoietic stem cell transplant, several studies have demonstrated NK-mediated anti-leukemic activity. Allogeneic NK cell infusions in patients with primary refractory or multiple-relapsed leukemia have been shown to be well tolerated and void of graft-versus-host disease (GVHD) effects. In this study, we seek to enhance the antitumor activity of a commonly used antibody to treat HER2+ breast and gastric cancer, trastuzumab, administered in combination with infusion of activated and expanded autologous NK cells.This is a lead-in phase I followed by a phase II study. Up to 9 patients will be enrolled in phase I to test two different doses of NK cells to be infused into the patient. This will then be followed by a phase II study where 20 patients will be enrolled. Eligible patients will undergo apheresis about 9 days (up to 11 days) prior to cycle 1 therapy to harvest NK cells. The collected NK cells will be expanded and activated ex vivo. On day 1 of cycle 1, the patient will receive herceptin and subcutaneous IL2, followed by NK cell infusion on day 2 of cycle 1. This will then be followed by 5 doses of s/c IL2 three times a week to keep the NK cells activated in vivo. The patient will then receive three more cycles of herceptin (every 21 days). In patients who achieve objective tumor response after cycle 2 or cycle 4, a second NK cell infusion along with s/c IL2 will be administered with cycle 4 or cycle 6 herceptin respectively.This study will determine the safety and efficacy of this novel therapeutic strategy in HER2 positive breast and gastric cancer. It will also provide valuable insights of the role of NK cell infusions in adult solid tumors.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer, Gastric Cancer
Keywords
NK cells, trastuzumab, immunotherapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
29 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Trastuzumab + NK cells
Arm Type
Experimental
Arm Description
During cycle 1, Day 1 patient will receive intravenous trastuzumab and subcutaneous IL-2 on day 1, followed by NK cell infusion on day 2, followed by subcutaneous IL-2 for an additional 5 doses three times a week to support NK cell viability and expansion in vivo. From cycles 2-4, patient will receive trastuzumab monotherapy alone every 21 days, except for patients who achieve objective tumor response after 2 cycles of therapy, who will then receive an additional infusion of NK cells along with trastuzumab during cycle 4 therapy at the same dose and schedule as in cycle 1. Patients will be taken off study after cycle 4, unless the patient has objective tumor response after 4 cycles of therapy with only stable disease after cycle 2, in which case the patient will be given another 2 cycles of trastuzumab with an additional NK cell infusion during cycle 6 therapy at the same dose and schedule as in cycle 1.
Intervention Type
Drug
Intervention Name(s)
Trastuzumab + NK cells
Other Intervention Name(s)
Herceptin
Primary Outcome Measure Information:
Title
Number of Participants with Serious and Non-Serious Adverse Events
Description
During cycle 1 (21 days) and for at least 21 days following a second NK cell infusion if administered: - Patients will be reviewed twice a week with Limited physical examination to include blood pressure, heart rate, weight Full blood count, renal function and liver function tests Toxicity rating using the NCI CTC scale Concomitant medication notation and number of units required for transfusions Any significant abnormalities or significant toxicities have to be followed until recovery to baseline or 30 days after patient withdraws from the study, whichever occurs later. During other cycles when only trastuzumab is administered (without NK cells infusion or IL-2) Patients will be reviewed once every cycle of every 3-weekly cycle
Time Frame
Up to 12-18 weeks
Title
Duration of Tumor Response Measure
Description
Among tumor responders, the duration of tumor response is measured from the date of enrolment until the first date of documented disease progression or death due to any cause, whichever occurs first. Duration of tumor response will be censored at the date of the last follow-up visit for tumor responders who are still alive and who have not progressed.
Time Frame
Up to 36 months
Title
Time-to-Event Outcome Measure
Description
Time to documented disease progression is defined as the time from the date of enrolment to the first date of documented disease progression. Time to documented disease progression will be censored at the date of death for patients who have not had documented disease progression. For patients who are still alive at the time of analysis and who have not had documented disease progression, time to documented disease progression will be censored at the date of the last follow-up visit.
Time Frame
Up to 36 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 18-65 Histologically confirmed diagnosis of HER2-positive breast or gastric cancer (defined as IHC 3+ or HER2 FISH amplification ratio >2.2) Metastatic disease Presence of measurable tumour by RECIST 1.1 criteria Must have failed at least two lines of trastuzumab-containing systemic therapy (documented relapse while receiving adjuvant or neoadjuvant trastuzumab for HER2 positive breast cancer is eligible) At least two weeks since receipt of any biological therapy, chemotherapy, and/or radiation therapy Left ventricular ejection fraction ≥50% Adequate organ function ANC ≥ 1500/µL Platelet count ≥ 100,000/µL Creatinine clearance ≥60ml/minute Total bilirubin ≤ 1.5 x upper limit normal (ULN) AST ≤ 2 x upper limit normal ALT ≤ 2 x upper limit normal ECOG performance status of 0-1 Life expectancy of at least 60 days Negative serum or urine pregnancy test result within 14 days prior to enrolment for women who are of childbearing potential Ability to provide informed consent. Otherwise, a legally authorized representative (LAR) must be present throughout the consent process and is allowed to give consent on the patient's behalf. Patients with reproductive potential must agree to use an approved contraceptive method Ability to comply with study procedures Exclusion Criteria: Treatment within the last 30 days with any investigational drug Concurrent administration of any other tumor therapy, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy Major surgery within 28 days of study drug administration Active infection that in the opinion of the investigator would compromise the patient's ability to tolerate therapy Lactating or pregnant. Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator; serious cardiac illness or medical conditions including but not limited to: Patients with dyspnea at rest. History of documented congestive heart failure High risk uncontrolled arrhythmias Angina pectoris requiring a medicinal product Clinically significant valvular disease Evidence of transmural infarction on ECG Poorly controlled hypertension Second primary malignancy that is clinically detectable at the time of consideration for study enrolment Symptomatic brain metastases Receipt of steroids during time period of 3 days prior to expanded NK cell infusion to 30 days after infusion (i.e. day -3 to day +30).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Soo Chin Lee, MBBS
Phone
(65) 6779 5555
Email
Soo_Chin_Lee@nuhs.edu.sg
First Name & Middle Initial & Last Name or Official Title & Degree
Joan Phee
Phone
(65) 6772 2404
Email
Joan_Phee@nuhs.edu.sg
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Soo Chin Lee, MBBS
Organizational Affiliation
National University Hospital, Singapore
Official's Role
Principal Investigator
Facility Information:
Facility Name
National University Hospital
City
Singapore
ZIP/Postal Code
119228
Country
Singapore
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Soo Chin Lee, MBBS
Phone
+65 6779 5555
Email
Soo_Chin_Lee@nuhs.edu.sg
First Name & Middle Initial & Last Name & Degree
Dario Campana, MBBS
Facility Name
National University Hospital
City
Singapore
ZIP/Postal Code
119228
Country
Singapore
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Soo Chin Lee, MBBS
Phone
(65) 6779 5555
Email
Soo_Chin_Lee@nuhs.edu.sg
First Name & Middle Initial & Last Name & Degree
Soo Chin Lee, MBBS

12. IPD Sharing Statement

Citations:
PubMed Identifier
18485193
Citation
Beano A, Signorino E, Evangelista A, Brusa D, Mistrangelo M, Polimeni MA, Spadi R, Donadio M, Ciuffreda L, Matera L. Correlation between NK function and response to trastuzumab in metastatic breast cancer patients. J Transl Med. 2008 May 16;6:25. doi: 10.1186/1479-5876-6-25.
Results Reference
background
PubMed Identifier
20937115
Citation
Voskens CJ, Watanabe R, Rollins S, Campana D, Hasumi K, Mann DL. Ex-vivo expanded human NK cells express activating receptors that mediate cytotoxicity of allogeneic and autologous cancer cell lines by direct recognition and antibody directed cellular cytotoxicity. J Exp Clin Cancer Res. 2010 Oct 11;29(1):134. doi: 10.1186/1756-9966-29-134.
Results Reference
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NK Cell Infusions With Trastuzumab for Patients With HER2+ Breast and Gastric Cancer

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