Bispecific Antibody Armed Activated T-cells With Aldesleukin and Sargramostim in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer
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| ClinicalTrials.gov Identifier: NCT02620865 |
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Recruitment Status :
Active, not recruiting
First Posted : December 3, 2015
Last Update Posted : February 12, 2019
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Metastatic Pancreatic Adenocarcinoma Recurrent Pancreatic Carcinoma Stage III Pancreatic Cancer Stage IV Pancreatic Cancer | Biological: Aldesleukin Biological: Antibody Therapy Drug: Fluorouracil Drug: Gemcitabine Hydrochloride Drug: Irinotecan Hydrochloride Other: Laboratory Biomarker Analysis Drug: Leucovorin Calcium Drug: Oxaliplatin Drug: Paclitaxel Albumin-Stabilized Nanoparticle Formulation Biological: Sargramostim | Phase 1 Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 2 participants |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | 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 |
| Study Start Date : | December 2015 |
| Estimated Primary Completion Date : | December 2020 |
| Estimated Study Completion Date : | December 2020 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Treatment (anti-CD3 x anti-EGFR BATs)
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.
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Biological: Aldesleukin
Given SC
Other Names:
Biological: Antibody Therapy Given anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells IV
Other Name: passive antibody therapy Drug: Fluorouracil Given IV
Other Names:
Drug: Gemcitabine Hydrochloride Given IV
Other Names:
Drug: Irinotecan Hydrochloride Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Leucovorin Calcium Given IV
Other Names:
Drug: Oxaliplatin Given IV
Other Names:
Drug: Paclitaxel Albumin-Stabilized Nanoparticle Formulation Given IV
Other Names:
Biological: Sargramostim Given SC
Other Names:
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- Overall survival (OS) [ Time Frame: Up to 18 months ]Descriptive statistics (point and exact 90% confidence interval estimates from the resultant Kaplan-Meier curve) will be generated for OS. The median OS will be estimated on an intention-to-treat basis (using all registered patients), and on a response-evaluable basis (using all patients who completed all BAT infusions) using the Kaplan-Meier method.
- Biomarker analysis (including CD3, CD4, CD8, PD1, PDL1, monocytes, MDSC, IFN-gamma, IL-10, and TILs) assessed using immunohistochemistry [ Time Frame: Up to 18 months ]
Each biomarker and computed biomarker will be evaluated for normality and transformed (including non-parametric) if necessary to achieve normality. Summary statistics (including means, medians, and standard deviations) will be produced for each variable and subsequently associate each variable with OS using Cox regression. In addition, a threshold for each variable associating with OS will be defined using classification and regression trees.
The tumor will be stained for inflammatory biomarkers. Specifically, T cells with undergo cytoplasmic staining for IFN and IL-10 and the level and ratio of these markers will be evaluated.
- Incidence of toxicity CTCAE version 4.0 [ Time Frame: Up to 18 months ]Toxicity rates will be estimated using all treated patients. Point and 90% Wilson's confidence intervals will be estimated to describe binary endpoints including toxicity rate.
- Progression free survival (PFS) [ Time Frame: Up to 18 months ]Descriptive statistics (point and exact 90% confidence interval estimates from the resultant Kaplan-Meier curve) will be generated for PFS. The median PFS will be estimated on an intention-to-treat basis (using all registered patients), and on a response-evaluable basis (using all patients who completed all BAT infusions) using the Kaplan-Meier method.
- Quantitative immune response [ Time Frame: Up to 18 months ]For the quantitative immune response variables, summary statistics (including means, medians, and standard deviations) will be produced pre- and post-BATs treatment. Subsequent analyses will compare the immune response variables (after a suitable transformation, if necessary) pre- and post-treatment using a paired t-test (or Wilcoxon sign ranked test if the data are not approximately normally distributed). To explore whether immune responses associate with clinical responses, the association between the baseline of each biomarker and clinical endpoints (such as response, or OS) will be analyze
- TTP [ Time Frame: Up to 18 months ]To explore whether immune responses associate with clinical responses, the association between the baseline of each biomarker and clinical endpoints (such as response, or OS) will be analyzed using logistic regression for binary endpoints and Cox regression for time to event endpoints.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
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): NCT02620865
| United States, Michigan | |
| Wayne State University/Karmanos Cancer Institute | |
| Detroit, Michigan, United States, 48201 | |
| Principal Investigator: | Anthony Shields | Barbara Ann Karmanos Cancer Institute |
| Responsible Party: | Anthony F. Shields, MD PhD, Principal Investigator, Barbara Ann Karmanos Cancer Institute |
| ClinicalTrials.gov Identifier: | NCT02620865 History of Changes |
| Other Study ID Numbers: |
2015-100 NCI-2015-01942 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 1510014428 2015-100 ( Other Identifier: Wayne State University/Karmanos Cancer Institute ) P30CA022453 ( U.S. NIH Grant/Contract ) |
| First Posted: | December 3, 2015 Key Record Dates |
| Last Update Posted: | February 12, 2019 |
| Last Verified: | January 2019 |
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Visilizumab Adenocarcinoma Pancreatic Neoplasms Carcinoma Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Digestive System Neoplasms Neoplasms by Site Endocrine Gland Neoplasms Digestive System Diseases Pancreatic Diseases Endocrine System Diseases Calcium, Dietary Leucovorin |
Folic Acid Gemcitabine Aldesleukin Paclitaxel Camptothecin Albumin-Bound Paclitaxel Oxaliplatin Irinotecan Fluorouracil Interleukin-2 Muromonab-CD3 Antibodies Immunoglobulins Sargramostim Antibodies, Bispecific |