Protocol Number: 08-H-0186

Title:

Safety and the Anti- Tumor Effects of Escalating Doses of Adoptively Infused Ex Vivo Expanded Autologous Natural Killer (NK) Cells Against Metastatic Cancers or Hematological Malignancies Sensitized to NK-TRAIL Cytotoxicity with Bortezomib

Number:

08-H-0186

Summary:

Natural killer (NK) cells are white blood cells that have a limited ability to kill cancer cells. This ability might be enhanced if they are given 24 hours after an injection of the drug bortezomib. This study will determine the following:

-What dose of NK cells can be given safely to subjects with metastatic solid tumors or leukemia.

-The effectiveness and side effects of NK cell therapy

-How the body handles NK cells.

People between 18 and 70 years of age who have a solid tumor or leukemia, and for whom standard treatments are not effective, may be eligible for this study. Participants undergo the following procedures:

Apheresis to collect NK cells. For this procedure, a catheter (plastic tube) is placed in a vein in the subject's arm. Blood flows from the vein into a cell separator machine, which separates the white cells from the other blood components. The white cells are extracted and the rest of the blood is returned to the body through a second tube placed in a vein in the other arm.

Chemotherapy with the drug pentostatin to suppress the immune system and prevent it from attacking the NK cells that will be infused.

Chemotherapy with bortezomib to increase NK cell function.

Infusion of the NK cells. In this dose-escalating study, successive groups of patients entering the study receive increasingly higher numbers of cells to determine the highest safe dose level. Up to four dose levels may be studied.

Interleukin-2 drug therapy to maintain NK cell activity.

Evaluations during therapy including:

-Clinical assessment, history and review of medications

-Blood draws for routine and research tests.

-Pharmacokinetics study after the NK infusion to see how the body handles the cells. For this test, the number of NK cells in the blood are measured over time. This requires drawing about 1 teaspoon of blood at 15 minutes, 30 minutes, 1, 2, 4, 8, 12, and 24 hours after the infusion (day 1); then every 24 hours on days 2 through 7, then once on days 10, 14, and 21.

-Bone marrow biopsy (subjects with leukemia only).

-Chest x-ray.

-CT scan, bone scan and PET scan, if indicated, for disease evaluation.

Patients who respond well after one treatment cycle may be eligible to continue NK cell therapy.

Sponsoring Institute:

National Heart, Lung and Blood Institute (NHLBI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

1. Diagnosed with histologically confirmed metastatic solid tumor - cancer of the lung (small cell or non small cell), prostate (adenocarcinoma), colorectum, kidney (renal cell carcinoma), pancreas (adenocarcinoma), or malignant melanoma, and disease confirmed to be metastatic and unresectable for which standard curative or beneficial treatments are no longer effective.

OR

Diagnosed with a hematological malignancy (chronic myelogenous leukemia [CML] or chronic lymphocytic leukemia [CLL] or small lymphocytic lymphoma [SLL]) and disease resistant or refractory to standard therapy and CLL/SLL patients are required to have failed prior treatment with at least one nucleoside analogue.

2. least 4 weeks since any prior systemic therapy (excluding corticosteroid therapy) to treat the underlying malignancy (standard or investigational).

3. At least 2 weeks since prior palliative radiotherapy.

4. Ages greater than or equal to 18 years and less than or equal to 70 years.

5. Evidence of progressive disease over a 3-month interval.

6. Hbg greater than 9.0 and RBC transfusion independent (solid tumor patients only).

EXCLUSION CRITERIA:

1. Disease not evaluable radiographically (applies to solid tumor patients only).

2. Disease involving greater than 25% of the liver radiographically (estimated based on review of liver lesions seen on CT scan ).

3. History of an allogeneic hematopoietic stem cell transplant.

4. Brain metastases (due to poor prognosis and potential for neurological dysfunction that would confound evaluation of neurological and other adverse events).

5. Peripheral neuropathy of grade greater than 1, which would require reduction of bortezomib dose.

6. Acute diffuse infiltrative pulmonary disease.

7. Acute pericardial disease.

8. Life expectancy less than 3 months.

9. ECOG performance status 2, 3 or 4.

10. Uncontrolled concurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, life threatening cardiac arrhythmia. Patients with symptoms of coronary artery disease, cardiac arrhythmias or an abnormal thallium stress test must be evaluated and cleared by cardiology prior to enrollment.

11. Ongoing or active infection.

12. Contraindication for administration of pentostatin, bortezomib, and/or interleukin-2.

13. Allergy or hypersensitivity to bortezomib, boron or mannitol by history.

14. Concurrent use of corticosteroids.

15. Organ and marrow function characterized by

-Leukocytes less than 2,500/mcL

-Absolute neutrophil count less than 1,500/mcL (must be present off growth factors)

-Platelets less than 100,000/mcL

-Total bilirubin greater than 3 times upper limit of normal

-AST (SGOT)/ALT (SGPT) greater than 4 times upper limit of normal

-Creatinine clearance less than 50 cc/min based on a 24 hour urine collection

-Left ventricular ejection fraction less than 40% by echocardiogram (ECHO)

-Hypercalcemia greater than 2.5 mmol/L

16. HIV-positive patients

17. Hepatitis C positive patients

18. Active Hepatitis B infection (Hep B surface antigen positive)

19. Pregnant or nursing

20. Psychiatric illness/social situations that would limit compliance with study requirements and ability to comprehend the investigational nature of the study and provide informed consent.

Special Instructions:

Currently Not Provided

Keywords:

Metastatic Solid Tumor

Chronic Myelogenous Leukemia (CML)

Small Lymphocytic Lymphoma (SLL)

Tumor Cytotoxicity

Chronic Lymphocytic Leukemia (CLL)

Recruitment Keyword(s):

Metastatic Solid Tumor

Lung Cancer

Prostate Cancer

Colon Cancer

Kidney Cancer

Pancreatic Cancer

Leukemia

Chronic Myelogenous Leukemia

CML

Small Lymphocytic Lymphoma

SLL

Chronic Lymphocytic Leukemia

CLL

Condition(s):

Lung or Prostatic Neoplasms

Colorectal or Kidney Neoplasms

Pancreatic Neoplasms

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Melanoma

Investigational Drug(s):

NK cells +CliniMACs CD3 and CD56 systems

Investigational Device(s):

None

Intervention(s):

Drug: NK cells +CliniMACs CD3 and CD56 systems

Supporting Site:

National Heart, Lung, and Blood Institute

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

Farag SS, Fehniger TA, Becknell B, Blaser BW, Caligiuri MA. New directions in natural killer cell-based immunotherapy of human cancer. Expert Opin Biol Ther. 2003 Apr;3(2):237-50. Review.

Farag SS, Caligiuri MA. Human natural killer cell development and biology. Blood Rev. 2006 May;20(3):123-37. Epub 2005 Dec 20. Review.

Goy A, Younes A, McLaughlin P, Pro B, Romaguera JE, Hagemeister F, Fayad L, Dang NH, Samaniego F, Wang M, Broglio K, Samuels B, Gilles F, Sarris AH, Hart S, Trehu E, Schenkein D, Cabanillas F, Rodriguez AM. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol. 2005 Feb 1;23(4):667-75. Epub 2004 Dec 21.

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
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