Laboratory-Treated T Cells After Second-Line Chemotherapy in Treating Women With HER2/Neu-Negative Metastatic Breast Cancer

• ClinicalTrials.gov Identifier: NCT01022138
• Recruitment Status: Unknown
• First Posted: December 1, 2009
• Last Update Posted: May 22, 2017
• Sponsor: Barbara Ann Karmanos Cancer Institute
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Amy Weise, Barbara Ann Karmanos Cancer Institute

Tracking Information

• First Submitted Date: November 26, 2009
• First Posted Date: December 1, 2009
• Last Update Posted Date: May 22, 2017
• Study Start Date: February 2011
• Estimated Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 6, 2013)

Progression-free survival [ Time Frame: At one year follow up ]

26 evaluable patients will be accrued in this study. There will be a two-stage phase II design, 19 patients will be accrued in the first stage. During the 1st stage, if there are 4 or fewer progression-free patients at the 1 year follow-up, then the trial will conclude early for lack of efficacy. Otherwise, 11 add'l patients will be accrued for the 2nd stage.

• Original Primary Outcome Measures (submitted: November 26, 2009): Progression-free survival

Current Secondary Outcome Measures (submitted: September 6, 2013)

• Overall survival [ Time Frame: Followed until death ]
• Toxicity [ Time Frame: Following chemotherapy ]
  Patients will be restaged and evaluated for chemo-related toxicities.
• Cytokine responses, phenotypic markers of differentiation, specificity, and antitumor cytotoxicity in blood and tumor samples (if accessible) [ Time Frame: At baseline ]
• Correlation between immunotherapy-induced changes in immune functions and clinical endpoints [ Time Frame: After immunotherapy ]
• Cytokine responses, phenotypic markers of differentiation, specificity, and antitumor cytotoxicity in blood and tumor samples (if accessible) [ Time Frame: After lymphodepletion ]
• Cytokine responses, phenotypic markers of differentiation, specificity, and antitumor cytotoxicity in blood and tumor samples (if accessible) [ Time Frame: After immunotherapy ]

Original Secondary Outcome Measures (submitted: November 26, 2009)

• Overall survival
• Toxicity
• Cytokine responses, phenotypic markers of differentiation, specificity, and anti-tumor cytotoxicity in blood and tumor samples (if accessible) at baseline, after lymphodepletion, and after immunotherapy
• Correlation between immunotherapy-induced changes in immune functions and clinical endpoints.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Laboratory-Treated T Cells After Second-Line Chemotherapy in Treating Women With HER2/Neu-Negative Metastatic Breast Cancer
• Official Title: A Phase II Study of Anti-CD3 x Anti-HER2/Neu Armed Activated T Cells After Second Line Chemotherapy in Women With HER2/Neu (0, 1+ or 2+) Metastatic Breast Cancers

Brief Summary

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Treating a patient's T cells in the laboratory may help the T cells kill more tumor cells when they are put back in the body. Giving laboratory-treated T cells after chemotherapy may be an effective treatment for breast cancer.

PURPOSE: This phase II trial is studying how well giving laboratory-treated T cells after second-line chemotherapy works in treating women with HER2/neu-negative metastatic breast cancer.

Detailed Description

OBJECTIVES:

• To determine in a phase II trial whether Her2Bi armed ATC infused after ChemoT for patients with HER2 0-2+ MBC or locally advanced, unresectable breast cancer would improve median PFS by 2 months beyond the median PFS of 2 months estimated from published trials in a one stage design.
• To determine the overall survival (OS) of patients with HER2 0-2+ MBC and locally advanced, unresectable breast cancer who receive aATC infusion after ChemoT.
• To confirm the toxicity profile for Her2Bi armed ATC given after ChemoT for patients with HER2 0-2+ MBC.
• To measure functional and phenotypic changes in immune cell populations (blood and tumor sites, if accessible) as a consequence of armed ATC (tumor biopsies done at KCI only). Cytokine responses, phenotypic markers of differentiation, and anti-tumor cytotoxicity will be examined.
• OUTLINE: Patients receive second-line chemotherapy for 4 courses or 4 months. Beginning as early as 1.5 weeks and as late as 4 weeks after chemotherapy, the patients will receive the first infusion of anti-CD3 x anti-HER2/neu bispecific antibody-armed activated T-cells (ATC) IV over 30-60 minutes once a week for 3 weeks. Low dose granulocyte-macrophage colony stimulating factor (250 µg/m2/twice per week) will start 3 days before the first aATC infusion and end with the last dose of aATC. Patients who are already on the protocol will be given a choice to add GM-CSF to their treatment regimen (after reconsenting) or continue to their treatment without GM-CSF. Patients then receive a boost of anti-CD3 x anti-HER2/neu bispecific antibody-armed ATC at 12 weeks after the 3rd ATC infusion.

Blood and tumor tissue samples may be collected periodically for biomarker and other analyses.

After completion of study therapy, patients are followed up periodically for ≥ 2 years.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Biological: HER2Bi-armed activated T cells
  Immediately after pheresis, the lymphocytes are activated with soluble monoclonal anti-CD3 antibody, which cross-links the CD3 receptors on T cells and activates them.
• Drug: Cyclophosphamide
  After recovering from the last cycle of chemotherapy (approx. two-four weeks) patients will be re-staged. If there are no residual chemotherapy related toxicities, they will be given lymphodepleting chemotherapy consisting of one dose of Cyclophosphamide 1.0 gm/m2 on day -7. Appropriate anti-emetics will be given as pre-medications before the dose of Cyclophosphamide
• Other: Laboratory biomarker analysis
  The association between the [18F]-FDG PET/CT assessments (percent changes from baseline in SUVpeak) and immunologic biomarker changes as well as tumor response will be explored.

Study Arms

Experimental: HER2Bi-armed activated T cells/Cyclophosphamide/biomarker

HER2Bi-armed activated T cells Immediately after pheresis, the lymphocytes are activated with soluble monoclonal anti-CD3 antibody, which cross-links the CD3 receptors on T cells and activates them.

Cyclophosphamide After recovering from the last cycle of chemotherapy (approx. two-four weeks) patients will be re-staged. If there are no residual chemotherapy related toxicities, they will be given lymphodepleting chemotherapy consisting of one dose of Cyclophosphamide 1.0 gm/m2 on day -7. Appropriate anti-emetics will be given as pre-medications before the dose of Cyclophosphamide

Laboratory biomarker analysis The association between the [18F]-FDG PET/CT assessments (percent changes from baseline in SUVpeak) and immunologic biomarker changes as well as tumor response will be explored.

Interventions:

• Biological: HER2Bi-armed activated T cells
• Drug: Cyclophosphamide
• Other: Laboratory biomarker analysis

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: November 26, 2009): 63
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 2018
• Estimated Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed metastatic breast cancer

  • All histological types allowed

• Recurrent disease after first-line chemotherapy in the metastatic setting, as defined by 1 of the following:

  • No objective response after administration of ≥ 4 courses of first-line chemotherapy
  • Progression while receiving first-line chemotherapy without experiencing any transient improvement
  • Brief objective response to first-line chemotherapy with subsequent progression while receiving the same therapy or within 12 months after the last dose of therapy
• Patients who just started second line chemotherapy within 1 month allowed provided there is no documented progressive disease on the second line chemotherapy

• HER2/neu-negative disease, defined as 0-2+ by IHC and/or FISH ratio (HER2 gene signals to chromosome 17 signals) ≤ 2.2

  • No HER2 overexpression by IHC or overamplification by FISH, as defined by any of the following:

    • 3+ IHC (uniform, intense membrane staining of > 30% of invasive tumor cells)
    • FISH result of > 6 HER2 gene copies per nucleus
    • FISH ratio > 2.2

• Measurable or evaluable metastatic disease as documented by radiograph, CT scan, PET/CT scan, MRI, bone scan, or physical exam

  • At least 1 bidimensionally measurable lesion (that has not been irradiated) with a minimum size in at least one diameter of ≥ 20 mm for liver lesions and ≥ 10 mm for lung, skin, and lymph node metastases
  • Biopsy of recurrent site(s) is not required

• No clinical evidence of active CNS metastases

  • Patients with treated brain metastases (i.e., those who have received definitive radiotherapy, chemotherapy, and/or surgical resection) are eligible
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• Menopausal status not specified
• Karnofsky performance status 70-100%
• Life expectancy ≥ 3 months
• Granulocytes ≥ 1,000/mm³
• Platelet count ≥ 50,000/mm³
• Hemoglobin ≥ 8 g/dL
• BUN ≤ 1.5 times normal
• Serum creatinine < 1.8 mg/dL
• Creatinine clearance ≥ 60 mL/min
• Bilirubin < 1.5 times normal
• ALT and AST < 5 times upper limit of normal (ULN)
• Alkaline phosphatase < 5 times ULN
• LVEF ≥ 45% at rest by MUGA or ECHO
• FEV_1, DLCO, and FVC ≥ 50% of predicted
• Negative pregnancy test
• No HIV positivity
• No myocardial infarction within the past year
• No current coronary symptoms requiring medications and/or evidence of depressed left ventricular function (LVEF < 45% by MUGA or ECHO)
• No clinical evidence of congestive heart failure requiring medical management (irrespective of MUGA/ECHO results)
• Patients whose systolic BP is consistently ≥ 140 mm Hg or diastolic BP is consistently ≥ 80 mm Hg are eligible provided their BP is controlled by antihypertensive medications for ≥ 7 days before the first activated T-cell infusion
• No other malignancy within the past 5 years except for basal cell skin carcinoma and carcinoma in situ of the cervix
• No serious medical or psychiatric illness that would preclude informed consent or intensive treatment

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No more than 3 prior chemotherapy regimen for metastatic disease
• Prior taxanes, anthracyclines, or any other chemotherapy allowed
• No hormonal therapy within 2 weeks before leukapheresis
• No radiotherapy to the axial skeleton within 4 weeks before leukapheresis
• No concurrent steroids except those administered for adrenal failure, septic shock, or pulmonary toxicity or hormones administered for nondisease-related conditions (e.g., insulin for diabetes)

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 120 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01022138
• Other Study ID Numbers: CDR0000657998; P30CA022453 ( U.S. NIH Grant/Contract ); WSU-2009-085
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Amy Weise, Barbara Ann Karmanos Cancer Institute
• Study Sponsor: Barbara Ann Karmanos Cancer Institute
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Amy Weise, M.D.; Barbara Ann Karmanos Cancer Institute

• PRS Account: Barbara Ann Karmanos Cancer Institute
• Verification Date: May 2017