Laboratory-Treated Autologous Lymphocytes, Aldesleukin, and GM-CSF in Treating Patients With Recurrent, Refractory, or Metastatic Non-Small Cell Lung Cancer

• ClinicalTrials.gov Identifier: NCT00569296
• Recruitment Status: Terminated
• First Posted: December 7, 2007
• Last Update Posted: March 25, 2015
• Sponsor: Roger Williams Medical Center
• Information provided by (Responsible Party): Roger Williams Medical Center

Tracking Information

• First Submitted Date: December 6, 2007
• First Posted Date: December 7, 2007
• Last Update Posted Date: March 25, 2015
• Study Start Date: November 2007
• Actual Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 27, 2012)

• Safety [ Time Frame: 4 weeks ]
• Maximum tolerated dose of EGFRBi-armed autologous activated T-cells [ Time Frame: 4 weeks ]
• Determination of immunologic changes by evaluation of cytokine profiles obtained before and after stimulation with OKT3 in vitro [ Time Frame: 4 weeks ]

Original Primary Outcome Measures (submitted: December 6, 2007)

• Safety
• Maximum tolerated dose of EGFRBi-armed autologous activated T cells
• Determination of immunologic changes by evaluation of cytokine profiles obtained before and after stimulation with OKT3 in vitro

Current Secondary Outcome Measures (submitted: January 27, 2012)

• Overall survival [ Time Frame: 2 years ]
• Progression-free survival [ Time Frame: 2 years ]
• Evaluation of tumor markers and human anti-mouse antibody responses as assessed by carcinoembryonic antigen (CEA) levels in serum samples and development of IgG and IgM anti-mouse antibody responses to the Bi-antibodies [ Time Frame: 4 weeks ]
• Determination of immunologic changes by evaluation of peripheral blood lymphocytes [ Time Frame: 4 weeks ]
• Determination of immunologic changes by evaluation of cytotoxic T-lymphocytes as measured by interferon gamma ELISPOTS directed at autologous tumor or lung cancer cell lines [ Time Frame: 4 weeks ]
• Determination of immunologic changes by evaluation of phenotypes of peripheral blood mononuclear cells before and after immunotherapy [ Time Frame: 4 weeks ]

Original Secondary Outcome Measures (submitted: December 6, 2007)

• Overall survival
• Progression-free survival
• Evaluation of tumor markers and human anti-mouse antibody responses as assessed by carcinoembryonic antigen (CEA) levels in serum samples and development of IgG and IgM anti-mouse antibody responses to the Bi-antibodies
• Determination of immunologic changes by evaluation of peripheral blood lymphocytes
• Determination of immunologic changes by evaluation of cytotoxic T lymphocytes as measured by interferon gamma ELISPOTS directed at autologous tumor or lung cancer cell lines
• Determination of immunologic changes by evaluation of phenotypes of peripheral blood mononuclear cells before and after immunotherapy

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

Descriptive Information

• Brief Title: Laboratory-Treated Autologous Lymphocytes, Aldesleukin, and GM-CSF in Treating Patients With Recurrent, Refractory, or Metastatic Non-Small Cell Lung Cancer
• Official Title: A Phase I Study of Anti-CD3 x Cetuximab-Armed Activated T Cells, Low Dose IL-2, and GM-CSF for EGFR-Positive, Advanced Non-Small Cell Lung Cancer

Brief Summary

RATIONALE: Giving autologous lymphocytes that have been treated in the laboratory with antibodies may stimulate the immune system to kill tumor cells. Aldesleukin may stimulate the lymphocytes to kill tumor cells. Colony-stimulating factors, such as GM-CSF, may increase the number of immune cells found in bone marrow or peripheral blood. Giving laboratory-treated autologous lymphocytes together with aldesleukin and GM-CSF may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of laboratory-treated autologous lymphocytes when given together with aldesleukin and GM-CSF in treating patients with recurrent, refractory, or metastatic non-small cell lung cancer.

FUNDING SOURCE--FDA OOPD

Detailed Description

OBJECTIVES:

Primary

• Determine the safety and maximum tolerated dose of EGFRBi-armed autologous activated T-cells (ATC) when administered in combination with low-dose aldesleukin and sargramostim (GM-CSF) in patients with recurrent, refractory, or extensive (metastatic) non-small cell lung cancer (NSCLC).

Secondary

• Assess clinical outcome based on tumor responses, overall survival, and progression-free survival.
• Monitor changes in sera concentrations of the tumor marker in association with EGFRBi-armed ATC administration throughout the study and at time points thereafter in patients with elevated levels of carcinoembryonic antigen (CEA) prior to beginning the study.
• Monitor patient sera for human anti-mouse antibodies (HAMA).
• Evaluate immune response, which may reflect immune augmentation in response to EGFRBi-armed ATC infusions, in peripheral blood mononuclear cell (PBMC) samples as well as purified immune cell populations.
• Investigate proliferation in response to ex vivo stimulation with NSCLC tumor-associated antigens, sera cytokine profiles (Th1 vs Th2), cytotoxicity of patient PBMC, and interferon gamma ELISPOTS as a surrogate marker for assessing generation of EGFR-specific cytotoxic T-lymphocytes (CTL).

OUTLINE: Peripheral blood mononuclear cells (PBMCs) are collected by 1 or 2 leukaphereses for the generation of activated T cells (ATCs). The PBMCs are activated with OKT3 (anti-CD3) and expanded in aldesleukin for up to 14 days. The ATCs are then armed with EGFRBi.

Patients receive EGFRBi-armed autologous ATCs IV over 30-60 minutes twice weekly for 4 weeks (a total of 8 infusions) in the absence of disease progression or unacceptable toxicity. Patients also receive low-dose aldesleukin subcutaneously (SC) once daily and sargramostim (GM-CSF) SC twice weekly beginning 3 days before the first ATC infusion and continuing for 1 week after the last ATC infusion.

After completion of study therapy, patients are followed periodically.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Lung Cancer

Intervention

• Biological: EGFRBi-armed autologous activated T cells
  Dose escalation, dosage depends on when entered in study. 8 infusions (twice a week over 4 weeks. Each infusion will be over at least 1 hour.
• Biological: aldesleukin
  300,00IU/m2/day beginning 3 days before the first Activated T-cell infusion and ending 1 week after the last infusion
  Other Name: IL-2
• Biological: sargramostim
  250 micrograms/m2/twice weekly beginning 3 days before the first activated T-cell infusion and ending 1 week after the last Activated T-cell infusion
  Other Name: GM-CSF

Study Arms

Experimental: T-cells

EGFRBi-armed autologous activated T cells

Interventions:

• Biological: EGFRBi-armed autologous activated T cells
• Biological: aldesleukin
• Biological: sargramostim

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: March 24, 2015): 5
• Original Enrollment (submitted: December 6, 2007): 24
• Actual Study Completion Date: March 2015
• Actual Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed non-small cell lung cancer (NSCLC)

  • Recurrent, refractory, or metastatic disease after ≥ 1 prior first-line regimen (chemotherapy or radiotherapy)
• Documented EGFR-positive disease (any expression level) by immunohistochemistry (IHC) (may be based on archival sample)
• Measurable or evaluable disease by radiograph, CT scan, MRI, and/or physical exam
• Appropriate slides of the primary lesion must be available for review of IHC staining assessment by a central pathology team

• No clinical evidence of active brain metastases

  • Patients with brain metastases are eligible provide they have received definitive radiotherapy or chemotherapy and/or have undergone surgical resection for brain metastases
• No prior hematological malignancy

PATIENT CHARACTERISTICS:

• Karnofsky performance status (PS) 60-100% OR ECOG PS 0-2
• Life expectancy ≥ 3 months
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Granulocytes ≥ 1,000/mm^3
• Platelet count ≥ 50,000/mm^3
• Hemoglobin ≥ 8 g/dL
• BUN ≤ 2.0 times normal
• Serum creatinine ≤ 2.0 mg/dL
• Bilirubin ≤ 1.5 times normal
• SGOT ≤ 1.5 times normal (with or without liver metastases)
• Hepatitis B surface antigen and HIV negative

• LVEF ≥ 45 % at rest (by MUGA)

  • No evidence of depressed left ventricular function
• FEV_1, DLCO, and FVC ≥ 50% of the predicted value

• No other malignancy, except for the following:

  • History of curatively treated in situ squamous cell carcinoma or basal cell carcinoma of the skin
  • History of other curatively treated malignancy (except those with a hematologic origin) for which the patient has remained in complete remission > 5 years after completing therapy (as documented by history, physical exams, tumor markers, and radiology scanning)
• No serious medical or psychiatric illness that would preclude giving informed consent or receiving intensive treatment
• No recent myocardial infarction (within the past year)
• No current angina/coronary symptoms requiring medications
• No clinical evidence of congestive heart failure requiring medical management (irrespective of MUGA results)

• No systolic blood pressure (BP) ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg

  • Patients with elevated BP must have it controlled by anti-hypertensive medications for at least 7 days prior to the first infusion

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• More than 4 weeks since prior chemotherapy or radiotherapy
• At least 4 weeks since prior cetuximab or small molecule EGFR-inhibitors including, but not limited to, gefitinib or erlotinib hydrochloride
• No concurrent radiotherapy
• No concurrent steroids except for treatment of adrenal failure, septic shock, or pulmonary toxicity or hormones for non-disease-related conditions (e.g., insulin for diabetes)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (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: NCT00569296
• Other Study ID Numbers: CDR0000577502; 349-32 ( Other Identifier: Roger Williams Medical Center ); 3422 ( Other Grant/Funding Number: FDA OOPD )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Roger Williams Medical Center
• Original Responsible Party: Not Provided
• Current Study Sponsor: Roger Williams Medical Center
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Abby Maizel, MD, PhD; Roger Williams Medical Center

• PRS Account: Roger Williams Medical Center
• Verification Date: March 2015