• Engraftment [ Designated as safety issue: No ]
• Acute and chronic graft-versus-host disease [ Designated as safety issue: Yes ]
• Transplant-related morbidity and mortality [ Designated as safety issue: Yes ]
• Graft-vs-tumor effect as measured by CAT scans at days 30, 60, and 100 following transplant [ Designated as safety issue: No ]
• Disease-free survival as measured by CAT scans at 6 months and 1 year [ Designated as safety issue: No ]

RATIONALE: Giving low doses of chemotherapy, such as cyclophosphamide and fludarabine, before a donor peripheral blood stem cell transplant helps stop the growth of tumor cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining tumor cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving antithymocyte globulin before the transplant and cyclosporine after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well cyclophosphamide, fludarabine, antithymocyte globulin, and peripheral stem cell transplant followed by cyclosporin and donor white blood cell transfusions work in treating patients with refractory metastatic solid tumors.

OBJECTIVES:

Primary:

• Identify an anti-tumor effect of allogeneic peripheral blood stem cell transplantation by induction of a graft-versus-tumor effect in patients with a diversity of metastatic solid tumors refractory to standard therapy.

Secondary:

• Determine engraftment in these patients.
• Determine the effects of donor lymphocyte infusion and cyclosporine withdrawal on tumor regression in these patients.

OUTLINE: Patients are stratified according to risk of graft rejection, which determines the preparative regimen received. High-risk patients include heavily transfused patients or patients who have received donor-directed blood products and single HLA-locus mismatched patients.

Preparative regimen: Patients receive cyclophosphamide IV over 1 hour on days -7 and -6 and fludarabine IV over 30 minutes on days -5 to -1. Patients at high risk also receive antithymocyte globulin IV on days -5 to -2.

Patients undergo allogeneic peripheral blood stem cell transplantation on day 0. Patients receive cyclosporine either by continuous infusion IV or orally twice a day on days -4 to 100 as graft-versus-host disease (GVHD) prophylaxis.

Patients with less than 100% donor T-cell chimerism or with evidence of tumor progression receive donor lymphocytes after day 100, every 4 weeks, until 100% donor T-cell chimerism, disease regression, and/or GVHD occurs.

Patients are followed at 4, 6, 8, 10, and 12 months, every 3 months for 2 years, and then every 6 months for 2 years.

PROJECTED ACCRUAL: Approximately 150 patients (10 for each cancer) will be accrued for this study.

• Breast Cancer
• Carcinoma of Unknown Primary
• Colorectal Cancer
• Esophageal Cancer
• Gallbladder Cancer
• Gastric Cancer
• Liver Cancer
• Lung Cancer
• Pancreatic Cancer
• Prostate Cancer
• Sarcoma

• Biological: anti-thymocyte globulin
• Biological: therapeutic allogeneic lymphocytes
• Drug: cyclophosphamide
• Drug: cyclosporine
• Drug: fludarabine phosphate
• Procedure: peripheral blood stem cell transplantation

• Gorak E, Geller N, Srinivasan R, Espinoza-Delgado I, Donohue T, Barrett AJ, Suffredini A, Childs R. Engraftment syndrome after nonmyeloablative allogeneic hematopoietic stem cell transplantation: incidence and effects on survival. Biol Blood Marrow Transplant. 2005 Jul;11(7):542-50.
• Srinivasan R, Balow JE, Sabnis S, Lundqvist A, Igarashi T, Takahashi Y, Austin H, Tisdale J, Barrett J, Geller N, Childs R. Nephrotic syndrome: an under-recognised immune-mediated complication of non-myeloablative allogeneic haematopoietic cell transplantation. Br J Haematol. 2005 Oct;131(1):74-9.
• Carvallo C, Geller N, Kurlander R, Srinivasan R, Mena O, Igarashi T, Griffith LM, Linehan WM, Childs RW. Prior chemotherapy and allograft CD34+ dose impact donor engraftment following nonmyeloablative allogeneic stem cell transplantation in patients with solid tumors. Blood. 2004 Feb 15;103(4):1560-3. Epub 2003 Oct 9.
• Childs RW, Barrett J. Nonmyeloablative allogeneic immunotherapy for solid tumors. Annu Rev Med. 2004;55:459-75. Review.
• Espinoza-Delgado I, Childs RW. Nonmyeloablative transplantation for solid tumors: a new frontier for allogeneic immunotherapy. Expert Rev Anticancer Ther. 2004 Oct;4(5):865-75. Review.
• Childs R, Srinivasan R. Advances in allogeneic stem cell transplantation: directing graft-versus-leukemia at solid tumors. Cancer J. 2002 Jan-Feb;8(1):2-11. Review.
• Nakamura R, Cortez K, Solomon S, Battiwalla M, Gill VJ, Hensel N, Childs R, Barrett AJ. High-dose acyclovir and pre-emptive ganciclovir to prevent cytomegalovirus disease in myeloablative and non-myeloablative allogeneic stem cell transplantation. Bone Marrow Transplant. 2002 Aug;30(4):235-42.
• Childs RW. Evolving trends in hematopoietic cell transplantation for solid tumors: tempering enthusiasm with clinical reality. Ann Oncol. 2004 Apr;15(4):543-4. No abstract available.
• Barrett J, Childs R. New directions in allogeneic stem cell transplantation. Semin Hematol. 2002 Jan;39(1):1-2. No abstract available.
• Childs R, Barrett J. Nonmyeloablative stem cell transplantation for solid tumors: expanding the application of allogeneic immunotherapy. Semin Hematol. 2002 Jan;39(1):63-71. Review.
• Childs RW. Immunotherapy of solid tumors: nonmyeloablative allogeneic stem cell transplantation. MedGenMed. 2002 Jun 26;4(3):13. Review. No abstract available.
• Graber C, de Almeider KN, Childs R, Barrett AJ, Gill VJ, Bennett JE. CMV reactivation in nonmyeloablative HSCT. Bone Marrow Transplant. 2001 Apr;27(7):775. No abstract available.
• Barrett J, Childs R. Non-myeloablative stem cell transplants. Br J Haematol. 2000 Oct;111(1):6-17. Review. No abstract available.
• Barrett J, Childs R. The benefits of an alloresponse: graft-versus-tumor. J Hematother Stem Cell Res. 2000 Jun;9(3):347-54. Review. No abstract available.

DISEASE CHARACTERISTICS:

• Histologically proven progressive and incurable metastatic solid tumors

  • Hepatocellular carcinoma
  • Pancreatic carcinoma
  • Cholangiocarcinoma
  • Esophageal carcinoma
  • Gastric carcinoma
  • Colon and rectal carcinoma
  • Breast carcinoma
  • Hormone-refractory prostate carcinoma
  • Soft tissue sarcomas
  • Bony sarcomas
• Refractory to standard therapy or no known curative therapy exists
• Bidimensionally evaluable metastatic disease by radiography
• HLA-identical or single HLA-locus mismatched family donor available
• No CNS metastases associated with intracranial bleeding, uncontrolled seizure disorder, or significant intracranial mass effect

• Hormone receptor status:

  • Not specified

PATIENT CHARACTERISTICS:

Age:

• 10 to 80

Sex:

• Not specified

Menopausal status:

• Not specified

Performance status:

• ECOG 0-2

Life expectancy:

• At least 3 months

Hematopoietic:

• Not specified

Hepatic:

• Bilirubin no greater than 4 mg/dL
• SGOT/SGPT no greater than 5 times upper limit of normal

Renal:

• Creatinine no greater than 2.5 mg/dL

Cardiovascular:

• LVEF at least 30%

Pulmonary:

• DLCO at least 40% predicted

Other:

• Not pregnant or nursing
• No psychiatric disorder or severe mental deficiency
• No other major illness or organ failure
• Oral intake at least 1,200 calories/day
• No recent weight loss of 10% or more
• No other malignant diseases liable to relapse or progress within 5 years
• No uncontrolled infection

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• Not specified

Endocrine therapy:

• Not specified

Radiotherapy:

• Not specified

Surgery:

• Not specified

Other:

• At least 30 days since prior cancer therapy