Stem Cell Transplantation for Metastatic Solid Tumors

Study Overview
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Brief Summary
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The goal of this research study is to identify other types of cancer (malignant neoplasms) that may be treatable with stem cell transplantation (allogenic peripheral blood stem cell transplantation. Patients with a variety of different types of cancerous tumors that have spread (metastasized) and whose conditions have not improved with stand therapy, will be eligible to participate. Those patients selected to participate in the study will undergo a procedure known as a mini-transplant. The mini-transplant is a transplantation of stem-cells collected from a sibling (brother or sister) of the patient. Unlike traditional bone marrow transplants, the mini-transplant does not require intense chemotherapy or radiation therapy. Because of this, patients experience fewer and less severe side effects. This study is open to patients diagnosed with a variety of metastatic solid tumors including esophageal, gastric (stomach), colon, rectal, liver tumors (hepatoma), cancer of the biliary system (cholangiocarcinoma), cancer of the pancreas, lung, breast, prostate, bone (sarcoma), adrenal basal cell, bladder, and adenocarcinomas of unk primary origin.

Detailed Description
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The main objective of this study is to identify metastatic neoplasms, which may be susceptible to the GVT effect. We will treat patients with progressive metastatic solid tumors refractory to standard therapy with a non-myeloablative allogeneic PBSC transplant from a family donor. A GVT effect from immunocompetent donor immune cells could extend life expectancy and possibly cure such patients. Eligible patients will be treated with an allogeneic peripheral blood stem cell transplant from an HLA identical or single HLA antigen-mismatched family donor, using an intensive immunosuppressive regimen without myeloablation (mini-transplant) in an attempt to decrease the transplant related toxicities while preserving the anti-malignancy and/or anti-host marrow effect of the graft. The low intensity non-myeloablative conditioning regimen should provide adequate immunosuppression to allow stem cell and lymphocyte engraftment. A T-cell replete, donor-derived, granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSC) will be used to establish hematopoietic and lymphoid reconstitution. We will infuse lymphocytes in patients with <100% donor T-cell chimerism or with evidence of tumor progression in an attempt to prevent graft rejection and enhance a graft-versus-malignancy effect, respectively. This trial is open to several different types of metastatic, treatment-refractory, solid neoplasms, breast, cholangiocarcinoma, small intestine/colon/rectal adenocarcinoma, esophageal/gastric, hepatocellular, pancreatic, prostate, and bony/soft tissue sarcomas. The trial design permits up to 10 patients with a specific tumor type to be enrolled to screen for anti-tumor effects. A single complete response in a specific tumor type is an indication to exclude further patients with that diagnosis from the study. Subsequently, a new protocol which focuses on further defining a GVT effect in that disease category will be instituted.

Official Title
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Exploratory Study of Non-Myeloablative Allogeneic Stem Cell Transplantation and Donor Lymphocyte Infusions for Metastatic Neoplasms Refractory to Standard Therapy

Conditions
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Neoplasm Metastasis

Intervention / Treatment
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* Drug: methotrexate
* Drug: Cyclosporin


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: PATIENTS: Patients with metastatic solid tumors ( breast, cholangiocarcinoma, small intestine/colon/rectal, adenocarcinoma, esophageal/gastric, hepatocellular, pancreatic, prostate, bony/soft tissue sarcomas, which are histologically confirmed, progressive and incurable. Due to low accrual, effective 12/19/2006, patients with adrenal, basal cell, transitional cell carcinoma of the bladder or uroepithelium, ovarian, small cell lung cancer, non small cell lung cancer, and adenocarcinomas of unknown primary origin are no longer eligible for the trial. Age greater than or equal to 10 to less than or equal to 80. No known standard therapy for the patient's disease that is potentially curative or definitely capable of extending life expectancy. Metastatic disease, which is bi-dimensionally evaluable radiographically. No prior treatment for neoplasm within 30 days. Ability to comprehend the investigational nature of the study and provide informed consent. Availability of HLA identical or single HLA-locus mismatched family donor. Willingness and availability to return to the NIH for scheduled follow-ups. DONOR: HLA identical or single HLA-locus mismatched family donor Age greater than or equal to 10 up to 80 years old. Ability to comprehend the investigational nature of the study and provide informed consent. EXCLUSION CRITERIA: PATIENT: Pregnant or lactating. Age less than 10 or greater than 80 years. ECOG performance status of 3 or more. Psychiatric disorder or mental deficiency severe as to make compliance with the BMT treatment unlikely, and making informed consent impossible. Major anticipated illness or organ failure incompatible with survival from PBSC transplant. DLCO: less than 40% predicted. Left ventricular ejection fraction: less than 30%. Serum creatinine greater than 2.5mg/dl or creatinine clearance less than 50 cc/min by 24 hr urine collection. Serum bilirubin greater than 4 mg/dl Transaminases greater than 5 times the upper limit of normal. Oral intake less than 1,200 calories/day. Recent weight loss of greater than or equal to 10% of actual body weight. Life expectancy less than 3 months Therapy for malignancy within 4 weeks of beginning protocol. CNS metastatic disease associated with intracranial bleeding, uncontrolled seizure disorder or significant intracranial mass effect. Other malignant diseases liable to relapse or progress within 5 years. Uncontrolled infection. DONOR: Pregnant or lactating. Donor unfit to receive G-CSF and undergo apheresis. (Uncontrolled hypertension, history of congestive heart failure or unstable angina, thrombocytopenia). Age less than 10 or greater than 80 years. HIV positive. Donors who are positive for HBV, HCV or HTLV-I may be used at the discretion of the investigator following counseling and approval from the recipient.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stem Cell Transplantation in Patients With Progressive and Incurable Metastatic Solid Tumors<br>Cyclosporin beginning day -4 then stem cells given on Day 0 followed by intravenous Methotrexate on days +1, +3, and +6. | Drug: methotrexate<br>* Cyclosporin beginning day -4 and intravenous Methotrexate on days +1, +3, and +6 will be given<br>* Other names: MTX (methotrexate);Drug: Cyclosporin<br>* Cyclosporin beginning day -4 and intravenous Methotrexate on days +1, +3, and +6 will be given<br>* Other names: CsA (Cyclosporin);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Based on Tumor Response Criteria With Anti-tumor Effect Induce by Graft-versus-tumor Effect. | To identify an anti-tumor effect of allogenic PNSC transplantation by induction of a graft-versus-tumor (GVT) effect in patients with a diversity of metastatic solid tumors, which are refractory to standard therapy. Tumor response assessed as follows: Complete response (CR): disappearance of all signs and symptoms of metastatic disease for a period of at least one month. Partial response (PR): a 50% or greater decrease in the sum of the products of the longest perpendicular diameters of all measured lesions lasting for a period of at least one month. No new metastatic lesions may appear. Stable disease (SD): tumor measurements not meeting the criteria of CR, PR, or PD. Progressive disease (PD): increase of 25% or greater in the sum of the products of the longest perpendicular diameters of all measured lesions compared to the smallest previous measurements, or the development of any new metastatic disease. | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Achieved Engraftment | Number of participants that achieved engraftment based on blood Chimerism Cluster of differentiation 3 (CD3) analysis that is greater than or equal to 95%. | Day 100 | 
| Number of Participants Who Received Donor Lymphocyte Infusion to Achieve Tumor Regression or Prevent Graft Failure | To evaluate the effects of donor lymphocyte infusion (DLI) and cyclosporine A (CSA) withdrawal on tumor regression in participants who show progressive disease off of CSA and in the absence of grade > II GVHD, or who are at risk for graft failure due to incomplete donor T-cell engraftment will receive one or more DLI. Tumor response assessed as follows: Complete response (CR): disappearance of signs & symptoms of metastatic disease at least one month. Partial response (PR): a 50% or greater decrease in the sum of the products of the longest perpendicular diameters of all measured lesions lasting at least one month. No new metastatic lesions may appear. Stable disease (SD): tumor measurements not meeting the criteria of CR, PR, or PD. Progressive disease (PD): increase of 25% or greater in the sum of the products of the longest perpendicular diameters of all measured lesions compared to the smallest previous measurements, or development of new metastatic disease. | 2 years | 
| Number of Participants Who Developed Acute GVHD Grade 2 and Higher | Number of participants who developed Acute Graft vs Host Disease (GVHD) Grades I, II, III, IV as defined by CIMBTR criteria for Organ Stages of Acute GVHD. Grades are defined as: Grade I: Skin = Maculopapular rash< 25% of body surface area (BSA); Liver = Total Bilirubin 2-3 mg/dL; Lower GI = stool output/day is 500-999 mL/day. Grade II: Skin = rash on 25-50 percent body surface area; Liver = Total Bilirubin 3.1-6.0 mg/dL; Lower GI = Diarrhea 1001-1500 mL/day. Grade III: Skin = Rash on >50% of body surface; Liver = Total Bilirubin 6.1 - 15.0 mg/dL; Lower GI = Diarrhea > 1500 mL/day. Grade IV: Skin = Generalized erythroderma plus bullous formation; Liver = Total Bilirubin >15 mg/dL; Lower GI = Severe abdominal pain with or without ileus. Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening. | Day 100 | 
| Number of Participants Who Developed Chronic GVHD | Number of participants who developed Chronic Graft vs Host Disease (GVHD). Chronic GVHD is defined as symptoms that persist or appear after 100 days since the time of stem cell transplantation. | Day 100 to year 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Engraftment, Peripheral Blood Stem Cells, Non-Myeloablative Bone Marrow Transplantation, Metastatic Solid Tumors, Graft-Versus-Host Disease, Cancer, Tumor