Bispecific Antibody Armed Activated T-cells With Aldesleukin and Sargramostim in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer

Phase Ib/II Treatment of Advanced Pancreatic Cancer With Anti-CD3 x Anti-EGFR-Bispecific Antibody Armed Activated T-Cells (BATs) in Combination With Low Dose IL-2 and GM-CSF

Sponsors

Lead Sponsor: Barbara Ann Karmanos Cancer Institute

Collaborator: National Cancer Institute (NCI)

Source Barbara Ann Karmanos Cancer Institute
Brief Summary

This phase Ib/II trial studies the side effects and best dose of bispecific antibody armed activated T-cells when given together with aldesleukin and sargramostim and to see how well they work in treating patients with pancreatic cancer that has spread from where it started to nearby tissue or lymph nodes (locally advanced) or other places in the body (metastatic). Bispecific antibody armed activated T-cells are the patient's own T cells that are coated with a bispecific antibody comprising 2 antibodies chemically joined together. These antibodies have specific targets and binding properties that may give the T cells a greater ability to seek out, attach to, and kill more cancer cells.

Detailed Description

PRIMARY OBJECTIVES: I. Confirm in a single dose phase I (3 to 6 patients [pts]) that 8 infusions of 10^10 epidermal growth factor receptor (EGFR) bispecific antibody armed activated T cells (BATs) given twice per week in combination with interleukin (IL)-2 (aldesleukin) (300,000 IU/m^2/day) and granulocyte-macrophage colony stimulating factor (GM-CSF) (sargramostim) (250 ug/m^2/twice weekly) beginning 3 days before the 1st infusion and ending on the day of the last infusion is safe. II. Perform a phase II clinical trial to estimate the clinical efficacy of 8 infusions of 10^10 EGFR BATs in combination with IL-2 and GM-CSF in 39 evaluable pts (including the 3-6 pts in the single dose phase I). SECONDARY OBJECTIVES: I. Determine if infusions of EGFR BATs significantly increase cellular or humoral anti-pancreatic cancer (PC) responses by peripheral blood mononuclear cells (PBMC) at different time points after last EGFR BATs infusion and if those responses persist beyond 2 months (mos). II. Obtain original tumor paraffin blocks prior to treatment and evaluate blocks for cluster of differentiation (CD)3, CD4, CD8, programmed cell death (PD)1/programmed cell death ligand (PDL)1, monocytes subpopulations, myeloid-derived suppressor cells (MDSC), and cytoplasmic interferon (IFN)-gamma and IL-10 by immunohistochemical staining to quantitate type and number of tumor infiltrating lymphocytes (TILs) in the tumor microenvironment to estimate whether the type and number correlate with clinical responses. III. To determine the time to progression (TTP). OUTLINE: This is a phase Ib, dose-escalation study of anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells followed by a phase II study. Patients receive one of the following standard chemotherapy regimens at the discretion of the treating physician: gemcitabine hydrochloride intravenously (IV) over 30 minutes; gemcitabine hydrochloride IV over 30 minutes and paclitaxel albumin-stabilized nanoparticle formulation IV over 30-40 minutes; oxaliplatin IV over 2 hours, fluorouracil IV over 46 hours and leucovorin calcium IV over 2 hours; or fluorouracil IV over 46 hours, leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV, and oxaliplatin IV over 2 hours. Approximately 2 weeks after standard chemotherapy completion, patients receive anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells IV over 5-30 minutes twice weekly for 4 weeks. Patients also receive aldesleukin subcutaneously (SC) and sargramostim SC on day -3 before the first anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells infusion and continuing twice weekly until the final infusion. After completion of study treatment, patients are followed up for 18 months.

Overall Status Active, not recruiting
Start Date 2015-12-01
Completion Date 2021-12-01
Primary Completion Date 2021-12-01
Phase Phase 1/Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Overall survival (OS) Up to 18 months
Secondary Outcome
Measure Time Frame
Biomarker analysis (including CD3, CD4, CD8, PD1, PDL1, monocytes, MDSC, IFN-gamma, IL-10, and TILs) assessed using immunohistochemistry Up to 18 months
Incidence of toxicity CTCAE version 4.0 Up to 18 months
Progression free survival (PFS) Up to 18 months
Quantitative immune response Up to 18 months
TTP Up to 18 months
Enrollment 2
Condition
Intervention

Intervention Type: Biological

Intervention Name: Aldesleukin

Description: Given SC

Arm Group Label: Treatment (anti-CD3 x anti-EGFR BATs)

Intervention Type: Biological

Intervention Name: Antibody Therapy

Description: Given anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells IV

Arm Group Label: Treatment (anti-CD3 x anti-EGFR BATs)

Other Name: passive antibody therapy

Intervention Type: Drug

Intervention Name: Fluorouracil

Description: Given IV

Arm Group Label: Treatment (anti-CD3 x anti-EGFR BATs)

Intervention Type: Drug

Intervention Name: Gemcitabine Hydrochloride

Description: Given IV

Arm Group Label: Treatment (anti-CD3 x anti-EGFR BATs)

Intervention Type: Drug

Intervention Name: Irinotecan Hydrochloride

Description: Given IV

Arm Group Label: Treatment (anti-CD3 x anti-EGFR BATs)

Intervention Type: Other

Intervention Name: Laboratory Biomarker Analysis

Description: Correlative studies

Arm Group Label: Treatment (anti-CD3 x anti-EGFR BATs)

Intervention Type: Drug

Intervention Name: Leucovorin Calcium

Description: Given IV

Arm Group Label: Treatment (anti-CD3 x anti-EGFR BATs)

Intervention Type: Drug

Intervention Name: Oxaliplatin

Description: Given IV

Arm Group Label: Treatment (anti-CD3 x anti-EGFR BATs)

Intervention Type: Drug

Intervention Name: Paclitaxel Albumin-Stabilized Nanoparticle Formulation

Description: Given IV

Arm Group Label: Treatment (anti-CD3 x anti-EGFR BATs)

Intervention Type: Biological

Intervention Name: Sargramostim

Description: Given SC

Arm Group Label: Treatment (anti-CD3 x anti-EGFR BATs)

Eligibility

Criteria:

Inclusion Criteria: - Histological or cytological proof of pancreatic adenocarcinoma; must have locally advanced or metastatic pancreatic cancer who have received at least first line chemotherapy and may have responding, stable or progressive disease - Expected survival >= 3 months - Karnofsky performance scale (KPS) >= 70% or Southwestern Oncology Group (SWOG) performance status 0 or 1 - Absolute neutrophil count (ANC) >= 1,000/mm^3 - Lymphocyte count >= 400/mm^3 - Platelet count >= 75,000/mm^3 - Hemoglobin >= 8 g/dL - Serum creatinine < 2.0 mg/dl, creatinine clearance >= 50 ml/mm (can be calculated or measured) - Total bilirubin =< 2 mg/dl (biliary stent is allowed) - Serum glutamate pyruvate transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) < 5.0 times normal - Left ventricular ejection fraction (LVEF) >= 45% at rest (multigated acquisition scan [MUGA] or echocardiogram [Echo]) - Females of childbearing potential, and males, must be willing to use an effective method of contraception - Females of childbearing potential must have a negative pregnancy test within 7 days of being registered for protocol therapy Exclusion Criteria: - Any chemotherapy related toxicities from prior treatment (> grade 2 per Common Terminology Criteria for Adverse Events [CTCAE] version [v]4.0) - Known hypersensitivity to cetuximab or other EGFR antibody - Treatment with any investigational agent within 14 days prior to being registered for protocol therapy - Symptomatic brain metastasis - Chronic treatment with systemic steroids or another immuno-suppressive agent - Serious non-healing wound, ulcer, bone fracture, major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to being registered for protocol therapy - Active liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis - Known human immunodeficiency virus (HIV) infection - Active bleeding or a pathological condition that is associated with a high risk of bleeding (therapeutic anticoagulation is allowed) - Has an active infection requiring systemic therapy - A serious uncontrolled medical disorder that in the opinion of the investigator may be jeopardized by the treatment with protocol therapy - Females must not be breastfeeding - Patient (Pt) may be excluded if, in the opinion of the principal investigator (PI) and investigator team, the pt is not capable of being compliant

Gender:

All

Minimum Age:

18 Years

Maximum Age:

N/A

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
Anthony Shields Principal Investigator Barbara Ann Karmanos Cancer Institute
Location
Facility: Wayne State University/Karmanos Cancer Institute
Location Countries

United States

Verification Date

2021-02-01

Responsible Party

Type: Principal Investigator

Investigator Affiliation: Barbara Ann Karmanos Cancer Institute

Investigator Full Name: Anthony F. Shields, MD PhD

Investigator Title: Principal Investigator

Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Label: Treatment (anti-CD3 x anti-EGFR BATs)

Type: Experimental

Description: Patients receive one of the following standard chemotherapy regimens at the discretion of the treating physician: gemcitabine hydrochloride IV over 30 minutes; gemcitabine hydrochloride IV over 30 minutes and paclitaxel albumin-stabilized nanoparticle formulation IV over 30-40 minutes; oxaliplatin IV over 2 hours, fluorouracil IV over 46 hours and leucovorin calcium IV over 2 hours; or fluorouracil IV over 46 hours, leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV, and oxaliplatin IV over 2 hours. Approximately 2 weeks after standard chemotherapy completion, patients receive anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells IV over 5-30 minutes twice weekly for 4 weeks. Patients also receive aldesleukin SC and sargramostim SC on day -3 before the first anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells infusion and continuing twice weekly until the final infusion.

Study Design Info

Allocation: N/A

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

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